FUSED RING-SUBSTITUTED SIX-MEMBERED HETEROCYCLIC COMPOUND, AND PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

Disclosed in the present invention is a compound as represented by formula (IA) or formula (IC) or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof. The definition of each group in the formula is shown in the description for details. Further disclosed are a pharmaceutical composition containing the compound and the use thereof in the preparation of a drug for preventing and/or treating diseases or conditions related to HPK1 activity.

Claims

1. A compound of formula (IA), or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof: ##STR00939## wherein Y is CH or N; R.sup.1 is H, C.sub.1-6 alkyl, C.sub.1-4 alkyl-hydroxy, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-carboxy, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dC(O)R.sup.c, C.sub.1-4 alkyl-NR.sup.dC(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2R.sup.c, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-S(O).sub.2R.sup.c, C.sub.1-4 alkyl-S(O).sub.2NR.sup.aR.sup.b, C(O)C.sub.1-6 alkyl, C(O)C.sub.3-20 cycloalkyl, C(O)-3- to 20-membered heterocyclyl, C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C(O)NR.sup.aR.sup.b, S(O).sub.2R.sup.c, or S(O).sub.2NR.sup.aR.sup.b; wherein the C.sub.1-6 alkyl and the C.sub.1-6 alkoxy are each independently optionally substituted with halogen, deuterium, cyano, or hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; Z, L.sup.1 and R.sup.4 are selected from one of the following combinations: (a) Z is N; -L.sup.1-R.sup.4 is absent; (b) Z is C; L.sup.1 is a bond, C.sub.1-4 alkyl-, C.sub.3-6 monocyclic cycloalkyl-, O, S, NH, C(O), S(O), or S(O).sub.2; R.sup.4 is selected from the group consisting of H, halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-hydroxyl, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-carboxyl, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.aR.sup.b, C.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dC(O)R.sup.c, C.sub.1-4 alkyl-NR.sup.dC(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-S(O).sub.2R.sup.c, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2R.sup.c, C.sub.1-4 alkyl-S(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2NR.sup.aR.sup.b, C(O)C.sub.1-6 alkyl, C(O)C.sub.3-20 cycloalkyl, C(O)-3- to 20-membered heterocyclyl, C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C(O)NR.sup.aR.sup.b, NR.sup.dC(O)R.sup.c, NR.sup.dC(O)NR.sup.aR.sup.b, S(O).sub.2R.sup.c, NR.sup.dS(O).sub.2R.sup.c, S(O).sub.2NR.sup.aR.sup.b, NR.sup.dS(O).sub.2NR.sup.aR.sup.b, NR.sup.aR.sup.b, OR.sup.c; the C.sub.1-6 alkyl and the C.sub.1-6 alkoxy are each independently optionally substituted with halogen, deuterium, cyano, or hydroxy; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; ##STR00940## is phenyl or 5- or 6-membered monocyclic heteroaryl; the 5- or 6-membered monocyclic heteroaryl contains 1, 2, or 3 heteroatom(s) independently selected from N, O, and S as ring atoms; the phenyl or the 5- or 6-membered monocyclic heteroaryl are each independently optionally substituted with m1 R.sup.2 group(s); m1 is 1, 2, 3, or 4; the R.sup.2 is ##STR00941## wherein R.sup.2a is H, deuterium, C.sub.1-6 alkyl, phenyl, or deuterated C.sub.1-6 alkyl, and R.sup.2b is H, deuterium, C.sub.1-6 alkyl, or deuterated C.sub.1-6 alkyl; or R.sup.2a and R.sup.2b together with the carbon atom to which the R.sup.2a and R.sup.2b are attached form a C.sub.3-6 monocyclic cycloalkyl group; and the bond between R.sup.2a and the carbon atom is a single bond; R.sup.2c is H, deuterium, C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.3-6 monocyclic cycloalkyl, or C.sub.3-6 monocyclic cycloalkyl; R.sup.2d is H, deuterium, C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.3-20 cycloalkyl, or 3- to 20-membered heterocyclyl; or when R.sup.2a and R.sup.2d together with the nitrogen atom to which the R.sup.2a and R.sup.2d are attached form a 3- to 20-membered heterocyclyl group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group, R.sup.2c is H, deuterium, C.sub.1-6 alkyl, or deuterated C.sub.1-6 alkyl; R.sup.2b is H, deuterium, C.sub.1-6 alkyl, or deuterated C.sub.1-6 alkyl, and the bond between R.sup.2a and the carbon atom is a single bond; or R.sup.2b is absent, and the bond between R.sup.2a and the carbon atom is a double bond; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl each independently contains one nitrogen atom and optionally 1 or 2 heteroatom(s) independently selected from N, O, and S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; or when R.sup.2c and R.sup.2d together with the nitrogen atom to which the R.sup.2c and R.sup.2d are attached form a 3- to 20-membered heterocyclyl group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group, R.sup.2a is H, deuterium, C.sub.1-6 alkyl, or deuterated C.sub.1-6 alkyl, R.sup.2b is H, deuterium, C.sub.1-6 alkyl, or deuterated C.sub.1-6 alkyl, and the bond between R.sup.2a and the carbon atom is a single bond; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl each independently contains one nitrogen atom and optionally 1 or 2 heteroatom(s) independently selected from N, O, and S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; or the R.sup.2 is ##STR00942## is 3- to 20-membered heterocyclyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl containing one nitrogen atom and attached to other moieties of a molecule through the nitrogen atom; ##STR00943## further optionally contains 1 or 2 heteroatom(s) independently selected from N, O, and S as ring atoms; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; ##STR00944## is phenyl or 5- or 6-membered monocyclic heteroaryl; the 5- or 6-membered monocyclic heteroaryl contains 1, 2, or 3 heteroatom(s) independently selected from N, O, and S as ring atoms; the phenyl and the 5- or 6-membered monocyclic heteroaryl are each independently optionally substituted with m2 R.sup.3 group(s); m2 is 1, 2, 3, or 4; each R.sup.3 is independently selected from the group consisting of H, oxo (O), halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, OC.sub.3-20 cycloalkyl, O-3- to 20-membered heterocyclyl, OC.sub.6-14 aryl, O-5- or 6-membered monocyclic heteroaryl, O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-hydroxyl, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.aR.sup.b, C.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dC(O)R.sup.c, C.sub.1-4 alkyl-NR.sup.dC(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-S(O).sub.2R.sup.c, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2R.sup.c, C.sub.1-4 alkyl-S(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-carboxy, C(O)C.sub.1-6 alkyl, C(O)OC.sub.1-6 alkyl, C(O)C.sub.1-4 alkyl-hydroxy, C(O)C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C(O)C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C(O)C.sub.3-20 cycloalkyl, C(O)OC.sub.3-20 cycloalkyl, C(O)C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C(O)-3- to 20-membered heterocyclyl, C(O)C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C(O)NR.sup.aR.sup.b, NR.sup.dC(O)R.sup.c, NR.sup.dC(O)NR.sup.aR.sup.b, S(O).sub.2R.sup.c, NR.sup.dS(O).sub.2R.sup.c, S(O).sub.2NR.sup.aR.sup.b, NR.sup.dS(O).sub.2NR.sup.aR.sup.b, NR.sup.aR.sup.b, OR.sup.c, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2; wherein the C.sub.1-6 alkyl and the C.sub.1-6 alkoxy are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from halogen, deuterium, cyano, 5- to 6-membered heterocyclyl, and hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S2; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; or ##STR00945## is C.sub.5-7 monocyclic cycloalkyl or 5-, 6- or 7-membered monocyclic heterocyclyl; the 5-, 6- or 7-membered heterocyclyl each independently contains 1, 2, or 3 heteroatom(s) independently selected from N, O, and S as ring atoms; the C.sub.5-7 monocyclic cycloalkyl and the 5-, 6- or 7-membered monocyclic heterocyclyl are each independently optionally substituted with m2 R.sup.3 group(s); m2 is 1, 2, 3, or 4; each R.sup.3 is independently selected from the group consisting of H, oxo (O), halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, OC.sub.3-20 cycloalkyl, O-3- to 20-membered heterocyclyl, OC.sub.6-14 aryl, O-5- or 6-membered monocyclic heteroaryl, O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-hydroxyl, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.aR.sup.b, C.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dC(O)R.sup.c, C.sub.1-4 alkyl-NR.sup.dC(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-S(O).sub.2R.sup.c, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2R.sup.c, C.sub.1-4 alkyl-S(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-carboxy, C(O)C.sub.1-6 alkyl, C(O)OC.sub.1-6 alkyl, C(O)C.sub.1-4 alkyl-hydroxy, C(O)C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C(O)C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C(O)C.sub.3-20 cycloalkyl, C(O)OC.sub.3-20 cycloalkyl, C(O)C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C(O)-3- to 20-membered heterocyclyl, C(O)C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C(O)NR.sup.aR.sup.b, NR.sup.dC(O)R.sup.c, NR.sup.dC(O)NR.sup.aR.sup.b, S(O).sub.2R.sup.c, NR.sup.dS(O).sub.2R.sup.c, S(O).sub.2NR.sup.aR.sup.b, NR.sup.dS(O).sub.2NR.sup.aR.sup.b, NR.sup.aR.sup.b, OR.sup.c, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2, CR.sup.3aR.sup.3b; wherein two hydrogen atoms attached to a same carbon atom can be substituted with two R.sup.3 groups such that the two R.sup.3 groups together with the carbon atom to which the two R.sup.3 groups are attached form a C.sub.3-6 monocyclic cycloalkyl group or a 3- to 6-membered monocyclic heterocyclyl group; or two hydrogen atoms attached to different carbon atoms are substituted with two R.sup.3 groups, and the two R.sup.3 groups join to form CH.sub.2, CH.sub.2CH.sub.2, or CH.sub.2CH.sub.2CH.sub.2; wherein the C.sub.1-6 alkyl and the C.sub.1-6 alkoxy are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from halogen, deuterium, cyano, 5- to 6-membered heterocyclyl, and hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S2; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; wherein R.sup.3a and R.sup.3b are each independently hydrogen, halogen, cyano, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, C.sub.6-14 aryl, or 5- or 6-membered monocyclic heteroaryl; the C.sub.6-14 aryl or the 5- or 6-membered monocyclic heteroaryl is optionally substituted with 1, 2, or 3 group(s) selected from halogen, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkyl, halogenated C.sub.1-4 alkoxy; or R.sup.3a and R.sup.3b together with the carbon atom to which the R.sup.3a and R.sup.3b are attached form a C.sub.3-6 monocyclic cycloalkyl group or a 3- to 6-membered monocyclic heterocyclyl group; the C.sub.3-6 monocyclic cycloalkyl or the 3- to 6-membered monocyclic heterocyclyl is optionally substituted with 1, 2, or 3 group(s) selected from halogen, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkyl, halogenated C.sub.1-4 alkoxy, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl; among the above groups, each group from group S1 is independently selected from the group consisting of oxo (O), halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, OC.sub.3-20 cycloalkyl, O-3- to 20-membered heterocyclyl, OC.sub.6-14 aryl, O-5- or 6-membered monocyclic heteroaryl, O-8- to 10-membered bicyclic heteroaryl, CCC.sub.3-20 cycloalkyl, CC-3- to 20-membered heterocyclyl, CCC.sub.6-14 aryl, CC-5- or 6-membered monocyclic heteroaryl, CC-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-hydroxy, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, S(O).sub.2C.sub.1-6 alkyl, S(O).sub.2C.sub.3-20 cycloalkyl, S(O).sub.2-3- to 20-membered heterocyclyl, S(O).sub.2-5- or 6-membered monocyclic heteroaryl, S(O).sub.2-8- to 10-membered bicyclic heteroaryl, C(O)OC.sub.1-6 alkyl, C(O)OC.sub.3-20 cycloalkyl, C(O)O-3- to 20-membered heterocyclyl, C(O)O-5- or 6-membered monocyclic heteroaryl, C(O)O-8- to 10-membered bicyclic heteroaryl, C(O)C.sub.1-6 alkyl, C(O)C.sub.3-20 cycloalkyl, C(O)C.sub.6-14 aryl, NR.sup.a1R.sup.b1, C(O)NR.sup.a1R.sup.b1, OR.sup.c1, C.sub.1-4 alkyl-S(O).sub.2C.sub.1-6 alkyl, C.sub.1-4 alkyl-S(O).sub.2C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-S(O).sub.2-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C(O)OC.sub.1-6 alkyl, C.sub.1-4 alkyl-C(O)OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-C(O)C.sub.1-6 alkyl, C.sub.1-4 alkyl-C(O)C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-C(O)NR.sup.a1R.sup.b1, CCC(O)NR.sup.a1R.sup.b1, CCC.sub.1-4 alkyl-C(O)NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-OR.sup.c1, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2, C.sub.1-4 alkyl-NR.sup.d1C(O)R.sup.c1, C.sub.1-4 alkyl-NR.sup.d1C(O)NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-NR.sup.d1S(O).sub.2R.sup.c1, C.sub.1-4 alkyl-S(O).sub.2NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-NR.sup.d1S(O).sub.2NR.sup.a1R.sup.b1NR.sup.d1C(O)R.sup.c1, NR.sup.d1C(O)NR.sup.a1R.sup.b1, NR.sup.d1S(O).sub.2R.sup.c1, S(O).sub.2NR.sup.a1R.sup.b1, NR.sup.d1S(O).sub.2NR.sup.a1R.sup.b1; wherein the C.sub.1-6 alkyl, the C.sub.1-6 alkoxy, the C.sub.2-6 alkenyl, and the C.sub.2-6 alkynyl are each independently optionally substituted with 1, 2, or 3 group(s) selected from halogen, deuterium, cyano, or hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S3; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; among the above groups, each group from group S2 is independently selected from the group consisting of oxo (O), halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, O-3- to 20-membered heterocyclyl, O-5- or 6-membered monocyclic heteroaryl, O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-hydroxyl, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, S(O).sub.2C.sub.1-6 alkyl, S(O).sub.2C.sub.3-20 cycloalkyl, S(O).sub.2-3- to 20-membered heterocyclyl, S(O).sub.2-5- or 6-membered monocyclic heteroaryl, S(O).sub.2-8- to 10-membered bicyclic heteroaryl, C(O)OC.sub.1-6 alkyl, C(O)OC.sub.3-20 cycloalkyl, C(O)O-3- to 20-membered heterocyclyl, C(O)O-5- or 6-membered monocyclic heteroaryl, C(O)O-8- to 10-membered bicyclic heteroaryl, NR.sup.a1R.sup.b1, C(O)NR.sup.a1R.sup.b1, OR.sup.c1C.sub.1-4 alkyl-C(O)OC.sub.1-6 alkyl, C.sub.1-4 alkyl-C(O)OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-C(O)NR.sup.a1R.sup.b1, CCC(O)NR.sup.a1R.sup.b1, CCC.sub.1-4 alkyl-C(O)NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-OR.sup.c1, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2, C.sub.1-4 alkyl-NR.sup.d1C(O)R.sup.c1, C.sub.1-4 alkyl-NR.sup.d1C(O)NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-NR.sup.d1S(O).sub.2R.sup.c1, C.sub.1-4 alkyl-S(O).sub.2NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-NR.sup.d1S(O).sub.2NR.sup.a1R.sup.b1, NR.sup.d1C(O)R.sup.c1, NR.sup.d1C(O)NR.sup.a1R.sup.b1, NR.sup.d1S(O).sub.2R.sup.c1, S(O).sub.2NR.sup.a1R.sup.b1, NR.sup.d1S(O).sub.2NR.sup.a1R.sup.b1; wherein the C.sub.1-6 alkyl, the C.sub.1-6 alkoxy, and the C.sub.2-6 alkynyl are each independently optionally substituted with 1, 2, or 3 group(s) selected from halogen, deuterium, cyano, or hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S3; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; among the above groups, each R.sup.a, R.sup.b, R.sup.a1, and R.sup.b1 is independently H, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-4 alkyl-hydroxy, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-halogenated C.sub.1-6 alkyl, C.sub.1-4 alkyl-deuterated C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-halogenated C.sub.1-6 alkoxy, C.sub.1-4 alkyl-deuterated C.sub.1-6 alkoxy, C.sub.3-6 monocyclic cycloalkyl, C.sub.1-4 alkyl-C.sub.3-6 monocyclic cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, C.sub.1-4 alkyl-3- to 6-membered monocyclic heterocyclyl, C.sub.1-4 alkyl-O-3- to 6-membered monocyclic heterocyclyl, phenyl, C.sub.1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, S(O).sub.2C.sub.1-6 alkyl, S(O).sub.2C.sub.3-6 monocyclic cycloalkyl, S(O).sub.2-3- to 6-membered monocyclic heterocyclyl, C(O)C.sub.1-6 alkyl, C(O)C.sub.3-6 monocyclic cycloalkyl, C(O)-3- to 6-membered monocyclic heterocyclyl; wherein the C.sub.3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclyl, the phenyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are optionally substituted with 1 or 2 group(s) selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogenated C.sub.1-6 alkoxy, deuterated C.sub.1-6 alkoxy, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2; or each R.sup.a and R.sup.b together with the nitrogen atom to which the R.sup.a and R.sup.b are attached form a 3- to 20-membered heterocyclyl group; each R.sup.a1 and R.sup.b1 together with the nitrogen atom to which the R.sup.a1 and R.sup.b1 are attached form a 3- to 20-membered heterocyclyl group; wherein the 3- to 20-membered heterocyclyl is each independently optionally substituted with 1 or 2 group(s) selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogenated C.sub.1-6 alkoxy, deuterated C.sub.1-6 alkoxy, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2; among the above groups, each R.sup.d and R.sup.d1 are independently H, C.sub.1-6 alkyl, or deuterated C.sub.1-6 alkyl; among the above groups, each R.sup.c and R.sup.c1 are independently H, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogenated C.sub.1-6 alkoxy, deuterated C.sub.1-6 alkoxy, C.sub.1-4 alkyl-halogenated C.sub.1-6 alkyl, C.sub.1-4 alkyl-deuterated C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-halogenated C.sub.1-6 alkoxy, C.sub.1-4 alkyl-deuterated C.sub.1-6 alkoxy, C.sub.3-6 monocyclic cycloalkyl, C.sub.1-4 alkyl-C.sub.3-6 monocyclic cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, C.sub.1-4 alkyl-3- to 6-membered monocyclic heterocyclyl, C.sub.1-4 alkyl-O-3- to 6-membered monocyclic heterocyclyl, phenyl, C.sub.1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, or C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl; the C.sub.3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclyl, the phenyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are optionally substituted with 1 or 2 group(s) selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogenated C.sub.1-6 alkoxy, deuterated C.sub.1-6 alkoxy, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2; among the above groups, each group from group S3 is independently selected from the group consisting of oxo (CO), cyano, halogen, hydroxy, carboxy, nitro, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogenated C.sub.1-6 alkoxy, deuterated C.sub.1-6 alkoxy, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2, 3- to 6-membered monocyclic heterocyclyl; among the above groups, the C.sub.1-4 alkyl- or the C.sub.3-6 monocyclic cycloalkyl- is unsubstituted; or hydrogen atoms of the C.sub.1-4 alkyl- are each independently substituted with a group selected from halogen, cyano, hydroxy, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, CH.sub.2-hydroxy, CH.sub.2-cyano, and phenyl, or two hydrogen atoms attached to a same carbon atom of the C.sub.1-4 alkyl are simultaneously substituted with (CH.sub.2).sub.j to form a cycloalkyl group, wherein j is 2, 3, 4, 5, or 6; hydrogen atoms of the C.sub.3-6 monocyclic cycloalkyl- are each independently substituted with a group selected from halogen, cyano, hydroxy, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl.

2. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 1, wherein the compound is a compound of formula (IA-1); ##STR00946## wherein R.sup.1, Y, ##STR00947## R.sup.2, m1, ##STR00948## R.sup.3, and m2 are as defined in claim 1; L.sup.1 is a bond, C.sub.1-4 alkyl-, C.sub.3-6 monocyclic cycloalkyl-, O, S, NH, C(O), S(O), or S(O).sub.2; R.sup.4 is selected from the group consisting of H, halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-hydroxyl, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-carboxyl, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.aR.sup.b, C.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dC(O)R.sup.c, C.sub.1-4 alkyl-NR.sup.dC(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-S(O).sub.2R.sup.c, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2R.sup.c, C.sub.1-4 alkyl-S(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2NR.sup.aR.sup.b, C(O)C.sub.1-6 alkyl, C(O)C.sub.3-20 cycloalkyl, C(O)-3- to 20-membered heterocyclyl, C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C(O)NR.sup.aR.sup.b, NR.sup.dC(O)R.sup.c, NR.sup.dC(O)NR.sup.aR.sup.b, S(O).sub.2R.sup.c, NR.sup.dS(O).sub.2R.sup.c, S(O).sub.2NR.sup.aR.sup.b, NR.sup.dS(O).sub.2NR.sup.aR.sup.b, NR.sup.aR.sup.b, OR.sup.c; the C.sub.1-6 alkyl and the C.sub.1-6 alkoxy are each independently optionally substituted with halogen, deuterium, cyano, or hydroxy; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; wherein R.sup.a, R.sup.b, R.sup.c, R.sup.d, and group S1 are each as defined in claim 1.

3. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 1, wherein the compound is a compound of formula (IA1), a compound of formula (IA2), a compound of formula (IA3), a compound of formula (IA4), a compound of formula (IA5), or a compound of formula (IA6); ##STR00949## in each formula, Y, L.sup.1, R.sup.1, R.sup.2, ##STR00950## R.sup.3, R.sup.4, and m2 are each independently as defined in claim 1.

4. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 1, wherein the compound is a compound of formula (IB); ##STR00951## wherein R.sup.1, ##STR00952## R.sup.2, m1, ##STR00953## R.sup.3, and m2 are as defined in claim 1.

5. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 4, wherein the compound is a compound of formula (IB1), a compound of formula (IB2), a compound of formula (IB3), a compound of formula (IB4), a compound of formula (IB5), or a compound of formula IB6); ##STR00954## in each formula, R.sup.1, R.sup.2, ##STR00955## R.sup.3, and m2 are each independently as defined in claim 4.

6. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 1, wherein R.sup.1 is ##STR00956## wherein R.sup.1a is C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogenated C.sub.1-6 alkoxy, deuterated C.sub.1-6 alkoxy, C.sub.1-4 alkyl-hydroxy, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-halogenated C.sub.1-6 alkoxy, or C.sub.1-4 alkyl-deuterated C.sub.1-6 alkoxy; R.sup.1b is H, halogen, C.sub.1-3 alkyl, halogenated C.sub.1-3 alkyl, deuterated C.sub.1-3 alkyl, C.sub.1-3 alkoxy, halogenated C.sub.1-3 alkoxy, or deuterated C.sub.1-3 alkoxy; or R.sup.1 is ##STR00957## wherein R.sup.1a is C.sub.3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, phenyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl; R.sup.1b is H, halogen, C.sub.1-3 alkyl, halogenated C.sub.1-3 alkyl, deuterated C.sub.1-3 alkyl, C.sub.1-3 alkoxy, halogenated C.sub.1-3 alkoxy, or deuterated C.sub.1-3 alkoxy; wherein the C.sub.3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclyl, the phenyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1.

7. A compound of formula (IC), or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof: ##STR00958## wherein X is CR.sup.5 or N; Y is CH or N; and X and Y cannot both be N; R.sup.5 is H, C.sub.1-6 alkyl, or C.sub.3-6 monocyclic cycloalkyl; ##STR00959## is phenyl or 5- or 6-membered monocyclic heteroaryl; the 5- or 6-membered monocyclic heteroaryl contains 1, 2, or 3 heteroatom(s) independently selected from N, O, and S as ring atoms; the phenyl or the 5- or 6-membered monocyclic heteroaryl are each independently optionally substituted with m1 R.sup.2 group(s); m1 is 1, 2, 3, or 4; the R.sup.2 is ##STR00960## wherein R.sup.2a is H, deuterium, C.sub.1-6 alkyl, phenyl, or deuterated C.sub.1-6 alkyl, and R.sup.2b is H, deuterium, C.sub.1-6 alkyl, or deuterated C.sub.1-6 alkyl; or R.sup.2a and R.sup.2b together with the carbon atom to which the R.sup.2a and R.sup.2b are attached form a C.sub.3-6 monocyclic cycloalkyl group, and a bond between R.sup.2a and the carbon atom is a single bond; R.sup.2c is H, deuterium, C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.3-6 monocyclic cycloalkyl, or C.sub.3-6 monocyclic cycloalkyl; R.sup.2d is H, deuterium, C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.3-20 cycloalkyl, or 3- to 20-membered heterocyclyl; or when R.sup.2a and R.sup.2d together with the nitrogen atom to which the R.sup.2a and R.sup.2d are attached form a 3- to 20-membered heterocyclyl group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group, R.sup.2c is H, deuterium, C.sub.1-6 alkyl, or deuterated C.sub.1-6 alkyl; R.sup.2b is H, deuterium, C.sub.1-6 alkyl, or deuterated C.sub.1-6 alkyl, and the bond between R.sup.2a and the carbon atom is a single bond; or R.sup.2b is absent, and the bond between R.sup.2a and the carbon atom is a double bond; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl each independently contains one nitrogen atom and optionally 1 or 2 heteroatom(s) independently selected from N, O, and S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; or when R.sup.2c and R.sup.2d together with the nitrogen atom to which the R.sup.2c and R.sup.2d are attached form a 3- to 20-membered heterocyclyl group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group, R.sup.2a is H, deuterium, C.sub.1-6 alkyl, or deuterated C.sub.1-6 alkyl; R.sup.2b is H, deuterium, C.sub.1-6 alkyl, or deuterated C.sub.1-6 alkyl; and the bond between R.sup.2a and the carbon atom is a single bond; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl each independently contains one nitrogen atom and optionally 1 or 2 heteroatom(s) independently selected from N, O, and S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; or the R.sup.2 is ##STR00961## is 3- to 20-membered heterocyclyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl containing one nitrogen atom and attached to other moieties of a molecule through the nitrogen atom; ##STR00962## further optionally contains 1 or 2 heteroatom(s) independently selected from N, O, and S as ring atoms; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; ##STR00963## is phenyl or 5- or 6-membered monocyclic heteroaryl; the 5- or 6-membered monocyclic heteroaryl contains 1, 2, or 3 heteroatom(s) independently selected from N, O, and S as ring atoms; the phenyl and the 5- or 6-membered monocyclic heteroaryl are each independently optionally substituted with m2 R.sup.3 group(s); m2 is 1, 2, 3, or 4; each R.sup.3 is independently selected from the group consisting of H, oxo (O), halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, OC.sub.3-20 cycloalkyl, O-3- to 20-membered heterocyclyl, OC.sub.6-14 aryl, O-5- or 6-membered monocyclic heteroaryl, O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-hydroxyl, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.aR.sup.b, C.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dC(O)R.sup.c, C.sub.1-4 alkyl-NR.sup.dC(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-S(O).sub.2R.sup.c, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2R.sup.c, C.sub.1-4 alkyl-S(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-carboxy, C(O)C.sub.1-6 alkyl, C(O)OC.sub.1-6 alkyl, C(O)C.sub.1-4 alkyl-hydroxy, C(O)C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C(O)C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C(O)C.sub.3-20 cycloalkyl, C(O)OC.sub.3-20 cycloalkyl, C(O)OC.sub.3-20 cycloalkyl, C(O)C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C(O)-3- to 20-membered heterocyclyl, C(O)C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C(O)NR.sup.aR.sup.b, NR.sup.dC(O)R.sup.c, NR.sup.dC(O)NR.sup.aR.sup.b, S(O).sub.2R.sup.c, NR.sup.dS(O).sub.2R.sup.c, S(O).sub.2NR.sup.aR.sup.b, NR.sup.dS(O).sub.2NR.sup.aR.sup.b, NR.sup.aR.sup.b, OR.sup.c, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2; wherein the C.sub.1-6 alkyl and the C.sub.1-6 alkoxy are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from halogen, deuterium, cyano, 5- to 6-membered heterocyclyl, and hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S2; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; or ##STR00964## is C.sub.5-7 monocyclic cycloalkyl or 5-, 6- or 7-membered monocyclic heterocyclyl; the 5-, 6- or 7-membered heterocyclyl each independently contains 1, 2, or 3 heteroatom(s) independently selected from N, O, and S as ring atoms; the C.sub.5-7 monocyclic cycloalkyl and the 5-, 6- or 7-membered monocyclic heterocyclyl are each independently optionally substituted with m2 R.sup.3 group(s); m2 is 1, 2, 3, or 4; each R.sup.3 is independently selected from the group consisting of H, oxo (O), halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, OC.sub.3-20 cycloalkyl, O-3- to 20-membered heterocyclyl, OC.sub.6-14 aryl, O-5- or 6-membered monocyclic heteroaryl, O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-hydroxyl, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.aR.sup.b, C.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dC(O)R.sup.c, C.sub.1-4 alkyl-NR.sup.dC(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-S(O).sub.2R.sup.c, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2R.sup.c, C.sub.1-4 alkyl-S(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-carboxy, C(O)C.sub.1-6 alkyl, C(O)OC.sub.1-6 alkyl, C(O)C.sub.1-4 alkyl-hydroxy, C(O)C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C(O)C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C(O)C.sub.3-20 cycloalkyl, C(O)OC.sub.3-20 cycloalkyl, C(O)C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C(O)-3- to 20-membered heterocyclyl, C(O)C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C(O)NR.sup.aR.sup.b, NR.sup.dC(O)R.sup.c, NR.sup.dC(O)NR.sup.aR.sup.b, S(O).sub.2R.sup.c, NR.sup.dS(O).sub.2R.sup.c, S(O).sub.2NR.sup.aR.sup.b, NR.sup.dS(O).sub.2NR.sup.aR.sup.b, NR.sup.aR.sup.b, OR.sup.c, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2, CR.sup.3aR.sup.3b; wherein two hydrogen atoms attached to a same carbon atom can be substituted with two R.sup.3 groups such that the two R.sup.3 groups together with the carbon atom to which the two R.sup.3 groups are attached form a C.sub.3-6 monocyclic cycloalkyl group or a 3- to 6-membered monocyclic heterocyclyl group; or two hydrogen atoms attached to different carbon atoms are substituted with two R.sup.3 groups, and the two R.sup.3 groups join to form CH.sub.2, CH.sub.2CH.sub.2, or CH.sub.2CH.sub.2CH.sub.2; wherein the C.sub.1-6 alkyl and the C.sub.1-6 alkoxy are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from halogen, deuterium, cyano, 5- to 6-membered heterocyclyl, and hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S2; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; wherein R.sup.3a and R.sup.3b are each independently hydrogen, halogen, cyano, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, C.sub.6-14 aryl, or 5- or 6-membered monocyclic heteroaryl; the C.sub.6-14 aryl or the 5- or 6-membered monocyclic heteroaryl is optionally substituted with 1, 2, or 3 group(s) selected from halogen, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkyl, halogenated C.sub.1-4 alkoxy; or R.sup.3a and R.sup.3b together with the carbon atom to which the R.sup.3a and R.sup.3b are attached form a C.sub.3-6 monocyclic cycloalkyl group or a 3- to 6-membered monocyclic heterocyclyl group; the C.sub.3-6 monocyclic cycloalkyl or the 3- to 6-membered monocyclic heterocyclyl is optionally substituted with 1, 2, or 3 group(s) selected from halogen, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkyl, halogenated C.sub.1-4 alkoxy, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl; ##STR00965## is 5- to 7-membered heteroaromatic ring; wherein the m3 hydrogen atom(s) of ##STR00966## are optionally substituted with m3 R.sup.4 group(s); m3 is 1, 2, 3, or 4; R.sup.4 is selected from the group consisting of H, oxo (CO), halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, CCC.sub.3-20 cycloalkyl, CC-3- to 20-membered heterocyclyl, CCC.sub.6-14 aryl, CC-5- or 6-membered monocyclic heteroaryl, CC-8- to 10-membered bicyclic heteroaryl, CCC(O)NR.sup.aR.sup.b, CCC.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-hydroxy, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-carboxy, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.aR.sup.bC.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dC(O)R.sup.c, C.sub.1-4 alkyl-NR.sup.dC(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-S(O).sub.2R.sup.c, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2R.sup.c, C.sub.1-4 alkyl-S(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2NR.sup.aR.sup.b, C(O)C.sub.1-6 alkyl, C(O)C.sub.3-20 cycloalkyl, C(O)-3- to 20-membered heterocyclyl, C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C(O)NR.sup.aR.sup.b, NR.sup.dC(O)R.sup.c, NR.sup.dC(O)NR.sup.aR.sup.b, S(O).sub.2R.sup.c, NR.sup.dS(O).sub.2R.sup.c, S(O).sub.2NR.sup.aR.sup.b, NR.sup.dS(O).sub.2NR.sup.aR.sup.b, NR.sup.aR.sup.b, OR.sup.c, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2; wherein the C.sub.1-6 alkyl, the C.sub.1-6 alkoxy, the C.sub.2-6 alkenyl, and the C.sub.2-6 alkynyl are each independently optionally substituted with 1, 2, or 3 group(s) selected from halogen, deuterium, cyano, or hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; or ##STR00967## is 5- to 7-membered heterocyclic ring; wherein the m3 hydrogen atom(s) of ##STR00968## are optionally substituted with m3 R.sup.4 group(s); m3 is 1, 2, 3, or 4; R.sup.4 is selected from the group consisting of H, oxo (CO), halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, CCC.sub.3-20 cycloalkyl, CC-3- to 20-membered heterocyclyl, CCC.sub.6-14 aryl, CC-5- or 6-membered monocyclic heteroaryl, CC-8- to 10-membered bicyclic heteroaryl, CCC(O)NR.sup.aR.sup.b, CCC.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-hydroxy, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-carboxy, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.aR.sup.b, C.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dC(O)R.sup.c, C.sub.1-4 alkyl-NR.sup.dC(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-S(O).sub.2R.sup.c, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2R.sup.c, C.sub.1-4 alkyl-S(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2NR.sup.aR.sup.b, C(O)C.sub.1-6 alkyl, C(O)C.sub.3-20 cycloalkyl, C(O)-3- to 20-membered heterocyclyl, C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C(O)NR.sup.aR.sup.b, NR.sup.dC(O)R.sup.c, NR.sup.dC(O)NR.sup.aR.sup.b, S(O).sub.2R.sup.c, NR.sup.dS(O).sub.2R.sup.c, S(O).sub.2NR.sup.aR.sup.b, NR.sup.dS(O).sub.2NR.sup.aR.sup.b, NR.sup.aR.sup.b, OR.sup.c, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2; the C.sub.1-6 alkyl, the C.sub.1-6 alkoxy, the C.sub.2-6 alkenyl, and the C.sub.2-6 alkynyl are each independently optionally substituted with 1, 2, or 3 group(s) selected from halogen, deuterium, cyano, or hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; among the above groups, each group from group S1 is independently selected from the group consisting of oxo (O), halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, OC.sub.3-20 cycloalkyl, O-3- to 20-membered heterocyclyl, OC.sub.6-14 aryl, O-5- or 6-membered monocyclic heteroaryl, O-8- to 10-membered bicyclic heteroaryl, CCC.sub.3-20 cycloalkyl, CC-3- to 20-membered heterocyclyl, CCC.sub.6-14 aryl, CC-5- or 6-membered monocyclic heteroaryl, CC-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-hydroxy, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, S(O).sub.2C.sub.1-6 alkyl, S(O).sub.2C.sub.3-20 cycloalkyl, S(O).sub.2-3- to 20-membered heterocyclyl, C(O)OC.sub.1-6 alkyl, C(O)OC.sub.3-20 cycloalkyl, C(O)C.sub.1-6 alkyl, C(O)C.sub.3-20 cycloalkyl, C(O)C.sub.6-14 aryl, NR.sup.a1R.sup.b1, C(O)NR.sup.a1R.sup.b1, OR.sup.c1, C.sub.1-4 alkyl-S(O).sub.2C.sub.1-6 alkyl, C.sub.1-4 alkyl-S(O).sub.2C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-S(O).sub.2-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C(O)OC.sub.1-6 alkyl, C.sub.1-4 alkyl-C(O)OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-C(O)C.sub.1-6 alkyl, C.sub.1-4 alkyl-C(O)C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-C(O)NR.sup.a1R.sup.b1, CCC(O)NR.sup.a1R.sup.b1, CCC.sub.1-4 alkyl-C(O)NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-OR.sup.c1, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2, C.sub.1-4 alkyl-NR.sup.d1C(O)R.sup.c1, C.sub.1-4 alkyl-NR.sup.d1C(O)NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-NR.sup.d1S(O).sub.2R.sup.c1, C.sub.1-4 alkyl-S(O).sub.2NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-NR.sup.d1S(O).sub.2NR.sup.a1R.sup.b1, NR.sup.d1C(O)R.sup.c1, NR.sup.d1C(O)NR.sup.a1R.sup.b1, NR.sup.d1S(O).sub.2R.sup.c1, S(O).sub.2NR.sup.a1R.sup.b1, NR.sup.d1S(O).sub.2NR.sup.a1R.sup.b1; wherein the C.sub.1-6 alkyl, the C.sub.1-6 alkoxy, the C.sub.2-6 alkenyl, and the C.sub.2-6 alkynyl are each independently optionally substituted with 1, 2, or 3 group(s) selected from halogen, deuterium, cyano, or hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S3; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; among the above groups, each group from group S2 is independently selected from the group consisting of oxo (O), halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, O-3- to 20-membered heterocyclyl, O-5- or 6-membered monocyclic heteroaryl, O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-hydroxyl, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, S(O).sub.2C.sub.1-6 alkyl, S(O).sub.2C.sub.3-20 cycloalkyl, S(O).sub.2-3- to 20-membered heterocyclyl, S(O).sub.2-5- or 6-membered monocyclic heteroaryl, S(O).sub.2-8- to 10-membered bicyclic heteroaryl, C(O)OC.sub.1-6 alkyl, C(O)OC.sub.3-20 cycloalkyl, C(O)O-3- to 20-membered heterocyclyl, C(O)O-5- or 6-membered monocyclic heteroaryl, C(O)O-8- to 10-membered bicyclic heteroaryl, NR.sup.a1R.sup.b1, C(O)NR.sup.a1R.sup.b1, OR.sup.c1, C.sub.1-4 alkyl-C(O)OC.sub.1-6 alkyl, C.sub.1-4 alkyl-C(O)OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-C(O)NR.sup.a1R.sup.b1, CCC(O)NR.sup.a1R.sup.b1, CCC.sub.1-4 alkyl-C(O)NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-OR.sup.c1, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2, C.sub.1-4 alkyl-NR.sup.d1C(O)R.sup.c1, C.sub.1-4 alkyl-NR.sup.d1C(O)NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-NR.sup.d1S(O).sub.2R.sup.c1, C.sub.1-4 alkyl-S(O).sub.2NR.sup.a1R.sup.b1, C.sub.1-4 alkyl-NR.sup.d1S(O).sub.2NR.sup.a1R.sup.b1, NR.sup.d1C(O)R.sup.c1, NR.sup.d1C(O)NR.sup.a1R.sup.b1, NR.sup.d1S(O).sub.2R.sup.c1, S(O).sub.2NR.sup.a1R.sup.b1, NR.sup.d1S(O).sub.2NR.sup.a1R.sup.b1; wherein the C.sub.1-6 alkyl, the C.sub.1-6 alkoxy, and the C.sub.2-6 alkynyl are each independently optionally substituted with 1, 2, or 3 group(s) selected from halogen, deuterium, cyano, or hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S3; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; among the above groups, each Ra, R.sup.b, R.sup.a1, and R.sup.b1 is independently H, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-4 alkyl-hydroxy, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-halogenated C.sub.1-6 alkyl, C.sub.1-4 alkyl-deuterated C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-halogenated C.sub.1-6 alkoxy, C.sub.1-4 alkyl-deuterated C.sub.1-6 alkoxy, C.sub.3-6 monocyclic cycloalkyl, C.sub.1-4 alkyl-C.sub.3-6 monocyclic cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, C.sub.1-4 alkyl-3- to 6-membered monocyclic heterocyclyl, C.sub.1-4 alkyl-O-3- to 6-membered monocyclic heterocyclyl, phenyl, C.sub.1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, S(O).sub.2C.sub.1-6 alkyl, S(O).sub.2C.sub.3-6 monocyclic cycloalkyl, S(O).sub.2-3- to 6-membered monocyclic heterocyclyl, C(O)C.sub.1-6 alkyl, C(O)C.sub.3-6 monocyclic cycloalkyl, C(O)-3- to 6-membered monocyclic heterocyclyl; wherein the C.sub.3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclyl, the phenyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are optionally substituted with 1 or 2 group(s) selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogenated C.sub.1-6 alkoxy, deuterated C.sub.1-6 alkoxy, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2; or each R.sup.a and R.sup.b together with the nitrogen atom to which the R.sup.a and R.sup.b are attached form a 3- to 20-membered heterocyclyl group; each R.sup.a1 and R.sup.b1 together with the nitrogen atom to which the R.sup.a1 and R.sup.b1 are attached form a 3- to 20-membered heterocyclyl group; wherein the 3- to 20-membered heterocyclyl is each independently optionally substituted with 1 or 2 group(s) selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogenated C.sub.1-6 alkoxy, deuterated C.sub.1-6 alkoxy, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2; among the above groups, each R.sup.d and R.sup.d1 are independently H, C.sub.1-6 alkyl, or deuterated C.sub.1-6 alkyl; among the above groups, each R.sup.c and R.sup.c1 are independently H, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogenated C.sub.1-6 alkoxy, deuterated C.sub.1-6 alkoxy, C.sub.1-4 alkyl-halogenated C.sub.1-6 alkyl, C.sub.1-4 alkyl-deuterated C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-halogenated C.sub.1-6 alkoxy, C.sub.1-4 alkyl-deuterated C.sub.1-6 alkoxy, C.sub.3-6 monocyclic cycloalkyl, C.sub.1-4 alkyl-C.sub.3-6 monocyclic cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, C.sub.1-4 alkyl-3- to 6-membered monocyclic heterocyclyl, C.sub.1-4 alkyl-O-3- to 6-membered monocyclic heterocyclyl, phenyl, C.sub.1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, or C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl; the C.sub.3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclyl, the phenyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are optionally substituted with 1 or 2 group(s) selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogenated C.sub.1-6 alkoxy, deuterated C.sub.1-6 alkoxy, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2; among the above groups, each group from group S3 is independently selected from the group consisting of oxo (CO), halogen, cyano, hydroxy, carboxy, nitro, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogenated C.sub.1-6 alkoxy, deuterated C.sub.1-6 alkoxy, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2, 3- to 6-membered monocyclic heterocyclyl; among the above groups, the C.sub.1-4 alkyl- or the C.sub.3-6 monocyclic cycloalkyl- is unsubstituted, or hydrogen atoms of the C.sub.1-4 alkyl- are each independently substituted with a group selected from halogen, cyano, hydroxy, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl, CH.sub.2-hydroxy, CH.sub.2-cyano, and phenyl, or two hydrogen atoms attached to a same carbon atom of the C.sub.1-4 alkyl are simultaneously substituted with (CH.sub.2).sub.j to form a cycloalkyl group, wherein j is 2, 3, 4, 5, or 6; hydrogen atoms of the C.sub.3-6 monocyclic cycloalkyl- are each independently substituted with a group selected from halogen, cyano, hydroxy, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, deuterated C.sub.1-6 alkyl.

8. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 7, wherein the compound is a compound of formula (IC1); ##STR00969## wherein X, Y, ##STR00970## R.sup.2, m1, ##STR00971## R.sup.3, and m2 are as defined in claim 7; B.sup.1 is CH or N; R.sup.4 is selected from the group consisting of H, oxo (CO), halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, CCC.sub.3-20 cycloalkyl, CC-3- to 20-membered heterocyclyl, CCC.sub.6-14 aryl, CC-5- or 6-membered monocyclic heteroaryl, CC-8- to 10-membered bicyclic heteroaryl, CCC(O)NR.sup.aR.sup.b, CCC.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-hydroxy, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-carboxy, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.aR.sup.b, C.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dC(O)R.sup.c, C.sub.1-4 alkyl-NR.sup.dC(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-S(O).sub.2R.sup.c, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2R.sup.c, C.sub.1-4 alkyl-S(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl- NR.sup.dS(O).sub.2NR.sup.aR.sup.b, C(O)C.sub.1-6 alkyl, C(O)C.sub.3-20 cycloalkyl, C(O)-3- to 20-membered heterocyclyl, C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C(O)NR.sup.aR.sup.b, NR.sup.dC(O)R.sup.c, NR.sup.dC(O)NR.sup.aR.sup.b, S(O).sub.2R.sup.c, NR.sup.dS(O).sub.2R.sup.c, S(O).sub.2NR.sup.aR.sup.b, NR.sup.dS(O).sub.2NR.sup.aR.sup.b, NR.sup.aR.sup.b, OR.sup.c, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2; wherein the C.sub.1-6 alkyl, the C.sub.1-6 alkoxy, the C.sub.2-6 alkenyl, and the C.sub.2-6 alkynyl are each independently optionally substituted with 1, 2, or 3 group(s) selected from halogen, deuterium, cyano, or hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; wherein R.sup.a, R.sup.b, R.sup.c, R.sup.d, and group S1 are each as defined in claim 7.

9. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 8, wherein the compound is a compound of formula (IC1a), a compound of formula (IC1b), a compound of formula (IC1c), a compound of formula (IC1d), a compound of formula (IC1e), or a compound of formula (IC1f); ##STR00972## in each formula, X, Y, R.sup.2, ##STR00973## R.sup.3, m2, B.sup.1, and R.sup.4 are each independently as defined in claim 8.

10. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 7, wherein the compound is a compound of formula (IC3); ##STR00974## wherein X, Y, ##STR00975## R.sup.2, m1, ##STR00976## R.sup.3, and m2 are as defined in claim 7; B.sup.2 is N or CH; R.sup.4 is selected from the group consisting of H, oxo (CO), halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, CCC.sub.3-20 cycloalkyl, CC-3- to 20-membered heterocyclyl, CCC.sub.6-14 aryl, CC-5- or 6-membered monocyclic heteroaryl, CC-8- to 10-membered bicyclic heteroaryl, CCC(O)NR.sup.aR.sup.b, CCC.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-hydroxy, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-carboxy, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.aR.sup.b, C.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dC(O)R.sup.c, C.sub.1-4 alkyl-NR.sup.dC(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-S(O).sub.2R.sup.c, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2R.sup.c, C.sub.1-4 alkyl-S(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2NR.sup.aR.sup.b, C(O)C.sub.1-6 alkyl, C(O)C.sub.3-20 cycloalkyl, C(O)-3- to 20-membered heterocyclyl, C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C(O)NR.sup.aR.sup.b, NR.sup.dC(O)R.sup.c, NR.sup.dC(O)NR.sup.aR.sup.b, S(O).sub.2R.sup.c, NR.sup.dS(O).sub.2R.sup.c, S(O).sub.2NR.sup.aR.sup.b, NR.sup.dS(O).sub.2NR.sup.aR.sup.b, NR.sup.aR.sup.b, OR.sup.c, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2; the C.sub.1-6 alkyl, the C.sub.1-6 alkoxy, the C.sub.2-6 alkenyl, and the C.sub.2-6 alkynyl are each independently optionally substituted with 1, 2, or 3 group(s) selected from halogen, deuterium, cyano, or hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; wherein R.sup.a, R.sup.b, R.sup.c, R.sup.d, and group S1 are each as defined in claim 7.

11. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 10, wherein the compound is a compound of formula (IC3a), a compound of formula (IC3b), a compound of formula (IC3c), a compound of formula (IC3d), a compound of formula (IC3e), or a compound of formula (IC3f); ##STR00977## in each formula, X, Y, R.sup.2, ##STR00978## R.sup.3, m2, B.sup.2, and R.sup.4 are each independently as defined in claim 10.

12. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 7, wherein the compound is a compound of formula (IC4); ##STR00979## wherein X, Y, ##STR00980## R.sup.2, m1, ##STR00981## R.sup.3, and m2 are as defined in claim 7; B.sup.3 is CHR.sup.4, NR.sup.4, or O; R.sup.4, R.sup.4, and R.sup.4 are each independently selected from the group consisting of H, oxo (CO), halogen, cyano, hydroxyl, carboxyl, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C.sub.6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, CCC.sub.3-20 cycloalkyl, CC-3- to 20-membered heterocyclyl, CCC.sub.6-14 aryl, CC-5- or 6-membered monocyclic heteroaryl, CC-8- to 10-membered bicyclic heteroaryl, CCC(O)NR.sup.aR.sup.b, CCC.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-hydroxy, C.sub.1-4 alkyl-cyano, C.sub.1-4 alkyl-carboxy, C.sub.1-4 alkyl-C.sub.1-6 alkyl, C.sub.1-4 alkyl-C.sub.1-6 alkoxy, C.sub.1-4 alkyl-C.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-OC.sub.3-20 cycloalkyl, C.sub.1-4 alkyl-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-O-3- to 20-membered heterocyclyl, C.sub.1-4 alkyl-C.sub.6-14 aryl, C.sub.1-4 alkyl-OC.sub.6-14 aryl, C.sub.1-4 alkyl-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, C.sub.1-4 alkyl-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, C.sub.1-4 alkyl-NR.sup.aR.sup.b, C.sub.1-4 alkyl-C(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dC(O)R.sup.c, C.sub.1-4 alkyl-NR.sup.dC(O)NR.sup.aR.sup.b, C.sub.1-4 alkyl-S(O).sub.2R.sup.c, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2R.sup.c, C.sub.1-4 alkyl-S(O).sub.2NR.sup.aR.sup.b, C.sub.1-4 alkyl-NR.sup.dS(O).sub.2NR.sup.aR.sup.b, C(O)C.sub.1-6 alkyl, C(O)C.sub.3-20 cycloalkyl, C(O)-3- to 20-membered heterocyclyl, C(O)C.sub.6-14 aryl, C(O)-5- or 6-membered monocyclic heteroaryl, C(O)-8- to 10-membered bicyclic heteroaryl, C(O)NR.sup.aR.sup.b, NR.sup.dC(O)R.sup.c, NR.sup.dC(O)NR.sup.aR.sup.b, S(O).sub.2R.sup.c, NR.sup.dS(O).sub.2R.sup.c, S(O).sub.2NR.sup.aR.sup.b, NR.sup.dS(O).sub.2NR.sup.aR.sup.b, NR.sup.aR.sup.b, OR.sup.c, C.sub.1-4 alkyl-P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.1-6 alkyl).sub.2; the C.sub.1-6 alkyl, the C.sub.1-6 alkoxy, the C.sub.2-6 alkenyl, and the C.sub.2-6 alkynyl are each independently optionally substituted with 1, 2, or 3 group(s) selected from halogen, deuterium, cyano, or hydroxyl; the C.sub.3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C.sub.6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 group(s) selected from group S1; the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl each independently contains 1, 2, 3, or 4 heteroatom(s) independently selected from N, O, and S as ring atoms; or R.sup.4 and R.sup.4 together with the carbon atom to which the R.sup.4 and R.sup.4 are attached form a carbonyl group (CO); wherein R.sup.a, R.sup.b, R.sup.c, R.sup.d, and group S1 are each as defined in claim 7.

13. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 12, wherein the compound is a compound of formula (IC4a), a compound of formula (IC4b), a compound of formula (IC4c), a compound of formula (IC4d), a compound of formula (IC4e), or a compound of formula (IC4f); ##STR00982## in each formula, X, Y, R.sup.2, ##STR00983## R.sup.3, m2, B.sup.3, R.sup.4, and R.sup.4 are each independently as defined in claim 12.

14. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 7, wherein the compound is selected from the group consisting of ##STR00984## ##STR00985## ##STR00986## ##STR00987## ##STR00988## ##STR00989## ##STR00990## ##STR00991## ##STR00992## ##STR00993## ##STR00994## ##STR00995## ##STR00996## ##STR00997## ##STR00998## ##STR00999## ##STR01000## ##STR01001## ##STR01002## ##STR01003## ##STR01004## ##STR01005## ##STR01006## ##STR01007## ##STR01008## ##STR01009## ##STR01010## ##STR01011## ##STR01012## ##STR01013## ##STR01014## ##STR01015## ##STR01016## ##STR01017## ##STR01018## ##STR01019## ##STR01020## ##STR01021## ##STR01022## ##STR01023## ##STR01024## ##STR01025## ##STR01026## ##STR01027## ##STR01028## ##STR01029## ##STR01030## ##STR01031## ##STR01032## ##STR01033## ##STR01034## ##STR01035## ##STR01036## ##STR01037## ##STR01038## ##STR01039##

15. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 7, wherein the compound is selected from Table (Q.

16. A pharmaceutical composition comprising the compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 7; and a pharmaceutically acceptable carrier.

17. A method for preventing and/or treating a disease or condition associated with HPK1 activity, comprising administering to an individual in need thereof: the compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 7, or a pharmaceutical composition comprising: the compound, or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the prodrug thereof of claim 7; and a pharmaceutically acceptable carrier.

18. The method of claim 17, wherein the disease or condition associated with HPK1 activity is cancer.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0255] FIG. 1 is an ellipsoid plot of the three-dimensional structure of the molecule in Example 356.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0256] The compounds of the present disclosure may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed in combination with other chemical synthetic methods, and equivalents well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0257] The following examples describe the present disclosure in detail, but they are not meant to impose any unfavorable limitation on the present disclosure. The present disclosure has been described in detail herein, and its specific embodiments are also disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments without departing from the spirit and scope of the present disclosure. Examples, where specific conditions are not specified, are implemented in accordance with general conditions or those recommended by a manufacturer. All of the used agents or instruments, which manufacturers are not specified, are conventional commercially-available products.

[0258] The structures of the compounds were determined by methods such as nuclear magnetic resonance (NMR) and mass spectrometry (MS).

[0259] The NMR determination was performed on a Bruker Avance NEO 400 or Bruker Avance NEO 500 nuclear magnetic resonance instrument. The chemical shift (6) was in parts per million (ppm). The solvents for determination were as shown in each of the examples. The internal standard was tetramethylsilane (TMS).

[0260] The MS determination was performed on an Agilent 1100 liquid chromatograph.

[0261] The high performance liquid chromatography (HPLC) analysis was performed on a Waters 2695 high performance liquid chromatograph.

[0262] The preparative high performance liquid chromatography was performed on a Waters 2767 high performance liquid chromatograph.

[0263] The chiral HPLC and ee value analysis were performed on a Waters 2695 high performance liquid chromatograph or a Waters Investigator SFC system.

[0264] The preparative chiral chromatography was performed on a gilson gx-281 chromatograph or a waters SFC-80 chromatograph. Qingdao GF254 or Yantai Huanghai HSGF254 silica gel plates were used as thin-layer chromatography silica gel plates. 0.15 mm to 0.2 mm silica gel plates were used for thin-layer chromatography (TLC). 0.4 mm to 0.5 mm silica gel plates were used for thin-layer chromatography product separation and purification.

[0265] The ISCO CombiFlash NextGen 300 column chromatography system was used for column chromatography, and the Agela Flash Column Silica-Cs series silica gel column was used.

[0266] The prep-HPLC used in the following examples, unless otherwise specified, may be performed under the following conditions:

[0267] Prep-HPLC (ammonium bicarbonate method): column type: Waters XBridge C18, 190250 mm, 5 m; mobile phase system: A: 0.1% aqueous ammonium bicarbonate solution; B: preparative grade acetonitrile; flow rate: 15 mL/min; B %=20%-100%; column temperature: room temperature.

[0268] Prep-HPLC (ammonium bicarbonate method-A): column type: Welch Xtimate, 21.2150 mm, 5 m; mobile phase A: 5 mmol/L aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile; flow rate: 15 mL/min; chromatographic conditions: 15 mL-35-85-13 min; column temperature: room temperature.

[0269] Prep-HPLC (ammonia water method): column type: Waters XBridge C18, 190250 mm, 5 m; mobile phase system: A: 0.1% ammonia water solution; B: preparative grade acetonitrile; flow rate: 15 mL/min; B %=20%-100%; column temperature: room temperature.

[0270] Prep-HPLC (ammonia water method-A): column type: Ultimate XB-C18, 50250 mm, 10 m, mobile phase system: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 mL/min, gradient: within 50 min, B/A=20%-90%, wavelength: 214 nm, column temperature: room temperature.

[0271] Prep-HPLC (formic acid method): column type: Waters XBridge C18, 190250 mm, 5 m; mobile phase system: A: 0.1% formic acid; B: preparative grade acetonitrile; flow rate: 15 mL/min; B %=20%-100%; column temperature: room temperature.

[0272] Prep-HPLC (trifluoroacetic acid method): column type: Waters XBridge C18, 190250 mm, 5 m; mobile phase system: A: 0.1% trifluoroacetic acid; B: preparative grade acetonitrile; flow rate: 15 mL/min; B %=20%-100%; column temperature: 60 room temperature.

[0273] Prep-HPLC (hydrochloric acid method): column type: Phenomenex luna C18, 8040 mm3 m; mobile phase system: [water (hydrochloric acid)-acetonitrile]; B %: 1%-30%; flow rate: 15 mL/min; column temperature: room temperature.

Preparation Example 1: Preparation of Intermediate 1a

##STR00246## ##STR00247##

[0274] Step 1: 2-Bromo-4-chlorobenzaldehyde (50 g, 227.8 mmol) was dissolved in 200 ml of methanol, and placed in an ice-water bath. Aminoacetaldehyde dimethyl acetal (24 g, 227.8 mmol) and acetic acid (3 ml) were added and stirred for 30 min. NaBH.sub.3CN (28.63 g, 455.6 mmol) was added in batches, and the system reacted at room temperature for 2 h. The reaction mixture was extracted with ethyl acetate, washed with sodium bicarbonate, dried, and concentrated to give a crude product (30 g) which was directly used in the next step. ES-API: [M+H].sup.+=308.0

[0275] Step 2: The above crude product N-(2-bromo-4-chlorobenzyl)-2,2-dimethoxyethanamine (30 g) was dissolved in 150 ml of dichloromethane, and placed in an ice-water bath. Triethylamine (29.3 g, 292.5 mmol) and TsCl (27.8 g, 146.5 mmol) were added successively, and the system reacted at room temperature overnight. After standing for 5 h, the mixture was filtered. The filtrate was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and purified to give N-(2-bromo-4-chlorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (35 g, crude product purity: 76%). ES-API: [M+H].sup.+=430.0

[0276] Step 3: The above N-(2-bromo-4-chlorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (35 g, 75.75 mmol) was dissolved in dried dichloromethane (300 ml), and placed in an ice-water bath. Aluminum trichloride (80.6 g, 606 mmol) was added, and the system reacted at room temperature overnight. Upon completion of the reaction, the reaction was quenched by being slowly introduced into the ice-water bath. An excess NaOH solution was slowly added and stirred until a clear solution was obtained. The organic layer was separated, washed with water, dried, and purified (30%-40% ethyl acetate/petroleum ether) to give 8-bromo-6-chloroisoquinoline (8 g, total yield of the three steps: 14.5%). ES-API: [M+H].sup.+=242.0

[0277] Step 4: The 8-bromo-6-chloroisoquinoline (1 g, 4.15 mmol) reacted with potassium vinyltrifluoroborate (1.66 g, 12.45 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (151 mg, 0.207 mmol), triethylamine (419 mg, 4.15 mmol) and ethanol (50 ml) overnight at 80 C. Ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and purified to give a product 6-chloro-8-vinylisoquinoline (667 mg, yield: 85%). ES-API: [M+H].sup.+=190.0

[0278] Step 5: The 6-chloro-8-vinylisoquinoline (600 mg, 3.17 mmol) was dissolved in 20 ml of tetrahydrofuran. 2,6-dimethylpyridine (339 mg, 3.17 mmol) was added at room temperature, followed by K.sub.2OsO.sub.4 2H.sub.2O (424 mg, 0.951 mmol) and NaIO.sub.4 (5.42 g, 25.36 mmol) in water (10 ml). The system reacted at room temperature for 5 h and was cooled to 0 C. The reaction was quenched by the addition of aqueous sodium thiosulfate solution. The reaction mixture was diluted with ethyl acetate, and filtered. The filtrate was washed with water, saturated aqueous sodium bicarbonate solution and brine successively, dried, concentrated, and purified to give 6-chloroisoquinoline-8-carbaldehyde (400 mg, yield: 66%). ES-API: [M+H].sup.+=192.0.

[0279] Step 6: The above 6-chloroisoquinoline-8-carbaldehyde (400 mg, 2.09 mmol) and tert-butylsulfinamide (760 mg, 6.27 mmol) were dissolved in 10 ml of dried dichloromethane. Ti(EtO).sub.4 (1.9 g, 8.36 mmol) was added, and the system reacted at room temperature for 3 h. Upon completion of the reaction, the reaction mixture was slowly introduced into 20 ml of saturated brine, and 20 ml of dichloromethane was added. The organic layer was separated, filtered, dried, and purified to give (E/Z)N-(((6-chloroisoquinolin-8-yl)methylene)-2-methylpropane-2-sulfinamide (420 mg, yield: 68%). ES-API: [M+H].sup.+=295.0.

[0280] Step 7: Preparation of Grignard reagent: 2-(2-bromoethyl)-1,3-dioxane (849 mg, 4.35 mmol, 8 eq), Mg (104 mg, 4.35 mmol, 8 eq), a catalytic amount of elemental I.sub.2 and 20 ml of dried tetrahydrofuran were added to a 50 ml three-necked flask, and the system reacted at room temperature in the presence of protective nitrogen until a colorless solution with heat and bubbles were generated. The obtained solution was transferred to an oil bath at 75 C., and the system reacted for 2 h until most of the magnesium powder disappeared, and was cooled to room temperature for later use. The (E/Z)N-(((6-chloroisoquinolin-8-yl)methylene)-2-methylpropane-2-sulfinamide (420 mg, 1.43 mmol) and 20 ml of dried tetrahydrofuran were added to a 100 ml three-necked flask, and placed in a dry ice bath at 78 C. in the presence of protective nitrogen. The above Grignard reagent solution (10 ml, 4 eq) was slowly added. After 10 min, the reaction was completed and quenched by the addition of saturated aqueous NH.sub.4Cl solution (20 ml). The organic layer was separated, washed with water, dried, concentrated, and purified to give N-(1-(1-chloroisoquinolin-8-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (469 mg, yield: 80%). ES-API: [M+H].sup.+=411.1.

[0281] Step 8: The N-(1-(1-chloroisoquinolin-8-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (469 mg, 1.14 mmol) was added to trifluoroacetic acid/water (6 ml/0.3 ml), and the system reacted at room temperature (<25 C.) for 30 min. Et.sub.3SiH (1.32 g, 11.4 mmol) was added, and the system reacted for 2 h. After concentration, the obtained concentrate was dissolved in tetrahydrofuran. TEA (921 mg, 9.12 mmol) and (Boc).sub.2O (745.5 mg, 3.42 mmol) were added. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed with saturated brine, and purified to give a product tert-butyl 2-(6-chloroisoquinolin-8-yl)pyrrolidine-1-carboxylate (3a, 189 mg, yield: 50%). ES-API: [M+H].sup.+=333.1.

[0282] Step 9: The above tert-butyl 2-(6-chloroisoquinolin-8-yl)pyrrolidine-1-carboxylate (189 mg, 0.569 mmol) and iodomethane (10 eq) were added to 5 ml of acetonitrile, and the system reacted at 90 C. in a sealed tube for 6 h. Upon completion of the reaction, the reaction mixture was concentrated to give a product 8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-chloro-isoquinolin-2-methyl salt (210 mg, crude product) which was directly used in the next step. ES-API: [M+H].sup.+=348.1.

[0283] Step 10: The above 8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-chloro-isoquinolin-2-methyl salt (210 mg, crude product) was dissolved in 5 ml of methanol, and placed in an ice-water bath. NaBH.sub.4 (8 eq) was added, and the system reacted in the ice-water bath for 2 h. The reaction was quenched with saturated NH.sub.4Cl. The reaction mixture was extracted with ethyl acetate, washed with brine, dried, and purified to give a product tert-butyl 2-(6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (intermediate 1a, 160 mg, yield of the two steps: 80%). ES-API: [M+H].sup.+=351.1.

Preparation Example 2: Preparation of Intermediate 2a

##STR00248## ##STR00249##

[0284] Step 1: 3,5-Dibromophenylacetic acid (7.5 g, 25.5 mmol) and 150 ml of tetrahydrofuran were added to a three-neck reaction flask, and placed in an ice-water bath in the presence of protective nitrogen. Borane in tetrahydrofuran (38.3 mL, 38.3 mmol) was slowly added dropwise and stirred at room temperature for 6 h. Upon completion of the reaction, methanol was slowly added until no more bubbles were generated. The obtained mixture was extracted with ethyl acetate, washed with sodium bicarbonate and saturated brine successively, dried, concentrated, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:20) to give 3,5-dibromophenylethanol (6.3 g, yield: 88.8%). ES-API: [M+H-18].sup.+=260.9.

[0285] Step 2: The 3,5-dibromophenylethanol (6.3 g, 22.5 mmol) was dissolved in 120 ml of dichloromethane, and placed in an ice-water bath. Diisopropylethylamine (14.5 g, 112.5 mmol) and 2-methoxyethoxymethyl chloride (8.37 g, 67.5 mmol) were added successively, and the system reacted at room temperature overnight. Upon completion of the reaction, the reaction mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:20) to give 1,3-dibromo-5-(2-((2-methoxyethoxy)methoxy)ethyl)benzene (7.2 g, yield: 87%). ES-API: [M+Na].sup.+=391.0.

[0286] Step 3: The 1,3-dibromo-5-(2-((2-methoxyethoxy)methoxy)ethyl)benzene (7.2 g, 19.56 mmol) was dissolved in dried dichloromethane (150 ml), and placed in an ice-water bath. Titanium tetrachloride (29.3 mL, 29.3 mmol) was added, and the system reacted in the ice-water bath for 2 h. The reaction was quenched by being slowly poured into saturated brine, and the reaction mixture was extracted with dichloromethane. The organic layer was separated, dried, and purified (ethyl acetate:petroleum ether=1:15) to give 6,8-dibromoisochroman (5.0 g, yield: 87.7%). ES-API: [M+H].sup.+=294.9.

[0287] Step 4: The 6,8-dibromoisochroman (3.5 g, 11.98 mmol) and dried tetrahydrofuran (100 mL) were added to a 250 ml three-necked flask, and the system was cooled in an acetone-dry ice bath at 78 C. in the presence of protective nitrogen. n-Butyllithium (5.27 mL, 2.5 M) was slowly added, and the system reacted at 78 C. for 0.5 h. Dried N,N-dimethylformamide (5 mL) was slowly added. After 10 min, the reaction was checked by LCMS for completion and quenched by the addition of IM dilute hydrochloric acid. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to give a product 6-bromoisochroman-8-carbaldehyde (1.8 g, yield: 44%). ES-API: [M+H].sup.+=241.0.

[0288] Step 5: The 6-bromoisochroman-8-carbaldehyde (1.8 g, 7.5 mmol) and tert-butylsulfinamide (1.81 g, 15 mmol) were dissolved in 50 ml of dichloromethane, and placed in an ice-water bath. Tetraethyl phthalate (3.42 g, 15 mmol) was added, and the system reacted at room temperature for 3 h. Upon completion of the reaction, the reaction mixture was poured into saturated brine, diluted with dichloromethane, and filtered. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:2) to give a product N-((6-bromoisochroman-8-yl)methylene)-2-methylpropane-2-sulfinamide (2.36 g, yield: 92%). ES-API: [M+H].sup.+=344.1.

[0289] Step 6: The N-((6-bromoisochroman-8-yl)methylene)-2-methylpropane-2-sulfinamide (1.86 g, 5.42 mmol) and 20 ml of dried tetrahydrofuran were added to a 100 ml three-necked flask, placed in a 78 C. dry ice bath in the presence of protective nitrogen. (2-(1,3-Dioxan-2-yl)ethyl)magnesium bromide (43.4 ml, 0.5M in tetrahydrofuran) was added. After 10 min, the reaction was completed and quenched by the addition of saturated aqueous NH.sub.4Cl solution (20 ml). The organic layer was separated, washed with water, dried, concentrated, and purified by silica gel (ethyl acetate:petroleum ether=1:1) to give N-(1-(6-bromoisochroman-8-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (2.1 g, yield: 85%). ES-API: [M+H].sup.+=460.2.

[0290] Step 7: The N-(1-(6-bromoisochroman-8-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (2.5 g, 7.29 mmol) was added to trifluoroacetic acid/water (30 ml/3 ml), and the system reacted at room temperature (<25 C.) for 30 min. Et.sub.3SiH (8.45 g, 11.6 mmol) was added, and the system reacted for 5 h. After concentration, trifluoroacetic acid was removed. The residue was dissolved in tetrahydrofuran, and triethylamine (2.21 g, 21.9 mmol) and (Boc).sub.2O (3.96 g, 18.2 mmol) were added. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed with saturated brine, and purified by silica gel (ethyl acetate:petroleum ether=1:4) to give a product tert-butyl 2-(6-bromoisochroman-8-yl)pyrrolidine-1-carboxylate (1.65 g, yield: 59%). ES-API: [M+H].sup.+=382.0.

[0291] Step 8: The tert-butyl 2-(6-bromoisochroman-8-yl)pyrrolidine-1-carboxylate (750 mg, 1.96 mmol) was chirally resolved by SFC (column type: ChiralpakIC 250 mm*4.6 mm*5 um, mobile phase: HEX-IPA=85:15, flow rate: 1 ml/min, column temperature: 30 C., 30 min) to give tert-butyl (S)-2-(6-bromoisochroman-8-yl)pyrrolidine-1-carboxylate (420 mg, yield: 56%, retention time: 9.619 min, ee value: 100%)). ES-API: [M+H].sup.+=382.1.

[0292] Step 9: The tert-butyl (S)-2-(6-bromoisochroman-8-yl)pyrrolidine-1-carboxylate (381 mg, 1 mmol), bis(pinacolato)diboron (762 mg, 3 mmol), Pd(dppf)Cl.sub.2 (73 mg, 0.1 mmol) and potassium acetate (294 mg, 3 mmol) were dissolved in 1,4-dioxane (8 ml), and the system reacted under microwave at 100 C. for 0.5 h. Upon completion of the reaction, ethyl acetate was added.

[0293] The obtained mixture was filtered, concentrated, and purified (petroleum ether:ethyl acetate=50:50) to give tert-butyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (400 mg, yield: 93%). ES-API: [M+H].sup.+=430.3.

Preparation Example 3: Preparation of Intermediate 4a and Isomers Thereof

##STR00250## ##STR00251##

[0294] Step 1: 8-Bromo-6-chloro-isoquinoline (1 g, 4.12 mmol) was dissolved in ethanol (20 mL). Potassium trifluoro(vinyl)borate (1.66 g, 12.4 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (302 mg, 0.41 mmol) and triethylamine (1.25 g, 12.4 mmol) were added, and the system was warmed to 80 C. and reacted for 3 h. The reaction mixture was spun to dryness and purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give 6-chloro-8-vinylisoquinoline (750 mg, yield: 95.9%). ES-API: [M+1].sup.+=190.1.

[0295] Step 2: 6-Chloro-8-vinylisoquinoline (750 mg, 3.95 mmol) was dissolved in tetrahydrofuran/water (10 mL/5 mL). 2,6-Lutidine (424 mg, 3.95 mmol), sodium periodate (6.77 g, 31.64 mmol) and potassium osmate dihydrate (437 mg, 1.19 mmol) were added, and the system was reacted at room temperature for 2 h. The reaction was quenched with an aqueous sodium thiosulfate solution, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, spun to dryness, and purified by column chromatography (petroleum ether/ethyl acetate=2/1) to give 6-chloroisoquinoline-8-carbaldehyde (390 mg, yield: 51%). ES-API: [M+1].sup.+=191.9.

[0296] Step 3: 6-Chloroisoquinoline-8-carbaldehyde (270 mg, 1.41 mmol) was dissolved in dichloromethane (10 mL). 2-(Tributylstannylmethoxy)ethanamine (513 mg, 1.41 mmol) and 4 A molecular sieves (300 mg) were added, and the system was reacted at room temperature overnight. The reaction mixture was filtered and spun to dryness to give 1-(6-chloro-8-isoquinolyl)-N-[2-(tributylstannylmethoxy)ethyl]methanamine as a crude product which was directly used in the next step without purification.

[0297] Step 4: (R,R)-2,2-Isopropylidenebis(4-phenyl-2-oxazoline) (94 mg, 0.28 mmol) was added in one portion to a suspension of copper triflate (510 mg, 1.41 mmol) in hexafluoroisopropanol (2.5 mL) followed by a solution of the 1-(6-chloro-8-isoquinolyl)-N-[2-(tributylstannylmethoxy)ethyl]methanamine (crude product) in hexafluoroisopropanol (2.5 mL), and the system was reacted at room temperature overnight. The reaction was quenched with 1 M sodium hydroxide solution, and the reaction mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and spun to dryness to give 3-(6-chloro-8-isoquinolyl)morpholine as a crude product which was directly used in the next step without purification. ES-API: [M+1].sup.+=249.1.

[0298] Step 5: 3-(6-Chloro-8-isoquinolyl)morpholine (crude product) was dissolved in tetrahydrofuran (5 mL). Triethylamine (428 mg, 4.23 mmol) and di-tert-butyl dicarbonate (615 mg, 2.82 mmol) were added, and the system was reacted at room temperature for 2 h. Upon completion of the reaction, the reaction was quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, spun to dryness, and purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give tert-butyl 3-(6-chloro-8-isoquinolyl)morpholine-4-carboxylate (200 mg, yield: 40.1%). ES-API: [M+1].sup.+=349.1.

[0299] Step 6: tert-Butyl 3-(6-chloro-8-isoquinolyl)morpholine-4-carboxylate (100 mg, 0.29 mmol) was dissolved in acetic acid (1.5 mL), and the system was cooled to 0 C. Sodium borohydride (43 mg, 1.15 mmol) was added, and the system was reacted at 0 C. for 1 h. Upon completion of the reaction, the reaction was quenched by the addition of water. The obtained mixture was basified with sodium carbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and spun to dryness to give tert-butyl 3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate as a crude product which was directly used in the next step without purification. ES-API: [M+1].sup.+=353.1.

[0300] Step 7: tert-Butyl 3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (crude product, 0.28 mmol) was dissolved in dichloromethane (1 mL). Triethylamine (85 mg, 0.84 mmol) was added, and the system was cooled to 0 C. Acetyl chloride (22 mg, 0.28 mmol) was then added, and the system was reacted at 0 C. for 0.5 h. Upon completion of the reaction, the reaction was quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, spun to dryness, and purified by column chromatography (petroleum ether/ethyl acetate=3/1) to give tert-butyl 3-(2-acetyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (4a, 80 mg, yield: 72%). ES-API: [M+1-100].sup.+=295.1.

[0301] Step 8: tert-Butyl 3-(2-acetyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (4a, 1.1 g, 2.79 mmol) was resolved by SFC (column type: IC: 5 m, 4.6250 mm, mobile phase: carbon dioxide:isopropanol=70:30, flow rate: 3 mL/min, column temperature: 40 C., column pressure: atmospheric pressure) to give two isomers, wherein a structure of one isomer was arbitrarily assigned as tert-butyl (S)-3-(2-acetyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (4a-1, 406 mg, yield: 37%, retention time: 8.10 min, purity: 100%, ee value: 100%), ES-API: [M+H].sup.+=395.0; a structure of the other isomer was arbitrarily assigned as tert-butyl (R)-3-(2-acetyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (4a-2, 471 mg, yield: 43%, retention time: 9.83 min, purity: 100%, ee value: 100%). ES-API: [M+H].sup.+=395.1.

Preparation Example 4: Preparation of Intermediate 5a

##STR00252##

[0302] Step 1: Compound tert-butyl (R)-3-(2-acetyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (4a-2, 471 mg, 1.19 mmol) and sodium hydroxide (167 mg, 4.18 mmol) in ethanol (5 mL) and water (1 mL) were stirred at 80 C. overnight. Upon completion of the reaction, the reaction mixture was concentrated, and ethyl acetate (30 mL) was added. The organic phase was washed with water (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 260 mg, crude product) which was directly used in the next step without purification. ES-API: [M+H].sup.+=353.0.

Preparation Example 5: Preparation of Intermediate 6a and Intermediates Thereof

##STR00253##

[0303] Step 1: 5-Bromo-7-chloro-1,2,3,4-tetrahydroisoquinoline (492 mg, 2 mmol), triethylamine (606 mg, 6 mmol), and dichloromethane (10 mL) were added to a 50 mL single-neck round-bottom flask. Acetic anhydride (310 mg, 3 mmol) was slowly added at 0 C., and the system was reacted at 0 C. for 1 h. Dichloromethane (20 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product 1-(5-bromo-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (582 mg, yield: 100%). ES-API: [M+H].sup.+=288.0.

[0304] Step 2: 1-(5-Bromo-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (1.5 g, 5.2 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (1.35 g, 4.33 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (320 mg, 0.43 mmol), potassium carbonate (1.8 g, 13.0 mmol), dioxane (20 mL), and water (3 mL) were added to a 50 mL round-bottom flask. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 3 h. Ethyl acetate (50 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (50 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=50:100) to give a desired product tert-butyl 5-(2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (1.88 g, crude product). ES-API: [M+H].sup.+=393.2.

[0305] Step 3: tert-Butyl 5-(2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (1.88 g, crude product), trifluoroacetic acid (20 mL), and dichloromethane (40 mL) was added to a 25 mL single-neck round-bottom flask. Sodium borohydride (0.73 g, 19 mmol) was slowly added to the mixed solution and stirred at room temperature for 3 h. The reaction mixture was spun to dryness. Ethyl acetate (50 mL) was added. The obtained mixture was washed with saturated brine (50 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=50:100) to give a desired product 1-(7-chloro-5-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (1.4 g, crude product). ES-API: [M+H].sup.+=294.9.

[0306] Step 4: 1-(7-Chloro-5-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (1.4 g, crude product), di-tert-butyl dicarbonate (5.18 g, 23.7 mmol), triethylamine (3.84 g, 38 mmol) and tetrahydrofuran (50 mL) were added to a 25 mL single-neck round-bottom flask, and stirred at room temperature for 1 h. Ethyl acetate (50 mL) was then added to the reaction mixture. The obtained mixture was washed with saturated brine (50 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=50:100) to give a desired product tert-butyl 3-(2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (6a, 1.5 g, yield of the 3 steps: 73%). ES-API: [M+H].sup.+=395.2.

[0307] Step 5: tert-Butyl 3-(2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (6a, 1 g, 2.5 mmol) was purified by chiral resolution (chromatographic column: IG column; mobile phase A: n-hexane; mobile phase B: ethanol; flow rate: 1 mL/min; B %=50%; column temperature: 30 C.) to give two isomeric compounds, wherein a structure of one isomer was arbitrarily assigned as tert-butyl (R)-3-(2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (6a-1, retention time: 8.559 min, 250 mg, yield: 25%). ES-API: [M+H].sup.+=395.2; a structure of the other isomer was arbitrarily assigned as tert-butyl (S)-3-(2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (6a-2, retention time: 7.134 min, 250 mg, yield: 25%). ES-API: [M+H].sup.+=395.2.

Example 1. Synthesis of Compound Z1

##STR00254##

[0308] Step 1: 5-Bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.18 mmol), bis(pinacolato)diboron (902 mg, 3.55 mmol), Pd(dppf)Cl.sub.2 (86 mg, 0.0118 mmol) and potassium acetate (173 mg, 1.77 mmol) were dissolved in 1,4-dioxane (20 ml), and the system reacted at 80 C. for 5 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified to give (3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (130 mg, yield: 62%). ES-API: [M+H].sup.+=177.0 Step 2: The (3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (16 mg, 0.09 mmol), tert-butyl 2-(6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (15 mg, 0.045 mmol), Sphos Pd G2 (3.2 mg, 0.0045 mmol) and K.sub.3PO.sub.4 (28.6 mg, 0.135 mmol) were added to 1,4-dioxane (1 ml) and water (0.2 ml). The system was replaced with nitrogen and reacted under microwave at 100 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified to give tert-butyl 2-(2-methyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (10 mg, yield: 50%). ES-API: [M+H].sup.+=447.2

[0309] Step 3: The tert-butyl 2-(2-methyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (10 mg, 0.022 mmol) was added to 4M hydrochloric acid-methanol solution (5 ml), and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and purified by prep-HPLC (formic acid method) to give 2-(2-methyl-6-(3-methyl-H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine (Z1, formate, 2.3 mg, yield: 23%). ES-API: [M+H].sup.+=347.2

Example 2. Synthesis of Compound Z2

##STR00255##

[0310] Step 1: 5-Bromo-3-iodopyridin-2-amine (1.49 g, 5 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (970 mg, 5 mmol), Pd(dppf)Cl.sub.2 (365 mg, 0.5 mmol) and potassium carbonate (2.07 g, 15 mmol) were dissolved in 1,4-dioxane (30 ml), and the system reacted at 85 C. for 20 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified to give 5-bromo-3-(1H-pyrazol-4-yl)pyridin-2-amine (350 mg, yield: 29%). ES-API: [M+H].sup.+=239.0

[0311] Step 2: The 5-bromo-3-(1H-pyrazol-4-yl)pyridin-2-amine (350 mg, 1.47 mmol), bis(pinacolato)diboron (1.12 g, 4.43 mmol), Pd(dppf)Cl.sub.2 (120 mg, 0.147 mmol) and potassium acetate (434 mg, 4.43 mmol) were dissolved in 1,4-dioxane (20 ml), and the system reacted at 80 C. for 20 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified to give (6-amino-5-(1H-pyrazol-4-yl)pyridin-3-yl)boronic acid (100 mg, yield: 33%). ES-API: [M+H].sup.+=205.0

[0312] Step 3: The (6-amino-5-(1H-pyrazol-4-yl)pyridin-3-yl)boronic acid (20 mg, 0.098 mmol), tert-butyl 2-(6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (34 mg, 0.098 mmol), Sphos Pd G2 (3.2 mg, 0.0049 mmol) and K.sub.3PO.sub.4 (62 mg, 0.294 mmol) were added to 1,4-dioxane (5 ml) and water (1 ml). The system was replaced with nitrogen and reacted under microwave at 100 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified to give tert-butyl 2-(6-(6-amino-5-(1H-pyrazol-4-yl)pyridin-3-yl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (10 mg, yield: 21%). ES-API: [M+H].sup.+=475.2

[0313] Step 4: The tert-butyl 2-(6-(6-amino-5-(1H-pyrazol-4-yl)pyridin-3-yl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (10 mg, 0.021 mmol) was added to 4M hydrochloric acid-methanol solution (5 ml), and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and purified by prep-HPLC (ammonium bicarbonate method) to give 5-(2-methyl-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(1H-pyrazol-4-yl)pyridin-2-amine (Z2, 1.79 mg, yield: 22%). ES-API: [M+H].sup.+=375.2.

Example 3. Synthesis of Compound Z3 and Isomers Thereof

##STR00256##

[0314] Step 1: (3-Methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (66 mg, 0.2 mmol), tert-butyl 2-(6-chloroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.4 mmol), Sphos Pd G2 (14.4 mg, 0.02 mmol) and K.sub.3PO.sub.4 (127 mg, 0.6 mmol) were added to 1,4-dioxane (2 ml) and water (0.2 ml). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified to give tert-butyl 2-(6-(3-(methyl-1H-pyrrolo[2,3-b]pyridin-5-yl]isoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, yield: 70%). ES-API: [M+H].sup.+=429.2

[0315] Step 2: The tert-butyl 2-(6-(3-(methyl-1H-pyrrolo[2,3-b]pyridin-5-yl]isoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.14 mmol) was added to 4M hydrochloric acid-methanol solution (5 ml), and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and purified by prep-HPLC (ammonium bicarbonate method) to give 6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)isoquinoline formate (Z3, 19 mg, yield: 41%). ES-API: [M+H].sup.+=329.2

[0316] Step 3: The compound Z3 (15 mg) obtained from the above steps was resolved by chiral preparation column (separation column IC 250 mm*4.6 mm*5 um, mobile phase: HEX-ETOH-DEA=50:50:2, flow rate: 1 ml/min, column temperature: 30 C.) to give two isomeric compounds. A structure of one isomeric compound was arbitrarily assigned as (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)isoquinoline (Z3-1, 3.5 mg, peak 1, retention time: 15.24 min, yield: 23%, ee: 100%), ES-API: [M+H].sup.+=329.2; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.46 (s, 1H), 9.62 (s, 1H), 8.66 (d, J=2.2 Hz, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.18 (d, J=1.8 Hz, 1H), 7.88 (d, J=5.6 Hz, 1H), 7.34-7.30 (m, 1H), 5.02 (t, J=7.6 Hz, 1H), 3.18 (dt, J=9.8, 6.3 Hz, 1H), 3.07 (dt, J=9.8, 7.4 Hz, 1H), 2.35 (d, J=1.1 Hz, 3H), 2.05-1.91 (m, 1H), 1.90-1.85 (m, 2H), 1.69-1.32 (m, 1H). A structure of the other isomeric compound was arbitrarily assigned as (R)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)isoquinoline (Z3-2, 4.5 mg, peak 2, retention time: 24.78 min, yield: 30%, ee: 100%), ES-API: [M+H].sup.+=329.2.

Example 4. Synthesis of Compound Z4

##STR00257##

[0317] Step 1: 5-Bromo-3-iodopyridin-2-amine (2 g, 6.69 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.08 mg, 10.0 mmol), Pd(dppf)Cl.sub.2 (273 mg, 0.05 mmol) and potassium carbonate (2.3 g, 16.72 mmol) were dissolved in 1,4-dioxane (30 ml) and water (3 ml), and the system reacted at 85 C. for 20 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified to give 5-bromo-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (900 mg, yield: 53.6%). ES-API: [M+H].sup.+=253.0

[0318] Step 2: The 5-bromo-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (900 mg, 3.55 mmol), bis(pinacolato)diboron (1.8 g, 7.11 mmol), Pd(dppf)Cl.sub.2 (145 mg, 0.177 mmol) and potassium acetate (697 mg, 7.11 mmol) were dissolved in 1,4-dioxane (20 ml), and the system reacted at 80 C. for 20 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified to give (6-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)boronic acid (220 mg, yield: 28%). ES-API: [M+H].sup.+=219.0

[0319] Step 3: The (6-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)boronic acid (218 mg, 1.0 mmol), tert-butyl 2-(6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (160 mg, 0.457 mmol), Sphos Pd G2 (72 mg, 0.1 mmol) and K.sub.2CO.sub.3 (414 mg, 3.0 mmol) were added to 1,4-dioxane (6 ml) and water (1 ml). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified to give tert-butyl 2-(6-(6-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (150 mg, yield: 67%). ES-API: [M+H].sup.+=489.2

[0320] Step 4: The tert-butyl 2-(6-(6-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (150 mg, 0.307 mmol) was added to 4M hydrochloric acid-methanol solution (8 ml), and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and purified by prep-HPLC (ammonium bicarbonate method) to give 3-(1-methyl-1H-pyrazol-4-yl)-5-(2-methyl-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-2-amine (60 mg, yield: 50.4%). ES-API: [M+H].sup.+=389.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.26 (d, J=2.4 Hz, 1H), 8.10 (s, 1H), 7.83 (d, J=4.3 Hz, 2H), 7.68 (s, 1H), 7.40 (d, J=1.8 Hz, 1H), 5.78 (s, 2H), 4.54-4.46 (m, 1H), 3.89 (s, 3H), 3.72 (d, J=15.4 Hz, 1H), 3.50 (d, J=15.2 Hz, 1H), 3.21 (t, J=7.9 Hz, 1H), 2.92-2.89 (m, 3H), 2.66-2.54 (m, 3H), 2.41 (s, 3H), 2.30 (t, J=10.4 Hz, 1H), 2.08-1.84 (m, 3H).

Example 5. Synthesis of Compound Z93 and Isomers Thereof

##STR00258##

[0321] Step 1: (6-Amino-5-(1H-pyrazol-4-yl)pyridin-3-yl)boronic acid (48 mg, 0.236 mmol), tert-butyl 2-(6-bromoisochroman-8-yl)pyrrolidine-1-carboxylate (45 mg, 0.118 mmol), Sphos Pd G2 (34 mg, 0.0472 mmol) and K.sub.2CO.sub.3 (98 mg, 0.708 mmol) were added to 1,4-dioxane (2 ml) and water (0.5 ml). The system was replaced with nitrogen and reacted under microwave at 100 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified (petroleum ether:ethyl acetate=10:90) to give tert-butyl 2-(6-(6-(6-amino-5-(1H-pyrazol-4-yl)pyridin-3-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (32 mg, yield: 60%). ES-API: [M+H].sup.+=462.2.

[0322] Step 2: The tert-butyl 2-(6-(6-(6-amino-5-(1H-pyrazol-4-yl)pyridin-3-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (32 mg, 0.069 mmol) was added to 4M hydrochloric acid-methanol solution (5 ml), and the system reacted at room temperature for 3 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with 7M ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (formic acid method) to give 3-(1H-pyrazol-4-yl)-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)pyridin-2-amine formate (20 mg, yield: 80%). ES-API: [M+H].sup.+=362.2.

[0323] Step 3: The 3-(1H-pyrazol-4-yl)-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)pyridin-2-amine formate (Z93, 20 mg) was resolved by chiral preparation column (separation column IC 250 mm*4.6 mm*5 um, mobile phase: HEX-ETOH-DEA=50:50:2, flow rate: 1 ml/min, column temperature: 30 C., 35 MIN) to give two isomeric compounds. A structure of one isomeric compound was arbitrarily assigned as (R)-3-(1H-pyrazol-4-yl)-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)pyridin-2-amine (Z93-1, 3.8 mg, peak 1, retention time: 9.20 min, yield: 19%, ee: 97%), ES-API: [M+H].sup.+=362.2; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.17 (d, J=2.4 Hz, 1H), 7.99 (s, 3H), 7.73 (d, J=2.4 Hz, 1H), 7.59 (d, J=1.9 Hz, 1H), 7.27 (d, J=1.9 Hz, 1H), 5.73 (s, 2H), 4.87-4.68 (m, 3H), 4.04 (t, J=7.7 Hz, 1H), 3.89-3.82 (m, 2H), 3.14-3.04 (m, 1H), 2.93-2.88 (m, 1H), 2.87-2.83 (m, 2H), 2.17-2.10 (m, 1H), 1.84-1.79 (m, 1H), 1.76-1.70 (m, 1H), 1.46-1.40 (m, 1H); a structure of the other isomeric compound was arbitrarily assigned as (S)-3-(1H-pyrazol-4-yl)-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)pyridin-2-amine (Z93-2, 3 mg, peak 2, retention time: 15.54 min, yield: 15%, ee: 96.8%), ES-API: [M+H].sup.+=362.2.

Example 6. Synthesis of Compound Z94 and Isomers Thereof

##STR00259##

[0324] Step 1: (6-Amino-5-(1H-pyrazol-4-yl)pyridin-3-yl)boronic acid (55 mg, 0.271 mmol), tert-butyl 2-(6-chloroisoquinolin-8-yl)pyrrolidine-1-carboxylate (45 mg, 0.135 mmol), Sphos Pd G2 (19.5 mg, 0.0271 mmol) and K.sub.2CO.sub.3 (56 mg, 0.405 mmol) were added to 1,4-dioxane (2 ml) and water (0.5 ml)). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified (dichloromethane:methanol=90:10) to give tert-butyl 2-(6-(6-(6-amino-5-(1H-pyrazol-4-yl)pyridin-3-yl)isoquinolin-8-yl)pyrrolidine-1-carboxylate (24 mg, yield: 39%). ES-API: [M+H].sup.+=457.2.

[0325] Step 2: The tert-butyl 2-(6-(6-(6-amino-5-(1H-pyrazol-4-yl)pyridin-3-yl)isoquinolin-8-yl)pyrrolidine-1-carboxylate (24 mg, 0.069 mmol) was added to 4M hydrochloric acid-methanol solution (5 ml), and the system reacted at room temperature for 3 h. Upon completion of the reaction, the reaction mixture was concentrated and purified by prep-HPLC (ammonium bicarbonate method) to give 3-(1H-pyrazol-4-yl)-5-(8-(pyrrolidin-2-yl)isoquinolin-6-yl)pyridin-2-amine (Z94, 10 mg, yield: 53%). ES-API: [M+H].sup.+=357.2.

[0326] Step 3: 3-(1H-pyrazol-4-yl)-5-(8-(pyrrolidin-2-yl)isoquinolin-6-yl)pyridin-2-amine (Z94, 10 mg) was resolved by chiral preparation column (separation column IC 250 mm*4.6 mm*5 um, mobile phase: HEX-ETOH-DEA=50:50:2, flow rate: 1 ml/min, column temperature: 30 C., 35 MIN) to give two isomeric compounds. A structure of one isomeric compound was arbitrarily assigned as (R)-3-(1H-pyrazol-4-yl)-5-(8-(pyrrolidin-2-yl)isoquinolin-6-yl)pyridin-2-amine (Z94-1, 3.9 mg, peak 1, retention time: 11.90 min, yield: 39%, ee value: 97%), ES-API: [M+H].sup.+=357.2; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.57 (s, 1H), 8.49 (d, J=5.6 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 8.03 (s, 2H), 7.94 (d, J=2.4 Hz, 1H), 7.81 (d, J=5.6 Hz, 1H), 5.96 (s, 2H), 4.96 (t, J=7.6 Hz, 1H), 3.15 (dt, J=9.9, 6.3 Hz, 1H), 3.07-3.02 (m, 1H), 2.46-2.41 (m, 1H), 1.94-1.79 (m, 3H), 1.65-1.58 (m, 1H); a structure of the other isomeric compound was arbitrarily assigned as (S)-3-(1H-pyrazol-4-yl)-5-(8-(pyrrolidin-2-yl)isoquinolin-6-yl)pyridin-2-amine (Z94-2, 3.5 mg, peak 2, retention time: 15.58 min, yield: 35%, ee value: 96.5%), ES-API: [M+H].sup.+=357.2.

Example 7. Synthesis of Compound Z95 and Isomers Thereof

##STR00260##

[0327] Step 1: 5-Bromo-3-isopropyl-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.05 mmol), bis(pinacolato)diboron (800 mg, 3.15 mmol), Pd(dppf)Cl.sub.2 (77 mg, 0.105 mmol) and potassium acetate (309 mg, 3.15 mmol) were added to dried 1,4-dioxane (8 mL). The system was replaced with nitrogen and reacted under microwave at 100 C. for 0.5 h. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, filtered, concentrated, and purified by silica gel (petroleum ether:ethyl acetate=80:20) to give 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (230 mg, yield: 76%). ES-API: [M+H].sup.+=287.2.

[0328] Step 2: The 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (61 mg, 0.3 mmol), tert-butyl 2-(6-chloroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.15 mmol), Sphos Pd G2 (21.6 mg, 0.03 mmol) and K.sub.2CO.sub.3 (62 mg, 0.45 mmol) were added to 1,4-dioxane (2 ml) and water (0.5 ml). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified to give tert-butyl 2-(6-(3-(isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl]isoquinolin-8-yl)pyrrolidine-1-carboxylate (45 mg, yield: 66%). ES-API: [M+H].sup.+=457.2.

[0329] Step 3: The tert-butyl 2-(6-(3-(isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl]isoquinolin-8-yl)pyrrolidine-1-carboxylate (45 mg, 0.099 mmol) was added to 4M hydrochloric acid-methanol solution (5 ml), and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and purified by prep-HPLC (ammonium bicarbonate method) to give 6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)isoquinoline (Z95, 18 mg, yield: 51%). ES-API: [M+H].sup.+=357.2.

[0330] Step 4: The 6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)isoquinoline (Z95, 15 mg) was chirally resolved by SFC (column type: Chiralpak IC 250 mm*4.6 mm*5 um, mobile phase: HEX-ETOH-DEA=40:60:2, flow rate: 1 ml/min, column temperature: 30 C., 35 MIN) to give two isomeric compounds. A structure of one isomeric compound was arbitrarily assigned as (R)-6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)isoquinoline (Z95-1, 3.8 mg, yield: 25%, retention time: 10.29 min, ee value: 100%). ES-API: [M+H].sup.+=357.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.48 (s, 1H), 9.62 (s, 1H), 8.64 (d, J=2.2 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.23 (d, J=1.9 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 7.89 (d, J=5.6 Hz, 1H), 7.29 (d, J=2.5 Hz, 1H), 5.00 (t, J=7.6 Hz, 1H), 3.27-3.23 (m, 1H), 3.16 (dt, J=9.8, 6.2 Hz, 1H), 3.06 (dt, J=9.8, 7.4 Hz, 1H), 2.46 (d, J=7.1 Hz, 1H), 2.04-1.80 (m, 3H), 1.66-1.62 (m, 1H), 1.36 (d, J=6.9 Hz, 6H); a structure of the other isomeric compound was arbitrarily assigned as (S)-6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)isoquinoline (Z95-2, 2.7 mg, yield: 18%, retention time: 16.30 min, ee value: 100%). ES-API: [M+H].sup.+=357.2.

Example 8. Synthesis of Compound Z96

##STR00261##

[0331] Step 1: 5-Bromo-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (250 mg, 0.947 mmol), bis(pinacolato)diboron (721 mg, 2.84 mmol), Pd(dppf)Cl.sub.2 (69 mg, 0.0947 mmol) and potassium acetate (278 mg, 2.84 mmol) were added to dried 1,4-dioxane (8 mL). The system was replaced with nitrogen and reacted under microwave at 110 C. for 0.5 h. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, filtered, concentrated, and purified by silica gel (petroleum ether:ethyl acetate=75:25) to give 3-(trifluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (240 mg, yield: 82%). ES-API: [M+H].sup.+=313.1.

[0332] Step 2: The 3-(trifluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (94 mg, 0.3 mmol), tert-butyl 2-(6-chloroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.15 mmol), Sphos Pd G2 (21.6 mg, 0.03 mmol) and K.sub.2CO.sub.3 (62 mg, 0.45 mmol) were added to 1,4-dioxane (2 ml) and water (0.5 ml). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified to give tert-butyl 2-(6-(3-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoquinolin-8-yl)pyrrolidine-1-carboxylate (46 mg, yield: 61%). ES-API: [M+H].sup.+=483.2.

[0333] Step 3: The tert-butyl 2-(6-(3-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoquinolin-8-yl)pyrrolidine-1-carboxylate (46 mg, 0.093 mmol) was added to 4M hydrochloric acid-methanol solution (5 ml), and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and purified by prep-HPLC (ammonium bicarbonate method) to give 6-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)isoquinoline (Z96, 10 mg, yield: 28%). ES-API: [M+H].sup.+=383.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.64 (s, 1H), 8.84 (d, J=2.1 Hz, 1H), 8.55 (d, J=5.6 Hz, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.27 (q, J=1.4 Hz, 1H), 8.24-8.22 (m, 2H), 7.92 (d, J=5.6 Hz, 1H), 5.00 (t, J=7.6 Hz, 1H), 3.15 (ddd, J=9.8, 6.8, 5.4 Hz, 1H), 3.06 (dt, J=9.8, 7.4 Hz, 1H), 2.46 (s, 1H), 1.85 (dq, J=10.1, 7.4 Hz, 3H), 1.65-1.58 (m, 1H).

Example 9. Synthesis of Compound Z97 and Isomers Thereof

##STR00262##

[0334] Step 1: Pinacol (3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)borate (76 mg, 0.296 mmol), tert-butyl 2-(6-bromoisochroman-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.148 mmol), Sphos Pd G2 (21 mg, 0.0296 mmol) and K.sub.2CO.sub.3 (61 mg, 0.444 mmol) were added to 1,4-dioxane (2 ml) and water (0.5 ml). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified (petroleum ether:ethyl acetate=20:80) to give tert-butyl 2-(6-(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (45 mg, yield: 70%). ES-API: [M+H].sup.+=434.1.

[0335] Step 2: The tert-butyl 2-(6-(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (45 mg, 0.108 mmol) was dissolved in dichloromethane (2 mL) and added to 1 mL of trifluoroacetic acid, and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with 7M ammonia/methanol solution (1 mL), the obtained mixture was concentrated again, and purified by prep-HPLC (ammonia water method) to give 3-methyl-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridine (Z97, 10 mg, yield: 27.8%). ES-API: [M+H].sup.+=334.1. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.32 (s, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.25 (dd, J=2.5, 1.3 Hz, 1H), 4.95-4.62 (m, 3H), 4.05 (t, J=7.7 Hz, 1H), 3.92-3.83 (m, 2H), 3.12-3.07 (m, 1H), 2.94-2.85 (m, 3H), 2.31 (t, J=1.9 Hz, 3H), 2.17-2.13 (m, 1H), 1.93- 1.61 (m, 3H), 1.48-1.42 (m, 1H).

[0336] Step 3: The 3-methyl-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridine (Z97, 80 mg) was chirally resolved by SFC (column type: Chiralpak IC 250 mm*4.6 mm*5 um, mobile phase: HEX-ETOH-DEA=50:50:2, flow rate: 1 ml/min, column temperature: 30 C., 35 MIN) to give two isomeric compounds. A structure of one isomeric compound was arbitrarily assigned as (R)-3-methyl-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridine (Z97-1, 30 mg, yield: 37.5%, retention time: 6.88 min, purity: 100%, ee value: 100%). ES-API: [M+H].sup.+=334.1. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.32 (s, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.70 (d, J=1.9 Hz, 1H), 7.34 (d, J=1.9 Hz, 1H), 7.25 (s, 1H), 4.87 (d, J=15.2 Hz, 1H), 4.75 (d, J=15.2 Hz, 1H), 4.04 (t, J=7.7 Hz, 1H), 3.90-3.86 (m, 2H), 3.50 (d, J=10.0 Hz, 1H), 3.10-1.06 (m, 1H), 2.89 (dt, J=10.3, 7.1 Hz, 3H), 2.31 (s, 3H), 2.15-2.10 (m, 1H), 1.80-1.76 (m, 2H), 1.45-1.40 (, 1H); a structure of the other isomeric compound was arbitrarily assigned as (S)-3-methyl-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridine (Z97-2, 30 mg, yield: 37.5%, retention time: 11.09 min, purity: 100%, ee value: 100%). ES-API: [M+H].sup.+=334.1. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.32 (s, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.70 (d, J=1.9 Hz, 1H), 7.34 (s, 1H), 7.25 (s, 1H), 4.91-4.71 (m, 2H), 4.05 (t, J=7.7 Hz, 1H), 3.90-3.86 (m, 2H), 3.67-3.42 (m, 1H), 3.10-1.06 (m, 1H), 2.89 (dt, J=11.3, 6.6 Hz, 3H), 2.31 (s, 3H), 2.20-2.11 (m, 1H), 1.88-1.71 (m, 2H), 1.48-1.39 (m, 1H).

Example 10. Synthesis of Compound Z98 and Isomers Thereof

##STR00263##

[0337] Step 1: Tert-butyl 2-(6-chloroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.18 mmol) was dissolved in 5 ml of acetic acid. NaBH.sub.4 (55 mg, 1.44 mmol) was added at room temperature, and the system reacted for 0.5 h. The obtained mixture was concentrated, extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated brine successively, dried, and concentrated to give a product tert-butyl 2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, crude product) which was directly used in the next step. ES-API: [M+H].sup.+=337.1.

[0338] Step 2: The tert-butyl 2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.178) was dissolved in dichloromethane. Triethylamine (54 mg, 0.534 mmoL) and acetyl chloride (21 mg, 0.267 mmol) were added successively under an ice-water bath condition, and the system reacted for 1 h. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried, concentrated, and purified by silica gel (petroleum ether:ethyl acetate=80:20) to give tert-butyl 2-(2-acetyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, yield of the two steps: 88%). ES-API: [M+H].sup.+=379.1.

[0339] Step 3: The tert-butyl 2-(2-acetyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.158 mmol), pinacol (3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)borate (56 mg, 0.317 mmol), Sphos Pd G2 (23 mg, 0.0317 mmol) and K.sub.2CO.sub.3 (65.4 mg, 0.474 mmol) were added to 1,4-dioxane (2 ml) and water (0.5 ml). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified to give tert-butyl 2-(2-acetyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, yield: 80%). ES-API: [M+H].sup.+=475.2.

[0340] Step 4: The tert-butyl 2-(2-acetyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.126 mmol) was dissolved in 3 ml of dichloromethane. 2 ml of trifluoroacetic acid was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated and purified by prep-HPLC (ammonia water method) to give 1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (Z98, 35 mg, yield: 74%). ES-API: [M+H].sup.+=374.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.32 (s, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.09 (d, J=2.5 Hz, 1H), 7.75 (dd, J=10.4, 2.0 Hz, 1H), 7.39 (t, J=3.0 Hz, 1H), 7.27-7.25 (m, 1H), 4.79 (t, J=17.1 Hz, 1H), 4.64-4.68 (m, 1H), 4.23-4.18 (m, 1H), 3.68 (t, J=5.9 Hz, 2H), 3.12-3.08 (m, 1H), 3.01-2.82 (m, 4H), 2.31 (t, J=1.5 Hz, 3H), 2.14-2.10 (m, 4H), 1.82-1.78 (m, 2H), 1.53-1.38 (m, 1H).

[0341] Step 5: The 1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (Z98, 35 mg) was chirally resolved by SFC (column type: ChiralpakIC 250 mm*4.6 mm*5 um, mobile phase: HEX-ETOH-DEA=50:50:2, flow rate: 1 ml/min, column temperature: 30 C., 30 MIN) to give two isomeric compounds. A structure of one isomeric compound was arbitrarily assigned as (R)-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (Z98-1, 10 mg, yield: 28.5%, retention time: 3.65 min, purity: 96%, ee value: 100%). ES-API: [M+H].sup.+=374.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.33 (s, 1H), 8.46 (d, J=2.2 Hz, 1H), 8.09 (d, J=2.3 Hz, 1H), 7.75 (dd, J=9.8, 2.0 Hz, 1H), 7.40 (dd, J=5.7, 1.8 Hz, 1H), 7.26 (s, 1H), 4.79 (t, J=17.1 Hz, 1H), 4.65-4.60 (m, 1H), 4.24 (dt, J=19.8, 7.7 Hz, 1H), 3.68 (t, J=5.9 Hz, 2H), 3.14-3.10 (m, 1H), 3.00-2.95 (m, 2H), 2.86 (t, J=6.1 Hz, 1H), 2.31 (s, 3H), 2.25-2.17 (m, 1H), 2.16-2.10 (m, 3H), 1.91-1.75 (m, 3H), 1.56-1.42 (m, 1H). A structure of the other isomeric compound was arbitrarily assigned as (S)-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (Z98-2, 10 mg, yield: 37.5%, retention time: 6.82 min, purity: 97%, ee value: 100%). ES-API: [M+H].sup.+=374.2.

Example 11. Synthesis of Compound Z99

##STR00264##

[0342] Step 1: Tert-butyl 2-(6-bromoisochroman-8-yl)pyrrolidine-1-carboxylate (381 mg, 1 mmol), bis(pinacolato)diboron (762 mg, 3 mmol), pd(dppf)Cl.sub.2 (73 mg, 0.1 mmol) and potassium acetate (294 mg, 3 mmol) were dissolved in 1,4-dioxane (8 ml), and the system reacted under microwave at 100 C. for 0.5 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was filtered, concentrated, and purified (petroleum ether:ethyl acetate=50:50) to give tert-butyl 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (400 mg, yield: 93%). ES-API: [M+H].sup.+=430.3.

[0343] Step 2: The tert-butyl 2-(6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (123.5 mg, 0.288 mmol), 5-bromo-3,4-dimethyl-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.222 mmol), Sphos Pd G.sub.2 (16 mg, 0.0222 mmol) ad K.sub.2CO.sub.3 (92 mg, 0.666 mmol) were added to 1,4-dioxane (2 ml) and water (0.5 ml). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified (petroleum ether:ethyl acetate=20:80) to give tert-butyl 2-(6-(3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (50 mg, yield: 50.5%). ES-API: [M+H].sup.+=448.2.

[0344] Step 3: Tert-butyl 2-(6-(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl]isochroman-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.108 mmol) was dissolved in dichloromethane (2 mL) and added to 1 mL of trifluoroacetic acid, and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with 7M 50 ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give 3-methyl-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridine (Z99, 34 mg, yield: 87%). ES-API: [M+H].sup.+=348.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.24-11.17 (m, 1H), 7.94 (s, 1H), 7.35 (d, J=1.9 Hz, 1H), 7.17 (s, 1H), 6.99 (dd, J=14.6, 1.8 Hz, 1H), 4.90-4.75 (m, 2H), 4.08 (t, J=7.5 Hz, 1H), 3.94-3.84 (m, 2H), 3.57-3.40 (m, 2H), 3.03-2.98 (m, 1H), 2.90-2.84 (m, 2H), 2.55 (d, J=5.6 Hz, 3H), 2.45 (d, J=1.1 Hz, 3H), 1.84-1.73 (m, 2H), 1.68-1.60 (m, 1H), 1.46-1.40 (m, 1H).

Example 12. Synthesis of Compound Z100 and Isomers Thereof

##STR00265##

[0345] Step 1: Tert-butyl 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.2 mmol), 5-bromo-3-(pyrimidin-4-yl)pyridin-2-amine (86 mg, 0.2 mmol), Sphos Pd G2 (28.8 mg, 0.04 mmol) and K.sub.2CO.sub.3 (83 mg, 0.6 mmol) were added to 1,4-dioxane (2 ml) and water (0.5 ml). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified (petroleum ether:ethyl acetate=10:90) to give tert-butyl 2-(6-(6-amino-5-(pyrimidin-4-yl)pyridin-3-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (57 mg, yield: 60%). ES-API: [M+H].sup.+=474.2.

[0346] Step 2: The tert-butyl 2-(6-(6-amino-5-(pyrimidin-4-yl)pyridin-3-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (57 mg, 0.120 mmol) was dissolved in dichloromethane (2 mL) and added to 1 mL of trifluoroacetic acid, and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with 7M ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give 3-(pyrimidin-4-yl)-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)pyridin-2-amine (Z100, 28 mg, yield: 63%). ES-API: [M+H].sup.+=374.2.

[0347] Step 3: The 3-(pyrimidin-4-yl)-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)pyridin-2-amine (Z100, 25 mg) was chirally resolved by SFC (column type: Chiralpak IC 250 mm*4.6 mm*5 um, mobile phase: HEX-ETOH-DEA=40:60:2, flow rate: 1 ml/min, column temperature: 30 C., 30 MIN) to give two isomers. A structure of one isomer was arbitrarily assigned as (R)-3-(pyrimidin-4-yl)-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)pyridin-2-amine (Z100-1, 8 mg, yield: 32%, retention time: 6.64 min, purity: 96%, ee value: 100%). ES-API: [M+H].sup.+=374.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.25 (d, J=1.3 Hz, 1H), 8.86 (d, J=5.6 Hz, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 8.25 (dd, J=5.7, 1.5 Hz, 1H), 7.75 (s, 2H), 7.64 (d, J=1.9 Hz, 1H), 7.35 (d, J=1.9 Hz, 1H), 4.88-4.72 (m, 2H), 4.01 (t, J=7.6 Hz, 1H), 3.93-3.83 (m, 2H), 3.70-3.47 (m, 1H), 3.10-3.06 (m, 1H), 2.90-2.86 (m, 3H), 2.14-2.10 (m, 1H), 1.87-1.70 (m, 2H), 1.44-1.40 (m, 1H); a structure of the other isomer was arbitrarily assigned as (S)-3-(pyrimidin-4-yl)-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)pyridin-2-amine (Z100-2, 8 mg, yield: 32%, retention time: 10.79 min, purity: 97%, ee value: 99%). ES-API: [M+H].sup.+=374.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.26 (d, J=1.4 Hz, 1H), 8.86 (d, J=5.6 Hz, 1H), 8.45 (d, J=2.3 Hz, 1H), 8.38 (d, J=2.3 Hz, 1H), 8.25 (dd, J=5.7, 1.4 Hz, 1H), 7.81-7.71 (m, 2H), 7.65 (d, J=2.0 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 4.88-4.73 (m, 2H), 4.05 (t, J=7.7 Hz, 1H), 3.91-3.83 (m, 2H), 3.71-3.46 (m, 1H), 3.10-3.06 (m, 1H), 2.95-2.84 (m, 3H), 2.14-2.10 (m, 1H), 1.87-1.70 (m, 2H), 1.52-1.44 (m, 1H).

Example 13. Synthesis of Compound Z101 and Isomers Thereof

##STR00266##

[0348] Step 1: 1-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylmethanamine (1 g, 3.95 mmol), iodomethane (2.8 g, 19.7 mmol) were added to dichloromethane/toluene (40 ml/80 ml), and the system reacted at room temperature in a sealed tube for 20 h. Upon completion of the reaction, the reaction mixture was concentrated to give 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N,N-trimethyl methanaminium (1.6 g, crude product). ES-API: [M+H].sup.+=269.2.

[0349] Step 2: The 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N,N-trimethyl methanaminium (1.0 g, 2.52 mmol) was dissolved in tetrahydrofuran (100 ml). TMSCN (554 mg, 5.59 mmol) and TBAF (11.2 ml, 11.2 mmol) were added successively, and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated, diluted with ethyl acetate, washed with aqueous sodium carbonate solution and saturated brine successively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel (petroleum ether:ethyl acetate=50:50) to give 2-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (480 mg, yield: 80%). ES-API: [M+H].sup.+=236.1/238.1.

[0350] Step 3: The 2-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (50 mg, 0.211 mmol), tert-butyl 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (90.5 mg, 0.211 mmol), Pd(dppf)Cl.sub.2 dichloromethane adduct (17.2 mg, 0.0211 mmol) and K.sub.2CO.sub.3 (87.3 mg, 0.633 mmol) were added to 1,4-dioxane (2 ml) and water (0.5 ml). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified (petroleum ether:ethyl acetate=10:90) to give tert-butyl 2-(6-(3-(cyanomethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (45 mg, yield: 47%). ES-API: [M+H].sup.+=459.2.

[0351] Step 4: Tert-butyl (6-(3-(cyanomethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (45 mg, 0.098 mmol) was dissolved in dichloromethane (2 mL) and added to 1 mL of trifluoroacetic acid, and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with 7M ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give 2-(5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (Z101, 22 mg, yield: 63%). ES-API: [M+H].sup.+=359.2.

[0352] Step 5: The 2-(5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (Z101, 20 mg) was chirally resolved by SFC (column type: Chiralpak IC 250 mm*4.6 mm*5 um, mobile phase: HEX-ETOH-DEA=50:50:2, flow rate: 1 ml/min, column temperature: 30 C., 30 MIN) to give two isomeric compounds. A structure of one isomeric compound was arbitrarily assigned as (R)-2-(5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (Z101-1, 8 mg, yield: 40%, retention time: 9.46 min, ee value: 100%). ES-API: [M+H].sup.+=359.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.78 (s, 1H), 8.57 (d, J=2.2 Hz, 1H), 8.29-8.25 (m, 2H), 7.74 (d, J=1.9 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H), 4.92-4.76 (m, 2H), 4.19 (t, J=7.9 Hz, 1H), 4.13 (s, 2H), 3.93-3.85 (m, 2H), 3.18 (d, J=7.2 Hz, 1H), 3.01 (q, J=8.3 Hz, 1H), 2.90 (q, J=6.5, 5.9 Hz, 2H), 2.36 (d, J=1.9 Hz, 1H), 2.22-2.18 (m, 1H), 1.90-1.85 (m, 2H), 1.64-1.60 (m, 1H); the structure pf the other isomeric compound was arbitrarily assigned as (S)-2-(5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (Z101-2, 8 mg, yield: 40%, retention time: 13.04 min, ee value: 99.55%). ES-API: [M+H].sup.+=359.2.

Example 14. Synthesis of Compound Z103

##STR00267##

[0353] Step 1: 6-Bromoisochroman-8-carbaldehyde (355 mg, 1.47 mmol) was dissolved in 1,2-dichloroethane (10 mL). 2.0M Dimethylamine in tetrahydrofuran (2.2 mL, 4.40 mmol), acetic acid (265 mg, 4.41 mmol) and sodium triacetoxyborohydride (623 mg, 2.94 mmol) were added successively and stirred at room temperature for 4 h. Dichloromethane (50 mL) was added to the reaction mixture. The obtained mixture was washed with saturated sodium bicarbonate (20 mL2) and saturated brine (20 mL) successively, dried, and concentrated. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0-5%) to give a desired product 1-(6-bromoisochroman-8-yl)-N,N-dimethylmethanamine (370 mg, yield: 93%) as a colorless liquid. ES-API: [M+H].sup.+=270.1/272.1.

[0354] Step 2: The 1-(6-bromoisochroman-8-yl)-N,N-dimethylmethanamine (50 mg, 0.18 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (62 mg, 0.24 mmol), potassium carbonate (75 mg, 0.54 mmol), 2-dicyclohexylphosphine-2,6-dimethoxy-biphenyl (8 mg, 0.018 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (13 mg, 0.018 mmol), 1,4-dioxane (2 mL) and water (0.5 mL) were added to a 5 mL microwave tube. The mixture was purged with nitrogen for 1 min, and the system reacted in a microwave reactor at 110 C. for 1 h. Water (10 mL) was added to the reaction mixture, and the obtained mixture was extracted with 40 mL of ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution (15 mL) and saturated brine (15 mL) successively, dried, and concentrated. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give a desired product N,N-dimethyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)methanamine (Z103, 32 mg, yield: 54%) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.32 (s, 1H), 8.46 (d, J=1.5 Hz, 1H), 8.12 (d, J=1.5 Hz, 1H), 7.43-7.38 (m, 2H), 7.25 (s, 1H), 4.84 (s, 2H), 3.88 (t, J=5.5 Hz, 2H), 3.33 (s, 2H), 2.89 (t, J=5.5 Hz, 2H), 2.30 (s, 3H), 2.16 (s, 6H). ES-API: [M+H].sup.+=322.1.

Example 15. Synthesis of Compound Z104 and Isomers Thereof

##STR00268##

[0355] Step 1: 1-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylmethanamine (1.0 g, 3.95 mmol) and iodomethane (2.8 g, 19.75 mmol) were added to a mixed solution of 40 ml of dichloromethane and 80 ml of toluene and stirred at room temperature for 20 h. Upon completion of the reaction, the reaction mixture was concentrated to give 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N,N-trimethyl methanaminium iodide (1.5 g, crude product) which was directly used in the next step. ES-API: [M+H].sup.+=268.0/270.0.

[0356] Step 2: The 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N,N-trimethyl methanaminium iodide (1.5 g, 3.93 mmol), trimethylsilyl cyanide (503 mg, 5.08 mmol) and tetrabutylammonium fluoride (11.8 ml, 11.8 mmol, 1M THE solution) were added to 50 ml of tetrahydrofuran and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel (petroleum ether:ethyl acetate=80:20) to give 2-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (520 mg, yield: 55%). ES-API: [M+H].sup.+=236.0/238.0.

[0357] Step 3: The 2-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (150 mg, 0.638 mmol) was dissolved in dichloromethane (10 ml). (Boc).sub.2O (209 mg, 0.957 mmol), diisopropylethyl amine (164 mg, 1.276 mmol) and DMAP (7.6 mg, 0.0638 mmol) were added successively, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated, diluted with ethyl acetate, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel (petroleum ether:ethyl acetate=80:20) to give tert-butyl 5-bromo-3-(cyanomethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (205 mg, yield: 95%). ES-API: [M+H].sup.+=337.2/339.2.

[0358] Step 4: The tert-butyl 5-bromo-3-(cyanomethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (80 mg, 0.238 mmol) was dissolved in dried N,N-dimethylformamide (5 ml), and the system was cooled in an ice-water bath. 60% NaH (28.5 mg, 0.714 mmol) and iodomethane (34 mg, 0.238 mmol) were added successively, and the system reacted for 0.5 h. Upon completion of the reaction, the reaction was quenched with ice water. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel (petroleum ether:ethyl acetate=80:20) to give tert-butyl 5-bromo-3-(1-cyanoethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (35 mg, yield: 42%). ES-API: [M+H].sup.+=350.0/252.0.

[0359] Step 5: The tert-butyl 5-bromo-3-(1-cyanoethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (35 mg, 0.10 mmol), tert-butyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (43 mg, 0.10 mmol), Sphos Pd G2 (7.2 mg, 0.01 mmol) and K.sub.2CO.sub.3 (41.4 mg, 0.3 mmol) were added to 1,4-dioxane (2 ml) and water (0.5 ml). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified (petroleum ether:ethyl acetate=10:90) to give (2S) tert-butyl 2-(6-(3-(1-cyanoethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (35 mg, yield: 74%). ES-API: [M+H].sup.+=473.2.

[0360] Step 6: The (2S) tert-butyl 2-(6-(3-(1-cyanoethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (35 mg, 0.074 mmol) was dissolved in dichloromethane (2 mL) and added to 1 mL of trifluoroacetic acid, and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with 7M ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give 2-(5-(8-((S)-pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)propanenitrile (Z104, 11 mg, yield: 48%). ES-API: [M+H].sup.+=373.2.

[0361] Step 7: The 2-(5-(8-((S)-pyrrolidinyl-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)propanenitrile (Z104, 8 mg) was chirally resolved by SFC (column type: Chiral pak IC 250 mm*4.6 mm*5 um, mobile phase: ACN-IPA-DEA=80-20-02, flow rate: 1 ml/min, column temperature: 30 C., 35 min) to give two isomeric compounds. A structure of one isomeric compound was arbitrarily assigned as (S)-2-(5-(8-((S)-pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)propanenitrile (Z104-1, 1.5 mg, yield: 18.7%, retention time: 8.36 min, purity: 75%, ee value: 95%). ES-API: [M+H].sup.+=373.2. A structure of the other isomer was arbitrarily assigned as (R)-2-(5-(8-((S)-pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)propanenitrile (Z104-2, 2.9 mg, yield: 36.2%, retention time: 10.379 min, purity: 86%, ee value: 96%). ES-API: [M+H].sup.+=373.2.

Example 16. Synthesis of Compound Z105

##STR00269##

[0362] Step 1: Tert-butyl 5-bromo-3-(cyanomethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (80 mg, 0.238 mmol) was dissolved in dried N,N-dimethylformamide (5 ml), and the system was cooled in an ice-water bath. 60% NaH (28.5 mg, 0.714 mmol) and iodomethane (168 mg, 1.19 mmol) were added successively, and the system reacted under the ice-water bath for 0.5 h. Upon completion of the reaction, the reaction was quenched with ice water. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel (petroleum ether:ethyl acetate=80:20) to give tert-butyl 5-bromo-3-(2-cyanopropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (70 mg, yield: 81%). ES-API: [M+H].sup.+=364.0/366.0.

[0363] Step 2: The tert-butyl 5-bromo-3-(2-cyanopropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (70 mg, 0.192 mmol), tert-butyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (90.6 mg, 0.211 mmol), Sphos Pd G2 (13.8 mg, 0.0192 mmol) and K.sub.2CO.sub.3 (0.576 mg, 79.5 mmol) was added to 1,4-dioxane (2 ml) and water (0.5 ml). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified (petroleum ether:ethyl acetate=10:90) to give tert-butyl (2S)-2-(6-(3-(2-cyanopropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (35 mg, yield: 37.5%). ES-API: [M+H].sup.+=487.2.

[0364] Step 3: The tert-butyl (2S)-2-(6-(3-(2-cyanopropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (35 mg, 0.072 mmol) was dissolved in dichloromethane (2 mL) and added to 1 mL of trifluoroacetic acid, and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with 7M ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (S)-2-methyl-2-(5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)propanenitrile (Z105, 11 mg, yield: 31%). ES-API: [M+H].sup.+=387.2.

Example 17. Synthesis of Compound Z106

##STR00270##

[0365] Step 1: 2-Bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine (1 g, 3.1 mmol) was dissolved in N,N-dimethylformamide (20 ml), 60% NaH (620 mg, 15.5 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (774 mg, 4.64 mmol) were added successively, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction was quenched with aqueous ammonium chloride solution. The reaction mixture was diluted with ethyl acetate, wash with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel (petroleum ether:ethyl acetate=80:20) to give 2-bromo-7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (1.2 g, yield: 85.7%). ES-API: [M+H].sup.+=453.9/455.9.

[0366] Step 2: The 2-bromo-7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (900 mg, 1.99 mmol) and bis(tri-tert-butylphosphine)palladium (204 mg, 0.4 mmol) were dissolved in dried tetrahydrofuran (5 ml). Dimethylzinc (2 ml, 2.0 mmol, 1M in n-hexane) was slowly added under an ice-water bath condition, and the system reacted in the ice-water bath for 0.5 h. Upon completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel (petroleum ether:ethyl acetate=80:20) to give 2-bromo-7-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (70 mg, yield: 10.2%). ES-API: [M+H].sup.+=342.0/244.0.

[0367] Step 3: The 2-bromo-7-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (34 mg, 0.10 mmol), tert-butyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (43 mg, 0.10 mmol), Sphos Pd G2 (7.2 mg, 0.01 mmol) and K.sub.2CO.sub.3 (41.4 mg, 0.3 mmol) were added to 1,4-dioxane (2 ml) and water (0.5 ml). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified (petroleum ether:ethyl acetate=10:90) to give tert-butyl (S)-2-(6-(7-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)isochroman 8-yl)pyrrolidine-1-carboxylate (20 mg, yield: 36%). ES-API: [M+H].sup.+=565.3.

[0368] Step 4: The tert-butyl (S)-2-(6-(7-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)isochroman 8-yl)pyrrolidine-1-carboxylate (20 mg, 0.035) was dissolved in dichloromethane (2 mL) and added to 1 mL of trifluoroacetic acid, and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. 7M Ammonia/methanol solution (5 mL) was added and stirred at room temperature for 3 h. The obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (S)-7-methyl-2-(8-(pyrrolidin-2-yl)isochroman-6-yl)-5H-pyrrolo[2,3-b]pyrazine (Z106, 2.9 mg, yield: 24.7%). ES-API: [M+H].sup.+=335.2.

Example 18. Synthesis of Compound Z107

##STR00271##

[0369] Step 1: 5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (300 mg, 1.24 mmol), 1-ethyl-3(3-dimethylpropylamine)carbodiimide (476 mg, 2.48 mmol) and 1-hydroxybenzotriazole (335 mg, 2.48 mmol) were dissolved in dichloromethane (10 mL) and dimethylsulfoxide (0.7 mL). N,N-diisopropylethyl amine (480 mg, 3.72 mmol) and (1-(aminomethyl)cyclobutyl)methanol (157 mg, 1.37 mmol) were added successively and stirred at room temperature for 16 h. Saturated sodium carbonate (8 mL) was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate (60 mL2). The organic phase was dried and concentrated. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 2-10%) to give a desired product 5-bromo-N-(((1-(hydroxymethyl)cyclobutyl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (265 mg, yield: 63%) as a white solid. ES-API: [M+H].sup.+=338.1/340.1.

[0370] Step 2: 1-(6-bromoisochroman-8-yl)-N,N-dimethylmethanamine (80 mg, 0.30 mmol), bis(pinacolato)diboron (91 mg, 0.36 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (22 mg, 0.03 mmol), potassium acetate (88 mg, 0.90 mmol), and 1,4-dioxane (2 mL) were added to a 5 mL microwave tube. The mixture was purged with nitrogen for 1 min, and the system reacted in a microwave reactor at 120 C. for 30 min. The reaction was cooled to room temperature. The reaction mixture was dissolved with dichloromethane (5 mL), filtered with diatomaceous earth, and washed with ethyl acetate. The obtained filtrate was concentrated to give crude N,N-dimethyl-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)methanamine (165 mg) as a pale brown crude product which was used without further purification. ES-API: [M+H].sup.+=318.3.

[0371] Step 3: The 5-bromo-N-(((1-(hydroxymethyl)cyclobutyl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (60 mg, 0.18 mmol), the N,N-dimethyl-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)methanamine (165 mg, crude product), potassium carbonate (75 mg, 0.54 mmol), 2-dicyclohexylphosphine-2,6-dimethoxy-biphenyl (8 mg, 0.018 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (13 mg, 0.018 mmol), 1,4-dioxane (2 mL) and water (0.4 mL) were added to a 5 mL microwave tube. The mixture was purged with nitrogen for 1 min, and the system reacted in a microwave reactor at 110 C. for 1 h. Water (5 mL) was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate (60 mL). The organic phase was washed with saturated brine (15 mL), dried, and concentrated. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give a desired product 5-(8-((dimethylamino)methyl)isochroman-6-yl)-N-((1-(hydroxymethyl)cyclobutyl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (Z107, 15 mg, yield: 18.5%) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.19 (s, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.23 (d, J=3.0 Hz, 1H), 8.07 (t, J=6.0 Hz, 1H), 7.39 (s, 2H), 4.84 (s, 2H), 4.72 (t, J=5.5 Hz, 1H), 3.88 (t, J=5.5 Hz, 2H), 3.41-3.34 (m, 6H), 2.90 (t, J=5.5 Hz, 2H), 2.16 (s, 6H), 1.88-1.66 (m, 6H). ES-API: [M+H].sup.+=449.2.

Example 19. Synthesis of Compound Z136

##STR00272##

[0372] Step 1: 2-Chloroquinoline-4-carboxylic acid (3.0 g, 14.49 mmol) was suspended in dichloromethane (25 mL). Oxalyl chloride (3.68 g, 28.98 mmol) and N,N-dimethylformamide (0.1 mL) were added at 0 C. and stirred at room temperature for 2 h. After the system was cooled to 0 C., methanol (20 mL) was slowly added dropwise and stirred at room temperature for 1 h. Water (40 mL) was added to the reaction mixture, and the obtained mixture was extracted with dichloromethane (80 mL2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give methyl 2-chloroquinoline-4-carboxylate (2.95 g, yield: 92%) as a pale brown solid. ES-API: [M+H].sup.+=222.1.

[0373] Step 2: The methyl 2-chloroquinoline-4-carboxylate (2.95 g, 13.35 mmol) was dissolved in methanol (50 mL). Sodium borohydride (1.52 g, 40.05 mmol) was added in batches at 0 C. and stirred at room temperature for 18 h. Saturated ammonium chloride solution (40 mL) and water (20 mL) were added to the reaction mixture, and methanol was removed by rotation. The obtained mixture was extracted with dichloromethane (100 mL3). The organic phase was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 1-5%) to give (2-chloroquinolin-4-yl)methanol (1.65 g, yield: 64%) as an off-white solid. ES-API: [M+H].sup.+=194.1.

[0374] Step 3: The (2-chloroquinolin-4-yl)methanol (1.55 g, 8.03 mmol) was dissolved in dichloromethane (50 mL), and the system was cooled to 0 C. Dess-Martin periodinane (4.08 g, 9.64 mmol) was added and stirred at room temperature for 2 h. A saturated sodium thiosulfate solution (60 mL) was added to the reaction mixture, and the obtained mixture was extracted with dichloromethane (60 mL2). The organic phase was washed with saturated sodium bicarbonate solution (60 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate/petroleum ether: 0-30%) to give 2-chloroquinoline-4-carbaldehyde (1.45 g, yield: 94%) as a white solid. ES-API: [M+H].sup.+=192.1.

[0375] Step 4: The 2-chloroquinoline-4-carbaldehyde (1.0 g, 5.23 mmol) and (S)-2-methylpropane-2-sulfinamide (1.26 g, 10.46 mmol) were dissolved in dichloromethane (25 mL). Tetraethoxytitanium (2.98 g, 13.08 mmol) was added and stirred at room temperature for 18 h. Saturated brine (100 mL) was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate (80 mL2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0-5%) to give (S,E)-N-((2-chloroquinolin-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.5 g, yield: 97%) as a white solid. ES-API: [M+H].sup.+=295.1.

[0376] Step 5: The (S,E)-N-((2-chloroquinolin-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.35 g, 4.59 mmol) was dissolved in tetrahydrofuran (20 mL). In the presence of protective nitrogen, (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide in tetrahydrofuran (27.5 mL, 13.77 mmol, 0.5M) was added dropwise at 78 C. and stirred at 78 C. for 30 min. The reaction was quenched with saturated ammonium chloride solution (20 mL), and water (20 mL) was added. The obtained mixture was extracted with ethyl acetate (50 mL2). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and concentrated to give (S)N((S)-1-(2-chloroquinolin-4-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (1.88 g, yield: 100%) as a white solid. ES-API: [M+H].sup.+=411.2.

[0377] Step 6: Trifluoroacetic acid (20 mL) and water (1 mL) were cooled to 0 C. The (S)N((S)-1-(2-chloroquinolin-4-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (1.88 g, 4.59 mmol) was added in batches and stirred at room temperature for 45 min. Triethylsilane (5.32 g, 45.90 mmol) was added and stirred at room temperature for 16 h. The reaction mixture was concentrated to give (S)-2-chloro-4-(pyrrolidin-2-yl)quinoline trifluoroacetate (4.1 g, crude product) which was directly used in the next step without further purification. ES-API: [M+H].sup.+=233.1 (free base).

[0378] Step 7: The (S)-2-chloro-4-(pyrrolidin-2-yl)quinoline trifluoroacetate (4.1 g, crude product) was dissolved in dichloromethane (40 mL). Triethylamine (1.62 g, 16.0 mmol) and di-tert-butyl dicarbonate (1.74 g, 8.0 mmol) were added at 0 C. and stirred at room temperature for 1 h. Dichloromethane (40 mL) was added to the reaction mixture. The obtained mixture was washed with water (25 mL) and saturated brine (25 mL) successively, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate/petroleum ether: 0-30%) to give tert-butyl (S)-2-(2-chloroquinolin-4-yl)pyrrolidine-1-carboxylate (1.15 g, yield of the 2 steps: 75%) as a viscous liquid. ES-API: [M+H].sup.+=333.2.

[0379] Step 8: The tert-butyl (S)-2-(2-chloroquinolin-4-yl)pyrrolidine-1-carboxylate (60 mg, 0.23 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (76 mg, 0.23 mmol), potassium carbonate (95 mg, 0.69 mmol), 2-dicyclohexylphosphine-2,6-dimethoxy-biphenyl (9 mg, 0.023 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (17 mg, 0.023 mmol), 1,4-dioxane (2 mL) and water (0.4 mL) were added to a 5 mL microwave tube. The mixture was purged with nitrogen for 1 min, and the system reacted in a microwave reactor at 110 C. for 1 h. Water (5 mL) was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0-3%) to give tert-butyl (S)-2-(2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)quinolin-4-yl)pyrrolidine-1-carboxylate (42 mg, yield: 42%) as a white solid. ES-API: [M+H].sup.+=429.3.

[0380] Step 9: The tert-butyl (S)-2-(2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)quinolin-4-yl)pyrrolidine-1-carboxylate (42 mg, 0.10 mmol) was dissolved in methanol (1 ml). 4M dioxane hydrochloride solution (3 ml) was added and stirred at room 50 temperature for 1 h. The reaction mixture was concentrated. 7.0M Ammonia/methanol solution (4 mL) was added, and a solvent was spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give (S)-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(pyrrolidin-2-yl)quinoline (Z136, 20 mg, yield: 62%) as a white solid. ES-API: [M+H].sup.+=329.1. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.49 (s, 1H), 9.09 (d, J=2.0 Hz, 1H), 8.68 (d, J=1.5 Hz, 1H), 8.34 (s, 1H), 8.19 (d, J=8.5 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.77-7.72 (m, 1H), 7.60-7.54 (m, 1H), 7.31 (s, 1H), 4.88 (t, J=7.5 Hz, 1H), 3.22-3.14 (m, 1H), 3.10-3.04 (m, 1H), 2.50-2.45 (m, 1H), 2.37 (s, 3H), 1.88-1.78 (m, 2H), 1.60-1.50 (m, 1H).

Example 20. Synthesis of Compound Z109

##STR00273##

[0381] Step 1: Compound tetrahydropyrrole (147 mg, 2.07 mmol) and acetic acid (13 mg, 0.21 mmol) were added to a solution of 6-bromoisochroman-8-carbaldehyde (100 mg, 0.41 mmol) in 1,2-dichloroethane (2 mL), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (52 mg, 0.83 mmol) was then added and stirred at room temperature overnight. Upon completion of the reaction, the reaction was quenched with aqueous ammonium chloride solution (5 mL), and the reaction mixture was extracted with dichloromethane (5 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-6% methanol (1% ammonia water)/dichloromethane) to give 1-((6-bromoisochroman-8-yl)methyl)pyrrolidine (90 mg, yield: 74%) as a colorless liquid. ES-API: [M+H].sup.+=296.0, 298.0.

[0382] Step 2: In the presence of protective nitrogen, a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (55 mg, 0.21 mmol), the 1-((6-bromoisochroman-8-yl)methyl)pyrrolidine (80 mg, 0.27 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.02 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (8 mg, 0.02 mmol) and potassium carbonate (87 mg, 0.63 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred under microwave irradiation at 110 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (ammonium bicarbonate method) to give 3-methyl-5-(8-(pyrrolidin-1-yl methyl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridine (Z109, 30 mg, yield: 41%) as a white solid. ES-API: [M+H].sup.+=348.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.33 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.43 (s, 1H), 7.40 (s, 1H), 7.26 (s, 1H), 4.85 (s, 2H), 3.88 (t, J=5.5 Hz, 2H), 2.88 (t, J=5.5 Hz, 2H), 2.45 (s, 4H), 2.31 (s, 3H), 1.69 (s, 4H).

Example 21. Synthesis of Compound Z114

##STR00274##

[0383] Step 1: Compound N-methylpiperazine (207 mg, 2.07 mmol) and acetic acid (13 mg, 0.21 mmol) were added to a solution of 6-bromoisochroman-8-carbaldehyde (100 mg, 0.41 mmol) in 1,2-dichloroethane (2 mL), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (52 mg, 0.83 mmol) was then added and stirred at room temperature overnight.

[0384] Upon completion of the reaction, the reaction was quenched with aqueous ammonium chloride solution (5 mL), and the reaction mixture was extracted with dichloromethane (5 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-6% methanol (1% ammonia water)/dichloromethane) to give 1-((6-bromoisochroman-8-yl)methyl)-4-methylpiperazine (100 mg, yield: 75%) as a colorless liquid. ES-API: [M+H].sup.+=325.1, 327.1.

[0385] Step 2: In the presence of protective nitrogen, a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (55 mg, 0.21 mmol), the 1-((6-bromoisochroman-8-yl)methyl)-4-methylpiperazine (88 mg, 0.27 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.02 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (8 mg, 0.02 mmol) and potassium carbonate (87 mg, 0.63 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred under microwave irradiation at 110 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (ammonium bicarbonate method) to give 3-methyl-5-(8-((4-methylpiperazin-1-yl)methyl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridine (Z114, 31 mg, yield: 39%) as a white solid. ES-API: [M+H].sup.+=377.4. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.33 (s, 1H), 8.46 (s, 1H), 8.12 (s, 1H), 7.40 (s, 2H), 7.26 (s, 1H), 4.85 (s, 2H), 3.88 (t, J=4.5, 2H), 3.42 (s, 2H), 3.34 (s, 4H), 2.89 (t, J=5.5, 2H), 2.37 (s, 4H), 2.31 (s, 3H), 2.14 (s, 3H).

Example 22. Synthesis of Compound Z115

##STR00275##

[0386] Step 1: Morpholine (180 mg, 2.07 mmol) and acetic acid (13 mg, 0.21 mmol) were added to a solution of 6-bromoisochroman-8-carbaldehyde (100 mg, 0.41 mmol) in 1,2-dichloroethane (2 mL), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (52 mg, 0.83 mmol) was then added and stirred at room temperature overnight. Upon completion of the reaction, the reaction was quenched with aqueous ammonium chloride solution (5 mL), and the reaction mixture was extracted with dichloromethane (5 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-6% methanol (1% ammonia water)/dichloromethane) to give 4-((6-bromoisochroman-8-yl)methyl)morpholine (90 mg, yield: 70%) as a colorless liquid. ES-API: [M+H].sup.+=312.0, 314.0.

[0387] Step 2: In the presence of protective nitrogen, a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (55 mg, 0.21 mmol), the 4-((6-bromoisochroman-8-yl)methyl)morpholine (80 mg, 0.27 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.02 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (8 mg, 0.02 mmol) and potassium carbonate (87 mg, 0.63 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred under microwave irradiation at 110 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (ammonium bicarbonate method) to give 4-((6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)methyl)morpholine (Z115.41 mg, yield: 52%) as a white solid. ES-API: [M+H].sup.+=364.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.33 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.42 (s, 2H), 7.26 (s, 1H), 4.87 (s, 2H), 3.89 (t, J=5.5 Hz, 2H), 3.55 (s, 4H), 3.43 (s, 2H), 2.89 (t, J=5.5 Hz, 2H), 2.37 (s, 4H), 2.31 (s, 3H).

Example 23. Synthesis of Compound Z111

##STR00276##

[0388] Step 1: Compound isopropylamine (122 mg, 2.07 mmol) and acetic acid (13 mg, 0.21 mmol) were added to a solution of 6-bromoisochroman-8-carbaldehyde (100 mg, 0.41 mmol) in 1,2-dichloroethane (2 mL), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (52 mg, 0.83 mmol) was then added and stirred at room temperature overnight. Upon completion of the reaction, the reaction was quenched with aqueous ammonium chloride solution (5 mL), and the reaction mixture was extracted with dichloromethane (5 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-6% methanol (1% ammonia water)/dichloromethane) to give N-((6-bromoisochroman-8-yl)methyl)propan-2-amine (90 mg, yield: 77%) as a colorless liquid. ES-API: [M+H].sup.+=284.1, 286.1.

[0389] Step 2: In the presence of protective nitrogen, a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (55 mg, 0.21 mmol), the N-((6-bromoisochroman-8-ylmethyl)propan-2-amine (77 mg, 0.27 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.02 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (8 mg, 0.02 mmol) and potassium carbonate (87 mg, 0.63 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred under microwave irradiation at 110 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (ammonium bicarbonate method) to give N-((6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)methyl)propan-2-amine (Z111, 40 mg, yield: 57%) as a white solid. ES-API: [M+H].sup.+=336.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.33 (s, 1H), 8.48 (d, J=1.5 Hz, 1H), 8.12 (s, 1H), 7.50 (s, 1H), 7.37 (s, 1H), 7.26 (s, 1H), 4.85 (s, 2H), 3.88 (t, J=5.5 Hz, 2H), 3.62 (s, 2H), 2.88 (t, J=5.0 Hz, 2H), 2.77 (dt, J=12.0, 6.0 Hz, 1H), 2.31 (s, 3H), 1.78 (br s, 1H), 1.04 (d, J=6.2 Hz, 6H).

Example 24. Synthesis of Compound Z112

##STR00277##

[0390] Step 1: Compound cyclopropylmethanamine (147 mg, 2.07 mmol) and acetic acid (13 mg, 0.21 mmol) were added to a solution of 6-bromoisochroman-8-carbaldehyde (100 mg, 0.41 mmol) in 1,2-dichloroethane (2 mL), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (52 mg, 0.83 mmol) was then added and stirred at room temperature overnight. Upon completion of the reaction, the reaction was quenched with aqueous ammonium chloride solution (5 mL), and the reaction mixture was extracted with dichloromethane (5 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-6% methanol (1% ammonia water)/dichloromethane) to give 1-(6-bromoisochroman-8-yl)-N-(cyclopropylmethyl)methanamine (90 mg, yield: 74%) as a colorless liquid. ES-API: [M+H].sup.+=296.0, 298.1.

[0391] Step 2: In the presence of protective nitrogen, a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (55 mg, 0.21 mmol), the 1-(6-bromoisochroman-8-yl)-N-(cyclopropylmethyl)methanamine (80 mg, 0.27 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.02 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (8 mg, 0.02 mmol) and potassium carbonate (87 mg, 0.63 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred under microwave irradiation at 110 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (ammonium bicarbonate method) to give 1-cyclopropyl-N-((6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)methyl)methanamine (Z112, 11 mg, yield: 15%) as a white solid. ES-API: [M+H].sup.+=348.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.33 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.26 (s, 1H), 4.83 (s, 2H), 3.88 (t, J=5.5 Hz, 2H), 3.66 (s, 2H), 2.88 (t, J=5.5 Hz, 2H), 2.45 (d, J=7.0 Hz, 2H), 2.31 (s, 3H), 0.93 (m, 1H), 0.50-0.31 (m, 2H), 0.12 (m, 2H).

Example 25. Synthesis of Compound Z113

##STR00278##

[0392] Step 1: Compound tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (264 mg, 1.25 mmol) and acetic acid (19 mg, 0.31 mmol) were added to a solution of 6-bromoisochroman-8-carbaldehyde (150 mg, 0.62 mmol) in 1,2-dichloroethane (2 mL), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (78 mg, 1.25 mmol) was then added and stirred at room temperature overnight. Upon completion of the reaction, the reaction was quenched with aqueous ammonium chloride solution (5 mL), and the reaction mixture was extracted with dichloromethane (5 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-6% methanol (1% ammonia water)/dichloromethane) to give tert-butyl 3-((6-bromoisochroman-8-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (180 mg, yield: 66%) as a colorless liquid. ES-API: [M+H].sup.+=437.2, 439.2.

[0393] Step 2: In the presence of protective nitrogen, lithium aluminum hydride in tetrahydrofuran (0.5 mL, 1.23 mmol, 2.5 M) was slowly added to a solution of the tert-butyl 3-((6-bromoisochroman-8-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (180 mg, 0.41 mmol) in tetrahydrofuran (2 mL) under an ice bath condition. The reaction mixture was stirred at 70 C. for 1 h and cooled to room temperature. The reaction was quenched with sodium sulfate decahydrate (20 g). The reaction mixture was filtered with diatomaceous earth, and the filtrate was spun to dryness to give 3-((6-bromoisochroman-8-yl)methyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane (150 mg, crude product). API: [M+H].sup.+=351.1, 353.1.

[0394] Step 3: In the presence of protective nitrogen, a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (55 mg, 0.21 mmol), the 3-((6-bromoisochroman-8-yl)methyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane (97 mg, 0.27 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.02 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (8 mg, 0.02 mmol) and potassium carbonate (87 mg, 0.63 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred under microwave irradiation at 110 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (ammonium bicarbonate method) to give 3-methyl-5-(8-((8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridine (Z113, 19 mg, yield: 22%) as a white solid. ES-API: [M+H].sup.+=403.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.32 (s, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.11 (d, J=1.5 Hz, 1H), 7.42-7.36 (m, 2H), 7.25 (s, 1H), 4.85 (s, 2H), 3.88 (t, J=5.5 Hz, 2H), 3.39 (s, 2H), 2.97 (s, 2H), 2.89 (t, J=5.0 Hz, 2H), 2.43 (d, J=8.0 Hz, 2H), 2.30 (s, 3H), 2.21 (d, J=10 Hz, 2H), 2.13 (s, 3H), 1.86-1.78 (m, 2H), 1.63-1.55 (m, 2H).

Example 26. Synthesis of Compound Z186

##STR00279##

[0395] Step 1: 8-Bromo-6-chloroisoquinoline (1 g, 4.12 mmol) was dissolved in acetonitrile (30 mL). Iodomethane (2.92 g, 20.6 mmol) was added, and the system was heated in a sealed tube for 5 h. Upon completion of the reaction, the system was cooled to room temperature, and the obtained mixture was concentrated to give 8-bromo-6-chloro-2-methylisoquinolin-2-ium iodide (1.5 g, crude product). ES-API: [M+H].sup.+=256.0, 258.0.

[0396] Step 2: The 8-bromo-6-chloro-2-methylisoquinolin-2-ium iodide (1.4 g, crude product) was dissolved in methanol (30 mL). Sodium borohydride (1.12 g, 29.4 mmol) was slowly added under an ice-water bath condition, and the system reacted at room temperature for 2 h. Upon completion of the reaction, ethyl acetate (100 mL) was added. The obtained mixture was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous sodium sulfate, and filtered. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=50:50) to give 8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (750 mg, yield of the 2 steps: 78%). ES-API: [M+Na].sup.+=260, 262.

[0397] Step 3: The 8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (520 mg, 2.0 mmol) was dissolved in dried carbon tetrachloride (20 mL) and acetonitrile (5 mL). Sodium periodate (1.28 g, 6.0 mmol) in water (10 mL) and ruthenium trichloride (124 mg, 0.6 mmoL) was added successively, and the system reacted at room temperature for 4 h. The reaction was quenched by the addition of aqueous sodium thiosulfate solution, and the reaction mixture was extracted with dichloromethane (30 mL2 times). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=80:20) to give 8-bromo-6-chloro-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (110 mg, yield: 20%). ES-API: [M+H].sup.+=274, 276.

[0398] Step 4: The 8-bromo-6-chloro-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.365 mmol) reacted with potassium vinyltrifluoroborate (146 mg, 1.09 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (29.7 mg, 0.0365 mmol), triethylamine (36.8 mg, 0.365 mmol) and ethanol (8 mL) under nitrogen replacement and microwave at 100 C. for 1 h. Ethyl acetate (50 mL) was added. The obtained mixture was washed with water (20 mL) and saturated brine (20 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give 6-chloro-2-methyl-8-vinyl-3,4-dihydroisoquinolin-1(2H)-one (50 mg, yield: 62%). ES-API: [M+H].sup.+=222.0.

[0399] Step 5: The 6-chloro-2-methyl-8-vinyl-3,4-dihydroisoquinolin-1(2H)-one (50 mg, 0.226 mmol) was dissolved in tetrahydrofuran (5 mL). An aqueous solution (2 mL) of potassium osmate dihydrate (25 mg, 0.0678 mmol) and sodium periodate (290 mg, 1.35 mmol) was added at room temperature. After reacting at room temperature for 2 h, the system was cooled to 0 C., and the reaction was quenched by the addition of aqueous sodium thiosulfate solution. The obtained mixture was diluted with ethyl acetate (20 mL), washed with water (20 mL) and saturated brine (20 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=3:1) to give 6-chloro-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-8-carbaldehyde (36 mg, yield: 72%). ES-API: [M+H].sup.+=224.0.

[0400] Step 6: The 6-chloro-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-8-carbaldehyde (36 mg, 0.161 mmol) was dissolved in tetrahydrofuran (10 mL). Dimethylamine in tetrahydrofuran (0.24 mL, 0.0483 mmol, 2M), glacial acetic acid (9.66 mg, 0.161 mmol) and sodium cyanoborohydride (20 mg, 0.322 mmoL) were added successively, and the system reacted at room temperature for 2 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated brine (20 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column (ethyl acetate:petroleum ether=90:10) to give 6-chloro-8-((dimethylamino)methyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (25 mg, yield: 61.7%). ES-API: [M+H].sup.+=253.1.

[0401] Step 7: The 6-chloro-8-((dimethylamino)methyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (25 mg, 0.1 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (25.8 mg, 0.1 mmol), Sphos G2 Pd (7.2 mg, 0.01 mmol) and potassium carbonate (41.4 mg, 0.3 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and the system reacted under microwave at 100 C. for 0.5 h. Upon completion of the reaction, the reaction mixture was filtered, concentrated, and purified by HPLC (ammonia water method) to give 8-((dimethylamino)methyl)-2-methyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (Z186, 3.5 mg, yield: 10%). ES-API: [M+H].sup.+=349.2.

Example 27. Synthesis of Compound Z131

##STR00280##

[0402] Step 1: tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.16 mmol) and triethylamine (48 mg, 0.48 mmol) were dissolved in N,N-dimethylformamide (2 mL). 2,2,2-Trifluoroethyl triflate (51 mg, 0.24 mmol) was added at room temperature and stirred at room temperature for 16 h. Water (5 mL) was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate (40 mL). The organic phase was washed with saturated brine (153 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (7M ammonia in methanol/dichloromethane: 0-5%) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, yield: 84%) as a pale yellow solid. ES-API: [M+H].sup.+=515.3.

[0403] Step 2: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (65 mg, 0.13 mmol) was added to 3M hydrochloric acid-methanol solution (4 ml) and stirred at room temperature for 1 h. The reaction mixture was concentrated. 7.0M Ammonia/methanol solution (5 mL) was added, and a solvent was spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline (Z131, 48 mg, yield: 92%) as a pale yellow solid. ES-API: [M+H]+ 415.1. .sup.1H NMR (500 MHz, CD.sub.3OD) 8.51 (d, J=2.0 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.26 (q, J=1.0 Hz, 1H), 4.79 (dd, J=10.0, 7.0 Hz, 1H), 4.11 (d, J=15.0 Hz, 1H), 4.00 (d, J=15.0 Hz, 1H), 3.65-3.56 (m, 1H), 3.52-3.44 (m, 1H), 3.40 (d, J=10.0 Hz, 1H), 3.36 (d, J=10.0 Hz, 1H), 3.10-2.98 (m, 4H), 2.58-2.48 (m, 1H), 2.39 (d, J=1.0 Hz, 3H), 2.37-2.19 (m, 3H).

Example 28. Synthesis of Compound Z190

##STR00281##

[0404] Step 1: 3-Bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (2.31 g, 10.0 mmol) was dissolved in dried N,N-dimethylformamide (5 mL). Zinc cyanide (1.17 mg, 10.0 mmol) and tetrakis(triphenylphosphine)palladium (1.15 g, 1.0 mmol) were added successively, and the system reacted at 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and diluted with dichloromethane (30 mL). Di-tert-butyl dicarbonate (3.27 g, 15 mmoL) and triethylamine (2.02 g, 20.0 mmoL) were added successively and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated. The crude product was purified by silica gel column (petroleum ether:ethyl acetate=70:30) to give tert-butyl 5-chloro-3-cyano-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (260 mg, yield: 9.3%). ES-API: [M+H].sup.+=278, 222.

[0405] Step 2: The tert-butyl 5-chloro-3-cyano-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (30 mg, 0.129 mmol), tert-butyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (55.7 mg, 0.129 mmol), Sphos Pd G2 (9.3 mg, 0.0129 mmol) and potassium carbonate (53.4 mg, 0.387 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate=10:90) to give tert-butyl (S)-5-(8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)isochroman-6-yl)-3-cyano-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (15 mg, yield: 21%). ES-API: [M+H].sup.+=545.2.

[0406] Step 3: The tert-butyl (S)-5-(8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)isochroman-6-yl)-3-cyano-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (15 mg, 0.027 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h, Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by HPLC (trifluoroacetic acid method) to give (S)-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Z190, trifluoroacetate, 2 mg, yield: 21.7%). ES-API: [M+H].sup.+=345.2.

Example 29. Synthesis of Compound Z199

##STR00282##

[0407] Step 1: 5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (2 g, 6.21 mmol) was dissolved in dichloromethane (50 mL). Di-tert-butyl dicarbonate (2.03 g, 9.31 mmol), triethylamine (1.25 g, 12.4 mmol) and dimethylamino pyridine (75 mg, 0.621 mmol) were added successively, and the system reacted at room temperature for 1 h. The obtained mixture was concentrated. The crude product was purified by silica gel column (petroleum ether:ethyl acetate=60:40) to give tert-butyl 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (2.3 g, yield: 87.7%) ES-API: [M+H].sup.+=423.0, 424.0.

[0408] Step 2: The tert-butyl 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (100 mg, 0.236 mmol) was dissolved in dried dioxane (8 ML). Pyridin-3-ylboronic acid (29 mg, 0.236 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (19.2 mg, 0.0236 mmol) were added successively, and the system reacted at 80 C. for 0.5 h. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column (petroleum ether:ethyl acetate=70:30) to give tert-butyl 5-bromo-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (40 mg, yield: 45%). ES-API: [M+H].sup.+=373, 375.

[0409] Step 3: The tert-butyl 5-bromo-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (40 mg, 0.11 mmol), tert-butyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (45 mg, 0.11 mmol), Sphos Pd G2 (7.7 mg, 0.011 mmol) and potassium carbonate (45 mg, 0.387 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate=10:90) to give tert-butyl (S)-5-(8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)isochroman-6-yl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (10 mg, yield: 15.3%). ES-API: [M+H].sup.+=597.3.

[0410] Step 4: The tert-butyl (S)-5-(8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)isochroman-6-yl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (10 mg, 0.017 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (S)-3-(pyridin-3-yl)-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridine (Z199, 3.3 mg, yield: 48%). ES-API: [M+H].sup.+=397.2.

Example 30. Synthesis of Compound Z116-1 and Compound Z116-2

##STR00283##

[0411] Step 1: In the presence of protective nitrogen, a mixed solution of 6,8-dibromoisochroman (300 mg, 1.03 mmol), D-prolinol (114 mg, 1.13 mmol), cuprous iodide (19 mg, 0.1 mmol), potassium carbonate (285 mg, 2.06 mmol) in N,N-dimethylformamide (3 mL) was stirred at 100 C. overnight. Upon completion of the reaction, the reaction mixture was poured into ethyl acetate (15 mL) and washed with saturated brine (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a preparative thin layer chromatography plate (petroleum ether:ethyl acetate=1:1) to give (R)-(1-(6-bromoisochroman-8-yl)pyrrolidin-2-yl)methanol (30 mg, yield: 9%) as a colorless liquid. ES-API: [M+H].sup.+=312.0, 314.0.

[0412] Step 2: In the presence of protective nitrogen, a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (20 mg, 0.08 mmol), the (R)-(1-(6-bromoisochroman-8-yl)pyrrolidin-2-yl)methanol (30 mg, 0.10 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7 mg, 0.01 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (4 mg, 0.01 mmol) and potassium carbonate (33 mg, 0.24 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred under microwave irradiation at 120 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidin-2-yl)methanol (Z116-1, 3 mg, yield: 10%) as a white solid. ES-API: [M+H].sup.+=364.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.26 (s, 1H), 6.39 (d, J=2.0 Hz, 1H), 6.36 (d, J=2.0 Hz, 1H), 4.74 (t, J=5.5 Hz, 1H), 4.44 (d, J=2.0 Hz, 2H), 3.89-3.81 (m, 2H), 3.69-3.64 (m, 1H), 3.55-3.46 (m, 1H), 3.42-3.34 (m, 1H), 3.17-3.10 (m, 1H), 3.03 (dd, J=16.1, 9.1 Hz, 1H), 2.80 (t, J=5.5 Hz, 2H), 2.26 (d, J=0.7 Hz, 3H), 2.05-1.79 (m, 4H).

[0413] Step 3: In the presence of protective nitrogen, a mixed solution of 6,8-dibromoisochroman (300 mg, 1.03 mmol), L-prolinol (114 mg, 1.13 mmol), cuprous iodide (19 mg, 0.1 mmol), potassium carbonate (285 mg, 2.06 mmol) in N,N-dimethylformamide (3 mL) was stirred at 100 C. overnight. Upon completion of the reaction, the reaction mixture was poured into ethyl acetate (15 mL) and washed with saturated brine (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a preparative chromatography plate (petroleum ether:ethyl acetate=1:1) to give (S)-(1-(6-bromoisochroman-8-yl)pyrrolidin-2-yl)methanol (30 mg, yield: 9%) as a colorless liquid. ES-API: [M+H].sup.+=312.0, 314.0.

[0414] Step 4: In the presence of protective nitrogen, a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (20 mg, 0.08 mmol), the (S)-(1-(6-bromoisochroman-8-yl)pyrrolidin-2-yl)methanol (30 mg, 0.10 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7 mg, 0.01 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (4 mg, 0.01 mmol) and potassium carbonate (33 mg, 0.24 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred under microwave irradiation at 120 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (ammonium bicarbonate method) to give (S)-(1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidin-2-yl)methanol (Z116-2, 4 mg, yield: 14%) as a white solid. ES-API: [M+H].sup.+=364.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.26 (s, 1H), 6.39 (d, J=2.0 Hz, 1H), 6.36 (d, J=2.5 Hz, 1H), 4.77-4.70 (m, 1H), 4.44 (s, 2H), 3.87-3.82 (m, 2H), 3.70-3.64 (m, 1H), 3.55-3.46 (m, 1H), 3.42-3.35 (m, 1H), 3.19-3.10 (m, 1H), 3.07-2.98 (m, 1H), 2.80 (t, J=5.6 Hz, 2H), 2.26 (s, 3H), 2.02-1.82 (m, 4H).

Example 31. Synthesis of Compound Z110

##STR00284##

[0415] Step 1: Compound diethylamine hydrochloride (227 mg, 2.07 mmol) was added to a solution of 6-bromoisochroman-8-carbaldehyde (100 mg, 0.41 mmol) in 1,2-dichloroethane (2 mL), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (52 mg, 0.83 mmol) was then added and stirred at room temperature overnight. Upon completion of the reaction, the reaction was quenched with aqueous ammonium chloride solution (5 mL), and the reaction mixture was extracted with dichloromethane (5 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-6% methanol (1% ammonia water)/dichloromethane) to give N-((6-bromoisochroman-8-yl)methyl)-N-ethylethanamine (90 mg, yield: 74%) as a colorless liquid. ES-API: [M+H].sup.+=298.1, 300.1.

[0416] Step 2: In the presence of protective nitrogen, a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (55 mg, 0.21 mmol), the N-((6-bromoisochroman-8-yl)methyl)-N-ethylethanamine (80 mg, 0.27 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.02 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (8 mg, 0.02 mmol) and potassium carbonate (87 mg, 0.63 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred under microwave irradiation at 110 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (ammonium bicarbonate method) to give N-ethyl-N-((6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)methyl)ethanamine (Z110, 14 mg, yield: 19%) as a white solid. ES-API: [M+H].sup.+=350.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.33 (s, 1H), 8.46 (s, 1H), 8.11 (s, 1H), 7.45 (s, 1H), 7.39 (s, 1H), 7.26 (s, 1H), 4.86 (s, 2H), 3.87 (s, 2H), 3.49 (s, 2H), 2.89 (s, 2H), 2.46 (d, J=6.5 Hz, 4H), 2.31 (s, 3H), 0.98 (t, J=6.5 Hz, 6H).

Example 32. Synthesis of Compound Z226

##STR00285##

[0417] Step 1: Oxalyl chloride (0.49 mL, 0.784 mmol) was added dropwise to a flask containing a solution of 2-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (100 mg, 0.392 mmol) in dichloromethane (10 mL) at 0 C., followed by N,N-dimethylformamide (0.024 mL, 0.313 mmol). The mixture was stirred at room temperature for 1 h. After concentration, dichloromethane (10 mL) and ammonia water (2 mL) were added and stirred at room temperature for 1 h. The obtained mixture was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:90) to give 2-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (40 mg, yield: 40%). ES-API: [M+H].sup.+=254.1, 256.1.

[0418] Step 2: The 2-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (40 mg, 0.157 mmol), tert-butyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (67 mg, 0.157 mmol), Sphos Pd G2 (11.3 mg, 0.0157 mmol) and potassium carbonate (65 mg, 0.472 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate=10:90) to give tert-butyl (S)-2-(6-(3-(2-amino-2-oxoethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (50 mg, crude product). ES-API: [M+H].sup.+=477.2.

[0419] Step 3: The tert-butyl (S)-2-(6-(3-(2-amino-2-oxoethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (50 mg, crude product) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (S)-2-(5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (Z226, 15 mg, yield of the 2 steps: 25.4%). ES-API: [M+H].sup.+=377.2.

Example 33. Synthesis of Compound Z233

##STR00286##

[0420] Step 1: 2M Dimethylamine in tetrahydrofuran (1 mL, 2 mmol) and acetic acid (13 mg, 0.21 mmol) were added to a solution of 6-bromoisochroman-8-carbaldehyde (100 mg, 0.41 mmol) in 1,2-dichloroethane (2 mL), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (52 mg, 0.83 mmol) was then added and stirred at room temperature overnight. Upon completion of the reaction, the reaction was quenched with aqueous ammonium chloride solution (5 mL), and the reaction mixture was extracted with dichloromethane (5 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-6% methanol (1% ammonia water)/dichloromethane) to give 1-(6-bromoisochroman-8-yl)-N,N-dimethylmethanamine (90 mg, yield: 81%) as a colorless liquid. ES-API: [M+H].sup.+=270.1, 272.1.

[0421] Step 2: In the presence of protective nitrogen, a mixed solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (43 mg, 0.18 mmol), the 1-(6-bromoisochroman-8-yl)-N,N-dimethylmethanamine (40 mg, 0.15 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7 mg, 0.01 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (4 mg, 0.01 mmol) and potassium carbonate (62 mg, 0.45 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred under microwave irradiation at 110 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-6% methanol (1% ammonia water)/dichloromethane) to give 1-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)-N,N-dimethylmethanamine (40 mg, yield: 88%) as a white solid. ES-API: [M+H].sup.+=308.2.

[0422] Step 3: N-Chlorosuccinimide (9 mg, 65 mol) was added to a solution of the 1-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)-N,N-dimethylmethanamine (20 mg, 65 mol) in acetonitrile (1 mL) and stirred at room temperature for 2 h. The reaction was quenched with sodium thiosulfate solution (1 mL). The reaction mixture was extracted with ethyl acetate (1 mL), spun to dryness, and purified by prep-HPLC (ammonium bicarbonate method) to give 1-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)-N,N-dimethylmethanamine (Z233, 8 mg, yield: 36%) as a white solid. ES-API: [M+H].sup.+=342.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.05 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.45 (s, 1H), 7.43 (s, 1H), 4.84 (s, 2H), 3.88 (t, J=5.5 Hz, 2H), 3.34 (s, 2H), 2.90 (t, J=5.5 Hz, 2H), 2.16 (s, 6H).

Example 34. Synthesis of Compound Z108-1

##STR00287##

[0423] Step 1: In the presence of protective nitrogen, 6,8-dibromoisochroman (2 g, 6.85 mmol) in tetrahydrofuran (30 mL) was cooled to 60 C. n-Butyllithium in tetrahydrofuran (2.74 mL, 6.85 mmol, 2.5 M) was slowly added dropwise and stirred at this temperature for 2 h. N-Methyl-N-methoxyacetamide (1.41 g, 13.70 mmol) was then added, and the system continued to be stirred for 10 min. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL), and the reaction mixture was extracted with ethyl acetate (10 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spun to dryness. The crude product was purified by a flash silica gel column (0-20% ethyl acetate/petroleum ether) to give 1-(6-bromoisochroman-8-yl)ethan-1-one (200 mg, yield: 11%). ES-API: [M+H].sup.+=255.

[0424] Step 2: Dimethylamine in tetrahydrofuran (1 mL, 2 mmol, 2 M) and titanium tetraisopropoxide (222 mg, 0.78 mmol) were added to a solution of the 1-(6-bromoisochroman-8-yl)ethan-1-one (200 mg, 0.78 mmol) in 1,2-dichloroethane (2 mL), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (98 mg, 1.56 mmol) was then added and stirred at room temperature overnight. Upon completion of the reaction, the reaction was quenched with aqueous ammonium chloride solution (5 mL), and the reaction mixture was extracted with dichloromethane (5 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-6% methanol (1% ammonia water)/dichloromethane) to give 1-(6-bromoisochroman-8-yl)-N,N-dimethylethane-1-amine (100 mg, yield: 45%) as a colorless liquid. ES-API: [M+H].sup.+=284.2, 286.2.

[0425] Step 3: In the presence of protective nitrogen, a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (90 mg, 0.35 mmol), the 1-(6-bromoisochroman-8-yl)-N,N-dimethylethane-1-amine (100 mg, 0.35 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (25 mg, 0.03 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (14 mg, 0.03 mmol) and potassium carbonate (145 mg, 1.05 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred under microwave irradiation at 120 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (ammonium bicarbonate method) to give N,N-dimethyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)ethan-1-amine (Z108-1, 40 mg, yield: 34%) as a white solid. ES-API: [M+H].sup.+=336.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.33 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.52 (s, 1H), 7.36 (s, 1H), 7.26 (s, 1H), 4.91 (d, J=15.5 Hz, 1H), 4.80 (d, J=15.5 Hz, 1H), 3.87 (t, J=5.5 Hz, 2H), 3.32-3.28 (m, 1H), 2.90 (t, J=5.5 Hz, 2H), 2.31 (s, 3H), 2.15 (s, 6H), 1.28 (d, J=6.5 Hz, 3H).

Example 35. Synthesis of Compound Z181

##STR00288## ##STR00289##

[0426] Step 1: In the presence of protective nitrogen, lithium bis(trimethylsilyl)amide in tetrahydrofuran (360 mL, 360 mmol, 1M) was slowly added dropwise to a solution of 2,6-dichloro-4-methylnicotinonitrile (22.4 g, 120 mmol) in tetrahydrofuran (200 mL) at 78 C. After 30 min, dimethyl carbonate (16.2 g, 180 mmol) was slowly added dropwise. The mixture was slowly warmed to 0 C. and stirred for 2 h. The obtained mixture was slowly poured into a chilled aqueous ammonium chloride solution (100 mL) and stirred for 10 min. Ethyl acetate (200 mL) was then added. The organic phase was separated, washed with water (100 mL) and saturated brine (100 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate=80:20) to give methyl 2-(2,6-dichloro-3-cyanopyridin-4-yl)acetate (6 g, yield: 20.5%). ES-API: [M+H].sup.+=245.0.

[0427] Step 2: The methyl 2-(2,6-dichloro-3-cyanopyridin-4-yl)acetate (4 g, 16.39 mmol) was dissolved in anhydrous ethanol (80 mL), and the system was cooled in an ice-water bath. Sodium borohydride (1.86 g, 49.18 mmol) was slowly added in batches, and the system reacted at 0 C. for 0.5 h. Upon completion of the reaction, the reaction was quenched with aqueous ammonium chloride solution (20 mL). Ethyl acetate (100 mL) was added. The obtained mixture was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate=40:60) to give 2,6-dichloro-4-(2-hydroxyethyl)nicotinonitrile (800 mg, yield: 22.5%). ES-API: [M+H].sup.+=217.0.

[0428] Step 3: Concentrated hydrochloric acid (20 mL) was added to the 2,6-dichloro-4-(2-hydroxyethyl)nicotinonitrile (800 mg, 3.7 mmol), and the system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was concentrated, and the concentrated hydrochloric acid was removed. Ethyl acetate (50 mL) was added. The obtained mixture was washed with water (30 mL), saturated aqueous sodium bicarbonate solution (50 mL) and saturated brine (30 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate=40:60) to give 6,8-dichloro-3,4-dihydro-1H-pyrano[3,4-c]pyridin-1-one (600 mg, yield: 75%). ES-API: [M+H].sup.+=218.0.

[0429] Step 4: The 6,8-dichloro-3,4-dihydro-1H-pyrano[3,4-c]pyridin-1-one (600 mg, 2.76 mmol) was dissolved in tetrahydrofuran (10 mL) and anhydrous ethanol (5 mL), and the system was cooled in an ice-water bath. Sodium borohydride (525 mg, 13.8 mmol) was slowly added in batches, and the system was heated to 60 C. for 0.5 h. Upon completion of the reaction, the reaction was quenched by the addition of ethyl acetate (20 mL). The reaction mixture was purified by column chromatography (petroleum ether:ethyl acetate=10:90) to give 2-(2,6-dichloro-3-(hydroxymethyl)pyridin-4-yl)ethan-1-ol (500 mg, yield: 82%). ES-API: [M+H].sup.+=222.

[0430] Step 5: The 2-(2,6-dichloro-3-(hydroxymethyl)pyridin-4-yl)ethan-1-ol (500 mg, 2.26 mmol) was dissolved in toluene (30 mL). p-Toluenesulfonic acid (778 mg, 4.52 mmol) was added, and the system was heated to 130 C. for 18 h. Upon completion of the reaction, the reaction mixture was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=30:70) to give 6,8-dichloro-3,4-dihydro-1H-pyrano[3,4-c]pyridine (360 mg, yield: 78%). ES-API: [M+H].sup.+=204.0.

[0431] Step 6: The 6,8-dichloro-3,4-dihydro-1H-pyrano[3,4-c]pyridine (360 mg, 1.77 mmol) reacted with potassium vinyltrifluoroborate (237 mg, 1.77 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (72 mg, 0.088 mmol), triethylamine (536 mg, 5.31 mmol) and ethanol (9 mL) at 80 C. for 1 h. Ethyl acetate (30 mL) was added. The obtained mixture was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate=40:60) to give a mixture of 6-chloro-8-vinyl-3,4-dihydro-1H-pyrano[3,4-c]pyridine and 8-chloro-6-vinyl-3,4-dihydro-1H-pyrano[3,4-c]pyridine (180 mg, yield: 52%). ES-API: [M+H].sup.+=196.1.

[0432] Step 7: the above mixture (180 mg, 0.92 mmol) was dissolved in tetrahydrofuran (20 mL). An aqueous solution (15 mL) of potassium osmate dihydrate (169 mg, 0.459 mmol) and sodium periodate (197 g, 9.23 mmol) was added at room temperature, and the system reacted at room temperature for 2 h. The obtained mixture was diluted with ethyl acetate (30 mL) and cooled to 0 C. The reaction was quenched by the addition of aqueous sodium thiosulfate solution. The reaction mixture was filtered. The filtrate was washed with water (20 mL) and saturated brine (20 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate=20:80) to give a mixture of 8-chloro-3,4-dihydro-1H-pyrano[3,4-c]pyridine-6-carbaldehyde and 6-chloro-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-carbaldehyde (100 mg, yield: 55.2%). ES-API: [M+H].sup.+=198.0.

[0433] Step 8: The above mixture (100 mg, 0.51 mmol) was dissolved in acetonitrile (20 mL). 2M Dimethylamine in tetrahydrofuran (2.5 mL, 5.0 mmol), glacial acetic acid (0.2 mL) and sodium triacetoxyborohydride (268 mg, 1.265 mmol) were added successively, and the system reacted at room temperature for 18 h. The obtained mixture was diluted with ethyl acetate (30 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and purified by preparative thin layer plate (ethyl acetate as a developing solvent) to give 1-(8-chloro-3,4-dihydro-1H-pyrano[3,4-c]pyridin-6-yl)-N,N-dimethylmethanamine (35 mg, Rf=0.3, yield: 30%), ES-API: M+H].sup.+=227.0; 1-(6-chloro-3,4-dihydro-1H-pyrano[3,4-c]pyridin-8-yl)-N,N-dimethylmethanamine (40 mg, Rf=0.5, yield: 34.7%). ES-API: [M+H].sup.+=227.0.

[0434] Step 9: The 1-(6-chloro-3,4-dihydro-1H-pyrano[3,4-c]pyridin-8-yl)-N,N-dimethylmethanamine (40 mg, 0.177 mg), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (68 mg, 0265 mmol), Sphos Pd G2 (12.7 mg, 0.0177 mmol) and potassium carbonate (73 mg, 0.531 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, and purified by HPLC (ammonium bicarbonate method) to give N,N-dimethyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydro-1H-pyrano[3,4-c]pyridin-8-yl)methanamine (Z181, 6.5 mg, yield: 10.5%). ES-API: [M+H].sup.+=323.0. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.38 (s, 1H), 8.91 (d, J=2.0 Hz, 1H), 8.50 (d, J=2.1 Hz, 1H), 7.75 (s, 1H), 7.26 (dd, J=2.5, 1.3 Hz, 1H), 4.87 (s, 2H), 3.90 (t, J=5.7 Hz, 2H), 3.52 (s, 2H), 2.90 (t, J=5.8 Hz, 2H), 2.32 (d, J=1.1 Hz, 3H), 2.18 (s, 6H).

Example 36. Synthesis of Compound Z229 and Compound Z230

##STR00290## ##STR00291##

[0435] Step 1: 2-(3,5-Dibromophenyl)acetic acid (5.0 g, 17.0 mmol) was dissolved in methanol (50 mL). Thionyl chloride (2.5 mL, 34.0 mmol) was added dropwise at 0 C. and the system was heated to reflux and stirred for 5 h. The reaction mixture was concentrated. Ethyl acetate (80 mL) was added. The obtained mixture was washed with saturated sodium bicarbonate solution (30 mL2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give methyl 2-(3,5-dibromophenyl)acetate (5.2 g, yield: 99%) as a pale brown liquid. ES-API: [M+H].sup.+=309.0.

[0436] Step 2: The methyl 2-(3,5-dibromophenyl)acetate (4.6 g, 14.94 mmol) and isopropyl titanate (848 mg, 2.99 mmol) were dissolved in tetrahydrofuran (20 mL). In the presence of protective nitrogen, 1M ethylmagnesium bromide in ethyl ether (41.8 mL, 41.80 mmol) was slowly added dropwise at 0 C., and the system continued to be stirred at 0 C. for 1 h. 1M Sulfuric acid solution (40 mL) was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate (100 mL2). The organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate/petroleum ether: 0-10%) to give 1-(3,5-dibromobenzyl)cyclopropane-1-ol (2.2 g, yield: 48%) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.66 (t, J=1.5 Hz, 1H), 7.51 (d, J=1.5 Hz, 2H), 5.24 (s, 1H), 2.74 (s, 2H), 0.62-0.55 (m, 2H), 0.55-0.50 (m, 2H). ES-API: [M+H].sup.+=306.9.

[0437] Step 3: The 1-(3,5-dibromobenzyl)cyclopropane-1-ol (2.05 g, 6.70 mmol) and N,N-diisopropylethyl amine (3.02 g, 23.45 mmol) were dissolved in dichloromethane (15 mL). 1-(Chloromethoxy)-2-methoxyethane (2.49 g, 20.10 mmol) was added dropwise at 0 C. and stirred at room temperature for 72 h. Water (15 mL) was added to the reaction mixture, and the obtained mixture was extracted with dichloromethane (50 mL2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (tetrahydrofuran/petroleum ether: 5-10%) to give 1,3-dibromo-5-((1-((2-methoxyethoxy)methoxy)cyclopropyl)methyl)benzene (1.35 g, yield: 51%) as a colorless liquid. ES-API: [M+Na].sup.+=417.0.

[0438] Step 4: The 1,3-dibromo-5-((1-((2-methoxyethoxy)methoxy)cyclopropyl)methyl)benzene (2.1 g, 5.32 mmol) was dissolved in dichloromethane (4 mL). In the presence of protective nitrogen, titanium tetrachloride in dichloromethane (8.0 mL, 8.0 mmol, 1.0M) was added dropwise at 0 C. and stirred at 0 C. for 1 h. Methanol (1.5 mL) and 1M saturated sodium bicarbonate solution (20 mL) were added dropwise to the reaction mixture, and the obtained mixture was extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (25 mL2), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate/petroleum ether: 0-5%) to give 6,8-dibromospiro[cyclopropane-1,3-isochroman](1.5 g, yield: 88%) as a pale yellow liquid. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.55 (d, J=2.0 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 4.61 (s, 2H), 2.84 (s, 2H), 0.96-0.89 (m, 2H), 0.57-0.50 (m, 2H). ES-API: [M+H].sup.+=318.9.

[0439] Step 5: The 6,8-dibromospiro[cyclopropane-1,3-isochroman](1.0 g, 3.14 mmol) was dissolved in tetrahydrofuran (10 mL). In the presence of protective nitrogen, n-butyllithium in n-hexane (1.25 mL, 3.14 mmol, 2.5M) was slowly added dropwise at 78 C. and stirred at 78 C. for 2 h. Ethyl formate (377 mg, 6.28 mmol) was then added dropwise and stirred at 78 C. for 45 min. A dry ice-acetone bath was removed, and the system continued to be stirred for 15 min. The reaction was quenched by the addition of water (10 mL), and the reaction mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate/petroleum ether: 0-5%) to give 6-bromospiro[cyclopropane-1,3-isochroman]-8-carbaldehyde (230 mg, yield: 27%) as a colorless liquid. ES-API: [M+H].sup.+=267.0.

[0440] Step 6: The 6-bromospiro[cyclopropane-1,3-isochroman]-8-carbaldehyde (275 mg, 1.03 mmol) and (S)-2-methylpropane-2-sulfinamide (249 mg, 2.06 mmol) were dissolved in dichloromethane (15 mL). Tetraethoxytitanium (587 mg, 2.58 mmol) was added and stirred at room temperature for 3 h. Saturated brine (30 mL) was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate (50 mL2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate/petroleum ether: 0-20%) to give (S,E)-N-((6-bromospiro[cyclopropane-1,3-isochroman]-8-yl)methylene)-2-methylpropane-2-sulfinamide (380 mg, yield: 100%) as a viscous liquid. ES-API: [M+H].sup.+=370.1, 372.0.

[0441] Step 7: The (S,E)-N-((6-bromospiro[cyclopropane-1,3-isochroman]-8-yl)methylene)-2-methylpropane-2-sulfinamide (350 mg, 0.95 mmol) was dissolved in tetrahydrofuran (7 mL). In the presence of protective nitrogen, (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide in tetrahydrofuran (5.7 mL, 2.85 mmol, 0.5M) was added dropwise at 78 C. and stirred at 78 C. for 30 min. The reaction was quenched with saturated ammonium chloride solution (10 mL), and water (10 mL) was added. The obtained mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and concentrated to give (S)N((S)-1-(6-bromospiro[cyclopropane-1,3-isochroman]-8-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (460 mg, yield: 100%) as a viscous liquid. ES-API: [M+H].sup.+=486.2, 488.1.

[0442] Step 8: Trifluoroacetic acid (20 mL) and water (1 mL) were cooled to 0 C. The above solution was added dropwise to the (S)N((S)-1-(6-bromospiro[cyclopropane-1,3-isochroman]-8-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (460 mg, 0.95 mmol) and stirred at room temperature for 45 min. Triethylsilane (1.1 g, 9.50 mmol) was added and stirred at room temperature for 16 h. The reaction mixture was concentrated to give (S)-2-(6-bromospiro[cyclopropane-1,3-isochroman]-8-yl)pyrrole trifluoroacetate (1.7 g, crude product) which was directly used in the next step without further purification. ES-API: [M+H].sup.+=308.0, 310.0 (free base).

[0443] Step 9: The (S)-2-(6-bromospiro[cyclopropane-1,3-isochroman]-8-yl)pyrrole trifluoroacetate (1.7 g, crude product) was dissolved in dichloromethane (10 mL). Triethylamine (384 mg, 3.80 mmol) and di-tert-butyl dicarbonate (414 mg, 1.90 mmol) were added at 0 C. and stirred at room temperature for 1 h. Dichloromethane (40 mL) was added to the reaction mixture. The obtained mixture was washed with water (15 mL) and saturated brine (15 mL) successively, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (tetrahydrofuran/petroleum ether: 0-10%) to give tert-butyl (S)-2-(6-bromospiro[cyclopropane-1,3-isochroman]-8-yl)pyrrolidine-1-carboxylate (300 mg, yield of the 2 steps: 73%) as a viscous liquid. ES-API: [M+H].sup.+=430.1, 432.0.

[0444] Step 10: The tert-butyl (S)-2-(6-bromospiro[cyclopropane-1,3-isochroman]-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.15 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (49 mg, 0.19 mmol), potassium carbonate (62 mg, 0.45 mmol), 2-dicyclohexylphosphine-2,6-dimethoxy-biphenyl (6 mg, 0.015 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (11 mg, 0.015 mmol), 1,4-dioxane (2 mL) and water (0.4 mL) were added to a 5 mL microwave tube. The mixture was purged with nitrogen for 1 min, and the system reacted in a microwave reactor at 110 C. for 45 min. Water (5 mL) was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0-3%) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)spiro[cyclopropane-1,3-isochroman]-8-yl)pyrrolidine-1-carboxylate (68 mg, yield: 100%) as a white solid. ES-API: [M+H].sup.+=460.3.

[0445] Step 11: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)spiro[cyclopropane-1,3-isochroman]-8-yl)pyrrolidine-1-carboxylate (68 mg, 0.15 mmol) was dissolved in methanol (1 mL). 4M Hydrochloric acid/dioxane solution (3 mL) was added and stirred at room temperature for 1 h. The reaction mixture was concentrated. 7.0M Ammonia/methanol solution (4 mL) was added, and a solvent was spun to dryness. The crude product was purified by prep-HPLC (formic acid method) followed by chiral prep-HPLC (separation column: Daicel CHIRALPAK IC 250*4.6 mm, 5 m, mobile phase: n-hexane (0.2% DEA):isopropyl alcohol (0.2% DEA)=50:50, flow rate: 1 ml/min, column temperature: 30 C.) to give (S)-3-methyl-5-(8-(pyrrolidin-2-yl)spiro[cyclopropane-1,3-isochroman]-6-yl)-1H-pyrrolo[2,3-b]pyridine (Z229, 5 mg, yield: 9%) as a pale pink solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.32 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.32 (d, J=1.5 Hz, 1H), 7.22 (q, J=1.0 Hz, 1H), 4.88-4.64 (m, 2H), 4.09 (t, J=7.5 Hz, 1H), 3.12-3.07 (m, 1H), 3.01-2.83 (m, 3H), 2.32 (d, J=1.0 Hz, 3H), 2.21-2.11 (m, 1H), 1.93-1.71 (m, 2H), 1.51-1.41 (m, 1H), 0.88-0.76 (m, 2H), 0.60-0.47 (m, 2H). ES-API: [M+H].sup.+=360.2;

[0446] (S)-3-methyl-5-(4-methylene-9-(pyrrolidin-2-yl)-1,3,4,5-tetrahydrobenzo[c]oxepin-7-yl)-1H-pyrrolo[2,3-b]pyridine (Z230, 7 mg, yield: 13%) as a pale pink solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.28-7.24 (m, 1H), 5.02-4.77 (m, 4H), 4.37-4.27 (m, 3H), 3.79-3.70 (m, 2H), 3.12-3.03 (m, 1H), 2.95-2.90 (m, 1H), 2.31 (d, J=1.0 Hz, 3H), 2.17-2.09 (m, 1H), 1.86-1.70 (m, 2H), 1.49-1.41 (m, 1H). ES-API: [M+H].sup.+=360.2.

Example 37. Synthesis of Compound Z234-1 and Compound Z234-2

##STR00292##

[0447] Step 1: In the presence of protective nitrogen, 6-bromoisochroman-8-carbaldehyde (300 mg, 1.24 mmol) in tetrahydrofuran (5 mL) was cooled to 0 C. Phenylmagnesium chloride in tetrahydrofuran (1.86 mL, 1.86 mmol, 1M) was slowly added, and the system was slowly warmed to room temperature and stirred for 2 h. The reaction was quenched with saturated ammonium chloride solution (5 mL), and the reaction mixture was extracted with ethyl acetate (5 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-50% ethyl acetate/petroleum ether) to give (6-bromoisochroman-8-yl)(phenyl)methanol (310 mg, yield: 78%) as a colorless liquid. ES-API: [M+H.sup.+H.sub.2O]=301.0, 303.0.

[0448] Step 2: Dess-Martin periodinane (598 mg, 1.41 mmol) was slowly added to a solution of the (6-bromoisochroman-8-yl)(phenyl)methanol (150 mg, 0.47 mmol) in dichloromethane (10 mL) under an ice bath condition and stirred at room temperature for 2 h. The reaction was quenched with sodium thiosulfate solution (10 mL) and sodium bicarbonate solution (10 mL) successively, and the reaction mixture was extracted with dichloromethane (15 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-50% ethyl acetate/petroleum ether) to give (6-bromoisochroman-8-yl)(phenyl)methanone (120 mg, yield: 80%). ES-API: [M+H].sup.+=317.1, 319.0.

[0449] Step 3: Methylamine hydrochloride (128 mg, 1.89 mmol) and titanium tetraisopropoxide (108 mg, 0.38 mmol) were added to a solution of the (6-bromoisochroman-8-yl)(phenyl)methanone (120 mg, 0.38 mmol) in 1,2-dichloroethane (5 mL), and the mixture was stirred at room temperature overnight. Sodium cyanoborohydride (71 mg, 1.13 mmol) was then added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction was quenched with aqueous ammonium chloride solution (5 mL), and the reaction mixture was extracted with dichloromethane (5 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-6% methanol (1% ammonia water)/dichloromethane) to give 1-(6-bromoisochroman-8-yl)-N-methyl-1-phenylmethanamine (80 mg, yield: 64%) as a colorless liquid. ES-API: [M+H].sup.+=332.0, 334.1.

[0450] Step 4: In the presence of protective nitrogen, a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (68 mg, 0.26 mmol), the 1-(6-bromoisochroman-8-yl)-N-methyl-1-phenylmethanamine (80 mg, 0.24 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.02 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (8 mg, 0.02 mmol) and potassium carbonate (99 mg, 0.72 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred under microwave irradiation at 110 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give N-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)-1-phenylmethanamine (60 mg, yield: 65%) as a white solid. ES-API: [M+H].sup.+=384.3.

[0451] Step 5: The N-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)-1-phenylmethanamine (60 mg, 0.16 mmol) was chirally resolved (column type: Chiralpak IG: 5 m, 4.6*250 mm, mobile phase: n-hexane (0.2% trifluoroacetic acid):ethanol (0.2% trifluoroacetic acid)=70:30, flow rate: 1 mL/min, column temperature: room temperature) to give two isomeric compounds. A structure of one isomeric compound was arbitrarily assigned as (S)N-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)-1-phenylmethanamine (Z234-1, trifluoroacetate, 36 mg, yield: 46%, retention time: 8.290 min, ee value: 100%). ES-API: [M+H].sup.+=384.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.47 (s, 1H), 9.70 (s, 2H), 8.61 (d, J=2.0 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.62 (s, 1H), 7.58-7.53 (m, 2H), 7.51-7.46 (m, 2H), 7.45-7.40 (m, 1H), 7.33-7.31 (m, 1H), 5.53 (t, J=6.0 Hz, 1H), 5.10 (d, J=15.5 Hz, 1H), 4.32 (d, J=15.5 Hz, 1H), 3.96-3.87 (m, 1H), 3.80-3.68 (m, 1H), 2.99-2.90 (m, 1H), 2.88-2.79 (m, 1H), 2.61 (t, J=5.0 Hz, 3H), 2.34 (d, J=1.0 Hz, 3H); a structure of the other isomeric compound was arbitrarily assigned as (R)N-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)-1-phenylmethanamine (Z234-2, trifluoroacetate, 23 mg, yield: 30%, retention time: 9.857 min, ee value: 100%). ES-API: [M+H].sup.+=384.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.44 (s, 1H), 9.69 (s, 2H), 8.61 (d, J=2.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.61 (s, 1H), 7.57-7.53 (m, 2H), 7.50-7.45 (m, 2H), 7.44-7.40 (m, 1H), 7.31 (s, 1H), 5.52 (d, J=6.5 Hz, 1H), 5.10 (d, J=15.5 Hz, 1H), 4.32 (d, J=15.5 Hz, 2H), 3.95-3.89 (m, 1H), 3.78-3.69 (m, 1H), 2.98-2.91 (m, 1H), 2.89-2.80 (m, 1H), 2.61 (t, J=5.0 Hz, 4H), 2.34 (d, J=1.0 Hz, 3H).

Example 38. Synthesis of Compound Z227

##STR00293## ##STR00294##

[0452] Step 1: Tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (7 g, 28.2 mmol) was dissolved in acetonitrile (150 mL), and the system was cooled to 0 C. in an ice-water bath. N-Bromosuccinimide (5.02 g, 28.2 mmol) was slowly added in batches, and the system reacted under the ice-water bath condition for 2 h. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution (150 mL) and saturated brine (150 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=80:20) to give tert-butyl 7-amino-8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (8.2 g, yield: 88%). ES-API: [M+H].sup.+=327.0, 329.0.

[0453] Step 2: The tert-butyl 7-amino-8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (7.4 g, 22.6 mmol) was dissolved in N,N-dimethylformamide (150 mL), and the system was cooled to 0 C. in an ice-water bath. N-Chlorosuccinimide (3.16 g, 23.7 mmol) was slowly added in batches, and the system was heated to 50 C. for 0.5 h. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution (150 mL) and saturated brine (150 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=80:20) to give tert-butyl 7-amino-6-chloro-8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (5.0 g, yield: 61%). ES-API: [M+H].sup.+=305, 307.

[0454] Step 3: The tert-butyl 7-amino-6-chloro-8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (5.0 g, 13.85 mmol) was dissolved in tetrahydrofuran (50 mL). Water (10 mL) and hypophosphorous acid (25 mL, 50% aqueous solution) were added successively, and the system was cooled to 0 C. Sodium nitrite (1.91 g, 27.7 mmol) was slowly added, and the system react at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was poured into ice water, and ethyl acetate (50 mL) was added. The obtained mixture was washed with saturated aqueous sodium bicarbonate solution (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 6-chloro-8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.34 g, yield: 70%), ES-API: [M+H].sup.+=346.1, 348.1.

[0455] Step 4: The tert-butyl 6-chloro-8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.34 g, 9.68 mmol) was dissolved in dichloromethane (20 mL). Trifluoroacetic acid (10 mL) was added, and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated to remove an excess of trifluoroacetic acid. Tetrahydrofuran (50 mL) was added, and the system was cooled to 0 C. Triethylamine (7 g, 29.04 mmoL) and benzyl chloroformate (2.48 g, 14.52 mmoL) were added successively, and the system was reacted at room temperature for 2 h. Upon completion of the reaction, ethyl acetate (50 mL) was added. The obtained mixture was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=50:50) to give benzyl 8-bromo-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.65 g, yield: 99%), ES-API: [M+H].sup.+=380.0, 382.0.

[0456] Step 5: The benzyl 8-bromo-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.4 g, 8.97 mmol) reacted with potassium vinyltrifluoroborate (2.38 g, 17.94 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (366 mg, 0.448 mmol), triethylamine (1.81 g, 17.94 mmol) and ethanol (60 mL) at 90 C. for 3 h. Ethyl acetate (100 mL) was added. The obtained mixture was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate=50:50) to give benzyl 6-chloro-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (2 g, yield: 68%). ES-API: [M+H].sup.+=328.1.

[0457] Step 6: The benzyl 6-chloro-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (2 g, 6.11 mmol) was dissolved in tetrahydrofuran (40 mL) and acetonitrile (20 mL). An aqueous solution (10 mL) of potassium osmate dihydrate (225 mg, 0.611 mmol) and sodium periodate (7.85 g, 36.7 mmol) was added, and the system reacted at room temperature for 2 h and then was cooled to 0 C. The reaction was quenched by the addition of aqueous sodium thiosulfate solution. Ethyl acetate (100 mL) was added. The obtained mixture was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate=20:80) to give benzyl 6-chloro-8-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.1 g, yield: 55%). ES-API: [M+H].sup.+=330.0.

[0458] Step 7: The benzyl 6-chloro-8-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (720 mg, 2.18 mmol) and (S)-tert-butylsulfinamide (529 mg, 4.37 mmol) were dissolved in dried dichloromethane (15 mL). Tetraethoxytitanium (1.99 g, 8.75 mmol) was added, and the system reacted at room temperature for 15 h. Upon completion of the reaction, the reaction mixture was slowly poured into saturated brine (20 mL). Dichloromethane (30 mL) was added. The organic layer was separated, filtered, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate:petroleum ether=2:1) to give (S)-benzyl 8-(((tert-butylsulfinyl)imino)methyl)-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (800 mg, yield: 85%). ES-API: [M+H].sup.+=433.1.

[0459] Step 8: The (S)-benzyl 8-(((tert-butylsulfinyl)imino)methyl)-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (800 mg, 1.85 mmol) and dried tetrahydrofuran (20 mL) were added to a 100 ml three-necked flask. (2-(1,3-Dioxan-2-yl)ethyl)magnesium bromide in tetrahydrofuran (14.5 mL, 0.5M) was slowly added under a dry ice bath condition at 78 C. in the presence of protective nitrogen and stirred for 10 min. Upon completion of the reaction, the reaction was quenched by the addition of 1M hydrochloric acid (8 mL). Ethyl acetate (50 mL) was added. The obtained mixture was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate:petroleum ether=9:1) to give benzyl 8-(1-(((S)-tert-butylsulfinyl)amino)-3-(1,3-dioxan-2-yl)propyl)-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (950 mg, yield: 94%). ES-API: [M+H].sup.+=549.1.

[0460] Step 9: The benzyl 8-(1-(((S)-tert-butylsulfinyl)amino)-3-(1,3-dioxan-2-yl)propyl)-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (950 mg, 1.73 mmol) was added to trifluoroacetic acid/water (10 mL/0.5 mL), and the system reacted at room temperature (<25 C.) for 30 min. Triethylsilane (2 g, 17.3 mmol) was added, and the system reacted for 2 h. After concentration, the concentrate was dissolved in tetrahydrofuran. Triethylamine (524 g, 5.19 mmol) and di-tert-butyl dicarbonate (564 mg, 2.59 mmol) were added. Upon completion of the reaction, ethyl acetate (50 mL) was added. The obtained mixture was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate:petroleum ether=3:1) to give (S)-benzyl 8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (220 mg, yield: 25%). ES-API: [M+H].sup.+=471.2.

[0461] Step 10: The (S)-benzyl 8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (220 mg, 0.468 mmoL), palladium chloride (9.94 mg, 0.0561 mmoL) and triethylamine (47.3 mg, 0.468 mg) were dissolved in dichloromethane (15 mL). Triethylsilane (217 mg, 1.87 mmoL) was slowly added dropwise. The system reacted at room temperature for 1 h. Upon completion of the reaction, dichloromethane (50 mL) was added. The obtained mixture was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane:methanol=10:1) to give tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (125 mg, yield: 80%). ES-API: [M+H].sup.+=337.0.

[0462] Step 11: The tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (125 mg, 0.372 mmol) was dissolved in dried dichloromethane (5 mL). 3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (117.5 mg, 0.744 mmol), triethylamine (112 mg, 1.11 mmol) and 2-(7-azabenzotriazol)-N,N,N,N-tetramethylurea hexafluorophosphate (283 mg, 0.744 mmol) were added successively, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was diluted with dichloromethane (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate:petroleum ether=3:1) to give (2S)-tert-butyl 2-(6-chloro-2-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (80 mg, yield: 45%). ES-API: [M+H].sup.+=477.0.

[0463] Step 12: The (2S)-tert-butyl 2-(6-chloro-2-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (80 mg, 0.168 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (65 mg, 0.252 mmol), Sphos Pd G2 (12.0 mg, 0.0168 mmol) and potassium carbonate (69.5 mg, 0.504 mmol) were added to 1,4-dioxane (3 mL) and water (0.5 mL). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, and purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give (2S)-tert-butyl 2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, yield: 41%). ES-API: [M+H].sup.+=573.1.

[0464] Step 13: The (2S)-tert-butyl 2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give 3,3,3-trifluoro-2-hydroxy-2-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z227, 15 mg, yield: 45%). ES-API: [M+H].sup.+=473.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.47 (d, J=2.2 Hz, 1H), 8.11 (d, J=2.2 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.41 (d, J=10.1 Hz, 1H), 7.26 (s, 1H), 7.20 (s, 1H), 5.32 (t, J=4.8 Hz, 1H), 4.85 (d, J=17.1 Hz, 1H), 4.65 (d, J=17.6 Hz, 1H), 4.26 (s, 1H), 3.17-2.90 (m, 2H), 2.34-2.29 (m, 3H), 2.27-2.19 (m, 1H), 1.99 (dt, J=17.1, 6.9 Hz, 2H), 1.88-1.83 (m, 1H), 1.57 (d, J=24.3 Hz, 3H).

Example 39. Synthesis of Compound Z231

##STR00295##

[0465] Step 1: 4-(6-bromoisochroman-8-yl)azetidin-2-one (30 mg, 0.11 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (33 mg, 0.13 mmol), sodium carbonate (35 mg, 0.33 mmol), 2-dicyclohexylphosphine-2,6-dimethoxy-biphenyl (4 mg, 0.01 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7 mg, 0.01 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL) were added to a 5 mL microwave tube. The mixture was purged with nitrogen for 1 min, and the system reacted in a microwave reactor at 110 C. for 45 min. Water (5 mL) was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give 4-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)azetidin-2-one (Z231, 11 mg, yield: 31%) as a white solid, ES-API: [M+H].sup.+=334.1. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.36 (s, 1H), 8.57-8.44 (m, 2H), 8.14 (d, J=2.0 Hz, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.27 (s, 1H), 4.82 (d, J=15.0 Hz, 1H), 4.69 (dd, J=4.0, 2.0 Hz, 1H), 4.55 (d, J=15.0 Hz, 1H), 3.97-3.80 (m, 2H), 3.44-3.37 (m, 1H), 2.98-2.82 (m, 2H), 2.63 (dd, J=14.5, 2.0 Hz, 1H), 2.31 (d, J=1.0 Hz, 3H).

Example 40. Synthesis of Compound Z138

##STR00296## ##STR00297##

[0466] Step 1: 2-(3,5-dibromophenyl)acetic acid (5.8 g, 19.7 mmol), ethylamine hydrochloride (3.2 g, 39.3 mmol) and tetrahydrofuran (100 mL) were added to a 250 mL single-neck round-bottom flask. After stirring at room temperature for 5 min, 2-(7-azabenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (22.5 g, 59.2 mmol) was added in batches and stirred at room temperature for 30 min. Ethyl acetate (300 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (300 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=10:100) to give 2-(3,5-dibromophenyl)-N-ethylacetamide (5.1 g, yield: 80%). ES-API: [M+H].sup.+=319.9.

[0467] Step 2: The 2-(3,5-dibromophenyl)-N-ethylacetamide (4.8 g, 14.9 mmol), paraformaldehyde (0.54 g, 18.0 mmol) and Eaton's reagent (15 mL) were added to a 100 mL single-neck flask and stirred at 80 C. for 4 h. Ethyl acetate (100 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (50 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=20:100) to give 6,8-dibromo-2-ethyl-1,4-dihydroisoquinolin-3(2H)-one (2.9 g, yield: 59%). ES-API: [M+H].sup.+=331.9.

[0468] Step 3: The 6,8-dibromo-2-ethyl-1,4-dihydroisoquinolin-3(2H)-one (1.5 g, 4.5 mmol), potassium vinylfluoroborate (0.63 g, 4.7 mmol), tetrakis(triphenylphosphine)palladium (0.5 g, 0.43 mmol), potassium carbonate (1.8 g, 13.0 mmol), dioxane (30 mL) and water (4 mL) were added to a 50 mL three-neck round-bottom flask. The system was replaced with nitrogen three times and reacted at 110 C. for 4 h in the presence of protective nitrogen. Ethyl acetate (100 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (50 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=40:100) to give 6-bromo-2-ethyl-8-vinyl-1,4-dihydroisoquinolin-3(2H)-one (2.37 g, crude product). ES-API: [M+H].sup.+=280.0.

[0469] Step 4: The 6-bromo-2-ethyl-8-vinyl-1,4-dihydroisoquinolin-3(2H)-one (2.37 g, crude product), sodium periodate (10 g, 46.7 mmol), tetrahydrofuran (50 mL) and water (40 mL) were added to a 50 mL single-neck round-bottom flask. Potassium osmate dihydrate (0.6 g, 1.63 mmol) was added in batches under an ice-water bath condition and then stirred at 0 C. for 2 h. Ethyl acetate (100 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (100 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=30:100) to give 6-bromo-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-8-carbaldehyde (300 mg, yield of the 2 steps: 23.6%). ES-API: [M+H].sup.+=282.0.

[0470] Step 5: The 6-bromo-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-8-carbaldehyde (300 mg, 1.1 mmol) and dichloromethane (10 mL) were added to a 50 mL single-neck round-bottom flask. (S)-2-Methylpropane-2-sulfinamide (260 mg, 2.1 mmol) and tetraethyl titanate (1 mL) were added under an ice-water bath condition and stirred at room temperature for 3 h. Ethyl acetate (30 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=20:100) to give (S,E)-N-((6-bromo-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl)methylene)-2-methylpropane-2-sulfinamide (350 mg, yield: 83%). ES-API: [M+H].sup.+=385.1.

[0471] Step 6: The (S,E)-N-((6-bromo-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl)methylene)-2-methylpropane-2-sulfinamide (250 mg, 0.65 mmol) and anhydrous tetrahydrofuran (3 mL) were added to a 5 mL three-neck round-bottom flask, and the system was replaced with nitrogen three times. A 0.5M solution of (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide in tetrahydrofuran (4 mL) was added at 78 C. in the presence of protective nitrogen, and the system continued to be stirred for 2 h. The reaction was quenched by the addition of a saturated ammonium chloride solution (5 mL). Ethyl acetate was added (30 mL). The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=20:100) to give (S)N-(1-(6-bromo-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (55 mg, crude product). ES-API: [M+H].sup.+=501.1.

[0472] Step 7: The (S)N-(1-(6-bromo-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (55 mg, crude product), trifluoroacetic acid (3 mL) and water (0.15 mL) were added to a 25 mL-neck round-bottom flask. Trimethylsilane (120 mg, 1.0 mmol) was added at 0 C. and stirred for 18 h. The reaction mixture was spun to dryness. Ethyl acetate (30 mL) was added. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, and concentrated to give (S)-6-bromo-2-ethyl-8-(pyrrolidin-2-yl)-1,4-dihydroisoquinolin-3(2H)-one (50 mg, crude product). ES-API: [M+H].sup.+=323.0.

[0473] Step 8: The (S)-6-bromo-2-ethyl-8-(pyrrolidin-2-yl)-1,4-dihydroisoquinolin-3(2H)-one (50 mg, crude product), di-tert-butyl dicarbonate (1 mL), triethylamine (46 mg, 0.45 mmol) and dichloromethane (5 mL) were added to a 25 mL single-neck round-bottom flask and stirred for 1 h. Dichloromethane (20 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl tert-butyl (S)-2-(6-bromo-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (58 mg, crude product). ES-API: [M+H].sup.+=423.0.

[0474] Step 9: The tert-butyl tert-butyl (S)-2-(6-bromo-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (58 mg, crude product), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (28 mg, 0.11 mmol), sphos-pd-g2 (10 mg, 0.01 mmol), potassium carbonate (40 mg, 0.29 mmol), dioxane (30 mL) and water (4 mL) were added to a 25 mL single-neck round-bottom flask. The system was replaced with nitrogen three times and reacted under microwave at 110 C. for 50 min in the presence of protective nitrogen. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (S)-2-(2-ethyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (27 mg, yield of the 4 steps: 8.7%). ES-API: [M+H].sup.+=475.3.

[0475] Step 10: The tert-butyl (S)-2-(2-ethyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (27 mg, 0.05 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The obtained mixture was spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method)(column: Waters XBridge C18, 190*250 mm, 5 m; mobile phase: A: 0.1% aqueous ammonium bicarbonate solution; mobile phase B: acetonitrile; flow rate: 15 ml/min; B %=20%-100%; column temperature: room temperature) to give (S)-2-ethyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-1,4-dihydroisoquinolin-3(2H)-one (Z138, 10 mg, yield: 53%). ES-API: [M+H].sup.+=375.3.

Example 41. Synthesis of Compound Z235

##STR00298## ##STR00299##

[0476] Step 1: Compound 5-chloro-2-methylbenzoic acid (10 g, 58.62 mmol), iron powder (1.64 g, 29.31 mmol) and bromine (40 mL) were placed in a sealed tank and stirred at room temperature for 48 h. The reaction mixture was slowly added dropwise to saturated aqueous sodium bicarbonate solution (400 mL) to quench the reaction, and extracted with ethyl acetate (100 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-bromo-5-chloro-2-methylbenzoic acid (18 g, crude product) as a white solid. ES-API: [M+H].sup.+=248.9.

[0477] Step 2: A mixed solution of the 3-bromo-5-chloro-2-methylbenzoic acid (18 g, 72.15 mmol), iodomethane (20.48 g, 144.30 mmol) and potassium carbonate (29.91 g, 216.44 mmol) in N,N-dimethylformamide (100 nL) was placed in a sealed tube and stirred at 60 C. for 2 h. The reaction mixture was dissolved in ethyl acetate (300 mL), and washed with dilute brine (100 mL3) and water (100 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-10% ethyl acetate/petroleum ether) to give methyl 3-bromo-5-chloro-2-methylbenzoate (14 g, yield of the 2 steps: 91%) as a white solid. ES-API: [M+H].sup.+=262.9.

[0478] Step 3: In the presence of protective nitrogen, a mixed solution of the methyl 3-bromo-5-chloro-2-methylbenzoate (7 g, 26.56 mmol), N-bromosuccinimide (4.73 g, 26.56 mmol) and azobisisobutyronitrile (4.36 g, 26.56 mmol) in carbon tetrachloride (100 mL) was stirred at 90 C. for 5 h. The reaction was monitored by TLC for completion. The system was cooled to room temperature, and washed with water (50 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-10% ethyl acetate/petroleum ether) to give methyl 3-bromo-2-(bromomethyl)-5-chlorobenzoate (6 g, yield: 66%) as a colorless liquid. ES-API: [M+H].sup.+=340.9.

[0479] Step 4: 7 M Ammonia/methanol solution (30 mL) was added to the methyl 3-bromo-2-(bromomethyl)-5-chlorobenzoate (6 g, 17.52 mmol), and the system reacted at 70 C. in a sealed tube for 2 h. A white solid was precipitated out, cooled to room temperature, filtered, and dried to give 4-bromo-6-chloroisoindolin-1-one (2 g, yield: 46%). ES-API: [M+H].sup.+=246.2, 248.2.

[0480] Step 5: 1 M Borane-tetrahydrofuran complex (40 mL) was added dropwise to a cloudy solution of the 4-bromo-6-chloroisoindolin-1-one (1 g, 4.06 mmol) in tetrahydrofuran (20 mL), and the system was heated to reflux overnight. The obtained mixture was cool to room temperature. 1 M Hydrochloric acid (40 mL) was added and continued to be stirred for 1 h. The obtained mixture was adjusted to pH 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (40 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-bromo-6-chloroisoindoline (1 g, crude product). ES-API: [M+H].sup.+=232.2, 234.2.

[0481] Step 6: N,N-diisopropylethyl amine (1.67 g, 12.90 mmol) and acetyl chloride (675 mg, 8.60 mmol) were added to a solution of the 4-bromo-6-chloroisoindoline (1 g, 4.30 mmol) in dichloromethane (20 mL) under an ice bath condition and stirred for 30 min. The reaction mixture was washed with saturated sodium bicarbonate solution (10 mL3). The organic phase was dried over anhydrous sodium sulfate, and concentrated to give 1-(4-bromo-6-chloroisoindolin-2-yl)ethan-1-one (1 g, crude product). ES-API: [M+H].sup.+=274.0, 276.0.

[0482] Step 7: In the presence of protective nitrogen, a mixed solution of the compound 1-(4-bromo-6-chloroisoindolin-2-yl)ethan-1-one (900 mg, 3.28 mmol), potassium vinylfluoroborate (1 g, 6.56 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (267 mg, 0.33 mmol), triethylamine (996 mg, 9.84 mmol) in ethanol (10 mL) was stirred at 80 C. for 2 h. The reaction mixture was dissolved in ethyl acetate (30 mL), and washed with saturated brine (20 mL) and water (20 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-50% ethyl acetate/petroleum ether) to give 1-(6-chloro-4-vinylisoindolin-2-yl)ethan-1-one (360 mg, yield: 50%). [M+H].sup.+=222.1.

[0483] Step 8: Potassium osmate dihydrate (100 mg, 0.27 mmol) and sodium periodate (1.73 g, 8.1 mmol) were added to the 1-(6-chloro-4-vinylisoindolin-2-yl)ethan-1-one (300 mg, 1.35 mmol) in tetrahydrofuran (6 mL) and water (6 mL) and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-50% ethyl acetate/petroleum ether) to give 2-acetyl-6-chloroisoindolin-4-carbaldehyde (165 mg, yield: 55%). [M+H].sup.+=224.1.

[0484] Step 9: In the presence of protective nitrogen, tetraethoxytitanium (899 mg, 3.94 mmol) was added dropwise to a solution of the 2-acetyl-6-chloroisoindolin-4-carbaldehyde (220 mg, 0.98 mmol) and S-tert-butylsulfinamide (238 mg, 1.97 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 h. Upon completion of the reaction, dichloromethane (5 mL) and water (1 mL) were added. The obtained mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-60% ethyl acetate/petroleum ether) to give (S,E)-N-((2-acetyl-6-chloroisoindolin-4-yl)methylene)-2-methylpropane-2-sulfinamide (220 mg, yield: 69%) as a yellow solid. [M+H].sup.+=327.0.

[0485] Step 10: In the presence of protective nitrogen, (1,3-dioxane-2-ethyl)magnesium bromide in tetrahydrofuran (6.24 mL, 3.12 mmol, 0.5 M) was added dropwise to a solution of the (S,E)-N-((2-acetyl-6-chloroisoindolin-4-yl)methylene)-2-methylpropane-2-sulfinamide (170 mg, 0.52 mmol) in tetrahydrofuran (10 mL) at 65 C. and stirred at this temperature for 1 h. The system was warmed to room temperature and then continued to be stirred overnight. The reaction was quenched with saturated ammonium chloride solution (20 mL), and the reaction mixture was extracted with ethyl acetate (30 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give (S)N((S)-1-(2-acetyl-6-chloroisoindolin-4-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (230 mg, crude product). [M+H].sup.+=443.2.

[0486] Step 11: Trifluoroacetic acid (2 mL) and water (0.12 mL) were added to the (S)N((S)-1-(2-acetyl-6-chloroisoindolin-4-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (230 mg, 0.52 mmol) under an ice bath condition and stirred at room temperature for 0.5 h. The obtained mixture was concentrated to give (S)-1-(6-chloro-4-(pyrrolidin-2-yl)isoindolin-2-yl)ethan-1-one (140 mg, crude product). [M+H].sup.+=265.2.

[0487] Step 12: Di-tert-butyl dicarbonate (227 mg, 1.04 mmol) was added to a solution of the (S)-1-(6-chloro-4-(pyrrolidin-2-yl)isoindolin-2-yl)ethan-1-one (140 mg, 0.52 mmol) and N,N-diisopropylamine (202 mg, 1.56 mmol) in dichloromethane (5 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. The crude product was purified by a flash silica gel column (0-50% ethyl acetate/petroleum ether) to give tert-butyl (S)-2-(2-acetyl-6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate (100 mg, yield of the 3 steps: 53%). [M+H].sup.+=365.2.

[0488] Step 13: In the presence of protective nitrogen, a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (93 mg, 0.36 mmol), the tert-butyl (S)-2-(2-acetyl-6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate (130 mg, 0.36 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (29 mg, 0.04 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (16 mg, 0.04 mmol) and potassium carbonate (149 mg, 1.08 mmol) in 1,4-dioxane (3 mL) and water (0.6 mL) was stirred under microwave irradiation at 110 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-80% ethyl acetate/petroleum ether) to give tert-butyl (S)-2-(2-acetyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-4-yl)pyrrolidine-1-carboxylate (100 mg, yield: 60%). [M+H].sup.+=461.2.

[0489] Step 14: Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of the tert-butyl (S)-2-(2-acetyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-4-yl)pyrrolidine-1-carboxylate (100 mg, 0.22 mmol) in dichloromethane (1 mL) under an ice bath condition and stirred at room temperature for 1 h. The obtained mixture was concentrated, and purified by prep-HPLC (formic acid method) to give (S)-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(pyrrolidin-2-yl)isoindolin-2-yl)ethan-1-one (Z235, formate, 17 mg, yield: 19%) as a white solid. ES-API: [M+H].sup.+=361.1. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.36 (s, 1H), 8.49 (t, J=2.0 Hz, 1H), 8.27 (s, 1H), 8.14 (t, J=2.5 Hz, 1H), 7.74 (s, 1H), 7.59 (d, J=9.5 Hz, 1H), 7.27 (s, 1H), 4.91 (d, J=18.4 Hz, 2H), 4.70 (d, J=24.1 Hz, 2H), 4.33-4.15 (m, 1H), 3.21-3.14 (m, 1H), 3.07-2.98 (m, 1H), 2.31 (d, J=1.0 Hz, 3H), 2.28-2.19 (m, 1H), 2.10 (d, J=7.0 Hz, 3H), 1.96-1.88 (m, 1H), 1.88-1.80 (m, 1H), 1.74-1.64 (m, 1H).

Example 42. Synthesis of Compound Z236

##STR00300## ##STR00301##

[0490] Step 1: A mixed solution of 4-bromo-6-chloroisoindolin-1-one (700 mg, 2.84 mmol), iodoethane (4.43 g, 28.40 mmol) and potassium carbonate (1.18 g, 8.52 mmol) in acetone (10 mL) was stirred at 50 C. in a sealed tube for 2 days. The reaction mixture was filtered and concentrated. The crude product was purified by a flash silica gel column (0-50% ethyl acetate/petroleum ether) to give 4-bromo-6-chloro-2-ethylisoindolin-1-one (250 mg, yield: 32%). ES-API: [M+H].sup.+=274.0, 276.0.

[0491] Step 2: In the presence of protective nitrogen, a solution of the compound 4-bromo-6-chloro-2-ethylisoindolin-1-one (200 mg, 0.73 mmol), potassium vinylfluoroborate (223 mg, 1.46 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (57 mg, 0.07 mmol) and triethylamine (222 mg, 2.19 mmol) in ethanol (4 mL) was stirred at 80 C. for 2 h. The reaction mixture was dissolved in ethyl acetate (30 mL), and washed with saturated brine (20 mL) and water (20 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-50% ethyl acetate/petroleum ether) to give 6-chloro-2-ethyl-4-vinylisoindolin-1-one (160 mg, yield: 99%). [M+H].sup.+=222.1.

[0492] Step 3: Potassium osmate dihydrate (50 mg, 0.68 mmol) and sodium periodate (873 mg, 4.08 mmol) were added to the 6-chloro-2-ethyl-4-vinylisoindolin-1-one (150 mg, 0.68 mmol) in tetrahydrofuran (3 mL) and water (3 mL) and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-50% ethyl acetate/petroleum ether) to give 6-chloro-2-ethyl-1-oxoisoindoline-4-carbaldehyde (55 mg, yield: 37%). [M+H].sup.+=224.0.

[0493] Step 4: In the presence of protective nitrogen, tetraethoxytitanium (286 mg, 1.25 mmol) was added dropwise to a solution of the 6-chloro-2-ethyl-1-oxoisoindoline-4-carbaldehyde (70 mg, 0.31 mmol) and S-tert-butylsulfinamide (76 mg, 0.63 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 1 h. Upon completion of the reaction, dichloromethane (5 mL) and water (1 mL) were added. The obtained mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-60% ethyl acetate/petroleum ether) to give (S)N-((6-chloro-2-ethyl-1-oxoisoindolin-4-yl)methylene)-2-methylpropane-2-sulfinamide (95 mg, yield: 93%) as a yellow solid. [M+H].sup.+=327.1.

[0494] Step 5: In the presence of protective nitrogen, (1,3-dioxane-2-ethyl)magnesium bromide in tetrahydrofuran (3.49 mL, 1.74 mmol, 0.5 M) was added dropwise to a solution of the (S)N-((6-chloro-2-ethyl-1-oxoisoindolin-4-yl)methylene)-2-methylpropane-2-sulfinamide (95 mg, 0.29 mmol) in tetrahydrofuran (10 mL) at 65 C. and stirred at this temperature for 1 h. The system was warmed to room temperature and then continued to be stirred overnight. The reaction was quenched with saturated ammonium chloride solution (20 mL), and the reaction mixture was extracted with ethyl acetate (30 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give (S)N((R)-1-(6-chloro-2-ethyl-1-oxoisoindolin-4-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (120 mg, yield: 93%). [M+H].sup.+=443.2.

[0495] Step 6: Trifluoroacetic acid (2 mL) and water (0.12 mL) were added to the (S)N((R)-1-(6-chloro-2-ethyl-1-oxoisoindolin-4-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (120 mg, 0.27 mmol) under an ice bath condition and stirred at room temperature for 0.5 h. The obtained mixture was concentrated to give (S)-6-chloro-2-ethyl-4-(pyrrolidin-2-yl)isoindolin-1-one (72 mg, yield: 100%). [M+H].sup.+=265.2.

[0496] Step 7: Di-tert-butyl dicarbonate (118 mg, 0.54 mmol) was added to a solution of the (S)-6-chloro-2-ethyl-4-(pyrrolidin-2-yl)isoindolin-1-one (72 mg, 0.27 mmol) and N,N-diisopropylamine (105 mg, 0.81 mmol) in dichloromethane (5 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. The crude product was purified by a flash silica gel column (0-50% ethyl acetate/petroleum ether) to give tert-butyl (S)-2-(6-chloro-2-ethyl-1-oxoisoindolin-4-yl)pyrrolidine-1-carboxylate (72 mg, yield: 73%). [M+H].sup.+=365.2.

[0497] Step 8: In the presence of protective nitrogen, a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (52 mg, 0.20 mmol), the tert-butyl (S)-2-(6-chloro-2-ethyl-1-oxoisoindolin-4-yl)pyrrolidine-1-carboxylate (72 mg, 0.20 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.02 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (8 mg, 0.02 mmol) and potassium carbonate (83 mg, 0.60 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was stirred under microwave irradiation at 110 C. for 0.5 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-80% ethyl acetate/petroleum ether) to give tert-butyl (S)-2-(2-ethyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-oxoisoindolin-4-yl)pyrrolidine-1-carboxylate (60 mg, yield: 65%). [M+H].sup.+=461.2.

[0498] Step 9: Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of the tert-butyl (S)-2-(2-ethyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-oxoisoindolin-4-yl)pyrrolidine-1-carboxylate (60 mg, 0.13 mmol) in dichloromethane (1 mL) under an ice bath condition and stirred at room temperature for 1 h. The obtained mixture was concentrated. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give (S)-2-ethyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(pyrrolidin-2-yl)isoindolin-1-one (Z236, 22 mg, yield: 47%) as a white solid. ES-API: [M+H].sup.+=361.1. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.38 (s, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.28 (s, 1H), 4.60 (d, J=8.0 Hz, 2H), 4.29 (t, J=8.0 Hz, 1H), 3.59 (q, J=7.5 Hz, 2H), 3.14-3.09 (m, 1H), 2.99-2.93 (m, 1H), 2.33 (d, J=1.0 Hz, 3H), 2.29-2.19 (m, 1H), 1.99-1.74 (m, 2H), 1.69-1.61 (m, 1H), 1.21 (t, J=7.5 Hz, 3H).

Example 43. Synthesis of Compound Z232

##STR00302## ##STR00303##

[0499] Step 1: 6-Bromoisochroman-8-carbaldehyde (1.0 g, 4.15 mmol) and methyltriphenylphosphonium bromide (4.44 g, 12.45 mmol) were dissolved in tetrahydrofuran (40 mL). In the presence of protective nitrogen, 60% sodium hydride (622 mg, 15.56 mmol) was added at 0 C. and stirred at 0 C. for 30 min. The system was then warmed to room temperature and continued to be stirred for 16 h. Water (40 mL) was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate/petroleum ether: 0-15%) to give 6-bromo-8-vinylisochroman (950 mg, yield: 96%) as a colorless liquid. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.43 (d, J=1.5 Hz, 1H), 7.19 (s, 1H), 6.58 (dd, J=17.5, 11.0 Hz, 1H), 5.63 (dd, J=17.5, 1.0 Hz, 1H), 5.36 (dd, J=11.0, 1.0 Hz, 1H), 4.75 (s, 2H), 3.91 (t, J=5.5 Hz, 2H), 2.84 (t, J=5.5 Hz, 2H).

[0500] Step 2: The 6-bromo-8-vinylisochroman (1.7 g, 7.11 mmol) was dissolved in dichloromethane (8 mL). In the presence of protective nitrogen, thioisocyanate chloride (1.52 g, 40.05 mmol) in dichloromethane was slowly added dropwise at room temperature and stirred at room temperature for 16 h. The reaction mixture was cooled to 0 C. An aqueous solution (15 mL) of sodium sulfite (1.34 g, 10.66 mmol) and sodium carbonate (2.26 g, 21.33 mmol) was added dropwise and stirred at room temperature for 1 h. Dichloromethane (80 mL) was added to the reaction mixture. The obtained mixture was filtered with diatomaceous earth. The filtrate was separated, and the obtained aqueous layer was extracted with dichloromethane (50 mL2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (tetrahydrofuran/petroleum ether: 0-50%) to give 4-(6-bromoisochroman-8-yl)azetidin-2-one (350 mg, yield: 17%) as a white solid. ES-API: [M+H].sup.+=282.1, 284.1.

[0501] Step 3: The 4-(6-bromoisochroman-8-yl)azetidin-2-one (280 mg, 0.99 mmol) was dissolved in tetrahydrofuran (10 mL), and the system was cooled to 0 C. 1M Borane in tetrahydrofuran (6.93 mL, 6.93 mmol) was added dropwise and stirred at room temperature for 30 min, and then the system was heated to reflux for 16 h. The reaction mixture was cooled to 0 C. 6M hydrochloric acid (10 mL) was slowly added dropwise, and then heated to reflux for 30 min. The reaction mixture was cooled to room temperature. 6M Sodium hydroxide solution was added to adjust pH=10, and the obtained mixture was extracted with ethyl acetate (50 mL2). The organic phases were combined, washed with saturated sodium chloride solution (3 mL), dried over anhydrous sodium sulfate, and concentrated to give 4-(6-bromoisochroman-8-yl)azetidine (950 mg, crude product) which was directly used in the next reaction without further purification.

[0502] Step 4: The 4-(6-bromoisochroman-8-yl)azetidine (950 mg, crude product) was dissolved in dichloromethane (80 mL). Triethylamine (505 mg, 5.0 mmol) and di-tert-butyl dicarbonate (1.09 g, 5.0 mmol) were added at 0 C. and stirred at 0 C. for 1 h. The reaction mixture was concentrated. Ethyl acetate (50 mL) was added. The obtained mixture was washed with water (25 mL2) and saturated brine (25 mL) successively, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (tetrahydrofuran/petroleum ether: 0-18%) to give tert-butyl 2-(6-bromoisochroman-8-yl)azetidine-1-carboxylate (175 mg, yield of the 2 steps: 48%) as a colorless liquid. ES-API: [M+Na].sup.+=390.1, 392.1.

[0503] Step 5: The tert-butyl 2-(6-bromoisochroman-8-yl)azetidine-1-carboxylate (70 mg, 0.19 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (59 mg, 0.23 mmol), sodium carbonate (60 mg, 0.57 mmol), 2-dicyclohexylphosphine-2,6-dimethoxy-biphenyl (4 mg, 0.01 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.019 mmol), 1,4-dioxane (2.0 mL) and water (0.5 mL) were added to a 5 mL microwave tube. The mixture was purged with nitrogen for 1 min, and the system reacted in a microwave reactor at 110 C. for 45 min. Water (5 mL) was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate (40 mL). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0-2%) to give tert-butyl 2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)azetidine-1-carboxylate (75 mg, yield: 94%) as a pale yellow solid. ES-API: [M+H].sup.+=420.3.

[0504] Step 6: The tert-butyl 2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)azetidine-1-carboxylate (65 mg, 0.15 mmol) was dissolved in 4M hydrogen chloride/dioxane solution (4 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated to give 3-chloro-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)propan-1-amine hydrochloride (60 mg, yield: 100%) as a pale yellow solid. ES-API: [M+H].sup.+=356.2 (free base).

[0505] Step 7: The 3-chloro-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)propan-1-amine hydrochloride (50 mg, 0.13 mmol) was dissolved in methanol (30 mL). 4M Sodium hydroxide solution (2 mL, 8.0 mmol) was added at 0 C. and stirred at room temperature for 16 h. The reaction mixture was extracted with dichloromethane (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by thin layer chromatography preparative plate (dichloromethane/7M ammonia in methanol=15:1) to give crude product, which was then purified by prep-HPLC (formic acid method) to give 5-(8-(azetidin-2-yl)isochroman-6-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine (Z232, 1 mg, yield: 2.6%) as a white solid. ES-API: [M+H].sup.+=320.2 (free base).

Example 44. Synthesis of Compound Z228-1 and Compound Z228-2

##STR00304##

[0506] Step 1: Tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (75 mg, 0.222 mmol) was dissolved in dried dichloromethane (5 mL). (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (70.3 mg, 0.444 mmol), triethylamine (67.2 mg, 0.666 mmol) and 2-(7-azobenzotriazol)-N,N,N,N-tetramethylurea hexafluorophosphate (169 mg, 0.444 mmol) were added successively, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was diluted with dichloromethane (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-(6-chloro-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (105 mg, yield: 99%). ES-API: [M+H].sup.+=477.0.

[0507] Step 2: The tert-butyl (S)-2-(6-chloro-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (105 mg, 0.22 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (113 mg, 0.44 mmol), Sphos Pd G2 (15.8 mg, 0.022 mmol) and potassium carbonate (91 mg, 0.66 mmol) were added to 1,4-dioxane (3 mL) and water (0.5 mL). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, and purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, yield: 32%). ES-API: [M+H].sup.+=573.1.

[0508] Step 3: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z228-1, 22 mg, yield: 66.6%). ES-API: [M+H].sup.+=473.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.33 (d, J=2.4 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.38 (s, 1H), 7.28-7.24 (m, 1H), 7.19 (s, 1H), 5.25-5.22 (m, 1H), 4.99-4.78 (m, 1H), 4.64 (d, J=17.4 Hz, 1H), 4.20 (t, J=7.7 Hz, 1H), 4.12 (s, 1H), 3.76-3.66 (m, 1H), 3.13-3.08 (m, 1H), 2.98-2.93 (m, 3H), 2.31 (d, J=1.2 Hz, 3H), 2.23-2.20 (m, 1H), 1.85-1.81 (m, 2H), 1.60 (d, J=21.9 Hz, 3H), 1.48-1.43 (m, 1H).

[0509] Step 4: The tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (75 mg, 0.222 mmol) was dissolved in dried dichloromethane (5 mL). (S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (70.3 mg, 0.444 mmol), triethylamine (67.2 mg, 0.666 mmol) and 2-(7-azobenzotriazol)-N,N,N,N-tetramethylurea hexafluorophosphate (169 mg, 0.444 mmol) were added successively, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was diluted with dichloromethane (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to tert-butyl (S)-2-(6-chloro-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (85 mg, yield: 81%). ES-API: [M+H].sup.+=477.0.

[0510] Step 5: The tert-butyl (S)-2-(6-chloro-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (85 mg, 0.178 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (92 mg, 0.357 mmol), Sphos Pd G2 (13 mg, 0.0178 mmol) and potassium carbonate (74 mg, 0.534 mmol) were added to 1,4-dioxane (3 mL) and water (0.5 mL. The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, and purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, yield: 39%). ES-API: [M+H].sup.+=573.1.

[0511] Step 6: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia water/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (S)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z228-2, 25 mg, yield: 75.7%). ES-API: [M+H].sup.+=473.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.33 (d, J=2.4 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.38 (s, 1H), 7.26 (s, 1H), 7.19 (d, J=6.7 Hz, 1H), 5.23-5.18 (m, 1H), 4.96-4.78 (m, 1H), 4.64 (d, J=17.1 Hz, 1H), 4.19 (t, J=7.7 Hz, 1H), 4.09 (s, 1H), 3.56 (d, J=28.4 Hz, 1H), 3.13-3.06 (m, 1H), 3.01-2.89 (m, 3H), 2.31 (s, 3H), 2.21 (s, 1H), 1.85-1.72 (m, 2H), 1.57 (d, J=21.9 Hz, 3H), 1.46 (m, 1H).

Example 45. Synthesis of Compound Z137

##STR00305##

[0512] Step 1: Tert-butyl 5-bromo-3-(cyanomethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (100 mg, 0.3 mmol) was dissolved in dried N,N-dimethylformamide (5 mL), and the system was cooled in an ice-water bath. 1,8-Diazabicyclo[5.4.0]undec-7-ene (136.8 mg, 0.9 mmol) and diphenyl(vinyl)sulfonium triflate (130 mg, 0.36 mmol) were added successively, and the system reacted for 1 h. Upon completion of the reaction, the reaction was quenched by the addition of a saturated aqueous ammonium chloride solution (10 mL). Ethyl acetate (30 mL) was added. The obtained mixture was washed with water (200 mL1) and saturated brine (20 mL1) successively, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=80:20) to give tert-butyl 5-bromo-3-(1-cyanocyclopropyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (75 mg, yield: 69.4%). ES-API: [M+H].sup.+=362.0.

[0513] Step 2: The tert-butyl 5-bromo-3-(1-cyanocyclopropyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (36 mg, 0.1 mmol), tert-butyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (43 mg, 0.10 mmol), Sphos Pd G2 (7.2 mg, 0.01 mmol) and potassium carbonate (41.4 mg, 0.3 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL). The system was replaced with nitrogen and reacted under microwave at 110 C. for 1 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate=10:90) to give tert-butyl (S)-5-(8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)isochroman-6-yl)-3-(1-cyanocyclopropyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (58 mg, yield: 98%). ES-API: [M+H].sup.+=585.3.

[0514] Step 3: The tert-butyl (S)-5-(8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)isochroman-6-yl)-3-(1-cyanocyclopropyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (58 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (S)-1-(5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropane-1-carbonitrile (Z137, 12 mg, yield: 31%). ES-API: [M+H].sup.+=385.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.84 (s, 1H), 8.53 (d, J=2.1 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.34 (d, J=1.9 Hz, 1H), 4.92-4.69 (m, 3H), 4.08 (t, J=7.7 Hz, 1H), 3.98-3.82 (m, 3H), 3.66-3.46 (m, 1H), 3.11-3.06 (m, 1H), 2.98-2.82 (m, 4H), 2.19-2.11 (m, 1H), 1.92-1.72 (m, 3H), 1.71-1.62 (m, 3H), 1.54-1.41 (m, 4H).

Example 46. Synthesis of Compound Z237

##STR00306##

[0515] Step 1: 3-Bromo-4-methylpyridine (500 mg, 2.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). Trimethylsilylacetylene (424.8 mg, 4.34 mmol), bis(triphenylphosphine)palladium chloride (203.3 mg, 0.29 mmol), cuprous iodide (110.2 mL, 0.58 mmol) and triethylamine (875.7 mg, 8.67 mmol) were added and stirred at room temperature for 2 min in the presence of protective nitrogen. Then the system was heated to 115 C. in an oil bath and stirred for 16 h. The reaction was monitored by LC-MS for completion. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (200 mL2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (tetrahydrofuran:petroleum ether=20%-40%) to give 4-methyl-3-((trimethylsilyl)ethynyl)pyridine (450 mg, yield: 82.4%). ES-API: [M+H].sup.+=190.2.

[0516] Step 2: The 4-methyl-3-((trimethylsilyl)ethynyl)pyridine (450 mg, 2.38 mmol) was dissolved in methanol (10 mL). Potassium carbonate (492.7 mg, 3.57 mmol) was added at room temperature and stirred for 2 h. The reaction was monitored by LC-MS for completion. The reaction mixture was filtered, concentrated, and purified by column chromatography (tetrahydrofuran:petroleum ether=20%-50%) to give 3-ethynyl-4-methylpyridine (250 mg, yield: 89.9%). ES-API: [M+H].sup.+=118.1.

[0517] Step 3: The 3-ethynyl-4-methylpyridine (250 mg, 2.13 mg) was dissolved in anhydrous triethylamine (10 mL). 5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (754.4 mg, 2.34 mmol), bis(triphenylphosphine)palladium chloride (147.2 mg, 0.21 mmol) and cuprous iodide (110.2 mL, 0.58 mmol) were added and stirred at room temperature for 2 min in the presence of protective nitrogen. Then the system was heated to 80 C. in an oil bath and stirred for 16 h. The reaction was monitored by LC-MS for completion, and water (20 mL) was added to the reaction mixture. The obtained mixture was extracted with ethyl acetate (50 mL2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (tetrahydrofuran:petroleum ether=50%-60%) to give 5-bromo-3-((4-methylpyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (312 mg, yield: 47.1%). ES-API: [M+H].sup.+=312.2, 314.2.

[0518] Step 4: The 5-bromo-3-((4-methylpyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (60 mg, 0.19 mmol) was dissolved in dioxane (5 mL) and water (1 mL). tert-butyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (97.8 mg, 0.23 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14.4 mg, 0.02 mmol) and potassium phosphate (127.2 mg, 0.60 mmol) were added at room temperature and stirred at 100 C. for 2 h in the presence of protective nitrogen. Dichloromethane (40 mL) was added to the reaction mixture. The obtained mixture was washed with water (10 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (tetrahydrofuran:petroleum ether=40%-60%) to give tert-butyl (S)-2-(6-(3-((4-methylpyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (31.2 mg, yield: 30.9%). ES-API: [M+H].sup.+=535.2.

[0519] Step 5: The tert-butyl (S)-2-(6-(3-((4-methylpyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (31.2 mg, 0.0584 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (3 mL) was added, and the system reacted at room temperature for 1 h. The reaction mixture was concentrated. 7.0M Ammonia/methanol solution (5 mL) was added, and a solvent was spun to dryness. The crude product was purified by prep-HPLC (trifluoroacetic acid method) to give (S)-3-((4-methylpyridin-3-yl)ethynyl)-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridine (Z237, 2.5 mg, yield: 10%). ES-API: [M+H].sup.+=435.2.

Example 47. Synthesis of Compound Z119 and Isomers Thereof

##STR00307## ##STR00308##

[0520] Step 1: 8-Bromo-6-chloro-isoquinoline (1 g, 4.12 mmol) was dissolved in ethanol (20 mL). Potassium trifluoro(vinyl)borate (1.66 g, 12.4 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (302 mg, 0.41 mmol) and triethylamine (1.25 g, 12.4 mmol) were added, and the system was warmed to 80 C. for 3 h. The reaction mixture was spun to dryness, and purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give 6-chloro-8-vinylisoquinoline (750 mg, yield: 95.9%). ES-API: [M+1].sup.+=190.1.

[0521] Step 2: The 6-chloro-8-vinylisoquinoline (750 mg, 3.95 mmol) was dissolved in tetrahydrofuran/water (10 mL/5 mL). 2,6-Lutidine (424 mg, 3.95 mmol), sodium periodate (6.77 g, 31.64 mmol) and potassium osmate dihydrate (437 mg, 1.19 mmol) were added, and the system reacted at room temperature for 2 h. The reaction was quenched with aqueous sodium thiosulfate solution, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, spun to dryness, and purified by column chromatography (petroleum ether/ethyl acetate=2/1) to give 6-chloroisoquinoline-8-carbaldehyde (390 mg, yield: 51%). ES-API: [M+1].sup.+=191.9.

[0522] Step 3: The 6-chloroisoquinoline-8-carbaldehyde (270 mg, 1.41 mmol) was dissolved in dichloromethane (10 mL). 2-(Tributylstannylmethoxy)ethanamine (513 mg, 1.41 mmol) and 4 A molecular sieves (300 mg) were added, and the system react at room temperature overnight. The reaction mixture was filtered and spun to dryness to give 1-(6-chloro-8-isoquinolyl)-N-[2-(tributylstannylmethoxy)ethyl]methanamine as a crude product which was directly used in the next step without purification.

[0523] Step 4: (R,R)-2,2-Isopropylidenebis(4-phenyl-2-oxazoline) (94 mg, 0.28 mmol) was added in one portion to a suspension of copper triflate (510 mg, 1.41 mmol) in hexafluoroisopropanol (2.5 mL) followed by a solution of the 1-(6-chloro-8-isoquinolyl)-N-[2-(tributylstannylmethoxy)ethyl]methanamine (crude product) in hexafluoroisopropanol (2.5 mL), and the system reacted at room temperature overnight. The reaction was quenched with 1M sodium hydroxide solution, and the reaction mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and spun to dryness to give 3-(6-chloro-8-isoquinolyl)morpholine as a crude product which was directly used in the next step without purification. ES-API: [M+1].sup.+=249.1.

[0524] Step 5: The 3-(6-chloro-8-isoquinolyl)morpholine (crude product) was dissolved in tetrahydrofuran (5 mL). Triethylamine (428 mg, 4.23 mmol) and di-tert-butyl dicarbonate (615 mg, 2.82 mmol) were added, and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction was quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, spun to dryness, and purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give tert-butyl 3-(6-chloro-8-isoquinolyl)morpholine-4-carboxylate (200 mg, yield: 40.1%). ES-API: [M+1].sup.+=349.1.

[0525] Step 6: The tert-butyl 3-(6-chloro-8-isoquinolyl)morpholine-4-carboxylate (100 mg, 0.29 mmol) was dissolved in acetic acid (1.5 mL), and the system was cooled to 0 C. Sodium borohydride (43 mg, 1.15 mmol) was added, and the system reacted at 0 C. for 1 h. Upon completion of the reaction, the reaction was quenched by the addition of water. The obtained mixture was basified with sodium carbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and spun to dryness to give tert-butyl 3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate as a crude product which was directly used in the next step without purification. ES-API: [M+1].sup.+=353.1.

[0526] Step 7: The tert-butyl 3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (crude product, 0.28 mmol) was dissolved in dichloromethane (1 mL). Triethylamine (85 mg, 0.84 mmol) was added, and the system was cooled to 0 C. Acetyl chloride (22 mg, 0.28 mmol) was then added, and the system reacted at 0 C. for 0.5 h. Upon completion of the reaction, the reaction was quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, spun to dryness, and purified by column chromatography (petroleum ether/ethyl acetate=3/1) to give tert-butyl 3-(2-acetyl-6-chloro-3,4-dihydro-1H-isoquinolin-8-yl)morpholine-4-carboxylate (80 mg, yield: 72%). ES-API: [M+1-100].sup.+=295.1.

[0527] Step 8: The tert-butyl 3-(2-acetyl-6-chloro-3,4-dihydro-1H-isoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.2 mmol) was dissolved in dioxane/water (1 mL/0.2 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (63 mg, 0.24 mmol), Sphos-Pd-G2 (14 mg, 0.02 mmol) and potassium carbonate (56 mg, 0.4 mmol) were added. The system was heated to 100 C. for 1.5 h. Upon completion of the reaction, the reaction mixture was spun to dryness and purified by a preparative thin layer chromatographic column (petroleum ether/ethyl acetate=2/1) to tert-butyl 3-[2-acetyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydro-1H-isoquinolin-8-yl]morpholine-4-carboxylate (62 mg, yield: 62%). ES-API: [M+1].sup.+=491.3.

[0528] Step 9: The tert-butyl 3-[2-acetyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydro-1H-isoquinolin-8-yl]morpholine-4-carboxylate (62 mg, 0.13 mmol) was dissolved in dichloromethane (1.3 mL). Trifluoroacetic acid (1.3 mL) was added, and the system react at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness and purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give 1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)ethan-1-one (Z119, 25 mg, yield: 51%). ES-API: [M+1].sup.+=391.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.53 (s, 1H), 8.05-7.96 (m, 1H), 7.95-7.85 (m, 1H), 7.30 (s, 1H), 7.11-7.04 (m, 1H), 5.26-4.65 (m, 1H), 4.64-4.28 (m, 1H), 4.01-3.77 (m, 4H), 3.76-3.50 (m, 3H), 3.38-3.05 (m, 2H), 3.03-2.83 (m, 2H), 2.33 (s, 3H), 2.29 (s, 1H), 2.18 (s, 2H).

[0529] Step 10: The 1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)ethan-1-one (Z119, 21 mg) was chirally resolved (mobile phase: HEX:ETOH=70:30); separation column: AB 250 mm*4.6 mm*5 um); flow rate: 1.0 ml/min; T: 30.0 C.) to give two isomeric compounds. A structure of one isomeric compound was arbitrarily assigned as (R)-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one: (Z119-1, retention time: 12.533 min, 9 mg, purity: 99%, devalue: 100%, yield: 42.9%). ES-API: [M+H].sup.+=391.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.35 (s, 1H), 8.49-8.43 (m, 1H), 8.14-8.07 (m, 1H), 7.82-7.75 (m, 1H), 7.50-7.45 (m, 1H), 7.27 (s, 1H), 4.92-4.55 (m, 2H), 4.09-3.94 (m, 1H), 3.84-3.49 (m, 5H), 3.24 (t, J=10.4 Hz, 1H), 3.05-2.90 (m, 3H), 2.87 (t, J=6.0 Hz, 1H), 2.32 (s, 3H), 2.21-2.07 (m, 3H).

[0530] A structure of the other isomeric compound was arbitrarily assigned as (S)-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Z119-2, retention time: 13.819 min, 10 mg, purity: 99%, de value: 100%, yield: 47.6%). ES-API: [M+H].sup.+=391.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.36 (s, 1H), 8.51-8.45 (m, 1H), 8.15-8.08 (m, 1H), 7.84-7.76 (m, 1H), 7.50 (s, 1H), 7.31-7.24 (m, 1H), 4.92-4.57 (m, 2H), 4.15-4.03 (m, 1H), 3.87-3.54 (m, 5H), 3.45-3.35 (m, 1H), 3.11-2.82 (m, 4H), 2.37-2.29 (m, 3H), 2.22-2.08 (m, 3H).

Example 48. Synthesis of Compound Z132

##STR00309##

[0531] Step 1: 8-Bromo-6-chloroisoquinoline (1.8 g, 7.469 mmol), potassium vinyltrifluoroborate (3 g, 22.41 mmol) and triethylamine (2.3 g, 22.41 mmol) were dissolved in ethanol (15 mL). 1,1-Bis(diphenylphosphino)ferrocene dichloropalladium (546 mg, 0.747 mmol) was then added, and the system was heated to 80 C. and stirred for 2 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was filtered, spun to dryness, extracted with ethyl acetate/water, spun to dryness, and purified by column chromatography (0-20% ethyl acetate/petroleum ether, petroleum ether/ethyl acetate=5/1, Rf=0.4) to give 6-chloro-8-vinylisoquinoline (850 mg, yield: 61%) ES-API: [M+H].sup.+=190.00.

[0532] Step 2: The 6-chloro-8-vinylisoquinoline (850 mg, 4.45 mmol) was dissolved in tetrahydrofuran (10 mL). 2,6-Lutidine (476 mg, 4.45 mmol) was added and stirred at room temperature. Sodium periodate (7.6 g, 35.6 mmol) and potassium osmate dihydrate (492 mg, 1.335 mmol) were added to water (5 mL). The aqueous solution was added to a reaction flask under an ice bath condition and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction was quenched by the addition of aqueous sodium thiosulfate solution. The obtained mixture was filtered, extracted with ethyl acetate, spun to dryness, and purified by column chromatography (0-30% ethyl acetate/petroleum ether, petroleum ether/ethyl acetate=2/1, Rf=0.5) to give 6-chloroisoquinoline-8-carbaldehyde (320 mg, yield: 37%). ES-API: [M+H].sup.+=192.0.

[0533] Step 3: The 6-chloroisoquinoline-8-carbaldehyde (260 mg, 1.36 mmol) was added to dichloromethane (5 mL). Dimethylamine hydrochloride (443 mg, 5.44 mmol) was added and stirred at room temperature for 2 h. Sodium borohydride acetate (865 mg, 4.08 mmol) was added. Upon completion of the reaction, a saturated sodium chloride solution was added. The obtained mixture was extracted with dichloromethane, spun to dryness, and purified by column chromatography (0-10% methanol/dichloromethane, dichloromethane/methanol=20/1, Rf=0.5) to give 1-(6-chloroisoquinolin-8-yl)-N,N-dimethylmethanamine (85 mg, yield: 28%) ES-API: [M+H].sup.+=221.1.

[0534] Step 4: Sodium borohydride (33 mg, 0.864 mmol) was added to a solution of the 1-(6-chloroisoquinolin-8-yl)-N,N-dimethylmethanamine (95 mg, 0.432 mmol) in acetic acid (3 mL) and stirred at 0 C. for 0.5 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of aqueous sodium bicarbonate solution. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-10%, methanol in dichloromethane, dichloromethane/methanol=10/1, Rf=0.4) to give 1-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)-N,N-dimethylmethanamine (90 mg, yield: 95%). ES-API: [M+H].sup.+=225.1.

[0535] Step 5: Triethylamine (203 mg, 2.01 mmol) and acetyl chloride (63 mg, 0.804 mmol) were added to a solution of the 1-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)-N,N-dimethylmethanamine (90 mg, 0.402 mmol) in tetrahydrofuran (1 mL) and stirred at 0 C. for 15 min. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give 1-(6-chloro-8-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (80 mg, yield: 75%). ES-API: [M+H].sup.+=267.1.

[0536] Step 6: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (116 mg, 0.45 mmol), S-phos Pd G2 (22 mg, 0.03 mmol) and potassium carbonate (124 mg, 0.9 mmol) were added to the 1-(6-chloro-8-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (80 mg, 0.3 mmol), and the system was heated to 110 C. and stirred in the presence of protective nitrogen. The reaction was monitored by LC-MS for completion. The reaction mixture was extracted with ethyl acetate/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 ml/min, gradient: within 50 min, B/A=20%-90%, wavelength: 214 nm, column temperature: room temperature) to give 1-(8-((dimethylamino)methyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (Z132, 24.4 mg, yield: 23%) as a white powder. ES-API: [M+H].sup.+=363.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.33 (s, 1H), 8.46 (s, 1H), 8.12 (s, 1H), 7.47 (s, 2H), 7.23 (s, 1H), 4.73 (d, J=21.6 Hz, 2H), 3.64 (t, J=5.2 Hz, 2H), 3.31 (s, 2H), 2.96-2.91 (m, 1H), 2.85-2.80 (m, 1H), 2.35-2.05 (m, 12H).

Example 49. Synthesis of Compound Z121

##STR00310##

[0537] Step 1: Sodium borohydride (360 mg, 9.6 mmol) was added to a solution of tert-butyl (S)-2-(6-chloroisoquinolin-8-yl)pyrrolidine-1-carboxylate (800 mg, 2.4 mmol) in acetic acid (30 mL) at 0 C. and stirred for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of sodium bicarbonate solution. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (900 mg, crude product). ES-API: [M+H].sup.+=337.2.

[0538] Step 2: In the presence of protective nitrogen, 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (921 mg, 3.57 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (173 mg, 0.24 mmol) and potassium carbonate (985 mg, 7.14 mmol) were added to a solution of the (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (800 mg, 2.38 mmol) in 1,4-dioxane (20 mL) and water (4 mL), and the mixture was stirred at 110 C. for 2 h. The obtained mixture was extracted with ethyl acetate/water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.4) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (495 mg, yield: 48%) as a yellow powder. ES-API: [M+H].sup.+=433.3.

[0539] Step 3: Triethylamine (21 mg, 0.21 mol) and 2-methoxyacetyl chloride (17 mg, 0.16 mmol) were added to a solution of the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.12 mmol) in tetrahydrofuran (1 mL) at 0 C. and stirred for 15 min. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (S)-2-(2-2-methoxyacetyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, yield: 95%). ES-API: [M+H].sup.+=501.3.

[0540] Step 4: Hydrochloric acid-methanol solution (4M, 1 mL) was added to the tert-butyl (S)-2-(2-2-methoxyacetyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.11 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution, extracted with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methoxyethyl ketone (Z121, 18.2 mg, yield: 38%) as a white powder. ES-API: [M+H].sup.+=405.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.60 (s, 1H), 8.52 (s, 1H), 7.95 (s, 1H), 7.93-7.82 (m, 1H), 7.23-7.14 (m, 1H), 7.13-7.04 (m, 1H), 4.94 (d, J=18.2 Hz, 1H), 4.81-4.65 (m, 1H), 4.62-4.46 (m, 1H), 4.34 (s, 1H), 4.18 (s, 1H), 3.87-3.58 (m, 2H), 3.45 (s, 3H), 3.30-3.12 (m, 1H), 3.06-2.75 (m, 3H), 2.44-2.25 (m, 4H), 2.16-1.76 (m, 4H).

Example 50. Synthesis of Compound Z122

##STR00311##

[0541] Step 1: Triethylamine (21 mg, 0.21 mmol) and cyclopropylcarbonyl chloride (17 mg, 0.14 mmol) to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.12 mmol) in dichloromethane (1 mL) were added under an ice bath condition and stirred for 15 min. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-5% methanol/dichloromethane, dichloromethane/methanol=20/1, Rf=0.6) to give tert-butyl (S)-2-(2-cyclopropylcarbamoyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, yield: 95%). ES-API: [M+H].sup.+=501.3.

[0542] Step 2: 4M Hydrochloric acid/methanol solution (1 mL) was added to the tert-butyl (S)-2-(2-cyclopropylcarbamoyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.11 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, extracted with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)cyclopropyl methyl ketone (Z122, 13.1 mg, yield: 25%) as a white powder. ES-API: [M+H].sup.+=401.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.42 (s, 1H), 8.52 (s, 1H), 8.08-7.88 (m, 1H), 7.83 (s, 1H), 7.25-7.17 (m, 1H), 7.16-6.98 (m, 1H), 4.93 (d, J=25.9 Hz, 1H), 4.80-4.37 (m, 2H), 4.02-3.83 (m, 2H), 3.81-3.66 (m, 2H), 3.23-2.78 (m, 2H), 2.32 (s, 3H), 2.15-1.72 (m, 4H), 1.29-1.18 (m, 1H), 1.11-0.98 (m, 2H), 0.91-0.78 (m, 2H).

Example 51. Synthesis of Compound Z126

##STR00312##

[0543] Step 1: Triethylamine (21.01 mg, 208.07 mol) and tert-butylcarbonyl chloride (17 mg, 144.27 mol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 120.12 mol) in dichloromethane (1 mL) and stirred at 0 C. for 15 min. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-5%, methanol in dichloromethane, dichloromethane/methanol=20/1, Rf=0.6) to give tert-butyl (S)-2-(2-tert-butylcarbamoyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, yield: 95%). ES-API: [M+H].sup.+=517.3.

[0544] Step 2: Hydrochloric acid-methanol solution was added to the tert-butyl (S)-2-(2-tert-butylcarbamoyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 111.94 mol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution, extracted with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)tert-butyl methyl ketone (Z126, 16.4 mg, yield: 33%) as a white powder. ES-API: [M+H].sup.+=417.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.55 (s, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 7.11 (s, 1H), 7.02 (s, 1H), 4.83 (s, 2H), 4.68-4.57 (m, 1H), 3.97-3.87 (m, 1H), 3.66-3.52 (m, 2H), 3.37-3.26 (m, 1H), 2.97-2.83 (m, 1H), 2.82-2.69 (m, 1H), 2.43-2.30 (m, 1H), 2.29 (s, 3H), 2.22-2.10 (m, 1H), 2.02-1.90 (m, 2H), 1.31 (s, 9H).

Example 52. Synthesis of Compound Z125

##STR00313##

[0545] Step 1: Triethylamine (21.01 mg, 208.07 mol) and cyclohexylcarbonyl chloride (21 mg, 144.27 mol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 120.12 mol) in dichloromethane (1 mL) and stirred at 0 C. for 15 min. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-5%, methanol in dichloromethane, dichloromethane/methanol=20/1, Rf=0.6) to give tert-butyl (S)-2-(2-cyclohexylformyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, yield: 95%). ES-API: [M+H].sup.+=543.4.

[0546] Step 2: Hydrochloric acid-methanol solution was added to the tert-butyl (S)-2-(2-cyclohexylformyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 111.94 mol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, extracted with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (column information: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)cyclohexyl methyl ketone (Z125, 15.3 mg, yield: 31%) as a white powder. ES-API: [M+H].sup.+=443.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.86 (s, 1H), 8.53 (s, 1H), 8.01-7.78 (m, 2H), 7.24-6.89 (m, 2H), 5.14-4.70 (m, 2H), 4.72-4.43 (m, 1H), 3.80-3.47 (m, 3H), 3.32-3.14 (m, 1H), 2.90-2.50 (m, 3H), 2.29 (s, 3H), 2.18-2.00 (m, 2H), 1.96-1.65 (m, 6H), 1.64-1.46 (m, 2H), 1.45-1.14 (m, 4H).

Example 53. Synthesis of Compound Z123

##STR00314##

[0547] Step 1: Triethylamine (21 mg, 0.21 mmol) and benzoyl chloride (20 mg, 0.14 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.12 mmol) in dichloromethane (1 mL) under an ice bath condition and stirred for 15 min. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-5% methanol/dichloromethane, dichloromethane/methanol=20/1, Rf=0.6) to give tert-butyl (S)-2-(2-benzoyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, yield: 95%). ES-API: [M+H].sup.+=537.30.

[0548] Step 2: 4M Hydrochloric acid/methanol solution (1 mL) was added to the tert-butyl (S)-2-(2-benzoyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.11 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, extracted with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give a product (S)-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)benzyl ketone (Z123, 11.3 mg, yield: 22%) as a white powder. ES-API: [M+H].sup.+=437.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.59 (s, 1H), 8.12-7.73 (m, 2H), 7.50-7.38 (m, 5H), 7.19-6.94 (m, 2H), 5.10-4.64 (m, 2H), 3.80-3.14 (m, 5H), 3.05-2.65 (m, 2H), 2.28 (s, 3H), 2.20-1.73 (m, 4H).

Example 54. Synthesis of Compound Z124

##STR00315##

[0549] Step 1: In the presence of protective nitrogen, 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (230 mg, 0.891 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (53 mg, 0.0742 mmol) and potassium carbonate (307 mg, 2.23 mmol) were added to tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (250 mg, 0.742 mmol), and the mixture was stirred at 110 C. for 3 h. The obtained mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-10% methanol (1% ammonia water):dichloromethane) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (220 mg, yield: 68%) as a yellow powder. ES-API: [M+H].sup.+=433.3.

[0550] Step 2: Picolinic acid (17 mg, 0.138 mmol), triethylamine (35 mg, 0.347 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (65 mg, 0.173 mmol) were added to a solution of the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.115 mmol) in N,N-dimethylformamide (1 ml) and stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-picolyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (55 mg, 89%). ES-API: [M+H].sup.+=538.3.

[0551] Step 3: 4M Hydrochloric acid/methanol solution (1 mL) was added to the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-picolyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (55 mg, 0.102 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin layer chromatography (methanol:dichloromethane=10:1) to give (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyridin-4-yl)methanone (Z124, 10.2 mg, yield: 23%) as a white powder. ES-API: [M+H].sup.+=438.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.74-8.59 (m, 2H), 8.43 (d, J=8.8 Hz, 1H), 7.82 (d, J=11.6 Hz, 1H), 7.78-7.53 (m, 1H), 7.34-7.20 (m, 2H), 7.20-7.05 (m, 1H), 6.96 (s, 1H), 5.09-4.53 (m, 2H), 4.52-3.86 (m, 1H), 3.51-2.38 (m, 6H), 2.21 (s, 3H), 2.15-1.48 (m, 4H).

Example 55. Synthesis of Compound Z127

##STR00316## ##STR00317##

[0552] Step 1: 2-Bromo-4-chlorobenzaldehyde (50 g, 0.22 mol) was dissolved in toluene, 2,2-Dimethoxyethanamine (34 g, 0.33 mmol) and acetic acid (4 mL) were added, and the system was heated to 110 C. and stirred for 3 h in the presence of protective nitrogen. The obtained mixture was spun to dryness. Methanol (200 mL) was added, and the system was cooled to 0 C. Sodium borohydride (15 g, 0.4 mol) was slowly added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the solution was poured into ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and spun to dryness to give N-(2-bromo-4-chlorobenzyl)-2,2-dimethoxyethanamine (61 g, crude product). ES-API: [M+H].sup.+=310.0.

[0553] Step 2: The N-(2-bromo-4-chlorobenzyl)-2,2-dimethoxyethanamine (61 g, 0.23 mmol) was added to dichloromethane (150 mL). Triethylamine (34.8 g, 0.344 mol) was added. p-Toluenesulfonyl chloride (65.6 g, 0.344 mol) was added under an ice-water bath condition, and the system reacted at room temperature overnight. Upon completion of the reaction, water was added. The obtained mixture was extracted with dichloromethane and spun to dryness. The crude product was beaten with petroleum ether to give N-(2-bromo-4-chlorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (35 g, yield: 38%). ES-API: [M+Na].sup.+=486.0.

[0554] Step 3: The N-(2-bromo-4-chlorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (35 g, 76 mmol) was added to anhydrous dichloromethane (150 mL). Aluminum trichloride (80 g, 0.6 mol) was added under an ice-water bath condition and stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was added to ice water. Sodium hydroxide solution was added until a clear solution was obtained. The obtained mixture was extracted with dichloromethane, spun to dryness, and purified by column chromatography (0-20% ethyl acetate/petroleum ether, petroleum ether/ethyl acetate=5/1, Rf=0.5 mobile phase) to give 8-bromo-6-chloroisoquinoline (3.5 g, yield: 19%). ES-API: [M+H].sup.+=243.9.

[0555] Step 4: The 8-bromo-6-chloroisoquinoline (3.5 g, 14.4 mmol), potassium vinyltrifluoroborate (5.912 g, 43.2 mmol) and triethylamine (4.37 g, 43.2 mmol) were dissolved in ethanol (35 mL). 1,1-Bis(diphenylphosphino)ferrocene dichloropalladium (1.05 g, 1.44 mmol) was then added, and the system was heated to 80 C. and stirred for 2 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was filtered, spun to dryness, extracted with ethyl acetate/water, spun to dryness, and purified by column chromatography (0-20% ethyl acetate/petroleum ether, petroleum ether/ethyl acetate=5/1, Rf=0.4 mobile phase) to give 6-chloro-8-vinylisoquinoline (1.6 g, yield: 57%). ES-API: [M+H].sup.+=190.0.

[0556] Step 5: The 6-chloro-8-vinylisoquinoline (1.6 g, 8.46 mmol) was dissolved in tetrahydrofuran (32 mL). 2,6-Lutidine (0.9 g, 8.46 mmol) was added and stirred at room temperature. Sodium periodate (14.47 g, 67.68 mmol) and potassium osmate dihydrate (0.93 g, 2.538 mmol) were added to water (16 mL). The aqueous solution was added to a reaction flask under an ice bath condition and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction was quenched by the addition of aqueous sodium thiosulfate solution. The reaction mixture was filtered, extracted with ethyl acetate, spun to dryness, and purified by column chromatography (0-30% ethyl acetate/petroleum ether, petroleum ether/ethyl acetate=2/1, Rf=0.5 mobile phase) to give 6-chloroisoquinoline-8-carbaldehyde (0.8 g, yield: 50%). ES-API: [M+H].sup.+=192.1.

[0557] Step 6: The 6-chloroisoquinoline-8-carbaldehyde (0.8 g, 4.18 mmol) and (S)-2-methylpropane-2-sulfinamide (1.0 g, 8.37 mmol) were added to dichloromethane (20 mL) followed by tetraethyl titanate (2.74 g, 16.72 mmol), and the system reacted at room temperature overnight. Upon completion of the reaction, saturated sodium chloride solution was added followed by dichloromethane. The obtained mixture was extracted and spun to dryness to give (S,E)-N-((6-chloroisoquinolin-8-yl)methylene)-2-methylpropane-2-sulfinamide (1.15 g, yield: 93%). ES-API: [M+H].sup.+=295.1.

[0558] Step 7: The (S,E)-N-((6-chloroisoquinolin-8-yl)methylene)-2-methylpropane-2-sulfinamide (1.15 g, 3.92 mmol) was added to tetrahydrofuran (20 mL), and the system was cooled to 78 C. in a dry ice bath. (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide (3.4 g, 3.92 mmol) was added and stirred for 10 min. The dry ice bath was removed, and a saturated ammonium chloride solution was added. The obtained mixture was extracted with ethyl acetate, spun to dryness, and purified by column chromatography (0-30% ethyl acetate/petroleum ether, petroleum ether/ethyl acetate=2/1, Rf=0.5) to give (S)N((S)-1-(6-chloroisoquinolin-8-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (2.0 g, crude product). ES-API: [M+H].sup.+=411.1.

[0559] Step 8: The (S)N((S)-1-(6-chloroisoquinolin-8-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (2.0 g, 4.87 mmol) was added to trifluoroacetic acid (50 mL) and water (2.5 mL) and stirred at room temperature for 30 min. Triethylsilane (5.66 g, 48.7 mmol) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness. Tetrahydrofuran (40 mL), triethylamine (4.9 g, 48.7 mmol) and di-tert-butyl dicarbonate (3.18 g, 14.61 mmol) were added and stirred at room temperature for 30 min. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate, spun to dryness, and purified by column chromatography (0-30% ethyl acetate/petroleum ether, petroleum ether/ethyl acetate=4/1, Rf=0.3 mobile phase) to give tert-butyl (S)-2-(6-chloroisoquinolin-8-yl)pyrrolidine-1-carboxylate (0.9 g, yield: 56%). ES-API: [M+H].sup.+=333.1.

[0560] Step 9: Sodium borohydride (18 mg, 0.48 mmol) was added to a solution of the tert-butyl (S)-2-(6-chloroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, 0.12 mmol) in acetic acid (1.5 mL) and stirred at 0 C. for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of sodium bicarbonate solution. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-10%, methanol in dichloromethane, dichloromethane/methanol=4/1, Rf=0.6) to give tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (18 mg, yield: 45%). ES-API: [M+H].sup.+=337.2.

[0561] Step 10: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (21 mg, 0.081 mmol), S-phosPdG2 (4 mg, 0.0054 mmol) and potassium carbonate (22 mg, 0.162 mmol) were added to the tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (18 mg, 0.054 mmol), and the mixture was heated to 110 C. and stirred in the presence of protective nitrogen. The reaction was monitored by LC-MS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase 0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.4) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (8 mg, yield: 35%) as a yellow powder. ES-API: [M+H].sup.+=433.3.

[0562] Step 11: Triethylamine (5.8 mg, 0.057 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (3.4 mg, 0.023 mmol) were added to a solution of the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin 5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (8 mg, 0.019 mmol) in tetrahydrofuran (1 mL) and stirred at 0 C. for 15 min. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (S)-2-(2-tetrahydro-2H-pyran-4-formyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (9 mg, yield: 87%). ES-API: [M+H].sup.+=545.4.

[0563] Step 12: Hydrochloric acid-methanol solution was added to the tert-butyl (S)-2-(2-tetrahydro-2H-pyran-4-formyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (9 mg, 0.016 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methyl ketone (Z127, 1.5 mg, yield: 21%) as a white powder. ES-API: [M+H].sup.+=445.2.

Example 56. Synthesis of Compound Z128

##STR00318##

[0564] Step 1: 2-Fluoropyridine (10.77 mg, 0.11 mmol) and cesium carbonate (90.44 mg, 277.42 mol) was added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, 92.47 mol) in N,N-dimethylacetamide (0.4 mL), and the system reacted under microwave at 160 C. for 2 h. The reaction was monitored by LC-MS for completion. The reaction mixture was post-treated with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-5% methanol in dichloromethane, dichloromethane/methanol=10/1, Rf=0.7) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyridine-1-carboxylate (28 mg, yield: 59.41%). ES-API: [M+H].sup.+=510.3.

[0565] Step 2: Hydrochloric acid-methanol solution was added to the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyridine-1-carboxylate (30 mg, 72.65 mol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-2-yl)-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z128, 3.5 mg, yield: 12.44%) as a white powder. ES-API: [M+H].sup.+=410.2.

Example 57. Synthesis of Compound Z130

##STR00319##

[0566] Step 1: Phenylboronic acid (34.75 mg, 284.99 mol), pyridine (37.57 mg, 474.98 mol, 38.26 L) and copper acetate (64.70 mg, 356.24 mol) were added to a solution of the tert-butyl 2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (80 mg, 237.49 mol) in dichloromethane (1 mL), and the mixture was stirred at 25 C. for 16 h. The reaction was monitored by LC-MS for completion. The reaction mixture was post-treated with dichloromethane and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-5%, methanol in dichloromethane) to give tert-butyl (S)-2-(6-chloro-2-phenyl-3,4-dihydro-1H-isoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, yield: 30.59%). ES-API: [M+H].sup.+=413.2.

[0567] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (28.13 mg, 108.97 mol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (5.24 mg, 7.26 mol) and potassium carbonate (30.12 mg, 217.94 mol) were added to a solution of the tert-butyl (S)-2-(6-chloro-2-phenyl-3,4-dihydro-1H-isoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 72.65 mol) in dioxane (0.5 mL), and the mixture was stirred at 110 C. for 2 h. The reaction was monitored by LC-MS for completion. The reaction mixture was treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-10%=methanol/dichloromethane) to give tert-butyl (S)-2-(6-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl-2-phenyl-3,4-dihydro-1H-isoquinolin-8-yl)pyrrolidine-1-carboxylate (20 mg, yield: 54.02%). ES-API: [M+H].sup.+=442.4.

[0568] Step 3: Hydrochloric acid-methanol solution was added to the tert-butyl (S)-2-(6-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl-2-phenyl-3,4-dihydro-1H-isoquinolin-8-yl)pyrrolidine-1-carboxylate (20 mg, 39.24 mol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (column information: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-phenyl-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z130, 2.4 mg, yield: 15%) as a white powder. ES-API: [M+H].sup.+=442.4.

Example 58. Synthesis of Compound Z210

##STR00320##

[0569] Step 1: Triethylamine (21.01 mg, 208.07 mol) and nicotinoyl chloride (11.78 mg, 83.23 mol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 69.36 mol) in dichloromethane (1 ml) and stirred at 0 C. for 15 min. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (S)-2-(2-nicotinoyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (35 mg, yield: 93.86%). ES-API: [M+H].sup.+=538.3.

[0570] Step 2: Hydrochloric acid-methanol solution was added to the tert-butyl (S)-2-(2-nicotinoyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (35 mg, 65.10 mol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (column information: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyridin-3-yl)methanone (Z210, 1.2 mg, yield: 4.2%) as a white powder. ES-API: [M+H].sup.+=438.2.

Example 59. Synthesis of Compound Z211

##STR00321##

[0571] Step 1: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (230 mg, 0.891 mmol), S-phosPdG2 (53 mg, 0.0742 mmol) and potassium carbonate (307 mg, 2.23 mmol) were added to tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (250 mg, 0.742 mmol), and the mixture was heated to 110 C. and stirred in the presence of protective nitrogen. The reaction was monitored by LC-MS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.4 mobile phase) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (220 mg, yield: 68%) as a yellow powder. ES-API: [M+H].sup.+=433.3.

[0572] Step 2: Picolinic acid (10.2 mg, 0.083 mmol), triethylamine (21 mg, 0.208 mmol) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (39.2 mg, 0.104 mmol) were added to a solution of the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in N,N-dimethylformamide (1 mL) was stirred at 25 C. for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-picolyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (24 mg, yield: 64%). ES-API: [M+H].sup.+=538.3.

[0573] Step 3: Hydrochloric acid-methanol solution was added to the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-picolyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (24 mg, 0.045 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone (Z211, 5.9 mg, yield: 30%) as a white powder. ES-API: [M+H].sup.+=438.2.

Example 60. Synthesis of Compound Z212

##STR00322##

[0574] Step 1: (6-Methylpyridin-3-yl)boronic acid (305 mg, 2.23 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II) (136 mg, 0.186 mmol) and potassium carbonate (513 mg, 3.72 mmol) were added to a solution of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (600 mg, 1.86 mmol) in dioxane/water (5 mL/1 mL) and stirred at 80 C. overnight. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-10%, methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.5) to give 5-bromo-3-(6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine (24 mg, yield: 4.5%). ES-API: [M+H].sup.+=288.0.

[0575] Step 2: tert-butyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (37 mg, 0.087 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6 mg, 0.0087 mmol) and potassium carbonate (24 mg, 0.173 mmol) were added to a solution of the 5-bromo-3-(6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine (35 mg, 0.087 mmol) in dioxane/water (1 mL/0.2 mL), and the system reacted under microwave at 100 C. for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-10%, methanol/dichloromethane) to give tert-butyl (S)-2-(6-(3-(6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (8 mg, yield: 18%). ES-API: [M+H].sup.+=511.3.

[0576] Step 3: Trifluoroacetic acid (0.2 mL) in dichloromethane (0.4 mL) was added to the tert-butyl (S)-2-(6-(3-(6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (8 mg, 0.016 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 mL/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-3-(6-methylpyridin-3-yl)-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridine (Z212, 0.7 mg, yield: 11%). ES-API: [M+H].sup.+=411.2.

Example 61. Synthesis of Compound Z213

##STR00323##

[0577] Step 1: 2-Methylisonicotinic acid (9.5 mg, 0.069 mmol), triethylamine (21 mg, 0.208 mmol) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (39.2 mg, 0.104 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in N,N-dimethylformamide (1 mL) and stirred at 25 C. for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methylisonicotinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, yield: 78%). ES-API: [M+H].sup.+=552.4.

[0578] Step 2: Hydrochloric acid/methanol solution was added to the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methylisonicotinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.054 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-methylpyridin-4-yl)methanone (Z213, 3.9 mg, yield: 15%) as a white powder. ES-API: [M+H].sup.+=452.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.63-8.50 (m, 2H), 7.99-7.79 (m, 2H), 7.20-6.96 (m, 4H), 4.97 (s, 1H), 4.82 (s, 1H), 4.63-4.29 (m, 1H), 3.85-3.66 (m, 1H), 3.58-3.44 (m, 2H), 3.40-3.25 (m, 1H), 3.06-2.70 (m, 1H), 2.61-2.57 (m, 3H), 2.50-2.33 (m, 1H), 2.28 (s, 3H), 2.24-1.90 (m, 4H).

Example 62. Synthesis of Compound Z214

##STR00324##

[0579] Step 1: 2,6-Dimethylisonicotinic acid (10.5 mg, 0.069 mmol), triethylamine (21 mg, 0.208 mmol) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (39.2 mg, 0.104 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in N,N-dimethylformamide (1 mL) and stirred at 25 C. for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane, dichloromethane/methanol/10/1, Rf=0.6) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,6-dimethylisonicotinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (31 mg, yield: 79%). ES-API: [M+H].sup.+=566.4.

[0580] Step 2: Hydrochloric acid/methanol solution was added to the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,6-dimethylisonicotinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (31 mg, 0.055 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (column information: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(2,6-dimethylpyridin-4-yl)methanone (Z214, 5.61 mg, yield: 22%) as a white powder. ES-API: [M+H].sup.+=466.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.52 (d, J=14.2 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.18-7.08 (m, 1H), 7.08-6.98 (m, 2H), 6.93 (s, 1H), 5.04-4.88 (m, 1H), 4.81-4.56 (m, 1H), 4.38-4.12 (m, 1H), 3.68-3.49 (m, 1H), 3.48-3.28 (m, 2H), 3.13-2.63 (m, 3H), 2.55 (s, 6H), 2.31 (s, 3H), 2.24-2.12 (m, 1H), 2.09-1.95 (m, 3H).

Example 63. Synthesis of Compound Z215

##STR00325##

[0581] Step 1: 2-Methoxyisonicotinic acid (10.6 mg, 0.069 mmol), triethylamine (21 mg, 0.208 mmol) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (39.2 mg, 0.104 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in N,N-dimethylformamide (1 mL) and stirred at 25 C. for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methoxyisonicotinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (31 mg, yield: 79%). ES-API: [M+H].sup.+=568.4.

[0582] Step 2: Hydrochloric acid-methanol solution was added to the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methoxyisonicotinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (31 mg, 0.055 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-methoxypyridin-4-yl)methanone (Z215, 2.6 mg, yield: 10%) as a white powder. ES-API: [M+H].sup.+=468.3.

Example 64. Synthesis of Compound Z216

##STR00326##

[0583] Step 1: 2-Hydroxy-2-methylpropanoic acid (7.2 mg, 0.069 mmol), triethylamine (21 mg, 0.208 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (39.2 mg, 0.104 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in N,N-dimethylformamide (1 mL) and stirred at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give tert-butyl (S)-2-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-methyl-H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, yield: 83%). ES-API: [M+H].sup.+=519.4.

[0584] Step 2: 4M Hydrochloric acid/methanol solution (1 mL) was added to the tert-butyl (S)-2-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.058 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-2-hydroxy-2-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z216, 3.1 mg, yield: 14%) as a white powder. ES-API: [M+H].sup.+=419.3.

Example 65. Synthesis of Compound Z34-1

##STR00327##

[0585] Step 1: Methyl chloroformate (7.86 mg, 0.069 mmol) and triethylamine (21 mg, 0.208 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in tetrahydrofuran (1 mL) and stirred at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give (S)-methyl 8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (30 mg, yield: 88%). ES-API: [M+H].sup.+=491.3.

[0586] Step 2: 4M Hydrochloric acid/methanol solution (1 mL) was added to the (S)-methyl 8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (30 mg, 0.058 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-methyl (6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)carboxylate (Z34-1, 4.9 mg, yield: 22%) as a white powder. ES-API: [M+H].sup.+=391.2.

Example 66. Synthesis of Compound Z54-1

##STR00328## ##STR00329##

[0587] Step 1: 5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (1 g, 3.11 mmol) was dissolved in tetrahydrofuran (10 mL). Sodium hydride (0.25 g, 6.22 mmol) was added and stirred at room temperature for 0.5 h. p-Toluenesulfonyl chloride (0.62 g, 3.26 mmol) was added in batches, and the system reacted at room temperature for 2 h. The reaction was quenched by the addition of water, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and spun to dryness to give 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.4 g, yield: 94.6%). ES-API: [M+H].sup.+=476.9.

[0588] Step 2: The 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.7 g, 1.47 mmol) was dissolved in dioxane/water (7.5/1.5 mL). N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine carboxamide (0.34 g, 1.77 mmol), potassium carbonate (0.41 g, 2.94 mmol) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II) (0.107 g, 0.147 mmol) were added, and the system reacted at 80 C. for 3 h in the presence of protective nitrogen. The reaction mixture was cooled, and water was added. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, purified by column chromatography (ethyl acetate/petroleum ether=1/5, Rf=0.6) to give 6-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylnicotinamide (0.53 g, yield: 72%). ES-API: [M+H].sup.+=499.1.

[0589] Step 3: The 6-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylnicotinamide (0.53 g, 1.07 mmol) was dissolved in dioxane/water (7.5/1.5 mL). (S)-(8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)isochroman-6-yl)boronic acid (0.34 g, 1.07 mmol), potassium carbonate (0.41 g, 2.94 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (0.107 g, 0.147 mmol) were added, and the system reacted under microwave at 100 C. for 3 h in the presence of protective nitrogen. The reaction mixture was cooled, and water was added. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (ethyl acetate/petroleum ether=1/1, Rf=0.5) to give tert-butyl (S)-2-(6-(3-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (366 mg, yield: 50%). ES-API: [M+H].sup.+=722.40.

[0590] Step 4: The tert-butyl (S)-2-(6-(3-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (366 mg, 0.5 mmol) was dissolved in methanol/water (5/0.5 mL). Sodium hydroxide (0.242 g, 6.1 mmol) was added, and the system reacted at 65 C. for 1 h. The reaction mixture was concentrated. Water was added. The obtained mixture was separated with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (column information: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give tert-butyl (S)-2-(6-(3-(6-(dimethylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (183.6 mg, yield: 65%). ES-API: ES-API: [M+H].sup.+=568.40.

[0591] Step 5: The tert-butyl (S)-2-(6-(3-(6-(dimethylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (183.6 mg, 0.25 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2 mL) was added, and the system reacted at room temperature for 2 h. The reaction mixture was concentrated, and water was added. The obtained mixture was extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, purified by prep-HPLC (column information: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)N,N-dimethyl-5-(5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridine carboxamide (Z54-1, 16 mg, yield: 10.5%). ES-API: [M+H].sup.+=468.40. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.32 (s, 1H), 9.38 (s, 1H), 8.93 (s, 1H), 8.72 (s, 1H), 8.56 (s, 1H), 8.06 (dd, J=8.0, 1.6 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.53-7.28 (m, 1H), 7.16 (s, 1H), 4.92 (d, J=15.2 Hz, 1H), 4.70 (d, J=15.2 Hz, 1H), 4.50 (s, 1H), 3.83 (t, J=5.6 Hz, 2H), 3.71 (d, J=10.7 Hz, 1H), 3.16 (s, 3H), 3.12 (s, 3H), 2.89-2.76 (m, 1H), 2.73-2.61 (m, 1H), 2.45-2.28 (m, 2H), 2.25-2.06 (m, 2H). ES-API: [M+H].sup.+=468.40.

Example 67. Synthesis of Compound Z217

##STR00330##

[0592] Step 1: Ethyl isocyanate (5 mg, 0.069 mmol) and triethylamine (21 mg, 0.208 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in tetrahydrofuran (1 mL) and stirred at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (S)-2-(2-(ethylcarbamoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, yield: 86%). ES-API: [M+H].sup.+=504.3.

[0593] Step 2: 4M Hydrochloric acid/methanol solution (1 mL) was added to the tert-butyl (S)-2-(2-(ethylcarbamoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.059 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)N-ethyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Z217, 4.9 mg, yield: 20%) as a white powder. ES-API: [M+H].sup.+=404.2.

Example 68. Synthesis of Compound Z37-1

##STR00331##

[0594] Step 1: Sodium borohydride (360 mg, 9.6 mmol) was added to a solution of tert-butyl (S)-2-(6-chloroisoquinolin-8-yl)pyrrolidine-1-carboxylate (800 mg, 2.4 mmol) in acetic acid (30 mL) under an ice bath condition and stirred for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of sodium bicarbonate. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.4) to give tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (900 mg, crude product). ES-API: [M+H].sup.+=337.2.

[0595] Step 2: Triethylamine (90 mg, 0.89 mmol) and methanesulfonyl chloride (40 mg, 0.356 mmol) were added to a solution of the tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.297 mmol) in dichloromethane (1 mL) under an ice bath condition and stirred for 15 min. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (S)-2-(6-chloro-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, yield: 81%). ES-API: [M+Na].sup.+=437.2.

[0596] Step 3: In the presence of protective nitrogen, 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (74.65 mg, 0.289 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (17.34 mg, 0.024 mmol) and potassium carbonate (99.77 mg, 0.723 mmol) were added to the tert-butyl (S)-2-(6-chloro-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.24 mmol), and the mixture was stirred at 110 C. for 3 h. The reaction was monitored by LC-MS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (80 mg, yield: 65%) as a yellow powder. ES-API: [M+H-100].sup.+=411.3.

[0597] Step 4: 4M Hydrochloric acid/methanol solution (1 mL) was added to the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (80 mg, 0.157 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonyl)-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z37-1, 23.6 mg, yield: 37%) as a white powder. ES-API: [M+H].sup.+=411.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.46 (s, 1H), 7.99 (s, 1H), 7.71 (s, 1H), 7.27-7.25 (m, 1H), 7.09 (s, 1H), 4.64 (d, J=16.4 Hz, 1H), 4.51 (d, J=15.6 Hz, 1H), 4.28 (t, J=8.0 Hz, 1H), 3.64-3.55 (m, 1H), 3.54-3.44 (m, 1H), 3.33-3.23 (m, 1H), 3.14-3.01 (m, 3H), 2.89 (s, 3H), 2.34 (s, 3H), 2.33-2.16 (m, 1H), 2.05-1.94 (m, 1H), 1.94-1.67 (m, 2H).

Example 69. Synthesis of Compound Z218

##STR00332##

[0598] Step 1: 2-(Tetrahydro-2H-pyran-4-yl)acetic acid (8 mg, 0.055 mmol), triethylamine (21 mg, 0.208 mmol) and 1-propylphosphonic anhydride (44 mg, 0.14 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (20 mg, 0.046 mmol) in dichloromethane (0.6 mL) and stirred at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)acetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (20 mg, yield: 77%). ES-API: [M+H].sup.+=559.3.

[0599] Step 2: 4M Hydrochloric acid/methanol solution (1 mL) was added to the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)acetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.055 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone (Z218, 3.5 mg, yield: 14%) as a white powder. ES-API: [M+H].sup.+=459.2.

Example 70. Synthesis of Compound Z219

##STR00333##

[0600] Step 1: Tetrahydrofuran-3-carboxylic acid (8 mg, 0.069 mmol), triethylamine (21 mg, 0.208 mmol) and 1-propylphosphonic anhydride (66 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in dichloromethane (0.6 mL) and stirred at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give (2S)-tert-butyl 2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, yield: 81%). ES-API: [M+H].sup.+=531.3.

[0601] Step 2: 4M hydrochloric acid/methanol solution (1 mL) was added to the (2S)-tert-butyl 2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.056 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(tetrahydrofuran-3-yl)methanone (Z219, 9.1 mg, yield: 37%) as a white powder. ES-API: [M+H].sup.+=431.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.60-8.50 (m, 1H), 7.99-7.88 (m, 1H), 7.87-7.74 (m, 1H), 7.12-7.03 (m, 1H), 7.02-6.86 (m, 1H), 4.92-4.80 (m, 1H), 4.76-4.60 (m, 3H), 4.15-3.93 (m, 1H), 3.92-3.79 (m, 3H), 3.77-3.53 (m, 3H), 3.39-3.29 (m, 1H), 2.86-2.67 (m, 2H), 2.42-2.30 (m, 1H), 2.29-2.24 (m, 3H), 2.23-2.17 (m, 2H), 2.15-2.10 (m, 1H), 2.07-1.85 (m, 2H).

Example 71. Synthesis of Compound Z220

##STR00334##

[0602] Step 1: 2-Cyclopropoxyacetic acid (8 mg, 0.069 mmol), triethylamine (21 mg, 0.208 mmol) and 1-propylphosphonic anhydride (66 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in dichloromethane (0.6 mL) and stirred at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give tert-butyl (S)-2-(2-(2-cyclopropoxyacetyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (15 mg, yield: 41%). ES-API: [M+H].sup.+=539.3.

[0603] Step 2: 4M Hydrochloric acid/methanol solution (1 mL) was added to the tert-butyl (S)-2-(2-(2-cyclopropoxyacetyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (15 mg, 0.028 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-2-cyclopropyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (Z220, 2.8 mg, yield: 23%) as a white powder. ES-API: [M+H].sup.+=439.2.

Example 72. Synthesis of Compound Z221

##STR00335##

[0604] Step 1: Pyrimidine-4-carboxylic acid (10.33 mg, 0.083 mmol), triethylamine (21 mg, 0.208 mmol) and 1-propylphosphonic anhydride (66 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in dichloromethane (0.6 mL) and stirred at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, yield: 80%). ES-API: [M+H].sup.+=539.4.

[0605] Step 2: 4 M Hydrochloric acid/methanol solution (1 mL) was added to the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.056 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyrimidin-4-yl)methanone (Z221, 5.2 mg, yield: 21%) as a white powder. ES-API: [M+H].sup.+=439.3.

Example 73. Synthesis of Compound Z222

##STR00336##

[0606] Step 1: Pyrimidine-5-carboxylic acid (10.33 mg, 0.083 mmol), triethylamine (21 mg, 0.208 mmol) and 1-propylphosphonic anhydride (66 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in dichloromethane (0.6 mL) and stirred at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, yield: 80%). ES-API: [M+H].sup.+=539.4.

[0607] Step 2: 4 M Hydrochloric acid/methanol solution was added to the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.056 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyrimidin-5-yl)methanone (Z222, 4.7 mg, yield: 19%) as a white powder. ES-API: [M+H].sup.+=439.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.28 (s, 1H), 8.94-8.84 (m, 1H), 8.80 (s, 1H), 8.54 (s, 1H), 8.00-7.80 (m, 2H), 7.10-6.95 (m, 2H), 4.97 (d, J=8.4 Hz, 2H), 4.80-4.68 (m, 1H), 3.80-3.66 (m, 1H), 3.63-3.34 (m, 3H), 2.91-2.75 (m, 1H), 2.70-2.55 (m, 1H), 2.29 (s, 3H), 2.25-2.15 (m, 1H), 2.15-1.80 (m, 3H).

Example 74. Synthesis of Compound Z223

##STR00337##

[0608] Step 1: 1-Methyl-1H-pyrazole-3-carboxylic acid (10.5 mg, 0.083 mmol), triethylamine (21 mg, 0.208 mmol) and 1-propylphosphonic anhydride (66 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in dichloromethane (0.6 mL) and stirred at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give tert-butyl (S)-2-(2-(1-methyl-1H-pyrazole-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, yield: 80%). ES-API: [M+H].sup.+=541.3

[0609] Step 2: 4M Hydrochloric acid/methanol solution (1 mL) was added to the tert-butyl (S)-2-(2-(1-methyl-1H-pyrazole-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.055 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(1-methyl-1H-pyrazol-3-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z223, 5.7 mg, yield: 23%) as a white powder. ES-API: [M+H].sup.+=441.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.54 (s, 1H), 7.98-7.68 (m, 2H), 7.41-7.35 (m, 1H), 7.03-6.82 (m, 2H), 6.79-6.65 (m, 1H), 5.27-4.96 (m, 1H), 4.92-4.67 (m, 2H), 4.12-3.74 (m, 5H), 3.69-3.36 (m, 2H), 2.95-2.59 (m, 2H), 2.26 (s, 3H), 2.22-1.80 (m, 4H).

Example 75. Synthesis of Compound 7224

##STR00338##

[0610] Step 1: 1-Methyl-1H-pyrazole-4-carboxylic acid (10.5 mg, 0.083 mmol), triethylamine (21 mg, 0.208 mmol) and 1-propylphosphonic anhydride (66 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in dichloromethane (0.6 mL) and stirred at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-6% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give tert-butyl (S)-2-(2-(1-methyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, yield: 80%). ES-API: [M+H].sup.+=541.3.

[0611] Step 2: 4M Hydrochloric acid/methanol solution (1 mL) was added to the tert-butyl (S)-2-(2-(1-methyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.055 mmol) and stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(1-methyl-1H-pyrazol-4-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z224, 3.1 mg, yield: 13%) as a white powder. ES-API: [M+H].sup.+=441.2.

Example 76. Synthesis of Compound Z225

##STR00339## ##STR00340##

[0612] Step 1: 1-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethyl-methanamine (0.2 g, 0.79 mmol) was dissolved in tetrahydrofuran (1 mL), and the system was cooled in an ice bath. Iodomethane (279 mg, 1.97 mmol) was added dropwise, and the system reacted at room temperature overnight. The reaction mixture was spun to dryness to give (5-bromo-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl-trimethylammonium iodide (300 mg, crude product). ES-API: [M+1].sup.+=268.0.

[0613] Step 2: The (5-bromo-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl-trimethylammonium iodide (300 mg, 0.75 mmol) was dissolved in tetrahydrofuran (5 mL). Tetrabutylammonium fluoride (394 mg, 1.51 mmol) and trimethylsilyl cyanide (187 mg, 1.88 mmol) were added, and the system reacted at room temperature for 4 h. The reaction was quenched with water, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, spun to dryness, and purified by column chromatography (dichloromethane/methanol=10/1, Rf=0.5) to give 2-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (100 mg, yield: 56%). ES-API: [M+1].sup.+=236.0.

[0614] Step 3: The 2-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (80 mg, 0.34 mmol) was dissolved in dioxane (2 mL). Bis(pinacolato)diboron (129 mg, 0.51 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (25 mg, 0.034 mmol) and potassium acetate (99 mg, 1.02 mmol) were then added, and the system was heated to 100 C. overnight. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spun to dryness to give [3-(cyanomethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]boronic acid as a crude product which was directly used in the next step without purification. ES-API: [M+1].sup.+=202.1.

[0615] Step 4: Tert-butyl 2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (95 mg, 0.79 mmol) was dissolved in dichloromethane (3 mL). Triethylamine (86 mg, 1.97 mmol) and 2-methoxyacetyl chloride (31 mg, 0.285 mmol) were added, and the system reacted at room temperature for 2 h. The reaction was quenched with water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and spun to dryness to give tert-butyl 2-[6-chloro-2-(2-methoxyacetyl)-3,4-dihydro-1H-isoquinolin-8-yl]pyrrolidine-1-carboxylate (100 mg, crude product). ES-API: [M+1-100].sup.+=309.2.

[0616] Step 5: The [3-(cyanomethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]boronic acid (crude product, 0.32 mmol) was dissolved in dioxane/water (1.5 mL/0.3 mL)). The tert-butyl 2-[6-chloro-2-(2-methoxyacetyl)-3,4-dihydro-1H-isoquinolin-8-yl]pyrrolidine-1-carboxylate (105 mg, 0.26 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (23 mg, 0.032 mmol) and potassium carbonate (132 mg, 0.96 mmol) were then added. The system was heated to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness and purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1, Rf=0.7) to give tert-butyl 2-[6-[3-(cyanomethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(2-methoxyacetyl)-3,4-dihydro-1H-isoquinolin-8-yl]pyrrolidine-1-carboxylate (33 mg, yield: 19%). ES-API: [M+1-100].sup.+=430.3.

[0617] Step 6: The tert-butyl 2-[6-[3-(cyanomethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(2-methoxyacetyl)-3,4-dihydro-1H-isoquinolin-8-yl]pyrrolidine-1-carboxylate (50 mg, 0.094 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness, extracted with dichloromethane and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, spun to dryness, and purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1, Rf=0.4) to give (S)-2-(5-(2-(2-methoxyacetyl)-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (Z225, 5.1 mg, yield: 12.6%). ES-API: [M+1].sup.+=430.2.

Example 77. Synthesis of Compound Z286

##STR00341##

[0618] Step 1: 1-Isopropyl-1H-pyrazole-4-carboxylic acid (12.83 mg, 0.083 mmol), 1-propylphosphonic anhydride (66.16 mg, 0.21 mmol) and triethylamine (21.01 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in dichloromethane (1 mL). The obtained mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (S)-2-(2-(1-isopropyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, crude product). ES-API: [M+H].sup.+=569.4.

[0619] Step 2: Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl (S)-2-(2-(1-isopropyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, 0.07 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was prepared and purified (column: Ultimate XB-C18, 50*250 mm, 10 um; mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile; flow rate: 80 ml/min; gradient: B/A=20%-90% over 50 min; wavelength: 214 nm; column temperature: room temperature) to give (S)-(1-isopropyl-1H-pyrazol-4-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z286, 1.8 mg, yield: 5.46%) as a white powder. ES-API: [M+H].sup.+=469.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.69 (s, 1H), 8.45 (s, 1H), 7.99 (s, 1H), 7.89 (s, 1H), 7.74 (s, 2H), 7.28 (s, 1H), 7.09 (s, 1H), 5.08-4.76 (m, 2H), 4.60-4.25 (m, 2H), 4.08-3.69 (m, 2H), 3.37-3.28 (m, 1H), 3.17-3.08 (m, 1H), 3.07-2.88 (m, 3H), 2.33 (s, 3H), 2.05-1.88 (m, 2H), 1.81-1.67 (m, 1H), 1.52 (d, J=3.3 Hz, 3H).

Example 78. Synthesis of Compound Z787 and Compound Z788

##STR00342##

[0620] Step 1: Nicotinaldehyde (1 g, 9.34 mmol) and acetic acid (10 mL) were dissolved in trimethylsilyl cyanide (326 mg, 9.34 mmol) under an ice bath condition, and the system was warmed to room temperature for 16 h. The reaction was quenched by the addition of water, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 2-hydroxy-2-(pyridin-3-yl)acetonitrile (1 g, yield: 80%) as a crude product. ES-API: [M+H].sup.+=135.1.

[0621] Step 2: The 2-hydroxy-2-(pyridin-3-yl)acetonitrile (2 g, 14.91 mmol) was dissolved in hydrochloric acid-methanol solution (20 mL), and the system reacted at room temperature for 16 h. Upon completion of the reaction, the reaction mixture was quenched by the addition of aqueous sodium bicarbonate solution, adjusted to pH 7, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product methyl 2-hydroxy-2-(pyridin-3-yl)acetate (219 mg, yield: 8.79%). ES-API: [M+H].sup.+=168.1.

[0622] Step 3: The methyl 2-hydroxy-2-(pyridin-3-yl)acetate (219 mg, 1.31 mmol) and lithium hydroxide (31.37 mg, 1.31 mmol) were dissolved in water (0.5 mL) and tetrahydrofuran (0.5 mL) and stirred at room temperature for 1 h. The obtained mixture was then spun to dryness to give 2-hydroxy-2-(3-pyridyl)acetic acid (200 mg, yield: 100%) as a crude product. ES-API: [M+H].sup.+=154.1.

[0623] Step 4: The 2-hydroxy-2-(3-pyridyl)acetic acid (12.74 mg, 0.083 mmol), tert-butyl (S)-2-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (30 mg, 0.069 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39.89 mg, 0.208 mmol) and 1-hydroxybenzotriazole (28.11 mg, 0.208 mmol) were dissolved in N,N-dimethylformamide (0.5 mL), and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (2S)-2-(2-(2-hydroxy-2-(pyridin-3-yl)acetyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (39 mg, yield: 100%) as a crude product. ES-API: [M+H].sup.+=568.8.

[0624] Step 5: The tert-butyl (2S)-2-(2-(2-hydroxy-2-(pyridin-3-yl)acetyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (39 mg, 0.068 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL), and the system reacted at room temperature for 1 h. After concentration, the concentrate was basified with ammonia water, and concentrated again. The crude product was prepared by HPLC (column: Ultimate XB-C18, 19 mm*150 mm, 10 um; mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile; flow rate: 5 mL/min; gradient: B/A=30%-40% over 9 min; wavelength: 214 nm; column temperature: room temperature) to give two isomeric compounds. A structure of one isomeric compound was arbitrarily assigned as (R)-2-hydroxy-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(pyridin-3-yl)ethan-1-one (Z287, 1 mg, yield: 3.2%, retention time: 1.296 min) ES-API: [M+H].sup.+=468.8; a structure of the other isomeric compound was arbitrarily assigned as (S)-2-hydroxy-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(pyridin-3-yl)ethan-1-one (Z288, 3.1 mg, yield: 9.8%, retention time: 1.307 min). ES-API: [M+H].sup.+=468.8.

Example 79. Synthesis of Compound Z289

##STR00343##

[0625] Step 1: (R)-2-Hydroxy-2-phenylacetic acid (12.66 mg, 0.083 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39.89 mg, 0.21 mmol), triethylamine (21.01 mg, 0.21 mmol) and 1-hydroxybenzotriazole (14.06 mg, 0.11 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in N,N-dimethylformamide (1 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (S)-2-(2-((R)-2-hydroxy-2-phenylacetyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, crude product). ES-API: [M+H].sup.+=567.4.

[0626] Step 2: Trifluoroacetic acid (0.5 mL) was added to a solution of the tert-butyl (S)-2-(2-((R)-2-hydroxy-2-phenylacetyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.053 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was checked by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was prepared and purified (column: Ultimate XB-C18, 50*250 mm, 10 um; mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile; flow rate: 80 ml/min; gradient: B/A=20%-90% over 50 min; wavelength: 214 nm; column temperature: room temperature) to give (R)-2-hydroxy-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-acetophenone (Z289, 2.2 mg, yield: 8.9%) as a white powder. ES-API: [M+H].sup.+=467.3.

Example 80. Synthesis of Compound Z290

##STR00344##

[0627] Step 1: (S)-2-Hydroxy-2-phenylacetic acid (12.66 mg, 0.083 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39.89 mg, 0.21 mmol), triethylamine (21.01, 0.21 mmol) and 1-hydroxybenzotriazole (14.06 mg, 0.11 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in N,N-dimethylformamide (1 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a product tert-butyl (S)-2-(2-((S)-2-hydroxy-2-phenylacetyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, crude product). ES-API: [M+H].sup.+=567.4.

[0628] Step 2: Trifluoroacetic acid (0.5 mL was added to a solution of the tert-butyl (S)-2-(2-((S)-2-hydroxy-2-phenylacetyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.053 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was prepared and purified (column: Ultimate XB-C18, 50*250 mm, 10 um; mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile; flow rate: 80 ml/min; gradient: B/A=20%-90% over 50 min; wavelength: 214 nm; column temperature: room temperature) to give (S)-2-hydroxy-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-acetophenone (Z290, 3.3 mg, yield: 13.4%) as a white powder. ES-API: [M+H].sup.+=467.3.

Example 81. Synthesis of Compound Z291

##STR00345##

[0629] Step 1: In the presence of protective nitrogen, a mixture of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (10 mg, 30 mol), 4-iodopyridine (12 mg, 59 mol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (3 mg, 4 mol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (2 mg, 5 mol) and cesium carbonate (30 mg, 92 mol) in toluene (1 mL) was stirred at 100 C. for 3 h. Upon completion of the reaction, the reaction mixture was concentrated. The crude product was purified by column chromatography (0-100% ethyl acetate/petroleum ether) to give tert-butyl (S)-2-(6-chloro-2-(pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (5 mg, yield: 40%). ES-API: [M+H].sup.+=414.2.

[0630] Step 2: In the presence of protective nitrogen, a mixed solution of the tert-butyl (S)-2-(6-chloro-2-(pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (25 mg, 60 mol), 3-methyl-5-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (31 mg, 120 mol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (5 mg, 7 mol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (3 mg, 7 mol) and potassium carbonate (25 mg, 181 mol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 120 C. for 2 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (methanol/dichloromethane=0-10%) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (25 mg, yield: 81.7%) as a clear oily liquid. ES-API: [M+H].sup.+=510.2.

[0631] Step 3: Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 59 mol) in dichloromethane (1 mL) under an ice bath condition and stirred at room temperature for 1 h. The obtained mixture was concentrated, and the crude product was purified by preparative chromatographic column (ammonium bicarbonate method) to give (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-4-yl)-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z291, 14.25 mg, purity: 100%, yield: 59%) as a white solid. ES-API: [M+H].sup.+=410.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.38 (s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.23-8.19 (m, 3H), 7.82 (s, 1H), 7.60 (s, 1H), 7.28 (s, 1H), 7.01 (d, J=6.0 Hz, 2H), 4.81-4.75 (m, 1H), 4.71 (d, J=16.5 Hz, 1H), 4.58 (d, J=16.0 Hz, 1H), 3.75-3.69 (m, 1H), 3.67-3.60 (m, 1H), 3.43-3.36 (m, 1H), 3.31-3.22 (m, 1H), 3.07-3.00 (m, 2H), 2.44-2.35 (m, 1H), 2.32 (s, 3H), 2.18-1.92 (m, 3H).

Example 82. Synthesis of Compound Z292

##STR00346## ##STR00347##

[0632] Step 1: 2-Bromo-4-chlorophenylacetic acid (26 g, 104.213 mmol) and ethylamine hydrochloride (10.1 g, 125.055 mmol) were dissolved in dichloromethane (200 mL). Ethyl diisopropylamine (51.051 mL, 312.638 mmol) and 1-propylphosphonic anhydride (97.699 mL, 156.319 mmol, 50% in ethyl acetate) were added under an ice-water bath condition. The mixture was stirred at room temperature for 1 h. The mixture was washed with water (100 mL2) and concentrated. Ethyl acetate was added to the residue, and the obtained mixture was filtered. The filter cake was dried to give 2-(2-bromo-4-chlorophenyl)-N-ethylacetamide (18 g, 65.085 mmol, yield: 62.45%). ES-API: [M+H].sup.+=275.9, 277.9.

[0633] Step 2: The 2-(2-bromo-4-chlorophenyl)-N-ethylacetamide (12 g, 43.390 mmol) was dissolved in Eaton's reagent (100 mL) solution. Paraformaldehyde (6.51 g, 216.951 mmol) was added. The mixture was stirred at 100 C. for 3 h. The obtained mixture was cooled, poured into ice water (100 mL), and extracted with ethyl acetate (100 mL3). The ethyl acetate layers were combined, washed with saturated sodium chloride solution (100 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/tetrahydrofuran=70/30) to give 5-bromo-7-chloro-2-ethyl-1,4-dihydroisoquinolin-3(2H)-one (14 g, crude product). ES-API: [M+H].sup.+=287.9, 289.9.

[0634] Step 3: Potassium vinyltrifluoroborate (13.00 g, 97.030 mmol), triethylamine (13.487 mL, 97.030 mmol) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium-dichloromethane complex (1.98 g, 2.426 mmol) were added to a solution of the 5-bromo-7-chloro-2-ethyl-1,4-dihydroisoquinolin-3(2H)-one (14 g, crude product) in ethanol (420 mL). The mixture was degassed with nitrogen and stirred at 100 C. for 4 h. The obtained mixture was poured into water (250 mL), and extracted with ethyl acetate (250 mL3). The ethyl acetate layers were combined, washed with saturated sodium chloride solution (200 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=40/60) to give 7-chloro-2-ethyl-5-vinyl-1,4-dihydroisoquinolin-3(2H)-one (5 g, 19.516 mmol, yield: 44.97%). ES-API: [M+H].sup.+=236.0.

[0635] Step 4: The 7-chloro-2-ethyl-5-vinyl-1,4-dihydroisoquinolin-3(2H)-one (5 g, 21.213 mmol) was dissolved in tetrahydrofuran (120 mL) solution under an ice-water bath condition, and slowly added to a solution of sodium periodate (27.22 g, 127.275 mmol) and potassium osmate dihydrate (0.23 g, 0.636 mmol) in water (60 mL). The mixture was stirred at room temperature for 1 h. The obtained mixture was poured into ethyl acetate (100 mL), and filtered. The filtrate was dried over anhydrous sulfuric acid, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=20/80) to give 7-chloro-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-5-carbaldehyde (2.8 g, 11.780 mmol, yield: 55.53%). ES-API: [M+H].sup.+=238.0.

[0636] Step 5: The 7-chloro-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-5-carbaldehyde (2.8 g, 11.780 mmol) and (S)-2-methylpropane-2-sulfinamide (2.86 g, 23.560 mmol) were dissolved in dried dichloromethane (30 mL). Tetraethyl titanate (10.75 g, 47.120 mmol) was added at room temperature. The mixture was stirred at room temperature for 18 h. The obtained mixture was poured into saturated brine (50 mL) and extracted with dichloromethane (100 mL3). The organic phases were combined, filtered, washed with saturated brine solution (100 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/tetrahydrofuran=30/70) to give (S)N-((7-chloro-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)methylene)-2-methylpropane-2-sulfinamide (3.34 g, 9.798 mmol, yield: 83.18%). ES-API: [M+H].sup.+=341.1.

[0637] Step 6: The (S)N-((7-chloro-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)methylene)-2-methylpropane-2-sulfinamide (3.34 g, 9.798 mmol) was dissolved in dried tetrahydrofuran (30 mL). (2-(1,3-Dioxan-2-yl)ethyl)magnesium bromide (78.4 mL, 39.2 mmol) was slowly added under a dry ice bath condition at 78 C. The mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (5 mL), and the reaction mixture was extracted with ethyl acetate (100 mL3). The organic phases were combined, washed with saturated brine solution (100 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/tetrahydrofuran=30/70) to give (S)N-(1-(7-chloro-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (700 mg, 1.56 mmol, yield: 15.9%). ES-API: [M+H].sup.+=457.1.

[0638] Step 7: The (S)N-(1-(7-chloro-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (0.70 g, 1.56 mmol) was dissolved in trifluoroacetic acid (5 mL), and water (0.25 mL) was added. The mixture was stirred at room temperature for 0.5 h. Triethylsilane (1.78 g, 15.316 mmol) was then added. The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated directly to give (S)-7-chloro-2-ethyl-5-[pyrrol-2-yl]-1,4-dihydroisoquinolin-3(2H)-one (700 mg, crude product). ES-API: [M+H].sup.+=279.1.

[0639] Step 8: The (S)-7-chloro-2-ethyl-5-[pyrrol-2-yl]-1,4-dihydroisoquinolin-3(2H)-one (700 mg, crude product) was dissolved in dichloromethane (20 mL). Triethylamine (0.178 mL, 1.281 mmol) and di-tert-butyl dicarbonate (0.147 mL, 0.640 mmol) were added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated. The crude product was purified by column chromatography (ethyl acetate/petroleum ether=40/60) to give tert-butyl (S)-2-(7-chloro-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (110 mg, 0.226 mmol, yield of the 2 steps: 14.48%). ES-API: [M+H].sup.+=379.1.

[0640] Step 9: The tert-butyl (S)-2-(7-chloro-2-ethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (110 mg, 0.290 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (112.41 mg, 0.435 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (20.90 mg, 0.029 mmol) and potassium carbonate (120.37 mg, 0.871 mmol) were added to 1,4-dioxane (20 mL) and water (2 mL). The system was replaced with nitrogen and heated in an oil bath at 120 C. for 1 h. Upon completion of the reaction, ethyl acetate (100 mL) was added. The obtained mixture was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (ethyl acetate/petroleum ether=80/20) to give tert-butyl (S)-2-(2-ethyl-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (40 mg, 0.064 mmol, yield: 22.06%). ES-API: [M+H].sup.+=475.2.

[0641] Step 10: The tert-butyl (S)-2-(2-ethyl-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (40 mg, 0.064 mmol) was dissolved in dichloromethane (5 mL) and added to trifluoroacetic acid (3 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again. The crude product was purified by prep-HPLC (ammonia water method) to give (S)-2-ethyl-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-1,4-dihydroisoquinolin-3(2H)-one (Z292, 12 mg, yield: 38.00%). ES-API: [M+H].sup.+=475.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.37 (d, J=2.4 Hz, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.81 (d, J=1.9 Hz, 1H), 7.55 (d, J=1.9 Hz, 1H), 7.28-7.25 (m, 1H), 4.58 (d, J=6.8 Hz, 2H), 4.34 (t, J=7.8 Hz, 1H), 3.64-3.57 (m, 2H), 3.48 (q, J=7.1 Hz, 3H), 3.20-3.13 (m, 1H), 3.05-2.98 (m, 1H), 2.32-2.31 (m, 3H), 2.23-2.19 (m, 1H), 1.87-1.81 (m, 2H), 1.59-1.52 (m, 1H), 1.13-1.10 (m, 3H).

Example 83. Synthesis of Compound Z293

##STR00348##

[0642] Step 1: 5-Bromo-7-chloro-1,2,3,4-tetrahydroisoquinoline (11.37 g, 46.120 mmol) was dissolved in tetrahydrofuran (100 mL) and water (30 mL). Potassium carbonate (19.12 g, 138.360 mmol) was added, and the system was cooled to 0 C. Benzyl chloroformate (16.334 mL, 115.300 mmol) was slowly added, and the system reacted at room temperature for 2 h. Ethyl acetate (100 mL) was added. The obtained mixture was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, and concentrated to give a crude solid. The crude product was beaten with dichloromethane (50 mL), filtered, and rinsed with petroleum ether. The filter cake was dried to give a product benzyl 5-bromo-7-chloro-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (15 g, yield: 83.73%). ES-API: [M+H].sup.+=380.1, 382.1.

[0643] Step 2: The benzyl 5-bromo-7-chloro-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (15 g, 38.616 mmol) and potassium vinyltrifluoroborate (10.56 g, 78.808 mmol) were dissolved in anhydrous ethanol (300 mL). Triethylamine (5.477 mL, 39.404 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (1.61 g, 1.970 mmol) were added. In the presence of protective nitrogen, the system was heated to 90 C. in an oil bath for 18 h. The obtained mixture was poured into ice water (100 mL), extracted with ethyl acetate (100 mL3), washed with saturated brine (50 mL1), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=80/20) to give benzyl 7-chloro-5-vinyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (12 g, yield: 92.90%). ES-API: [M+H].sup.+=328.1.

[0644] Step 3: The benzyl 7-chloro-5-vinyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (12 g, 36.607 mmol) was dissolved in tetrahydrofuran (400 mL) and water (200 mL). Sodium periodate (46.98 g, 219.639 mmol) and potassium osmate dihydrate (0.30 g, 0.805 mmol) were slowly added successively, and the system reacted at room temperature for 2 h. Ethyl acetate (200 mL) was added, and the obtained mixture was stirred and filtered. The filtrate was washed with water (100 mL) and saturated brine (200 mL1) successively, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=80/20) to give a product benzyl 7-chloro-5-formyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (9 g, yield: 74.55%). ES-API: [M+H].sup.+=330.1.

[0645] Step 4: The benzyl 7-chloro-5-formyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (9 g, 27.291 mmol) and (S)-2-methylpropane-2-sulfinamide (8.27 g, 68.227 mmol) were dissolved in dried dichloromethane (180 mL). Tetraethyl titanate (24.90 g, 109.164 mmol) was added at room temperature and stirred at room temperature for 18 h. The obtained mixture was poured into brine (200 mL) and extracted with dichloromethane (100 mL3). The organic phases were combined, filtered, washed with saturated aqueous sodium chloride solution (200 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/tetrahydrofuran=30/70) to give (S)-benzyl 5-(((tert-butylsulfinyl)imino)methyl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (10.5 g, yield: 88.83%). ES-API: [M+H].sup.+=433.1.

[0646] Step 5: The (S)-benzyl 5-(((tert-butylsulfinyl)imino)methyl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (10 g, 23.096 mmol) was dissolved in dried tetrahydrofuran (100 mL). (2-(1,3-Dioxan-2-yl)ethyl)magnesium bromide (184.770 mL, 92.385 mmol, 0.5M in tetrahydrofuran) was slowly added under a dry ice bath condition at 78 C. The mixture was stirred at room temperature for 0.5 h. The reaction was quenched by the addition of aqueous ammonium chloride solution (50 mL), and the reaction mixture was extracted with ethyl acetate (100 mL2). The organic phases were combined, washed with saturated aqueous sodium chloride solution (200 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/tetrahydrofuran=30/70) to give benzyl 5-(1-(((S)-tert-butylsulfinyl)amino)-3-(1,3-dioxan-2-yl)propyl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (11.67 g, yield: 92%). ES-API: [M+H].sup.+=549.2.

[0647] Step 6: The benzyl 5-(1-(((S)-tert-butylsulfinyl)amino)-3-(1,3-dioxan-2-yl)propyl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (11.67 g, 21.249 mmol) was dissolved in trifluoroacetic acid (100 mL), and water (5 mL) was added. The mixture was stirred at room temperature for 0.5 h. Triethylsilyl hydride (33.851 mL, 212.518 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated to give (S)-benzyl 7-chloro-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (15 g, crude product). ES-API: [M+H].sup.+=371.1.

[0648] Step 7: The (S)-benzyl 7-chloro-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (15 g, crude product) was dissolved in tetrahydrofuran (150 mL). N,N-diisopropylethyl amine (26.737 mL, 161.777 mmol) and di-tert-butyl dicarbonate (11.150 mL, 48.533 mmol) were added. The mixture was stirred at room temperature for 1 h. Ethyl acetate (100 mL) was added. The obtained mixture was washed with water (100 mL1) and saturated brine (100 mL1) successively and concentrated. The crude product was purified by silica gel column chromatography (tetrahydrofuran/petroleum ether=40/60) to give (S)-benzyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (10 g, yield of the 2 steps: 65.62%). ES-API: [M+H].sup.+=471.2.

[0649] Step 8: The (S)-benzyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.00 g, 2.123 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (660 mg, 2.548 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (0.08 g, 0.106 mmol) and potassium carbonate (0.88 g, 6.369 mmol) were added to 1,4-dioxane (20 mL) and water (2 mL). The system was replaced with nitrogen and heated in an oil bath at 120 C. for 1 h. Upon completion of the reaction, ethyl acetate (100 mL) was added. The obtained mixture was washed with water (100 mL) and saturated brine (100 mL) successively, dried over anhydrous sodium sulfate, and concentrated to give (S)-benzyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.8 g, crude product). ES-API: [M+H].sup.+=567.3.

[0650] Step 9: The (S)-benzyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.8 g, crude product) was dissolved in dichloromethane (30 mL) solution. Di-tert-butyl dicarbonate (0.471 mL, 2.049 mmol) and 4-dimethylamino pyridine (0.03 g, 0.273 mmol) were added successively. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give (S)-benzyl 7-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (600 mg, yield of the 2 steps: 59.29%). ES-API: [M+H].sup.+=667.2.

[0651] Step 10: The (S)-benzyl 7-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (600 mg, 0.810 mmol) was dissolved in dichloromethane (10 mL). Palladium chloride (159.56 mg, 0.900 mmol), triethylamine (0.250 mL, 1.800 mmol) and triethylsilane (418.51 mg, 3.599 mmol) were added successively at room temperature, and the system reacted for 0.5 h. Dichloromethane (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (S)-5-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (500 mg, crude product). ES-API: [M+H].sup.+=533.3.

[0652] Step 11: The tert-butyl (S)-5-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (100 mg, 0.188 mmol) was dissolved in dichloromethane (5 mL). (R)-Tetrahydrofuran-3-carboxylic acid (32.70 mg, 0.282 mmol), triethylamine (0.078 mL, 0.563 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (142.76 mg, 0.375 mmol) were added, and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, dichloromethane (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (ethyl acetate/petroleum ether=30%-80%) to give tert-butyl 5-(5-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-((R)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin)-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (45 mg, yield: 36.00%). ES-API: [M+H].sup.+=631.3.

[0653] Step 12: The tert-butyl 5-(5-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-((R)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin)-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (45 mg, 0.068 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-tetrahydrofuran-3-yl)methanone (Z293, 18 mg, yield: 57.00%). ES-API: [M+H].sup.+=431.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.34 (d, J=6.5 Hz, 1H), 8.47 (t, J=2.6 Hz, 1H), 8.11 (dd, J=7.5, 2.2 Hz, 1H), 7.76 (dd, J=12.1, 2.0 Hz, 1H), 7.44 (dd, J=11.1, 1.9 Hz, 1H), 7.26 (d, J=5.6 Hz, 1H), 4.91-4.61 (m, 3H), 4.24 (t, J=7.7 Hz, 1H), 3.94 (t, J=8.1 Hz, 1H), 3.83 (dt, J=11.4, 5.7 Hz, 1H), 3.77-3.67 (m, 5H), 3.66-3.59 (m, 1H), 3.48 (p, J=7.4 Hz, 2H), 3.13-3.08 (m, 1H), 2.98-2.82 (m, 3H), 2.31 (s, 3H), 2.20-2.16 (m, 1H), 2.14-1.94 (m, 3H), 1.83-1.75 (m, 2H), 1.50-1.40 (, 1H).

Example 84. Synthesis of Compound Z294

##STR00349##

[0654] Step 1: tert-butyl (S)-5-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (100 mg, 0.188 mmol) was dissolved in dichloromethane (5 mL). (S)-Tetrahydrofuran-3-carboxylic acid (32.70 mg, 0.282 mmol), triethylamine (0.078 mL, 0.563 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (142.76 mg, 0.375 mmol) were added, and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, dichloromethane (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (ethyl acetate/petroleum ether=30%-80%) to give tert-butyl 5-(5-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-((S)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (80 mg, yield: 66.67%). ES-API: [M+H].sup.+=631.3.

[0655] Step 2: The tert-butyl 5-(5-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-((S)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (80 mg, 0.127 mmol) was dissolved in dichloromethane (5 mL) and added to trifluoroacetic acid (3 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-tetrahydrofuran-3-yl)methanone (Z294, 20 mg, yield: 38.00%). ES-API: [M+H].sup.+=431.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.34 (d, J=6.8 Hz, 1H), 8.47 (t, J=2.6 Hz, 1H), 8.11 (dd, J=7.5, 2.2 Hz, 1H), 7.76 (dd, J=11.3, 1.9 Hz, 1H), 7.45 (d, J=10.6 Hz, 1H), 7.27 (d, J=5.3 Hz, 1H), 4.82-4.89 (m, 2H), 4.70-4.65 (m, 1H), 4.26 (t, J=7.7 Hz, 1H), 3.94 (d, J=7.9 Hz, 1H), 3.76-3.67 (m, 5H), 3.48 (t, J=7.9 Hz, 1H), 3.13-3.09 (m, 1H), 2.99-2.84 (m, 3H), 2.31 (t, J=1.4 Hz, 3H), 2.22-2.16 (m, 1H), 2.13-1.98 (m, 3H), 1.82-1.78 (m, 2H).

Example 85. Synthesis of Compound Z295

##STR00350##

[0656] Step 1: Ethyl isocyanate (42 mg, 0.59 mmol) was added to a solution of tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (200 mg, 0.59 mmol) in dichloromethane (2 mL) and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated, and purified by silica gel column chromatography (0-80% tetrahydrofuran/petroleum ether) to give tert-butyl (S)-2-(7-chloro-2-(ethylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (55 mg, yield: 22%). ES-API: [M+H].sup.+=430.1.

[0657] Step 2: In the presence of protective nitrogen, a mixed solution of the tert-butyl (S)-2-(7-chloro-2-(ethylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (50 mg, 0.12 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (38 mg, 0.15 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9 mg, 12 mol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (5 mg, 12 mol) and potassium carbonate (50 mg, 0.36 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 120 C. for 2 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (methanol/dichloromethane=0-10%) to give tert-butyl (S)-2-(2-formyl-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl) pyrrolidine-1-carboxylate (40 mg, yield: 65%) as a clear oily liquid. ES-API: [M+H].sup.+=504.3.

[0658] Step 3: Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of the tert-butyl (S)-2-(2-formyl-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl) pyrrolidine-1-carboxylate (40 mg, 79 mol) in dichloromethane (1 mL) under an ice bath condition and stirred at room temperature for 1 h. The obtained mixture was concentrated, and purified by preparative chromatographic column (ammonium bicarbonate method) to give (S)N-ethyl-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Z295, 10 mg, purity: 100%, yield: 31%). ES-API: [M+H].sup.+=404.2.

Example 86. Synthesis of Compound Z296

##STR00351##

[0659] Step 1: Tert-butyl 7-amino-3,4-dihydro-1H-isoquinolin-2-carboxylate (25 g, 60.41 mmol) was dissolved in acetonitrile (500 mL). N-Bromosuccinimide (17.92 g, 100.68 mmol) was added, and the reaction mixture was stirred at 5 C.-0 C. for 4 h. The reaction mixture was quenched by the addition of aqueous sodium thiosulfate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give tert-butyl 7-amino-8-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (30 g, yield: 76.1%). ES-API: [M+1].sup.+=271.

[0660] Step 2: The tert-butyl 7-amino-8-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (30 g, 91.68 mmol) was dissolved in N,N-dimethylformamide (130 mL). N-Chlorosuccinimide (12.86 g, 96.26 mmol) was added, and the system reacted at 50 C. for 4 h. The reaction mixture was quenched with aqueous sodium thiosulfate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give tert-butyl 7-amino-8-bromo-6-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylate (22 g, yield: 66.4%). ES-API: [M+1].sup.+=305.0.

[0661] Step 3: The tert-butyl 7-amino-8-bromo-6-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylate (22 g, 60.84 mmol) was dissolved in tetrahydrofuran (54 mL), water (86 mL) and hypophosphorous acid (214 mL). Sodium nitrite (6.3 g, 91.24 mmol) was added, and the system reacted at room temperature for 4 h. The reaction mixture was quenched with aqueous sodium thiosulfate solution, extracted with ethyl acetate, and washed with a sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and spun to dryness to give tert-butyl 8-bromo-6-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylate as a crude product which was directly used in the next step. ES-API: [M+1].sup.+=290.0.

[0662] Step 4: The tert-butyl 8-bromo-6-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylate (21 g, 60.58 mmol) was dissolved in a solution of dichloromethane (50 mL) and trifluoroacetic acid (50 mL), and the system reacted at room temperature for 4 h. The reaction mixture was concentrated to give 8-bromo-6-chloro-1,2,3,4-tetrahydroisoquinoline as a crude product which was directly used in the next step. ES-API: [M+1].sup.+=245.90.

[0663] Step 5: The 8-bromo-6-chloro-1,2,3,4-tetrahydroisoquinoline (15 g, 60.84 mmol) was dissolved in dichloromethane (50 mL). Benzylcarbonyl chloride (15.57 g, 91.27 mmol) and triethylamine (18.47 g, 182.53 mmol) were added, and the system reacted at room temperature for 4 h. Upon completion of the reaction, the reaction was quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give a product benzyl 8-bromo-6-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylate (15 g, yield: 60.4%). ES-API: [M+1].sup.+=380.0.

[0664] Step 6: The benzyl 8-bromo-6-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylate (15 g, 39.4 mmol) was dissolved in ethanol (110 mL). Potassium trifluorovinyl borate (15.84 g, 118.21 mmol), triethylamine (11.96 g, 118.21 mmol) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (2.88 g, 3.94 mmol) were added. The system reacted at 80 C. for 4 h. Upon completion of the reaction, the reaction mixture was concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give a product benzyl 6-chloro-8-vinyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (12 g, yield: 92.7%). ES-API: [M+1].sup.+=328.0.

[0665] Step 7: 2,6-Lutidine (1.96 g, 36.6 mmol), sodium periodate (62.64 g, 292.86 mmol) and potassium osmate dihydrate (3.42 g, 10.98 mmol) were added to a solution of the benzyl 6-chloro-8-vinyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (12 g, 36.6 mmol) in tetrahydrofuran/water (200 mL/100 mL), and the system reacted at room temperature for 2 h. The reaction mixture was quenched with aqueous sodium thiosulfate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give benzyl 6-chloro-8-formyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (4.5 g, yield: 37.3%). ES-API: [M+1].sup.+=330.1.

[0666] Step 8: 2-((Tributylstannyl)methoxy)ethanamine (220.85 mg, 0.61 mmol) and 4 A molecular sieves were added to a solution of the benzyl 6-chloro-8-formyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (200 mg, 0.61 mmol) in dichloromethane (6 mL) and stirred at 30 C. for 16 h. Upon completion of the reaction, the reaction mixture was filtered and spun to dryness to give benzyl 6-chloro-8-[(E)-2(tributylstannomethoxy)ethyliminomethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (410 mg, crude product) as a crude product which was directly used in the next step.

[0667] Step 9: (R,R)-2,2-Isopropylidene bis(4-phenyl-2-oxazoline) (40.57 mg, 0.12 mmol) was added to a suspension of copper (II) triflate (219.39 mg, 0.6 mmol) in hexafluoroisopropanol (2.5 mL) followed by a solution of the benzyl 6-chloro-8-[(E)-2(tributylstannomethoxy)ethyliminomethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (410 mg, 0.6 mmol) in hexafluoroisopropanol (2.5 mL), and the reaction mixture was stirred at 30 C. for 16 h. The reaction was monitored by LCMS for completion. IN sodium hydroxide was added. The mixture was stirred, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated to give a product benzyl 6-chloro-8-(morpholin-3-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (235.00 mg, crude product) as a yellow oil which was directly used in the next step. ES-API: [M+H].sup.+=387.2.

[0668] Step 10: Triethylamine (184.4 mg, 1.82 mmol) and di-tert-butyl dicarbonate (264.84 g, 1.21 mmol) were added to a solution of the benzyl 6-chloro-8-(morpholin-3-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (235 mg, 0.6 mmol,) in tetrahydrofuran (5 mL) and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate and concentrated. The crude product was purified by column chromatography (ethyl acetate/petroleum ether=1/5) to give tert-butyl 3-(2-((benzyloxy)carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (90 mg, yield: 30.42%) ES-API: [M+H-100].sup.+=387.1.

[0669] Step 11: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (72.06 mg, 0.28 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (16.74 mg, 0.023 mmol) and potassium carbonate (96.31 mg, 0.69 mmol) were added to a solution of the tert-butyl 3-(2-((benzyloxy)carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (90 mg, 0.23 mmol) in dioxane/water (2 mL/0.4 mL). The mixture was heated to 110 C. and stirred for 2 h in the presence of protective nitrogen, and the reaction was monitored by LCMS for completion. The obtained mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (dichloromethane/methanol=10/1) to give a product tert-butyl 3-(2-((benzyloxy)carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, yield: 29.51%). ES-API: [M+H].sup.+=583.4.

[0670] Step 12: Palladium on carbon (10 mg) was added to a solution of 3-(2-((benzyloxy)carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.069 mmol) in methanol (1 mL), and the mixture was stirred under hydrogen atmosphere at 25 C. for 1 h. The reaction was monitored by LCMS for completion, the reaction mixture was filtered. The filtrate was dried over anhydrous sodium sulfate, and concentrated to give a product tert-butyl 3-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (25 mg, yield: 81.19%). ES-API: [M+H].sup.+=449.3.

[0671] Step 13: (S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (114.18 mg, 0.722 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44.87 mg, 0.23 mmol), 1-hydroxybenzotriazole (15.81 mg, 0.12 mmol) and triethylamine (23.64 mg, 0.23 mmol) were added to a solution of the tert-butyl 3-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (35 mg, 0.078 mmol) in N,N-dimethylformamide (1 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (dichloromethane/methanol=10/1) to give a product tert-butyl 3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (10 mg, yield: 21.77%). ES-API: [M+H].sup.+=589.4.

[0672] Step 14: Trifluoroacetic acid (0.5 mL) was added to a solution of the tert-butyl 3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (10 mg, 0.017 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was prepared and purified (column: Ultimate XB-C18, 50*250 mm, 10 um; mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile; flow rate: 80 ml/min; gradient: B/A=20%-90% over 50 min; wavelength: 214 nm; column temperature: room temperature) to give (2S)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z296, 3.8 mg, yield: 45.79%) as a white powder. ES-API: [M+H].sup.+=489.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.11 (s, 1H), 7.91-7.53 (m, 3H), 7.08 (s, 1H), 4.87-4.44 (m, 2H), 4.39-4.06 (m, 2H), 4.04-3.49 (m, 4H), 3.45-2.72 (m, 4H), 2.62-2.36 (m, 1H), 2.30 (s, 3H), 1.89-1.86 (m, 3H).

Example 87. Synthesis of Compound Z297

##STR00352##

[0673] Step 1: 3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propanoic acid (188.85 mg, 0.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170.73 mg, 0.9 mmol), 1-hydroxybenzotriazole (120.34 mg, 0.9 mmol) and triethylamine (90.12 mg, 0.9 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.3 mmol) in N,N-dimethylformamide (3 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-(6-chloro-2-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (18 mg, yield: 11.42%). ES-API: [M+H-100].sup.+=431.1.

[0674] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (10.5 mg, 0.04 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (2.44 mg, 0.003 mmol) and potassium carbonate (14.04 mg, 0.102 mmol) were added to a solution of the tert-butyl (S)-2-(6-chloro-2-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (18 mg, 0.034 mmol) in dioxane/water (2 mL/0.4 mL), and the mixture was heated to 110 C. and stirred for 2 h in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (12 mg, yield: 56.48%). ES-API: [M+H].sup.+=627.3.

[0675] Step 3: Trifluoroacetic acid (0.5 mL) was added to a solution of the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (12 mg, 0.02 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was prepared and purified (column: Ultimate XB-C18, 50*250 mm, 10 um; mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile; flow rate: 80 ml/min; gradient: B/A=20%-90% over 50 min; wavelength: 214 nm; column temperature: room temperature) to give (S)-3,3,3-trifluoro-2-hydroxy-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(trifluoromethyl)propan-1-one (Z297, 1.3 mg, yield: 12.89%) as a white powder. ES-API: [M+H].sup.+=527.2.

Example 88. Synthesis of Compound Z298

##STR00353##

[0676] Step 1: 6-Bromoisochroman-8-carbaldehyde (100 mg, 0.415 mmol), methylamine hydrochloride (84 mg, 1.244 mmol) and dichloromethane (10 mL) were added to a 25 mL single-neck round-bottom flask. The obtained mixture was stirred at room temperature for 6 h. Sodium cyanoborohydride (78.2 mg, 1.244 mmol) was added in batches and then stirred at room temperature overnight. Ethyl acetate (30 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=10:100) to give 1-(6-bromoisochroman-8-carbaldehyde)-N-methylmethanamine (20 mg, yield: 19%). ES-API: [M+H].sup.+=256.1.

[0677] Step 2: The 1-(6-bromoisochroman-8-carbaldehyde)-N-methylmethanamine (20 mg, 0.078 mmol), di-tert-butyl dicarbonate (51 mg, 0.23 mmol), triethylamine (24 mg, 0.23 mmol) and dichloromethane (10 mL) were added to a 25 mL single-neck round-bottom flask and stirred for 1 h. Dichloromethane (20 mL) was added. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl ((6-bromoisochroman-8-yl)methyl)(methyl)carbamate (18 mg, yield: 64%) as a crude product. ES-API: [M+H].sup.+=356.1.

[0678] Step 3: The tert-butyl ((6-bromoisochroman-8-yl)methyl)(methyl)carbamate (18 mg, 0.051 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (26 mg, 0.10 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (3.6 mg, 0.005 mmol), potassium carbonate (21 mg, 0.15 mmol), dioxane (3 mL) and water (0.3 mL) were added to a 25 mL single-neck round-bottom flask. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system reacted under microwave at 110 C. for 50 min, and ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl methyl ((6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)methyl)carbamate (20 mg, crude product). ES-API: [M+H].sup.+=408.2.

[0679] Step 4: The tert-butyl methyl ((6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)methyl)carbamate (20 mg, crude product), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude product was purified by prep-HPLC (column: Waters XBridge C18, 190*250 mm, 5 m; mobile phase: A: 0.1% aqueous ammonium bicarbonate solution; mobile phase B: acetonitrile; flow rate: 15 ml/min; column temperature: room temperature) to give N-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)methanamine (Z298, 7 mg, yield: 44.5%). ES-API: [M+H].sup.+=308.2.

Example 89. Synthesis of Compound Z299

##STR00354##

[0680] Step 1: tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 0.297 mmol) was dissolved in dried 1,4-dioxane (3 mL). 3-Iodopyridine (91.28 mg, 0.445 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.69 mg, 0.015 mmol) and cesium carbonate (193.45 mg, 0.594 mmol) were added successively, and the system was heated to 100 C. under microwave for 3 h. The obtained mixture was diluted with ethyl acetate (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=1/20) to give tert-butyl (S)-2-(7-chloro-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (22 mg, yield: 17.90%). ES-API: [M+H].sup.+=414.2.

[0681] Step 2: The tert-butyl (S)-2-(7-chloro-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (22 mg, 0.053 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (20.58 mg, 0.08 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (3.83 mg, 0.005 mmol) and potassium carbonate (22.04 mg, 0.159 mmol) were added to 1,4-dioxane (3 mL) and water (0.5 mL). The system was replaced with nitrogen three times and reacted under microwave at 115 C. for 1 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, and dried over anhydrous sodium sulfate. The crude product was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (15 mg, yield: 55.37%). ES-API: [M+H].sup.+=510.3.

[0682] Step 3: The tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (15 mg, 0.029 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (formic acid method) to give (S)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-3-yl)-5-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z299, formate, 3.5 mg, yield: 27.59%). ES-API: [M+H].sup.+=410.2.

Example 90. Synthesis of Compound Z300

##STR00355##

[0683] Step 1: Triethylamine (90.12 mg, 890.59 mol) and pivaloyl chloride (42.95 mg, 356.24 mol) were added to a solution of tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 296.86 mol) in dichloromethane (1 mL) and stirred at 0 C. for 15 min. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (methanol/dichloromethane=0-5%) to give a product tert-butyl (S)-2-(7-chloro-2-pivaloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, yield: 77.9%). ES-API: [M+H-56].sup.+=376.1.

[0684] Step 2: The compound tert-butyl (S)-2-(7-chloro-2-pivaloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (53 mg, 125.90 mol,) was dissolved in dioxane/water (2 mL/0.4 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (39 mg, 151.6 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9 mg, 12.59 mol) and potassium carbonate (52.12 mg, 377.7 mol) were added. The system was heated to 100 C. for 2 h. Hydrochloric acid-methanol solution was added and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-(2-pivaloyl-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinol-5-yl)pyrrolidine-1-carboxylate (40 mg, yield: 62%). ES-API: [M+H].sup.+=517.3.

[0685] Step 3: The tert-butyl (S)-2-(2-pivaloyl-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinol-5-yl)pyrrolidine-1-carboxylate (40 mg, 77.52 mol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction monitored by LCMS, the reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-2,2-dimethyl-1-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z300, 6.63 mg, yield: 20.6%). ES-API: [M+1].sup.+=417.2.

Example 91. Synthesis of Compound Z301

##STR00356##

[0686] Step 1: Triethylamine (90.12 mg, 890.59 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg, 593.7 mol) and 1-hydroxybenzotriazole (80.22 mg, 593.7 mol) were added to a solution of tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 286.86 mol) and 2-hydroxy-2-methylpropanoic acid (37.29 mg, 356.24 mol) in N,N-dimethylformamide (3 mL) and stirred at 25 C. for 1 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (methanol/dichloromethane=0-5%) to give a product tert-butyl (S)-2-(7-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, yield: 82.4%). ES-API: [M+H-56].sup.+=367.2.

[0687] Step 2: The compound tert-butyl (S)-2-(7-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 236.44 mol) was dissolved in dioxane/water (2 mL/0.4 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (74 mg, 286 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (18 mg, 24 mol) and potassium carbonate (98 mg, 712 mol) were added. The system was heated to 100 C. for 2 h. Hydrochloric acid/methanol solution was added and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (tetrahydrofuran/petroleum ether=30/70) to give a product tert-butyl (S)-2-(2-(1-hydroxycyclopropanecarbonyl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, yield: 81.4%). ES-API: [M+H].sup.+=519.3.

[0688] Step 3: The tert-butyl (S)-2-(2-(1-hydroxycyclopropanecarbonyl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 192.81 mol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction monitored by LCMS, the reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-2-hydroxy-2-methyl-1-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z301, 20 mg, yield: 25%). ES-API: [M+1].sup.+=419.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.61-9.97 (m, 1H), 8.34-7.98 (m, 1H), 7.89-7.51 (m, 2H), 6.97 (s, 1H), 6.88 (s, 1H), 5.20-4.05 (m, 4H), 3.75-3.59 (m, 2H), 3.48-3.36 (m, 1H), 2.85-2.38 (m, 2H), 2.24 (s, 5H), 2.14-1.97 (m, 2H), 1.53 (s, 6H).

Example 92. Synthesis of Compound Z302

##STR00357##

[0689] Step 1: Triethylamine (90.12 mg, 890.59 mol) and cyclopropylcarbonyl chloride (37.24 mg, 356 mol) were added to a solution of tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 296.86 mol) in dichloromethane (1 mL) and stirred at 0 C. for 15 min. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (methanol/dichloromethane=0-5%) to give a product tert-butyl (S)-2-(7-chloro-2-(cyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, yield: 83.6%). ES-API: [M+H-56].sup.+=349.1.

[0690] Step 2: The compound tert-butyl (S)-2-(7-chloro-2-(cyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 247.5 mol) was dissolved in dioxane/water (2 mL/0.4 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (91.79 mg, 355.6 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (21 mg, 29 mol) and potassium carbonate (122.7 mg, 889 mol) were added. The system was heated to 100 C. for 2 h. Hydrochloric acid-methanol solution was added and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-(2-(cyclopropanecarbonyl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, yield: 80.8%). ES-API: [M+H].sup.+=501.3.

[0691] Step 3: The tert-butyl (S)-2-(2-(cyclopropanecarbonyl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 200 mol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-cyclopropyl (7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z302, 30 mg, yield: 37.5%). ES-API: [M+1].sup.+=401.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.84-10.47 (m, 1H), 8.55-8.41 (m, 1H), 8.14-7.64 (m, 2H), 7.07-6.86 (m, 2H), 5.15-4.69 (m, 2H), 4.59-4.44 (m, 1H), 3.95-3.71 (m, 2H), 3.63-3.25 (m, 3H), 3.00-2.67 (m, 1H), 2.31-1.95 (m, 7H), 1.79 (s, 1H), 1.09-0.94 (m, 2H), 0.84-0.75 (m, 2H).

Example 93. Synthesis of Compound Z303

##STR00358##

[0692] Step 1: 4-Cyanobenzoic acid (52.41 mg, 356.24 mol), 1-propylphosphonic anhydride (283.21 mg, 890.59 mol) and triethylamine (89.95 mg, 890.59 mol) were added to a solution of tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 286.86 mol) in dichloromethane (1 mL) and stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (0-6% methanol/dichloromethane) to give a product tert-butyl (S)-2-(7-chloro-2-(4-cyanobenzoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (70 mg, yield: 52.6%). ES-API: [M+H-56].sup.+=410.2.

[0693] Step 2: The compound tert-butyl (S)-2-(7-chloro-2-(4-cyanobenzoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (70 mg, 151.17 mol) was dissolved in dioxane/water (1 mL/0.2 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (73.58 mg, 285.05 mol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (17.09 mg, 23.75 mol) and potassium carbonate (98.34 mg, 712.64 mol) were added. The system was heated to 100 C. for 2 h. Hydrochloric acid-methanol solution was added and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (methanol/dichloromethane=0-6%) to give a product tert-butyl (S)-2-(2-(4-cyanobenzoyl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (68 mg, yield: 76.5%). ES-API: [M+H].sup.+=562.3.

[0694] Step 3: The tert-butyl (S)-2-(2-(4-cyanobenzoyl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (68 mg, 115.6 mol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction monitored by LCMS, the reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-4-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzonitrile (Z303, 17 mg, yield: 31.8%). ES-API: [M+1].sup.+=462.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.82 (s, 1H), 8.63-8.2 (m, 1H), 7.87-7.61 (m, 4H), 7.33-7.25 (m, 2H), 7.20-6.70 (m, 2H), 5.55-3.75 (m, 3H), 3.72-3.19 (m, 4H), 2.86-2.66 (m, 1H), 2.47-1.91 (m, 8H).

Example 94. Synthesis of Compound Z304

##STR00359##

[0695] Step 1: 2-(4-Fluorophenyl)acetic acid (54.91 mg, 356.24 mol), 1-propylphosphonic anhydride (283.21 mg, 890.59 mol) and triethylamine (89.95 mg, 890.59 mol) were added to a solution of tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 286.86 mol) in dichloromethane (1 ml) and stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (methanol/dichloromethane=0-6%) to give a product tert-butyl (S)-2-(7-chloro-2-(2-(4-fluorophenyl)acetyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (80 mg, yield: 60%). ES-API: [M+H-56].sup.+=417.1.

[0696] Step 2: The compound tert-butyl (S)-2-(7-chloro-2-(2-(4-fluorophenyl)acetyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (80 mg, 169.14 mol) was dissolved in dioxane/water (1 mL/0.2 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (52.39 mg, 202.97 mol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (12.17 mg, 16.93 mol) and potassium carbonate (70.02 mg, 507.42 mol) were added. The system was heated to 100 C. for 2 h. Hydrochloric acid-methanol solution was added and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (methanol/dichloromethane=0-6%) to give a product tert-butyl (S)-2-(2-(2-(4-fluorophenyl)acetyl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (78 mg, yield: 81%). ES-API: [M+H].sup.+=569.4.

[0697] Step 3: The tert-butyl (S)-2-(2-(2-(4-fluorophenyl)acetyl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (78 mg, 137.3 mol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-2-(4-fluorophenyl)-1-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Z304, 38.92 mg, yield: 60%). ES-API: [M+1].sup.+=469.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.78-10.09 (m, 1H), 8.55-8.31 (m, 1H), 8.12-7.64 (m, 2H), 7.32-7.25 (m, 2H), 7.18-7.00 (m, 3H), 6.96-6.84 (m, 1H), 5.06-4.81 (m, 1H), 4.81-4.30 (m, 2H), 4.01-3.54 (m, 4H), 3.51-2.96 (m, 3H), 2.76-2.61 (m, 1H), 2.37-2.06 (m, 5H), 2.04-1.76 (m, 2H).

Example 95. Synthesis of Compound Z305

##STR00360##

[0698] Step 1: Palladium chloride (241 mg, 1.4 mmol), triethylamine (1.0 g, 10.9 mmol) and triethylsilane (3.95 g, 34 mmol) were added to a solution of benzyl (S)-benzyl-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.6 g, 3.4 mmol) in dichloromethane (20 ml) and stirred at room temperature for 30 min. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (methanol/dichloromethane=0-5%) to give a product tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (700 mg, yield: 61.7%). ES-API: [M+H].sup.+=337.1.

[0699] Step 2: Triethylamine (90.12 mg, 890.59 mol) and methylcarbonyl chloride (37.24 mg, 356 mol) were added to a solution of tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 296.86 mol) in dichloromethane (1 mL) and stirred at 0 C. for 15 min. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (methanol/dichloromethane=0-5%) to give a product (S)-methyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, yield: 83.6%). ES-API: [M+H-100].sup.+=295.1.

[0700] Step 3: The compound (S)-methyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 247.5 mol) was dissolved in dioxane/water (2 mL/0.4 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (91.79 mg, 355.6 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (21 mg, 29 mol) and potassium carbonate (122.7 mg, 889 mol) were added. The system was heated to 100 C. for 2 h. Hydrochloric acid-methanol solution was added and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was prepared and purified (column: Waters XBridge C18, 190*250 mm, 5 m; mobile phase: A: 0.1% aqueous ammonium bicarbonate solution; mobile phase B: acetonitrile; flow rate: 15 ml/min; column temperature: room temperature) to give a product (S)-methyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, yield: 80.8%). ES-API: [M+H].sup.+=491.2.

[0701] Step 4: The (S)-methyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 200 mol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product methyl (S)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Z305, 30 mg, yield: 37.5%). ES-API: [M+1].sup.+=391.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.74-10.40 (m, 1H), 8.60-8.43 (m, 1H), 8.09-7.64 (m, 2H), 7.00-6.81 (m, 2H), 5.07-4.80 (m, 1H), 4.65-4.11 (m, 2H), 3.72 (s, 3H), 3.69-3.34 (m, 4H), 3.25-2.85 (m, 1H), 2.64 (d, J=15.7 Hz, 1H), 2.31-1.98 (m, 7H).

Example 96. Synthesis of Compound Z306

##STR00361##

[0702] Step 1: Lithium hydroxide hydrate (275.84 mg, 6.57 mmol) was added to a solution of methyl 1-(2,2-difluoroethyl)pyrazole-4-carboxylate (250 mg, 1.31 mmol) in tetrahydrofuran (1 mL), and the mixture was stirred at 25 C. for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was extracted with ethyl acetate/water. The aqueous layer was adjusted to pH 1, extracted with ethyl acetate/water, dried over anhydrous sodium sulfate, and concentrated to give a product 1-(2,2-difluoroethyl)pyrazole-4-carboxylic acid (140.00 mg, crude product) as a yellow solid. ES-API: [M+H].sup.+=177.1.

[0703] Step 2: 1-Propylphosphonic anhydride (141.68 mg, 445.30 mol), 1-(2,2-difluoroethyl)pyrazole-4-carboxylic acid (62.74 mg, 0.36 mmol) and triethylamine (90.12 mg, 0.89 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 296.86 mol) in dichloromethane (2 mL), and the mixture was stirred at 25 C. for 16 h. The reaction was monitored by LCMS for completion. The reaction mixture was extracted with dichloromethane/water, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (methanol/dichloromethane=0-6%) to give a product tert-butyl (S)-2-[6-chloro-2-[1-(2,2-difluoroethyl)pyrazole-4-carbonyl]-3,4-dihydro-1H-isoquinolin-8-yl]pyrrolidine-1-carboxylate (78.00 mg, yield: 53.08%) as a yellow oil. ES-API: [M+H-100].sup.+=395.2.

[0704] Step 3: The tert-butyl (S)-2-[6-chloro-2-[1-(2,2-difluoroethyl)pyrazole-4-carbonyl]-3,4-dihydro-1H-isoquinolin-8-yl]pyrrolidine-1-carboxylate (78 mg, 0.157 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (61.02 mg, 0.236 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (22.68 mg, 0.031 mmol) and potassium carbonate (65.34 mg, 0.472 mmol) were dissolved in 1,4-dioxane solution (1 mL) and water (0.1 mL), and the system was warmed to 100 C. for 2 h. Upon completion of the reaction monitored by LCMS, the reaction mixture was quenched by the addition of water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[2-[1-(2,2-difluoroethyl)pyrazole-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydro-1H-isoquinolin-8-yl]pyrrolidine-1-carboxylate (90 mg, yield: 96.69%). ES-API: [M+H].sup.+=591.6.

[0705] Step 4: The tert-butyl (S)-2-[2-[1-(2,2-difluoroethyl)pyrazole-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydro-1H-isoquinolin-8-yl]pyrrolidine-1-carboxylate (90 mg, 0.152 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid solution (2 mL) and stirred at room temperature for 1 h. The reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-[1-(2,2-difluoroethyl)pyrazol-4-yl]-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydro-1H-isoquinolin-2-yl]methanone (Z306, 10.9 mg, yield: 14.58%). ES-API: [M+H].sup.+=491.5.

Example 97. Synthesis of Compound Z307

##STR00362##

[0706] Step 1: tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 0.297 mmol), 5-bromo-1-methyl-1H-pyrazole (47.8 mg, 0.297 mmol), tris(dibenzylideneacetone)dipalladium (54.4 mg, 0.059 mmol), 1,1-binaphthyl-2,2-bis(diphenyl) (81.4 mg, 0.13 mmol), sodium tert-butoxide (85.5 mg, 0.89 mmol) and tert-butanol (3 mL) were added to a 10 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system reacted under microwave at 110 C. for 50 min. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (10 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=10:100) to give tert-butyl (S)-2-(7-chloro-2-(1-methyl-1H-pyrazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (15 mg, yield: 12%). ES-API: [M+H].sup.+=417.2.

[0707] Step 2: The tert-butyl (S)-2-(7-chloro-2-(1-methyl-1H-pyrazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (15 mg, 0.036 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (19 mg, 0.072 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (2.59 mg, 0.004 mmol), potassium carbonate (14.9 mg, 0.108 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 10 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system reacted under microwave at 110 C. for 50 min. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (methanol:dichloromethane=10:100) to give a desired product tert-butyl (S)-2-(2-(1-methyl-1H-pyrazol-5-yl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (8 mg, yield: 43%). ES-API: [M+H].sup.+=513.2.

[0708] Step 3: The tert-butyl (S)-2-(2-(1-methyl-1H-pyrazol-5-yl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (8 mg 0.016 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude product was purified by prep-HPLC (formic acid method) to give (S)-2-(1-methyl-1H-pyrazol-5-yl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z307, formate, 1.1 mg, yield: 17.0%). ES-API: [M+H].sup.+=413.3.

Example 98. Synthesis of Compound Z308

##STR00363##

[0709] Step 1: Tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 0.297 mmol), 2,2,2-trifluoroethyl triflate (103 mg, 0.445 mmol), triethylamine (90 mg, 0.891 mmol) and N,N-dimethylformamide (10 ml) were added to a 50 mL single-neck round-bottom flask and stirred at room temperature overnight. Ethyl acetate (30 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=10:100) to give a desired product tert-butyl (S)-2-(7-chloro-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (30 mg, yield: 24%). ES-API: [M+H].sup.+=419.2.

[0710] Step 2: The tert-butyl (S)-2-(7-chloro-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (30 mg, 0.072 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (37 mg, 0.143 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (5.16 mg, 0.007 mmol), potassium carbonate (29.7 mg, 0.215 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 10 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system reacted under microwave at 110 C. for 50 min. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (methanol:dichloromethane=10:100) to give a desired product tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (20 mg, yield: 54%). ES-API: [M+H].sup.+=515.3.

[0711] Step 3: The tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (20 mg, 0.035 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude product was purified by prep-HPLC (formic acid method) to give (S)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline (Z308, formate, 7 mg, yield: 48.1%). ES-API: [M+H].sup.+=415.3.

Example 99. Synthesis of Compound Z309-1 and Compound Z309-2

##STR00364##

[0712] Step 1: Compound (2S)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (50 mg, 0.102 mmol) was chirally resolved (column type: Chiralpak AB: 5 m, 4.6*250 mm, mobile phase: n-hexane:ethanol:diethylamine=40:60:0.2, flow rate: 1 mL/min, column temperature: room temperature) to give two isomeric compounds. A structure of one isomeric compound was arbitrarily assigned as (S)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z309-1, 19 mg, yield: 38%, retention time: 5.656 min, purity: 100%, ee value: 100%). ES-API: [M+H].sup.+=489.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.46 (s, 1H), 7.40-7.14 (m, 2H), 5.42-5.16 (m, 1H), 4.99-4.59 (m, 1H), 4.31-4.02 (m, 1H), 3.97 (d, J=8.8 Hz, 1H), 3.92-3.65 (m, 3H), 3.60-3.50 (m, 1H), 3.28-3.21 (m, 1H), 3.08-2.82 (m, 4H), 2.31 (s, 3H), 1.59 (s, 3H).

[0713] A structure of the other isomeric compound was arbitrarily assigned as (S)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z309-2, 15 mg, yield: 30%, retention time: 9.572 min, purity: 100%, ee value: 100%). ES-API: [M+H].sup.+=489.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.35 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.45 (s, 1H), 7.39-7.13 (m, 2H), 5.42-5.06 (m, 1H), 5.00-4.57 (m, 1H), 4.23-4.02 (m, 1H), 4.02-3.92 (m, 1H), 3.85-3.61 (m, 3H), 3.54 (td, J=10.8, 3.2 Hz, 1H), 3.29-3.24 (m, 1H), 3.10-2.83 (m, 4H), 2.32 (s, 3H), 1.66-1.51 (m, 3H).

Example 100. Synthesis of Compound Z310

##STR00365##

[0714] Step 1: 1-Hydroxycyclopropane carboxylic acid (58.5 mg, 573.7 mol), triethylamine (90.12 mg, 890.59 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg, 593.7 mol) and 1-hydroxybenzotriazole (80.22 mg, 593.7 mol) were added to a solution of tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 286.86 mol) in N,N-dimethylformamide (3 mL) and stirred at 25 C. for 1 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (methanol/dichloromethane=0-5%) to give a product tert-butyl (S)-2-(7-chloro-2-(1-hydroxycyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (50 mg, yield: 40.2%). ES-API: [M+H].sup.+=421.0.

[0715] Step 2: The compound tert-butyl (S)-2-(7-chloro-2-(1-hydroxycyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (50 mg, 119 mol) was dissolved in dioxane/water (1 mL/0.2 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (37 mg, 143 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9 mg, 12 mol) and potassium carbonate (49 mg, 356 mol) were added, and the system was heated to 100 C. for 2 h. Hydrochloric acid-methanol solution was added and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (methanol/dichloromethane=0-5%) to give a product tert-butyl (S)-2-(2-(1-hydroxycyclopropanecarbonyl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (16.8 mg, yield: 27.4%). ES-API: [M+H].sup.+=517.3.

[0716] Step 3: The tert-butyl (S)-2-(2-(1-hydroxycyclopropanecarbonyl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (16.8 mg, 32 mol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction monitored by LCMS, the reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-(1-hydroxycyclopropyl)(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z310, 4.5 mg, yield: 34%). ES-API: [M+1].sup.+=417.3.

Example 101. Synthesis of Compound Z311

##STR00366##

[0717] Step 1: 1-Propylphosphonic anhydride (284 mg, 0.45 mmol) was added to a solution of tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 0.3 mmol) in dichloromethane (10 mL) under an ice-water bath condition and stirred at 0 C. for 10 min. Tetrahydropyran-4-acetic acid (65 mg, 0.45 mmol) was slowly added and stirred at room temperature for 1 h. The obtained mixture was poured into water (10 mL), extracted with dichloromethane (10 mL3), washed with saturated sodium chloride solution (10 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (S)-2-(7-chloro-2-(2-(tetrahydro-2H-pyran-4-yl)acetyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (70 mg, yield: 51%). ES-API: [M+H].sup.+=463.

[0718] Step 2: Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10 mg, 0.005 mmol) and potassium carbonate (64.64 mg, 0.468 mmol) were added to a solution of the tert-butyl (S)-2-(7-chloro-2-(2-(tetrahydro-2H-pyran-4-yl)acetyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (70 mg, 0.156 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.31 mmol) in dioxane (2 ml) and water (0.5 ml). The mixture was degassed with nitrogen and stirred at 110 C. for 2 h. Water (3 mL) was added, and the reaction mixture was extracted with ethyl acetate (3 mL3). The organic phases were combined, washed with sodium chloride solution (3 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)acetyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (60 mg, yield: 71%) ES-API: [M+H].sup.+=559.2.

[0719] Step 3: The tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)acetyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (60 mg, 0.055 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system reacted at room temperature for 2 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again, and purified by prep-HPLC (formic acid method) to give 1-[7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-[(2S)-tetrahydro-1H-pyrrol-2-yl]-1,2,3,4-tetrahydroisoquinolin-2-yl]-2-(3,4,5,6-tetrahydro-2H-pyran-4-yl)ethan-1-one (Z311, 21 mg, yield: 43%). ES-API: [M+H].sup.+=459.2.

Example 102. Synthesis of Compound Z312

##STR00367##

[0720] Step 1: 1-Propylphosphonic anhydride (284 mg, 0.45 mmol) was added to a solution of tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 0.3 mmol) in dichloromethane (5 mL) under an ice-water bath condition and stirred at 0 C. for 10 min. Tetrahydro-2H-pyran-4-carboxylic acid (65 mg, 0.45 mmol) was slowly added and stirred at room temperature for 1 h. The obtained mixture was poured into water (10 mL), extracted with dichloromethane (10 mL3), washed with saturated sodium chloride solution (10 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (S)-2-(7-chloro-2-(tetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (70 mg, yield: 51%). ES-API: [M+H].sup.+=449.

[0721] Step 2: Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10 mg, 0.005 mmol) and potassium carbonate (64.64 mg, 0.468 mmol) were added to a solution of the tert-butyl (S)-2-(7-chloro-2-(tetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (70 mg, 0.156 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.31 mmol) in dioxane (2 mL) and water (0.5 mL). The mixture was degassed with nitrogen and stirred at 110 C. for 2 h. Water (3 mL) was added, and the reaction mixture was extracted with ethyl acetate (3 mL3). The combined organic phase was washed with sodium chloride solution (3 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (60 mg, yield: 71%) ES-API: [M+H].sup.+=545.2.

[0722] Step 3: The tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (60 mg, 0.055 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system reacted at room temperature for 2 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again, and purified by prep-HPLC (ammonium bicarbonate method) to give (S)-1-[7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-[pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl](tetrahydro-2H-pyran-4-yl)methanone (Z312, 8.7 mg, yield: 23%). ES-API: [M+H].sup.+=445.

Example 103. Synthesis of Compound Z313 and Compound Z38-1

##STR00368##

[0723] Step 1: tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100 mg, 0.297 mmol) was dissolved in dried 1,4-dioxane (3 mL). 5-Bromo-2-methylthiazole (105.71 mg, 0.594 mmol), tris(dibenzylideneacetone)dipalladium (27.18 mg, 0.030 mmol), 1,1-binaphthyl-2,2-bis(diphenylphosphine) (36.97 mg, 0.059 mmol) and sodium tert-butoxide (71.33 mg, 0.742 mmol) were added successively, and the system was heated to 100 C. under microwave for 3 h. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (methanol/dichloromethane=1/20) to give tert-butyl (S)-2-(7-chloro-2-(2-methylthiazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (10 mg, yield: 7.76%). ES-API: [M+H].sup.+=434.2; tert-butyl (S)-2-(7-chloroisoquinolin-5-yl)pyrrolidine-1-carboxylate (30 mg, yield: 30.3%). ES-API: [M+H].sup.+=333.1.

[0724] Step 2: The tert-butyl (S)-2-(7-chloro-2-(2-methylthiazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (10 mg, 0.023 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (8.92 mg, 0.035 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.30 mg, 0.012 mmol) and potassium carbonate (3.18 mg, 0.023 mmol) were added to 1,4-dioxane (3 mL) and water (0.5 mL). The system was replaced with nitrogen and reacted under microwave at 115 C. for 1 h. The reaction was monitored by LCMS for completion, and ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give (2S)-tert-butyl 2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methylthiazol-5-yl)-1,2,3,4,4a,8a-hexahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (8 mg, yield: 65.68%). ES-API: [M+H].sup.+=532.3.

[0725] Step 3: The (2S)-tert-butyl 2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methylthiazol-5-yl)-1,2,3,4,4a,8a-hexahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (8 mg, 0.019 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again, and purified by prep-HPLC (formic acid method) to give (S)-2-methyl-5-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrol-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole (Z313, formate, 1.1 mg, yield: 12.1%). ES-API: [M+H].sup.+=432.2.

[0726] Step 4: The tert-butyl (S)-2-(7-chloroisoquinolin-5-yl)pyrrolidine-1-carboxylate (30 mg, 0.090 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (23.22 mg, 0.090 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.48 mg, 0.009 mmol) and potassium carbonate (37.26 mg, 0.27 mmol) were added to 1,4-dioxane (3 mL) and water (0.5 mL). The system was replaced with nitrogen and reacted under microwave at 115 C. for 1 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL1) and saturated brine (10 mL1), and dried over anhydrous sodium sulfate. The crude product was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4a,8a-dihydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (8 mg, yield: 21.1%). ES-API: [M+H].sup.+=429.1.

[0727] Step 5: The tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4a,8a-dihydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (8 mg, 0.019 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again, and purified by prep-HPLC (formic acid method) to give (S)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methylthiazol-5-yl)-5-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z38-1, formate, 3.5 mg, yield: 56.1%). ES-API: [M+H].sup.+=329.1. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.46 (s, 1H), 9.39 (s, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.52 (d, J=5.9 Hz, 1H), 8.38 (q, J=2.0 Hz, 2H), 8.34 (d, J=2.2 Hz, 1H), 8.28 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.32 (s, 1H), 4.92 (t, J=7.7 Hz, 1H), 3.2-3.08 (m, 3H), 2.47-2.43 (m, 1H), 2.36-2.35 (m, 3H), 1.93-1.87 (m, 2H), 1.72-1.63 (m, 1H).

Example 104. Synthesis of Compound Z314

##STR00369## ##STR00370## ##STR00371##

[0728] Step 1: 5-Chloroisoindolin-1-one (5 g, 29.83 mmol) was dissolved in concentrated sulfuric acid (60 mL). Concentrated nitric acid (2.3 mL) was added dropwise under ice bath cooling, and the system reacted in an ice bath for 1 h. Upon completion of the reaction, the reaction mixture was poured into ice water, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and spun to dryness to give a product 5-chloro-6-nitroisoindolin-1-one (6 g, yield: 95%). ES-API: [M+H].sup.+=213.0.

[0729] Step 2: 5-Chloro-6-nitroisoindolin-1-one (4.5 g, 21.2 mmol) was dissolved in ethanol/water (100 mL/10 mL). Reduced iron powder (7.1 g, 127 mmol) and ammonium chloride (6.8 g, 127 mmol) were added, and the system was heated to 90 C. for 2 h. Upon completion of the reaction, the reaction mixture was filtered, washed with methanol, and spun to dryness to give a crude product. The crude product was purified by column chromatography (dichloromethane/methanol=3/1) to give a product 6-amino-5-chloroisoindolin-1-one (2.3 g, yield: 55%). ES-API: [M+H].sup.+=183.0.

[0730] Step 3: The 6-amino-5-chloroisoindolin-1-one (2.2 g, 12.1 mmol) was dissolved in dichloromethane/methanol (50 mL/10 mL). N-bromosuccinimide (2.6 g, 14.5 mmol) was added, and the system reacted at room temperature for 1 h. The reaction mixture was spun to dryness to give a crude product. The crude product was purified by column chromatography (dichloromethane/methanol=10/1) to give a product 6-amino-7-bromo-5-chloro-isoindolin-1-one (3 g, crude product). ES-API: [M+H].sup.+=261.0.

[0731] Step 4: The 6-amino-7-bromo-5-chloro-isoindolin-1-one (3 g, 11.5 mmol) was dissolved in tetrahydrofuran/water (10 mL/10 mL) and hypophosphorous acid (20 mL), and the system was cooled in an ice bath. Sodium nitrite (1.6 g, 22.9 mmol) was added, and the system was warmed to room temperature for 1 h. Upon completion of the reaction, the reaction mixture was extracted with water and dichloromethane, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and spun to dryness to give a crude product. The crude product was beaten with petroleum ether/ethyl acetate (5/1) to give a product 7-bromo-5-chloro-isoindolin-1-one (900 mg, crude product). ES-API: [M+H].sup.+=247.9.

[0732] Step 5: The 7-bromo-5-chloro-isoindolin-1-one (900 mg, 3.6 mmol) was dissolved in tetrahydrofuran (20 mL). Borane tetrahydrofuran (36.5 mL, 36.5 mmol) was added, and the system was heated to 70 C. overnight. The reaction mixture was quenched with 2M hydrochloric acid, heated to 70 C. and stirred for 30 min, and extracted with dichloromethane. The aqueous phase was neutralized with sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and spun to dryness to give a product 4-bromo-6-chloro-isoindoline (500 mg, crude product). ES-API: [M+H].sup.+=231.9.

[0733] Step 6: The 4-bromo-6-chloro-isoindoline (500 mg, 2.2 mmol) was dissolved in dichloromethane (10 mL). Benzyl chloroformate (734 mg, 4.3 mmol) and triethylamine (653 mg, 6.4 mmol) were added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was extracted with water and dichloromethane, dried over anhydrous sodium sulfate, and spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give a product benzyl 4-bromo-6-chloro-isoindoline-2-carboxylate (367 mg, yield: 43%). ES-API: [M+23].sup.+=390.0.

[0734] Step 7: The benzyl 4-bromo-6-chloro-isoindoline-2-carboxylate (367 mg, 1.0 mmol) was dissolved in ethanol (8 mL). Potassium vinyl trifluoroborate (402 mg, 3.0 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (73 mg, 0.1 mmol) and triethylamine (304 mg, 3.0 mmol) were added, and the system was heated to 80 C. for 3 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give a product benzyl 6-chloro-4-vinyl-isoindoline-2-carboxylate (300 mg, yield: 90%). ES-API: [M+H].sup.+=314.1.

[0735] Step 8: The benzyl 6-chloro-4-vinyl-isoindoline-2-carboxylate (300 mg, 0.96 mmol) was dissolved in tetrahydrofuran/water (6 mL/3 mL). Sodium periodate (1.64 g, 7.6 mmol) and potassium osmate dihydrate (106 mg, 0.27 mmol) were added, and the system reacted at room temperature for 2 h. The reaction mixture was quenched with aqueous sodium thiosulfate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether/ethyl acetate=2/1) to give a product benzyl 6-chloro-4-formyl-isoindoline-2-carboxylate (120 mg, yield: 33%). ES-API: [M+23].sup.+=338.1.

[0736] Step 9: The benzyl 6-chloro-4-formyl-isoindoline-2-carboxylate (120 mg, 0.38 mmol) was dissolved in dichloromethane (3 mL). (S)-2-Methylpropane-2-sulfinamide (92 mg, 0.76 mmol) and tetraethyl titanate (347 mg, 1.5 mmol) were added, and the system reacted at room temperature overnight. Upon completion of the reaction, the reaction was quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and spun to dryness to give a product benzyl 4-[(E)-[(S)-tert-butylsulfinyl]iminomethyl]-6-chloro-isoindoline-2-carboxylate (120 mg, crude product). ES-API: [M+H].sup.+=419.2.

[0737] Step 10: The benzyl 4-[(E)-[(S)-tert-butylsulfinyl]iminomethyl]-6-chloro-isoindoline-2-carboxylate (120 mg, 0.29 mmol) was dissolved in tetrahydrofuran (2 mL), and the system was cooled under a dry ice/ethanol bath condition. [2-(1,3-dioxan-2-yl)ethyl]magnesium bromide (2.3 mL, 1.2 mmol) was added dropwise, and the system reacted for 2 h with cooling. The reaction mixture was quenched by being poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spun to dryness to give a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give a product benzyl 6-chloro-4-((S)-1-((S)-1,1-dimethylethylsulfonamido)-3-(1,3-dioxan-2-yl)propyl)isoindoline-2-carboxylate (145 mg, yield: 95%). ES-API: [M+H].sup.+=535.2.

[0738] Step 11: The benzyl 6-chloro-4-((S)-1-((S)-1,1-dimethylethylsulfonamido)-3-(1,3-dioxan-2-yl)propyl)isoindoline-2-carboxylate (145 mg, 0.27 mmol) was dissolved in trifluoroacetic acid (1 mL). Water (0.1 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, triethylsilane (315 mg, 2.7 mmol) was added, and the system reacted at room temperature overnight. The reaction mixture was spun to dryness. Tetrahydrofuran/water (1 mL/I mL) was added, and the obtained mixture was basified with sodium bicarbonate. Di-tert-butyl dicarbonate (89 mg, 0.4 mmol) was then added, and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate/water, dried over anhydrous sodium sulfate, and spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether/ethyl acetate=3/1) to give a product (S)-benzyl 4-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-chloroisoindolin-2-carboxylate (70 mg, yield: 56%). ES-API: [M+H-100].sup.+=357.1.

[0739] Step 12: Palladium chloride (14 mg, 0.08 mmol), triethylamine (0.04 mL, 0.31 mmol) and triethylsilane (0.1 mL, 0.61 mmol) were added successively to a solution of the (S)-benzyl 4-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-chloroisoindolin-2-carboxylate (70 mg, 0.15 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction mixture was quenched with methanol (2 mL), filtered, and concentrated to give tert-butyl (S)-2-(6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate (50 mg, crude product). ES-API: [M+H].sup.+=323.4.

[0740] Step 13: N,N-Diisopropylethyl amine (180 mg, 1.39 mmol) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (106 mg, 0.28 mmol) were added successively to a solution of the tert-butyl (S)-2-(6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate (45 mg, 0.14 mmol) and (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (44 mg, 0.28 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. Dichloromethane (10 mL) was added to the reaction mixture, and the obtained mixture was washed with water (5 mL) and saturated brine (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (tetrahydrofuran/petroleum ether=0-50%) to give tert-butyl (S)-2-(6-chloro-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (40 mg, yield: 62%). ES-API: [M+H].sup.+=407.2.

[0741] Step 14: In the presence of protective nitrogen, a mixed solution of the tert-butyl (S)-2-(6-chloro-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (40 mg, 0.09 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (29 mg, 0.11 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6 mg, 0.01 mmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (4 mg, 0.01 mmol) and potassium carbonate (24 mg, 0.17 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 120 C. for 2 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=0-10%) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (25 mg, yield: 52%). ES-API: [M+H].sup.+=559.3.

[0742] Step 15: Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (25 mg, 45 mol) in dichloromethane (1 mL) under an ice bath condition and stirred at room temperature for 1 h. The reaction mixture was concentrated, and purified by prep-HPLC (ammonium bicarbonate method) to give (S)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-((S)-pyrrolidin-2-yl)isoindolin-2-yl)propan-1-one (Z314, 9.5 mg, purity: 100%, yield: 46%) as a white solid. ES-API: [M+H].sup.+=459.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.35 (s, 1H), 8.53-8.41 (m, 1H), 8.18-8.06 (m, 1H), 7.70 (d, J=5.2 Hz, 1H), 7.59 (d, J=6.4 Hz, 1H), 7.35-7.06 (m, 2H), 5.31-5.11 (m, 2H), 4.85 (s, 1H), 4.80 (s, 1H), 4.27-4.07 (m, 1H), 3.19-3.07 (m, 1H), 3.03-2.91 (m, 1H), 2.31 (s, 3H), 2.26-2.13 (m, 1H), 1.97-1.74 (m, 2H), 1.69-1.53 (m, 4H).

Example 105. Synthesis of Compound Z315

##STR00372##

[0743] Step 1: tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.297 mmol) was dissolved in dried N,N-dimethylformamide (5 mL). 4-Chloropyrimidine (102.00 mg, 0.891 mmol) and potassium carbonate (204.83 mg, 1.484 mmol) were added, and the system was heated to 50 C. for 18 h. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=1/20) to give tert-butyl (S)-2-(6-chloro-2-(pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (80 mg, yield: 64.95%). ES-API: [M+H].sup.+=415.1.

[0744] Step 2: The tert-butyl (S)-2-(6-chloro-2-(pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (80 mg, 0.193 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (74.65 mg, 0.289 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (13.89 mg, 0.019 mmol) and potassium carbonate (79.94 mg, 0.578 mmol) were added to 1,4-dioxane (3 mL) and water (0.5 mL). The system was replaced with nitrogen and reacted under microwave at 115 C. for 1 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, and dried over anhydrous sodium sulfate. The crude product was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyrimidin-4-yl))-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, yield: 60.94%). ES-API: [M+H].sup.+=511.3.

[0745] Step 3: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyrimidin-4-yl))-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.117 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added, and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyrimidin-4-yl)-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z315, 30 mg, yield: 62.5%). ES-API: [M+H].sup.+=411.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.35 (d, J=2.4 Hz, 1H), 8.56 (d, J=1.2 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 8.23 (d, J=6.1 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.27-7.26 (m, 1H), 6.92 (dd, J=6.3, 1.3 Hz, 1H), 5.00 (d, J=16.7 Hz, 1H), 4.75 (d, J=16.5 Hz, 1H), 4.33 (t, J=7.7 Hz, 1H), 3.83 (s, 2H), 3.16-3.10 (m, 1H), 3.01 (t, J=6.1 Hz, 2H).

Example 106. Synthesis of Compound Z316

##STR00373##

[0746] Step 1: Triethylamine (7.64 mg, 0.076 mmol) and di-tert-butyl dicarbonate (16.64 mg, 0.076 mmol) were added to tert-butyl (R)-3-(2-((benzyloxy)carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.069 mmol) and stirred at room temperature overnight. The mixture was washed with water (2 mL2) and brine (2 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (R)-3-(2-((benzyloxy)carbonyl)-6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (45 mg, yield: 95%). ES-API: [M+H].sup.+=683.

[0747] Step 2: Palladium on carbon (10 mg) was added to a solution (3 mL) of the tert-butyl (R)-3-(2-((benzyloxy)carbonyl)-6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (45 mg, 0.06 mmol) in isopropanol, and the system reacted at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure to give tert-butyl (R)-3-(6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, yield: 91%) ES-API: [M+H].sup.+=549.2.

[0748] Step 3: The tert-butyl (R)-3-(6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL). 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (50 mg, 0.1 mmol), methanesulfonyl chloride (34 mg, 0.1 mmol), and N,N-diisopropyl ethylenediamine (40 mg, 0.15 mmol) were added successively, and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was diluted with dichloromethane (10 mL). The organic phase was washed with water (5 mL) and sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=50:50) to give tert-butyl (R)-3-(6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, yield: 81%) ES-API: [M+H].sup.+=627.2.

[0749] Step 4: The tert-butyl (R)-3-(6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, 0.045 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again, and purified by prep-HPLC (ammonium bicarbonate method) to give 2-(methyldioxo-6-sulfanyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[(3R)-1,4-oxazecyclohex-3-yl]-1,2,3,4-tetrahydroisoquinoline (Z316, 1.07 mg, yield: 8%). ES-API: [M+H].sup.+=427.

Example 107. Synthesis of Compound Z317

##STR00374##

[0750] Step 1: tert-butyl (R)-3-(6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.07 mmol) was dissolved in dichloromethane (1 mL). 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (50 mg, 0.1 mmol), (R)-2-trifluoromethyl-2-hydroxypropanoic acid (18 mg, 0.1 mmol), and N,N-diisopropyl ethylenediamine (40 mg, 0.15 mmol) were added successively, and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was diluted with dichloromethane (10 mL). The organic phase was washed with water (5 mL) and sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=50:50) to give tert-butyl (R)-3-(6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, yield: 862.3%) ES-API: [M+H].sup.+=689.2.

[0751] Step 2: The tert-butyl (R)-3-(6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.045 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system reacted at room temperature for 2 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again, and purified by prep-HPLC (ammonium bicarbonate method) to give (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-[6-(3-methyl-H-pyrrolo[2,3-b]pyridin-5-yl)-8-[(R)-morpholin-3-yl]-3,4-dihydroisoquinolin-2(1H)-yl]propan-1-one (Z317, 1.2 mg, yield: 8%). ES-API: [M+H].sup.+=588.

Example 108. Synthesis of Compound Z318

##STR00375##

[0752] Step 1: tert-butyl (R)-3-(6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.07 mmol) was dissolved in dichloromethane (1 mL). 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (50 mg, 0.1 mmol), 2,6-dimethyl-4-pyridinecarboxylic acid (16 mg, 0.1 mmol), and N,N-diisopropyl ethylenediamine (40 mg, 0.15 mmol) were added successively, and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was diluted with dichloromethane (10 mL). The organic phase was washed with water (5 mL) and sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=50:50) to give tert-butyl (R)-3-(6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,6-dimethylisonicotinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, yield: 62%) ES-API: [M+H].sup.+=682.

[0753] Step 2: The tert-butyl (R)-3-(6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,6-dimethylisonicotinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.045 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system reacted at room temperature for 2 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again, and purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(2,6-dimethylpyridin-4-yl)[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[morpholin-3-yl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone (Z318, 17.76 mg, yield: 77%).

[0754] ES-API: [M+H].sup.+=482.

Example 109. Compound Z319

##STR00376##

[0755] Step 1: Methyl 1H-pyrazole-4-carboxylate (500 mg, 3.97 mmol) was dissolved in 1,2-dichloroethane (25 mL). Cyclopropylboronic acid (683 mg, 7.94 mmol), sodium carbonate (842 mg, 7.94 mmol), 2,2-bipyridine (619 mg, 3.97 mmol) and copper acetate (718 mg, 3.97 mmol) were added, and the system was heated to 70 C. overnight in the presence of protective nitrogen. The reaction was quenched by the addition of water, and the reaction product was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spun to dryness. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=2/1) to give methyl 1-cyclopropyl-1H-pyrazole-4-carboxylate (430 mg, yield: 65%). ES-API: [M+H].sup.+=167.1.

[0756] Step 2: The methyl 1-cyclopropyl-1H-pyrazole-4-carboxylate (200 mg, 1.2 mmol) was dissolved in tetrahydrofuran/methanol/water (3 mL/3 mL/1 mL). Lithium hydroxide monohydrate (253 mg, 6.02 mmol) was added, and the system was heated to 50 C. for 1 h. Upon completion of the reaction, the reaction mixture was extracted with water and ethyl acetate. The aqueous phase was adjusted to pH 2 with 1M hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spun to dryness to give a product 1-cyclopropyl-1H-pyrazole-4-carboxylic acid (160 mg, yield: 87%). ES-API: [M+H].sup.+=153.1.

[0757] Step 3: tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (120 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL). The 1-cyclopropyl-1H-pyrazole-4-carboxylic acid (160 mg, 1.05 mmol), 2-(7-azobenzotriazol)-N,N,N,N-tetramethylurea hexafluorophosphate (271 mg, 0.71 mmol) and triethylamine (108 mg, 1.07 mmol) were added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction was quenched by the addition of water. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether/ethyl acetate=1/1) to give a product tert-butyl (S)-2-(6-chloro-2-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (200 mg, crude product). (Rf=0.4, petroleum ether/ethyl acetate=1/1). ES-API: [M+H].sup.+=471.2.

[0758] Step 4: The tert-butyl (S)-2-(6-chloro-2-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (200 mg, 0.42 mmol) was dissolved in dioxane/water (2 mL/0.4 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (131 mg, 0.51 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (30 mg, 0.042 mmol) and potassium carbonate (117 mg, 0.85 mmol) were added. The system was heated to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=20/1) to give a product tert-butyl (S)-2-(2-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, yield: 41%). ES-API: [M+1].sup.+=567.3.

[0759] Step 5: The tert-butyl (S)-2-(2-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1.5 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness, extracted with dichloromethane and saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-(1-cyclopropyl-1H-pyrazol-4-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z319, 26.8 mg, yield: 32%). ES-API: [M+1].sup.+=467.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.85 (s, 1H), 8.48 (s, 1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.80-7.67 (m, 2H), 7.29 (s, 1H), 7.08 (s, 1H), 5.11-4.99 (m, 1H), 4.93-4.71 (m, 1H), 4.55-4.17 (m, 1H), 3.91 (s, 2H), 3.67-3.59 (m, 1H), 3.36-3.27 (m, 1H), 3.14-2.98 (m, 3H), 2.34 (s, 3H), 2.26-2.14 (m, 1H), 2.06-1.85 (m, 4H), 1.18-1.12 (m, 2H), 1.08-1.03 (m, 2H).

Example 110. Synthesis of Compound Z320

##STR00377##

[0760] Step 1: tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.297 mmol) was dissolved in dried 1,4-dioxane (2 mL). 4-Iodo-2-methylpyridine (130.04 mg, 0.594 mmol), (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (14.91 mg, 0.018 mmol), 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (27.70 mg, 0.059 mmol) and potassium carbonate (123.09 mg, 0.891 mmol) were added successively, and the system was heated to 140 C. under microwave for 5 h. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=1/20) to give tert-butyl (S)-2-(6-chloro-2-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (80 mg, yield: 63%). ES-API: [M+H].sup.+=428.1.

[0761] Step 2: The tert-butyl (S)-2-(6-chloro-2-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (80 mg, 0.193 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (72.38 mg, 0.280 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (13.47 mg, 0.019 mmol) and potassium carbonate (77.51 mg, 0.561 mmol) were added to 1,4-dioxane (3 mL) and water (0.5 mL). The system was replaced with nitrogen and reacted under microwave at 115 C. for 1 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, and dried over anhydrous sodium sulfate. The crude product was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methylpyridin-4-yl))-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, yield: 61.29%). ES-API: [M+H].sup.+=524.3.

[0762] Step 3: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methylpyridin-4-yl))-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.115 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again, and purified by prep-HPLC (formic acid method) to give (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methylpyridin-4-yl)-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline formate (Z320, 45 mg, yield: 92%). ES-API: [M+H].sup.+=424.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.41 (d, J=2.3 Hz, 1H), 8.59 (d, J=2.2 Hz, 1H), 8.29 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.13 (d, J=6.2 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.64 (d, J=1.8 Hz, 1H), 7.29 (dd, J=2.3, 1.3 Hz, 1H), 7.00 (d, J=2.5 Hz, 1H), 6.97 (dd, J=6.4, 2.6 Hz, 1H), 4.88 (t, J=8.2 Hz, 1H), 4.78 (d, J=16.4 Hz, 1H), 4.63 (d, J=16.4 Hz, 1H), 3.77 (dd, J=12.3, 6.0 Hz, 1H), 3.65 (dt, J=12.6, 6.2 Hz, 1H), 3.45 (q, J=7.6, 6.0 Hz, 1H), 3.33 (s, 1H), 3.04 (d, J=6.0 Hz, 2H), 2.42 (s, 3H), 2.32 (d, J=1.0 Hz, 3H), 2.18-2.02 (m, 4H).

Example 111. Synthesis of Compound Z246

##STR00378##

[0763] Step 1: Cyclopropanol (207.69 mg, 3.58 mmol) followed by pyridine (259.29 mg, 3.28 mmol) was added to (4-nitrophenyl)carbonyl chloride (600 mg, 2.98 mmol) at 0 C., and the mixture was stirred at 0 C. for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was diluted with dichloromethane (5 mL) and 0.1M aqueous sulfuric acid solution (10 mL), and washed with saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to a volume of about 5 mL. Cyclohexane (10 mL) was added. The obtained mixture was filtrated and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=50/50) to give a product cyclopropyl(4-nitrophenyl) carbonate (450 mg, yield: 67.66%). ES-API: [M+H-100].sup.+=224.1.

[0764] Step 2: The cyclopropyl(4-nitrophenyl) carbonate (15.48 mg, 0.069 mmol) and N,N-diisopropyl ethylenediamine (26.89 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in dichloromethane (1 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=50/50) to give a product (S)-cyclopropyl 8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (30 mg, yield: 83.73%). ES-API: [M+H].sup.+=517.3.

[0765] Step 3: Trifluoroacetic acid (1 mL) was added to a solution of the (S)-cyclopropyl 8-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (30 mg, 0.058 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um; mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile; flow rate: 80 ml/min; gradient: B/A=20%-90% over 50 min; wavelength: 214 nm; column temperature: room temperature) to give (S)-cyclopropyl 6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Z246, 1.8 mg, yield: 7.44%) as a white powder. ES-API: [M+H].sup.+=417.2.

Example 112. Synthesis of Compound Z285-1

##STR00379##

[0766] Step 1: tert-butyl (S)-5-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (100 mg, 0.188 mmol) was dissolved in dichloromethane (5 mL). (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (22.26 mg, 0.141 mmol), triethylamine (0.013 mL, 0.094 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (35.69 mg, 0.094 mmol) were added successively, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was diluted with dichloromethane (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel (petroleum ether/ethyl acetate=1/1) to give tert-butyl 5-(5-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (30 mg, yield: 47.51%). ES-API: [M+H].sup.+=673.3.

[0767] Step 2: The tert-butyl 5-(5-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (30 mg, 0.045 mmol) was dissolved in dichloromethane (3 mL) and added to trifluoroacetic acid (2 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (S)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z285-1, 9 mg, yield: 42.75%). ES-API: [M+H].sup.+=473.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.47 (d, J=2.1 Hz, 1H), 8.12 (d, J=2.2 Hz, 1H), 7.77 (s, 1H), 7.44 (s, 1H), 7.26 (d, J=2.1 Hz, 1H), 5.17 (s, 1H), 4.85-4.62 (m, 2H), 4.26 (t, J=7.7 Hz, 2H), 4.01 (s, 1H), 3.75 (s, 1H), 3.13-3.09 (m, 1H), 2.94 (q, J=8.1 Hz, 2H), 2.31 (d, J=1.1 Hz, 3H), 2.20 (dt, J=12.6, 6.3 Hz, 1H), 2.05-1.97 (m, 1H), 1.85-1.75 (, 2H).

Example 113. Synthesis of Compound Z151-1

##STR00380## ##STR00381##

[0768] Step 1: 1,3-Dihydroisobenzofuran-5-amine (1.8 g, 13.317 mmol) and N-chlorosuccinimide (2.66 g, 19.975 mmol) were dissolved in N,N-dimethylformamide (20 mL) and stirred at room temperature for 1 h. Ethyl acetate (100 mL) was added. The obtained mixture was washed with water (100 mL3) and concentrated. The crude product was purified by silica gel column chromatography (tetrahydrofuran/petroleum ether=10/90) to give 6-chloro-1,3-dihydroisobenzofuran-5-amine (550 mg, yield: 24.35%). ES-API: [M+H].sup.+=170.0.

[0769] Step 2: The 6-chloro-1,3-dihydroisobenzofuran-5-amine (550 mg, 3.243 mmol) was dissolved in acetonitrile (30 mL) solution. N-bromosuccinimide (634.86 mg, 3.567 mmol) was added. The mixture was stirred at room temperature for 1 h. Ethyl acetate (100 mL) was added. The obtained mixture was washed with saturated sodium chloride solution (100 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (tetrahydrofuran/petroleum ether=10/90) to give 4-bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine (480 mg, yield: 59.57%). ES-API: [M+H].sup.+=248.0, 250.0.

[0770] Step 3: The 4-bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine (480 mg, 1.932 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (2 mL). Hypophosphorous acid (5 mL) and sodium nitrite (213.25 mg, 3.091 mmol) were added successively, and the system reacted at room temperature for 2 h. The obtained mixture was poured into water (10 mL), and extracted with ethyl acetate (20 mL3). The ethyl acetate layers were combined, washed with saturated aqueous sodium bicarbonate solution (30 mL1) and saturated sodium chloride solution (30 mL1) successively, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (tetrahydrofuran/petroleum ether=10/90) to give 4-bromo-6-chloro-1,3-dihydroisobenzofuran (210 mg, yield: 46.7%). ES-API: [M+H].sup.+=233.0, 235.0.

[0771] Step 4: The 4-bromo-6-chloro-1,3-dihydroisobenzofuran (210 mg, 0.90 mmol) was dissolved in dried tetrahydrofuran (15 mL), and the system was cooled to 65 C. in a dry ice bath. n-Butyllithium (0.514 mL, 1.285 mmol) was slowly added and stirred at 65 C. for 10 min. The reaction was quenched by dropwise addition of saturated aqueous ammonium chloride solution (1 mL). Ethyl acetate (30 mL) was added. The obtained mixture was washed with water (30 mL1) and saturated sodium chloride solution (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=20/80) to give 6-chloro-1,3-dihydroisobenzofuran-4-carbaldehyde (120 mg, yield: 73.2%). ES-API: [M+H].sup.+=183.0.

[0772] Step 5: The 6-chloro-1,3-dihydroisobenzofuran-4-carbaldehyde (120 mg, 0.659 mmol) and (S)-2-methylpropane-2-sulfinamide (159.5 mg, 1.318 mmol) were dissolved in dried dichloromethane (10 mL). Tetraethyl titanate (0.599 mL, 2.629 mmol) was added at room temperature and stirred for 1 h. The obtained mixture was poured into brine (30 mL) and extracted with dichloromethane (50 mL3). The organic phases were combined, filtered, washed with saturated sodium chloride solution (100 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/tetrahydrofuran=30/70) to give (S)N-((6-chloro-1,3-dihydroisobenzofuran-4-yl)methylene)-2-methylpropane-2-sulfinamide (63 mg, yield: 33.54%). ES-API: [M+H].sup.+=286.1.

[0773] Step 6: The (S)N-((6-chloro-1,3-dihydroisobenzofuran-4-yl)methylene)-2-methylpropane-2-sulfinamide (63 mg, 0.220 mmol) was dissolved in dried tetrahydrofuran (10 mL). (2-(1,3-Dioxan-2-yl)ethyl)magnesium bromide (1.76 mL, 0.88 mmol) was slowly added under a dry ice bath condition at 78 C. The mixture was stirred at room temperature for 0.5 h. The reaction was quenched by the addition of aqueous ammonium chloride solution (5 mL), and the reaction mixture was extracted with ethyl acetate (10 mL2). The organic phases were combined, washed with saturated sodium chloride solution (100 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/tetrahydrofuran=30/70) to give (S)N((S)-1-(6-chloro-1,3-dihydroisobenzofuran-4-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (70 mg, yield: 79.00%). ES-API: [M+H].sup.+=402.1.

[0774] Step 7: The (S)N((S)-1-(6-chloro-1,3-dihydroisobenzofuran-4-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (70 mg, 0.174 mmol) was dissolved in trifluoroacetic acid (3 mL), and water (0.15 mL) was added. The mixture was stirred at room temperature for 0.5 h. Triethylsilane (202.3 mg, 1.74 mmol) was added. The mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated to give (S)-2-(6-chloro-1,3-dihydroisobenzofuran-4-yl)pyrrolidine (40 mg, crude product). ES-API: [M+H].sup.+=224.0.

[0775] Step 8: The (S)-2-(6-chloro-1,3-dihydroisobenzofuran-4-yl)pyrrolidine (40 mg, crude product) was dissolved in dichloromethane (20 mL). Triethylamine (87.8 mg, 0.87 mmol) and di-tert-butyl dicarbonate (75 mg, 0.348 mmol) were added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=40/60) to give tert-butyl (S)-2-(6-chloro-1,3-dihydroisobenzofuran-4-yl)pyrrolidine-1-carboxylate (46 mg, yield of the 2 steps: 81.6%). ES-API: [M+H].sup.+=324.1.

[0776] Step 9: The tert-butyl (S)-2-(6-chloro-1,3-dihydroisobenzofuran-4-yl)pyrrolidine-1-carboxylate (46 mg, 0.142 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (55.00 mg, 0.213 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.24 mg, 0.014 mmol) and potassium carbonate (58.90 mg, 0.426 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL). The system was replaced with nitrogen and heated to 115 C. under microwave for 1.5 h. Upon completion of the reaction, ethyl acetate (10 mL) was added. The obtained mixture was washed with water (10 mL1) and saturated brine (10 mL1), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=80/20) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-dihydroisobenzofuran-4-yl)pyrrolidine-1-carboxylate (55 mg, yield: 92.2%). ES-API: [M+H].sup.+=420.2.

[0777] Step 10: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-dihydroisobenzofuran-4-yl)pyrrolidine-1-carboxylate (55 mg, 0.131 mmol) was dissolved in dichloromethane (3 mL) and added to trifluoro (2 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again, and purified by prep-HPLC (formic acid method) to give (S)-3-methyl-5-(7-(pyrrolidin-2-yl)-1,3-dihydroisobenzofuran-5-yl)-1H-pyrrolo[2,3-b]pyridine (Z151-1, 25 mg, yield: 59.8%). ES-API: [M+H].sup.+=320.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.41-11.36 (m, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.33 (s, 1H), 8.17 (d, J=2.1 Hz, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 7.28 (s, 1H), 5.14 (s, 2H), 5.07 (s, 2H), 4.25 (dd, J=9.4, 7.0 Hz, 1H), 3.24-3.19 (m, 1H), 3.10-3.05 (m, 1H), 2.31 (s, 3H), 2.23 (dtd, J=11.8, 7.4, 3.7 Hz, 1H), 1.97-1.92 (m, 1H), 1.90-1.82 (m, 1H), 1.78 (dt, J=12.1, 8.8 Hz, 1H).

Example 114. Synthesis of Compound Z247

##STR00382##

[0778] Step 1: Sodium hydride (319.11 mg, 7.978 mmol) was added to a solution of (4-bromopyridin-2-yl)methanol (500 mg, 2.659 mmol) in N,N-dimethylformamide (10 mL) under an ice-water bath condition. The mixture was stirred at 0 C. for 10 min. Iodomethane (0.248 mL, 3.989 mmol) was slowly added and stirred at room temperature for 1 h. The obtained mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL3), washed with saturated sodium chloride solution (100 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=80/20) to give 4-bromo-2-(methoxymethyl)pyridine (350 mg, yield: 65.14%). ES-API: [M+H].sup.+=201.9, 203.9.

[0779] Step 2: tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.089 mmol) was dissolved in dried 1,4-dioxane (2 mL). The 4-bromo-2-(methoxymethyl) pyridine (53.98 mg, 0.267 mmol), (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (14.91 mg, 0.018 mmol), 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (8.31 mg, 0.018 mmol) and potassium carbonate (36.93 mg, 0.267 mmol) were added successively, and the system was heated to 140 C. under microwave for 5 h. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=1/20) to give tert-butyl (S)-2-(6-chloro-2-(2-(methoxymethyl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (25 mg, yield: 61.29%). ES-API: [M+H].sup.+=458.2.

[0780] Step 3: The tert-butyl (S)-2-(6-chloro-2-(2-(methoxymethyl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (25 mg, 0.055 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (28.18 mg, 0.109 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.87 mg, 0.011 mmol) and potassium carbonate (22.63 mg, 0.164 mmol) were added to 1,4-dioxane (3 mL) and water (0.5 mL). The system was replaced with nitrogen and reacted under microwave at 115 C. for 1 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, and dried over anhydrous sodium sulfate. The crude product was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-(methoxymethyl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (22 mg, yield: 72.16%). ES-API: [M+H].sup.+=554.3.

[0781] Step 4: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-(methoxymethyl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (22 mg, 0.036 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again, and purified by prep-HPLC (ammonium bicarbonate method) to give (S)-2-(2-(methoxymethyl)pyridin-4-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z247, 9 mg, yield: 44.4%). ES-API: [M+H].sup.+=454.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.35 (s, 1H), 8.48 (d, J=2.1 Hz, 1H), 8.16-8.10 (m, 2H), 7.76 (d, J=2.0 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.27 (s, 1H), 6.92 (d, J=2.6 Hz, 1H), 6.84 (dd, J=6.1, 2.6 Hz, 1H), 4.73-4.53 (m, 3H), 4.43 (d, J=8.6 Hz, 1H), 4.38 (s, 2H), 3.66 (q, J=6.0 Hz, 2H), 3.36 (d, J=1.6 Hz, 3H), 3.17 (s, 1H), 3.03 (d, J=6.4 Hz, 3H), 2.31 (d, J=1.1 Hz, 3H), 2.03-1.97 (m, 1H), 1.95-1.79 (m, 3H).

Example 115. Synthesis of Compound Z88-1

##STR00383##

[0782] Step 1: N,N-Diisopropylethyl amine (230 mg, 1.78 mmol) and methanesulfonyl chloride (68 mg, 0.59 mmol) were added to a solution of tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (200 mg, 0.59 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (tetrahydrofuran/petroleum ether=0-80%) to give tert-butyl (S)-2-(7-chloro-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (55 mg, yield: 22%). ES-API: [M+H].sup.+=437.1.

[0783] Step 2: In the presence of protective nitrogen, a mixed solution of the tert-butyl (S)-2-(7-chloro-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (50 mg, 0.12 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (37 mg, 0.14 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9 mg, 12 mol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (5 mg, 12 mol) and potassium carbonate (50 mg, 0.36 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 120 C. for 2 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to give tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (40 mg, yield: 65%) as a clear oily liquid. ES-API: [M+H].sup.+=511.3.

[0784] Step 3: Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of the tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (40 mg, 78 mol) in dichloromethane (1 mL) under an ice bath condition and stirred at room temperature for 1 h. The reaction mixture was concentrated to give a crude product. The product was purified by preparative chromatographic column (ammonium bicarbonate method) to give (S)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonyl)-5-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z88-1, 17 mg, purity: 100%, yield: 53%) as a white solid. ES-API: [M+H].sup.+=411.1. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.39 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.82 (s, 1H), 7.67 (s, 1H), 7.29 (d, J=1.0 Hz, 1H), 4.78-4.71 (m, 1H), 4.49 (s, 2H), 3.51 (t, J=6.0 Hz, 2H), 3.49-3.42 (m, 1H), 3.38-3.33 (m, 1H), 3.11-3.00 (m, 2H), 2.99 (s, 3H), 2.45-2.36 (m, 1H), 2.32 (s, 3H), 2.21-2.01 (m, 3H).

Example 116. Synthesis of Compound Z340

##STR00384##

[0785] Step 1: Thionyl chloride (0.8 mL, 10.9 mmol) was added to a solution of 2-methylpyrimidine-4-carboxylic acid (1.0 g, 7.2 mmol) in methanol (20 mL) and stirred at 70 C. for 16 h. The reaction mixture was concentrated. A saturated aqueous sodium bicarbonate solution was added, and the obtained mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to give methyl 2-methylpyrimidine-4-carboxylate (0.6 g, crude product) as a yellow solid. ES-API: [M+H].sup.+=153.10.

[0786] Step 2: N-Bromosuccinimide (701.9 mg, 3.9 mmol) and 2,2-azobis(2-methylpropionitrile) (64.8 mg, 0.4 mmol) were added to a solution of the methyl 2-methylpyrimidine-4-carboxylate (0.6 g, 3.9 mmol) in carbon tetrachloride (12 mL) and stirred at 80 C. for 40 h. The reaction mixture was concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give methyl 2-(bromomethyl)pyrimidine-4-carboxylate (130.0 mg, yield: 14.27%) as a yellow oil. ES-API: [M+H].sup.+=230.9/233.0.

[0787] Step 3: In the presence of protective nitrogen, sodium methoxide (60.8 mg, 1.2 mmol) was added to a solution of methyl 2-(bromomethyl)pyrimidine-4-carboxylate (0.13 g, 0.6 mmol) in methanol (8 mL) and stirred at 25 C. for 16 h. The mixture was quenched with hydrochloric acid (1N), and extracted with dichloromethane:methanol (10:1). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a product 2-(methoxymethyl)pyrimidine-4-carboxylic acid (0.1 g, crude product) as a yellow solid. ES-API: [M+H].sup.+=169.1.

[0788] Step 4: The 2-(methoxymethyl)pyrimidine-4-carboxylic acid (69.9 mg, 0.4 mmol), 1-propylphosphonic anhydride (254.4 mg, 0.4 mmol, 50% in ethyl acetate) and triethylamine (72.1 mg, 0.7 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (0.08 g, 0.2 mmol) in dichloromethane (8 mL), and stirred at 25 C. for 2 h. Water was added to the mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a preparative thin layer chromatographic column (petroleum ether:ethyl acetate=1:2) to give tert-butyl (S)-2-[6-chloro-2-[2-(methoxymethyl)pyrimidine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (85.0 mg, yield: 73.5%) as a yellow oil. ES-API: [M+H-100].sup.+=387.30.

[0789] Step 5: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (54.1 mg, 0.2 mmol), potassium carbonate (72.3 mg, 0.5 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (12.6 mg, 17.4 mol) were added to a solution of the tert-butyl (S)-2-[6-chloro-2-[2-(methoxymethyl)pyrimidine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (0.085 g, 0.2 mmol) in 1,4-dioxane (4 mL) and water (0.8 mL). The system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness and purified by a preparative thin layer chromatographic column (ethyl acetate) to give a product tert-butyl (S)-2-[2-[2-(methoxymethyl)pyrimidine-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (65.0 mg, yield: 63.91%) as a yellow oil. ES-API: [M+H-100].sup.+=583.4.

[0790] Step 6: The tert-butyl (S)-2-[2-[2-(methoxymethyl)pyrimidine-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (65 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, spun to dryness, and purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-[2-(methoxymethyl)pyrimidin-4-yl]-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone (Z340, 30.3 mg, yield: 56.29%). ES-API: [M+1].sup.+=483.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.15 (s, 1H), 8.94-8.92 (m, 1H), 8.51-8.46 (m, 1H), 8.03-7.96 (m, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.58-7.51 (m, 1H), 7.32-7.26 (m, 1H), 7.09 (s, 1H), 5.15-4.86 (m, 2H), 4.78-4.75 (m, 2H), 4.42 (t, J=7.6 Hz, 1H), 4.10-3.99 (m, 1H), 3.80-3.72 (m, 1H), 3.57 (s, 3H), 3.34-3.25 (m, 1H), 3.17-3.01 (m, 3H), 2.37-2.30 (m, 3H), 2.04-1.77 (m, 4H).

Example 117. Synthesis of Compound Z355

##STR00385##

[0791] Step 1: 2,5-Dimethylpyrazole-3-carboxylic acid (58.8 mg, 0.42 mmol), 1-propylphosphonic anhydride (197.2 mg, 0.31 mmol, 50% in ethyl acetate) and triethylamine (63.08 mg, 0.62 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in dichloromethane (6 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by a preparative thin layer chromatographic column (petroleum ether/ethyl acetate=1/1) to give a product tert-butyl (S)-2-[6-chloro-2-(2,5-dimethylpyrazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (80.00 mg, yield: 83.88%) as a yellow oil. ES-API: [M+1].sup.+=459.2.

[0792] Step 2: The tert-butyl (S)-2-[6-chloro-2-(2,5-dimethylpyrazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (80 mg, 0.17 mmol) was dissolved in dioxane/water (4 mL/0.0.8 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (53.99 mg, 0.21 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (12.55 mg, 17.43 mol) and potassium carbonate (72.16 mg, 0.52 mmol) were added. The system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness and purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[2-(2,5-dimethylpyrazole-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (80.00 mg, yield: 82.75%). ES-API: [M+1].sup.+=555.3.

[0793] Step 3: The (S)-2-[2-(2,5-dimethylpyrazole-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (80 mg, 0.14 mmol) was dissolved in dichloromethane (2.0 mL). Trifluoroacetic acid (2.0 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-(1,3-dimethyl-1H-pyrazol-5-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z355, 27.00 mg, yield: 41.18%) as a yellow solid. ES-API: [M+1].sup.+=455.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.40 (s, 1H), 8.50 (s, 1H), 8.03 (s, 1H), 7.84-7.66 (m, 1H), 7.30 (s, 1H), 7.11 (s, 1H), 6.18 (s, 1H), 5.13-4.99 (m, 0.5H), 4.91-4.83 (m, 1H), 4.45-4.35 (m, 0.5H), 3.97-3.80 (m, 5H), 3.36-2.92 (m, 4H), 2.35 (s, 3H), 2.29 (s, 3H), 2.21-1.78 (m, 4H), 1.73-1.55 (m, 1H).

Example 118. Synthesis of Compound Z346

##STR00386##

[0794] Step 1: 1-Cyclopropyl-3-methyl-pyrazole-4-carboxylic acid (35.52 mg, 213.74 mol), 1-propylphosphonic anhydride (169.8 mg, 267.18 mol, 50% in ethyl acetate) and triethylamine (0.05 mL) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 178.12 mol) in dichloromethane (2 mL), and the mixture was stirred at 20 C. for 2 h. The reaction mixture was spun to dryness to remove a solvent and obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-[6-chloro-2-(1-cyclopropyl-5-methyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (65.00 mg, yield: 71.48%) as a yellow oil. ES-API: [M+H].sup.+=485.23.

[0795] Step 2: The tert-butyl (S)-2-[6-chloro-2-(1-cyclopropyl-5-methyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (65.00 mg, 134.02 mol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (44.06 mg, 0.17 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.24 mg, 0.014 mmol) and potassium carbonate (39.32 mg, 0.28 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.1 mL), and the system was warmed to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was quenched by the addition of water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=10/1) to give tert-butyl (S)-2-[2-(1-cyclopropyl-5-methyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (50.00 mg, yield: 57.50%) as a white solid. ES-API: [M+H].sup.+=581.32.

[0796] Step 3: The tert-butyl (S)-2-[2-(1-cyclopropyl-5-methyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (45 mg, 77.49 mol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid solution (2 mL) and stirred at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=5/1) to give a product to give (S)-(1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone (Z346, 18.00 mg, yield: 39.33%) as a pale yellow solid. ES-API: [M+H].sup.+=481.27. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.38 (s, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.33-8.28 (m, 1H), 7.90 (s, 1H), 7.64-7.56 (m, 2H), 7.28-7.23 (m, 1H), 4.95 (d, J=17.1 Hz, 1H), 4.80 (d, J=17.2 Hz, 1H), 4.73-4.59 (m, 1H), 3.80-3.72 (m, 2H), 3.61-3.42 (m, 2H), 2.99-2.95 (m, 2H), 2.41 (s, 3H), 2.30 (s, 3H), 2.21-1.93 (m, 3H), 1.25-1.20 (m, 2H), 1.09-0.97 (m, 4H).

Example 119. Synthesis of Compound Z341

##STR00387##

[0797] Step 1: Cyclopropylboronic acid (1.11 g, 13 mmol) and sodium carbonate (1.38 g, 13 mmol) were added to a solution of ethyl 3-methyl-1H-pyrazole-4-carboxylate (1 g, 6.49 mmol) in 1,2-dichloroethane (50 mL), and the mixture was warmed to 70 C. 2,2-Bipyridine (1.01 g, 6.49 mmol) and copper (II) acetate (1.18 g, 6.49 mmol) were added, and the reaction was continued at this temperature for 16 h. The mixture was poured into water (20 mL), extracted with dichloromethane, and concentrated to give a crude product as a yellow liquid. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give ethyl 1-cyclopropyl-3-methyl-pyrazole-4-carboxylate and ethyl 1-cyclopropyl-5-methyl-1H-pyrazole-4-carboxylate (610.00 mg, crude product) as a yellow liquid. ES-API: [M+H].sup.+=195.11.

[0798] Step 2: Sodium hydroxide (314 mg, 7.85 mmol) was added to a solution of a mixture (610 mg, 3.14 mmol) of the ethyl 1-cyclopropyl-3-methyl-pyrazole-4-carboxylate and the ethyl 1-cyclopropyl-5-methyl-1H-pyrazole-4-carboxylate in 1,4-dioxane (5 mL) and water (5 mL), and the system was then warmed to 70 C. for 3 h. Upon completion of the reaction, 1N hydrochloric acid was added to the solution to adjust the pH to 4. The reaction mixture was then extracted with ethyl acetate 3 times. The organic phases were combined and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Xbridge C18 19 mm*250 mm; mobile phase: acetonitrile:water:trifluoroacetic acid=30:70:0.04; flow rate: 1 ml/min, 9 min; column temperature: 30 C.) to give two monomers: 1-cyclopropyl-3-methyl-pyrazole-4-carboxylic acid (relative retention time was supplemented) (180.00 mg, peak 1, retention time: 6.55 min, yield: 34.49%). ES-API: [M+H].sup.+=167.08. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.11 (s, 1H), 3.67-3.62 (m, 1H), 2.25 (s, 3H), 1.17-0.78 (m, 4H). cyclopropyl-5-methyl-1H-pyrazole-4-carboxylic acid (relative retention time was supplemented) (120.00 mg, retention time: 7.40 min, yield: 22.99%). ES-API: [M+H].sup.+=167.08. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.61 (s, 1H), 3.54-3.48 (m, 1H), 2.52 (s, 3H), 1.04-0.96 (m, 4H).

[0799] Step 3: The ethyl 1-cyclopropyl-5-methyl-1H-pyrazole-4-carboxylate (35.52 mg, 213.74 mol), 1-propylphosphonic anhydride (169.8 mg, 267.18 mol, 50% in ethyl acetate) and triethylamine (0.05 mL) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 178.12 mol) in dichloromethane (2 mL), and the obtained mixture was stirred at 20 C. for 2 h. The reaction mixture was spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-[6-chloro-2-(1-cyclopropyl-3-methyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.00 mg, yield: 76.98%) as a yellow oil. ES-API: [M+H].sup.+=485.23.

[0800] Step 4: The tert-butyl (S)-2-[6-chloro-2-(1-cyclopropyl-3-methyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70 mg, 144.32 mol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (44.06 mg, 0.17 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.24 mg, 0.014 mmol) and potassium carbonate (39.32 mg, 0.28 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.1 mL), and the system was warmed to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was quenched by the addition of water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=10/1) to give tert-butyl (S)-2-[2-(1-cyclopropyl-3-methyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (45.00 mg, yield: 51.75%) as a white solid. ES-API: [M+H].sup.+=581.32.

[0801] Step 5: The tert-butyl (S)-2-[2-(1-cyclopropyl-3-methyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (45 mg, 77.49 mol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid solution (2 mL) and stirred at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=5/1) to give a product (S)-(1-cyclopropyl-3-methyl-1H-pyrazol-4-yl(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z341, 18.80 mg, yield: 44.13%) as a pale yellow solid.

Example 120. Synthesis of Compound Z314-1

##STR00388##

[0802] Step 1: N,N-Diisopropylethyl amine (400 mg, 3.10 mmol) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (175 mg, 0.46 mmol) were added to a mixture of tert-butyl (S)-2-(6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate (100 mg, 0.31 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (98 mg, 0.62 mmol) in dichloromethane (5 mL) successively and stirred at room temperature for 1 h. The reaction mixture was dissolved in dichloromethane (10 mL), and washed with water (5 mL) and saturated brine (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-50% tetrahydrofuran/petroleum ether) to give tert-butyl (S)-2-(6-chloro-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (70 mg, yield: 49%). ES-API: [M+H].sup.+=463.1.

[0803] Step 2: In the presence of protective nitrogen, a mixed solution of the tert-butyl (S)-2-(6-chloro-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (70 mg, 0.15 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (58 mg, 0.23 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (11 mg, 0.02 mmol) and potassium carbonate (63 mg, 0.46 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 120 C. for 2 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-10% methanol/dichloromethane) to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (50 mg, yield: 59%). ES-API: [M+H].sup.+=559.3.

[0804] Step 3: Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of the tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (50 mg, 90 mol) in dichloromethane (1 mL) under an ice bath condition and stirred at room temperature for 1 h. The reaction mixture was concentrated, and purified by prep-HPLC (formic acid method) to give (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-((S)-pyrrolidin-2-yl)isoindolin-2-yl)propan-1-one formate (Z314-1, 36 mg, purity: 100%, yield: 79%) as a white solid. ES-API: [M+H].sup.+=459.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.36 (s, 1H), 8.54-8.47 (m, 1H), 8.31 (s, 1H), 8.21-8.13 (m, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.27 (s, 1H), 5.31-5.17 (m, 2H), 4.84 (d, J=3.6 Hz, 1H), 4.81 (d, J=3.6 Hz, 1H), 4.38-4.21 (m, 1H), 3.29-3.17 (m, 1H), 3.15-3.01 (m, 1H), 2.33 (s, 3H), 2.29-2.17 (m, 1H), 2.08-1.83 (m, 2H), 1.84-1.72 (m, 1H), 1.66-1.57 (m, 3H).

Example 121. Synthesis of Compound Z347

##STR00389##

[0805] Step 1: Cyclopropylboronic acid (1.1 g, 13.0 mmol), sodium carbonate (1.3 g, 13.0 mmol), 2,2-bipyridine (1.0 g, 6.5 mmol) and copper acetate (1.3 g, 6.5 mmol) were added to a solution of ethyl 4-methyl-1H-pyrazole-3-carboxylate (1.0 g, 6.5 mmol) in 1,2-dichloroethane (20 mL) and stirred at 70 C. for 16 h. The reaction mixture was cooled to room temperature and then filtered out, poured into water, and extracted with ethyl acetate. The organic layers were combined, and dried over anhydrous sodium sulfate. The reaction mixture was spun to dryness, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give ethyl 1-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylate (0.3 g, yield: 23.8%) as a yellow oil. ES-API: [M+H].sup.+=195.1. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.23 (s, 1H), 4.35 (q, J=7.2 Hz, 2H), 3.62-3.55 (m, 1H), 2.23 (s, 3H), 1.36 (t, J=7.2 Hz, 3H), 1.13-1.07 (m, 2H), 1.04-0.96 (m, 2H).

[0806] Step 2: Sodium hydroxide (123.6 mg, 3.09 mmol) was added to a solution of the ethyl 1-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylate (0.3 g, 1.54 mmol) in methanol (5 mL) and water (15 mL) and stirred at 25 C. for 16 h. The mixture was concentrated. 1M Hydrochloric acid was added, and the obtained mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to give 1-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylic acid (200.00 mg, crude product) as a white solid. ES-API: [M+H].sup.+=167.1.

[0807] Step 3: The 1-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylic acid (69 mg, 0.4 mmol), 1-propylphosphonic anhydride (190.8 mg, 0.3 mmol, 50% in ethyl acetate) and triethylamine (63.1 mg, 0.6 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.2 mmol) in dichloromethane (2 mL) and stirred at 25 C. for 4 h. Water was added to the mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium chloride, filtered, concentrated, and purified by a preparative thin layer chromatographic column (petroleum ether:ethyl acetate=1:1) to give tert-butyl (S)-2-[6-chloro-2-(1-cyclopropyl-4-methyl-1H-pyrazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.0 mg, yield: 69.45%) as a yellow oil. ES-API: [M+H].sup.+=485.3.

[0808] Step 4: The tert-butyl (S)-2-[6-chloro-2-(1-cyclopropyl-4-methyl-1H-pyrazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (0.07 g, 0.14 mmol) was dissolved in dioxane/water (4 mL/0.8 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (44.7 mg, 0.17 mmol), potassium carbonate (59.75 mg, 0.43 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.4 mg, 14.4 mol) were added. The system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane:methanol=10:1) to give a product tert-butyl (S)-2-[2-(1-cyclopropyl-4-methyl-1H-pyrazole-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.0 mg, yield: 83.52%) as a yellow oil. ES-API: [M+H].sup.+=581.5.

[0809] Step 5: The tert-butyl (S)-2-[2-(1-cyclopropyl-4-methyl-1H-pyrazole-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.0 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane:methanol=8:1) to give (S)-(1-cyclopropyl-4-methyl-1H-pyrazol-3-yl)-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydro-1H-isoquinolin-2-yl]methanone (Z347, 14.8 mg, yield: 25.55%) as a yellow solid. ES-API: [M+H].sup.+=481.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.75 (s, 1H), 8.51 (s, 1H), 8.10-7.94 (m, 1H), 7.88-7.68 (m, 1H), 7.38-7.27 (m, 2H), 7.09 (s, 1H), 5.23-5.05 (m, 1H), 4.94-4.67 (m, 1H), 4.55-4.25 (m, 1H), 4.12-3.85 (m, 2H), 3.67-3.52 (m, 1H), 3.43-3.28 (m, 1H), 3.18-2.94 (m, 3H), 2.34 (s, 3H), 2.17 (s, 3H), 2.12-1.96 (m, 2H), 1.96-1.82 (m, 1H), 1.80-1.64 (m, 1H), 1.21-1.09 (m, 2H), 1.07-0.96 (m, 2H).

Example 122. Synthesis of Compound Z342

##STR00390##

[0810] Step 1: Cyclopropylboronic acid (1.1 g, 13.0 mmol), sodium carbonate (1.3 g, 13.0 mmol), 2,2-bipyridine (1.0 g, 6.5 mmol) and copper acetate (1.3 g, 6.5 mmol) were added to a solution of ethyl 4-methyl-1H-pyrazole-3-carboxylate (1.0 g, 6.5 mmol) in 1,2-dichloroethane (20 mL) and stirred at 70 C. for 16 h. The reaction mixture was cooled to room temperature and then filtered out, poured into water, and extracted with ethyl acetate. The organic layers were combined, and dried over anhydrous sodium sulfate. The reaction mixture was spun to dryness, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give ethyl 1-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylate (0.5 g, yield: 39.7%) as a yellow oil. ES-API: [M+H].sup.+=195.1. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.21 (s, 1H), 4.34 (q, J=7.2 Hz, 2H), 4.16-4.09 (m, 1H), 2.22 (s, 3H), 1.38 (t, J=7.2 Hz, 3H), 1.21-1.16 (m, 2H), 1.02-0.96 (m, 2H).

[0811] Step 2: Sodium hydroxide (185.3 mg, 4.63 mmol) was added to a solution of the ethyl 1-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylate (0.5 g, 2058 mmol) in methanol (5 mL) and water (15 mL) and stirred at 25 C. for 16 h. The mixture was concentrated. IM Hydrochloric acid was added, and the obtained mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to give 1-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylic acid (300.00 mg, crude product) as a white solid. ES-API: [M+H].sup.+=167.1.

[0812] Step 3: The 1-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylic acid (69 mg, 0.4 mmol), 1-propylphosphonic anhydride (190.8 mg, 0.3 mmol, 50% in ethyl acetate) and triethylamine (63.1 mg, 0.6 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.2 mmol) in dichloromethane (2 mL) and stirred at 25 C. for 4 h. Water was added to the mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a preparative thin layer chromatographic column (petroleum ether:ethyl acetate=1:1) to give tert-butyl (S)-2-[6-chloro-2-(1-cyclopropyl-4-methyl-1H-pyrazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60.00 mg, yield: 59.53%) as a yellow oil. ES-API: [M+H].sup.+=485.3.

[0813] Step 4: The tert-butyl (S)-2-[6-chloro-2-(1-cyclopropyl-4-methyl-1H-pyrazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60 mg, 0.12 mmol) was dissolved in dioxane/water (4 mL/0.8 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (38.3 mg, 0.15 mmol), potassium carbonate (51.21 mg, 0.37 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.91 mg, 12.37 mol) were added. The system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness and purified by a preparative thin layer chromatographic column (dichloromethane:methanol=10:1) to give a product tert-butyl (S)-2-[2-(1-cyclopropyl-4-methyl-1H-pyrazole-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60.00 mg, yield: 83.52%) as a yellow oil. ES-API: [M+H].sup.+=581.4.

[0814] Step 5: The tert-butyl (S)-2-[2-(1-cyclopropyl-4-methyl-1H-pyrazole-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60.0 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane:methanol=8:1) to give (S)-(1-cyclopropyl-4-methyl-1H-pyrazol-3-yl)-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydro-2(1H)-isoquinolin-yl]methanone (Z342, 30.00 mg, yield: 60.42%) as a yellow solid. ES-API: [M+H].sup.+=481.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.19 (s, 1H), 8.57 (s, 1H), 8.01-7.79 (m, 2H), 7.21-7.19 (m, 1H), 7.12-6.96 (m, 2H), 5.21-4.85 (m, 1H), 4.81-4.66 (m, 1H), 4.62-4.27 (m, 1H), 3.73-3.23 (m, 5H), 3.06-2.60 (m, 2H), 2.46-2.36 (m, 1H), 2.25 (s, 3H), 2.20-1.89 (m, 6H), 1.35-1.17 (m, 2H), 0.96-0.75 (m, 2H).

Example 123. Synthesis of Compound Z327

##STR00391##

[0815] Step 1: 1-(4-Methyl-2-pyridyl)ethanone (1 g, 7.40 mmol) was dissolved in tetrahydrofuran (20 mL) in a three-neck flask under a dry nitrogen atmosphere. The flask was cooled in an ice bath, and methylmagnesium bromide (2.65 g, 22.20 mmol, 20 mL) was added dropwise. The solution was warmed to 40 C. and stirred for 3 h. The reaction was monitored by LCMS for completion. The reaction mixture was then cooled in an ice bath, quenched by the addition of saturated aqueous ammonium chloride solution (50 ml), and then extracted with ethyl acetate (40 ml5). The organic was washed with saturated brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-35% ethyl acetate in petroleum ether) to give a product 2-(4-methyl-2-pyridyl)propan-2-ol (375.00 mg, yield: 33.52%) as a yellow liquid. ES-API: [M+H-100].sup.+=152.2.

[0816] Step 2: Potassium permanganate (1.57 g, 9.92 mmol) was added to a solution of the 2-(4-methyl-2-pyridyl)propan-2-ol (375 mg, 2.48 mmol) in water (15 mL) at 60 C. The reaction was heated to 100 C. and stirred for 20 h. The reaction was monitored by LCMS for completion. The suspension was cooled to 25 C. and then filtered with diatomaceous earth. The aqueous phase was washed with ethyl acetate. Water was then removed, and the obtained mixture was freeze-dried to give a product 2-(1-hydroxy-1-methyl-ethyl)pyridine-4-carboxylic acid (450 mg, crude product) as a white solid. ES-API: [M+H].sup.+=182.0.

[0817] Step 3: The 2-(1-hydroxy-1-methyl-ethyl)pyridine-4-carboxylic acid (64.55 mg, 0.36 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (101.53 mg, 0.27 mmol) and triethylamine (180.24 mg, 1.78 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1, 2, 3, 4-tetrahydroisoquinolin-8-yl) pyrrolidine-1-carboxylate (60 mg, 0.18 mmol) in dichloromethane (2 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/1, Rf=0.5) to give a product tert-butyl (S)-2-(6-chloro-2-(2-(2-hydroxypropan-2-yl)isonicotinoyl)-1,2,3,4-tetrahydroisoquinol-8-yl)pyrrolidine-1-carboxylate (34 mg, yield: 38.17%). ES-API: [M+H].sup.+=500.3.

[0818] Step 4: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2, 3-b]pyridine (29.73 mg, 0.12 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II (6.91 mg, 0.0096 mmol) and potassium carbonate (39.74 mg, 0.29 mmol) were added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-(2-(2-hydroxypropan-2-yl)isonicotinoyl)-1,2,3,4-tetrahydroisoquinol-8-yl)pyrrolidine-1-carboxylate (48 mg, 0.096 mmol) in dioxane/water (2 ml/0.4 ml), and the mixture was heated to 110 C. and stirred in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(2-(2-(2-hydroxypropan-2-yl)isonicotinoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (45 mg, yield: 78.69%). ES-API: [M+H].sup.+=596.4.

[0819] Step 5: Trifluoroacetic acid (1 mL) was added to a solution of the compound tert-butyl (S)-2-(2-(2-(2-hydroxypropan-2-yl)isonicotinoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (45 mg, 0.076 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(2-(2-hydroxypropan-2-yl)pyridin-4-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z327, 13.6 mg, yield: 36.33%) as a white powder. ES-API: [M+H].sup.+=496.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.55-9.34 (m, 1H), 8.67-8.60 (m, 1H), 8.49 (d, J=15.0 Hz, 1H), 7.97 (d, J=12.6 Hz, 1H), 7.89-7.62 (m, 1H), 7.58-7.46 (m, 1H), 7.31-7.27 (m, 1H), 7.24-7.18 (m, 1H), 7.09 (s, 1H), 5.14-4.79 (m, 2H), 4.63-4.50 (m, 1H), 4.11-3.78 (m, 1H), 3.63-3.39 (m, 2H), 3.31-3.16 (m, 1H), 3.11-2.79 (m, 3H), 2.47-2.36 (m, 1H), 2.34 (s, 3H), 2.15-1.89 (m, 2H), 1.87-1.76 (m, 1H), 1.64-1.52 (m, 6H).

Example 124. Synthesis of Compound Z333

##STR00392##

[0820] Step 1: 2-(2-Methylpyridin-4-yl)acetic acid (179.7 mg, 1.19 mmol), 1-propylphosphonic anhydride (756.8 mg, 1.19 mmol, 50% in ethyl acetate) and triethylamine (0.05 mL) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (200 mg, 0.595 mmol) in dichloromethane (2 mL), and the obtained mixture was stirred at 20 C. for 2 h. The reaction mixture was spun to dryness to remove a solvent and obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-[7-chloro-2-[2-(2-methyl-4-pyridyl)acetyl]-1,2,3,4-tetrahydroisoquinolin-5-yl]pyrrolidine-1-carboxylate as a yellow oil (160 mg, yield: 57.1%). ES-API: [M+H].sup.+=470.20

[0821] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (105.45 mg, 408.51 mol), potassium carbonate (140.94 mg, 1.02 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (24.51 mg, 34.04 mol) were added to a solution of the compound tert-butyl (S)-2-[7-chloro-2-[2-(2-methyl-4-pyridyl)acetyl]-1,2,3,4-tetrahydroisoquinolin-5-yl]pyrrolidine-1-carboxylate (0.16 g, 340.42 mol) in dioxane/water (4 mL/0.8 mL), and the mixture was heated to 100 C. and stirred in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-(2-methylpyridin-4-yl) acetyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100.00 mg, yield: 51.93%) as a yellow oil. ES-API: [M+H].sup.+=566.40.

[0822] Step 3: Trifluoroacetic acid (2 ml) was added to a solution of the compound tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-(2-methylpyridin-4-yl) acetyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (100.00 mg, 176.77 mol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give (S)-2-(2-methyl-4-pyridyl)-1-[7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-pyrrolidin-2-yl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (Z333, 20.00 mg, yield: 24.30%) as a yellow solid. ES-API: [M+H].sup.+=467.3.

Example 125. Synthesis of Compound Z365

##STR00393##

[0823] Step 1: tert-butyl (S)-2-(6-bromoisochroman-8-yl)pyrrolidine-1-carboxylate (660 mg, 1.726 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (632.12 mg, 2.590 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (124.30 mg, 0.173 mmol), potassium carbonate (714.73 mg, 5.18 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 10 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system reacted under microwave at 110 C. for 50 min. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (S)-2-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (500 mg, yield: 69%). ES-API: [M+H].sup.+=420.3.

[0824] Step 2: The tert-butyl (S)-2-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (500 mg, 1.2 mmol), N-bromosuccinimide (254.5 mg, 1.43 mmol) and acetonitrile (20 mL) were added to a 25 mL single-neck round-bottom flask and stirred at room temperature for 1 h. Ethyl acetate (30 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (S)-2-(6-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (550 mg, yield: 92.6%). ES-API: [M+H].sup.+=498.1.

[0825] Step 3: The tert-butyl (S)-2-(6-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.2 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one (208.7 mg, 0.8 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14.5 mg, 0.02 mmol), sodium bicarbonate (50.6 mg, 0.6 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 25 mL single-neck round-bottom flask. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system reacted under microwave at 100 C. for 20 min. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with 5 mL of saturated brine (5 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (S)-2-(6-(3-(3-oxo-1,3-dihydroisobenzofuran-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (60 mg, yield: 54%). ES-API: [M+H].sup.+=552.3.

[0826] Step 4: The tert-butyl (S)-2-(6-(3-(3-oxo-1,3-dihydroisobenzofuran-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.11 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness.

[0827] The crude product was purified by prep-HPLC (formic acid method) to give (S)-6-(5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)isobenzofuran-1(3H)-one (Z365, 30 mg, yield: 55.4%). ES-API: [M+H].sup.+=452.3.

Example 126. Synthesis of Compound Z364

##STR00394##

[0828] Step 1: tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (200 mg, 0.59 mmol), 3-bromopyridine (281.4 mg, 1.78 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (108.7 mg, 0.12 mmol), cesium carbonate (580.7 mg, 1.78 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 10 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system reacted under microwave at 110 C. for 3 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (S)-2-(6-chloro-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (130 mg, yield: 52.9%). ES-API: [M+H].sup.+=414.2.

[0829] Step 2: The tert-butyl (S)-2-(6-chloro-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (20 mg, 0.05 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (18.7 mg, 0.07 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (3.48 mg, 0.005 mmol), potassium carbonate (20 mg, 0.145 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 25 mL single-neck round-bottom flask. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system reacted under microwave at 110 C. for 1 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (20 mg, yield: 81%). ES-API: [M+H].sup.+=510.3.

[0830] Step 3: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (20 mg, 0.04 mmol), trifluoroacetic acid (1 mL) and dichloromethane (2 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude product was purified by prep-HPLC (formic acid method) to give (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-3-yl)-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z364, 4 mg, yield: 24.9%). ES-API: [M+H].sup.+=410.2.

Example 127. Synthesis of Compound Z323

##STR00395##

[0831] Step 1: In the presence of protective nitrogen, a mixed solution of tert-butyl (S)-2-(6-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (74 mg, 0.15 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (44 mg, 0.18 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II) (11 mg, 0.02 mmol) and potassium carbonate (62 mg, 0.45 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 85 C. for 1 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-10% methanol/dichloromethane) to give tert-butyl (S)-2-(6-(3-(imidazo[1,2-a]pyridin-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (40 mg, yield: 50%) as a clear oily liquid. ES-API: [M+H].sup.+=536.3.

[0832] Step 2: Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of the tert-butyl (S)-2-(6-(3-(imidazo[1,2-a]pyridin-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (40 mg, 75 mol) in dichloromethane (1 mL) under an ice bath condition and stirred at room temperature for 1 h. The reaction mixture was concentrated, neutralized with 7M amine-methanol (5 mL), concentrated, and then purified by prep-HPLC (formic acid) to give (S)-7-(5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[1,2-a]pyridine carboxylate (Z323, 11 mg, purity: 100%, yield: 31%) as a white solid. ES-API: [M+H].sup.+=436.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.21 (s, 1H), 8.67-8.44 (m, 3H), 8.34 (s, 1H), 8.15 (s, 1H), 8.09-7.85 (m, 2H), 7.79 (s, 1H), 7.69-7.44 (m, 2H), 7.40 (d, J=7.1 Hz, 1H), 5.03-4.86 (m, 1H), 4.88-4.73 (m, 1H), 4.35 (t, J=8.8 Hz, 1H), 4.00-3.82 (m, 3H), 3.36-3.24 (m, 1H), 3.20- 3.09 (m, 1H), 3.00-2.83 (m, 1H), 2.36-2.21 (m, 1H), 2.07-1.71 (m, 3H).

Example 128. Synthesis of Compound Z330

##STR00396##

[0833] Step 1: 2-Methylpyrimidine-4-carboxylic acid (29.5 mg, 213.74 mol), 1-propylphosphonic anhydride (169.8 mg, 267.18 mol, 50% in ethyl acetate) and triethylamine (0.05 mL) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 178.12 mol) in dichloromethane (2 mL), and the obtained mixture was stirred at 20 C. for 2 h. The reaction mixture was spun to dryness to remove a solvent and obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-[6-chloro-2-(2-methylpyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate as a yellow oil (70.00 mg, yield: 86.00%). ES-API: [M+H].sup.+=457.20.

[0834] Step 2: The tert-butyl (S)-2-[6-chloro-2-(2-methylpyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.00 mg, 153.18 mol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (47.45 mg, 0.18 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.24 mg, 0.014 mmol) and potassium carbonate (42.34 mg, 0.31 mmol) were dissolved in 1,4-dioxane solution (2 mL) and water (0.1 mL), and the system was warmed to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was quenched by the addition of water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=10/1) to give tert-butyl (S)-2-[2-(2-methylpyrimidine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (50.00 mg, yield: 60.42%) as a white solid. ES-API: [M+H].sup.+=553.29.

[0835] Step 3: The tert-butyl (S)-2-[2-(2-methylpyrimidine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (50 mg, 90.47 mol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid solution (2 mL) and stirred at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane:methanol=5/1) to give a product (S)-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl](2-methylpyrimidin-4-yl)methanone (Z330, 14.0 mg, yield: 33.51%) as a pale yellow solid. ES-API: [M+H].sup.+=453.24.

Example 129. Synthesis of Compound Z331

##STR00397##

[0836] Step 1: 6-Methylpyrimidine-4-carboxylic acid (49.20 mg, 0.36 mmol), 1-propylphosphonic anhydride (337.1 mg, 0.53 mmol, 50% in ethyl acetate) and triethylamine (54.07 mg, 0.53 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.18 mmol) in dichloromethane (2 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/1, Rf=0.5) to give a product tert-butyl (S)-2-(6-chloro-2-(6-methylpyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (58 mg, yield: 71.26%). ES-API: [M+H-100].sup.+=357.2.

[0837] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (39.31 mg, 0.15 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.13 mg, 0.013 mmol) and potassium carbonate (52.55 mg, 0.38 mmol) were added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-(6-methylpyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (58 mg, 0.13 mmol) in dioxane/water (2 mL/0.4 mL), and the mixture was heated to 110 C. and stirred in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(6-methylpyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, yield: 71.28%). ES-API: [M+H].sup.+=553.4.

[0838] Step 3: Trifluoroacetic acid (1 mL) was added to a solution of the compound tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(6-methylpyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.09 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water), B: pure acetonitrile, flow rate: 80 mL/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(6-methylpyrimidin-4-yl)methanone (Z331, 14.2 mg, yield: 34.6%) as a white powder. ES-API: [M+H].sup.+=453.3. .sup.1HNMR (400 MHz, CDCl.sub.3) 9.53-9.27 (m, 1H), 9.14 (s, 1H), 8.54-8.48 (m, 1H), 7.95 (d, J=11.6 Hz, 1H), 7.88-7.69 (m, 1H), 7.53 (d, J=19.3 Hz, 1H), 7.22 (d, J=19.0 Hz, 1H), 7.07 (s, 1H), 5.16-4.88 (m, 2H), 4.67-4.06 (m, 1H), 3.91-3.59 (m, 2H), 3.51-3.27 (m, 1H), 3.29-2.95 (m, 3H), 2.62 (s, 3H), 2.42-2.34 (m, 1H), 2.33 (s, 3H), 2.15-1.79 (m, 3H).

Example 130. Synthesis of Compound Z328

##STR00398##

[0839] Step 1: 2-Methylpyrimidine-5-carboxylic acid (29.5 mg, 213.74 mol), 1-propylphosphonic anhydride (170 mg, 267.18 mol, 50% in ethyl acetate) and triethylamine (0.05 mL) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 178.12 mol) in dichloromethane (2 mL). The mixture was stirred at 20 C. for 2 h. The reaction mixture was spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-[6-chloro-2-(2-methylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.00 mg, yield: 86.00%) as a yellow oil. ES-API: [M+H].sup.+=457.20.

[0840] Step 2: The tert-butyl (S)-2-[6-chloro-2-(2-methylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.00 mg, 153.18 mol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (47.45 mg, 0.18 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.24 mg, 0.014 mmol) and potassium carbonate (42.34 mg, 0.31 mmol) were dissolved in 1,4-dioxane solution (2 mL) and water (0.1 mL), and the system was warmed to 100 C. for 2 h. The reaction was monitored by LCMS for completion. The reaction mixture was quenched by the addition of water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, and then purified by a thin layer chromatographic column (dichloromethane/methanol=10/1) to give tert-butyl (S)-2-[2-(2-methylpyrimidine-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60.00 mg, yield: 70.87%) as a white solid. ES-API: [M+H].sup.+=553.29.

[0841] Step 3: The tert-butyl (S)-2-[2-(2-methylpyrimidine-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (50 mg, 90.47 mol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid solution (2 mL) and stirred at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=5/1) to give (S)-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl](2-methylpyrimidin-5-yl)methanone (Z328, 13.7 mg, yield: 33.13%) as a pale yellow solid. ES-API: [M+H].sup.+=453.24. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.49-9.11 (m, 1H), 8.87-8.73 (m, 2H), 8.46 (s, 1H), 7.99 (s, 1H), 7.89-7.62 (m, 1H), 7.25-7.19 (m, 1H), 7.08 (s, 1H), 5.07-4.79 (m, 2H), 4.61-4.02 (m, 1H), 3.69-3.38 (m, 2H), 3.30-3.17 (m, 1H), 3.14-2.85 (m, 3H), 2.81 (s, 3H), 2.46-2.38 (m, 1H), 2.34 (s, 3H), 2.04-1.85 (m, 3H).

Example 131. Synthesis of Compound Z336

##STR00399##

[0842] Step 1: 1-(Difluoromethyl)-1H-pyrazole-4-carboxylic acid (60.0 mg, 0.42 mmol), 1-propylphosphonic anhydride (337.1 mg, 0.53 mmol, 50% in ethyl acetate) and triethylamine (0.1 mL) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (120 mg, 0.18 mmol) in dichloromethane (2 mL), and the mixture was stirred at 20 C. for 2 h. The reaction mixture was spun to dryness to remove a solvent and obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-[6-chloro-2-(1-(difluoromethyl)-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate as a yellow oil (160.00 mg, yield: 55.02%). ES-API: [M+H].sup.+=481.18.

[0843] Step 2: The tert-butyl (S)-2-[6-chloro-2-(1-(difluoromethyl)-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (160 mg, 332.69 mol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (103.06 mg, 0.40 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (23.94 mg, 0.033 mmol) and potassium carbonate (91.96 mg, 0.67 mmol) were dissolved in 1,4-dioxane solution (2 mL) and water (0.1 mL), and the system was warmed to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was quenched by the addition of water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, and then purified by a thin layer chromatographic column (dichloromethane/methanol=10/1) to give tert-butyl (S)-2-[2-(1-(difluoromethyl)-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (120.00 mg, yield: 62.55%) as a white solid. ES-API: [M+H].sup.+=577.27.

[0844] Step 3: The tert-butyl (S)-2-[2-(1-(difluoromethyl)-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (120 mg, 208.10 mol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid solution (2 mL) and stirred at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=5/1) to give a product (S)-(1-(difluoromethyl)-1H-pyrazol-4-yl)-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone (Z336, 35.0 mg, yield: 31.80%) as a pale yellow solid. ES-API: [M+H].sup.+=477.22.

Example 132. Synthesis of Compound Z335

##STR00400##

[0845] Step 1: 1-Ethylpyrazole-4-carboxylic acid (99.85 mg, 0.71 mmol), 1-propylphosphonic anhydride (337 mg, 0.53 mmol, 50% in ethyl acetate) and triethylamine (108 mg, 1.07 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (0.12 g, 0.36 mmol) in dichloromethane (5 mL) and stirred at 25 C. for 4 h. Water was added to the mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium chloride, filtered, concentrated, and purified by a preparative thin layer chromatographic column (petroleum ether:ethyl acetate=1:2) to give tert-butyl (S)-2-[6-chloro-2-(1-ethyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]pyrrolidine-1-carboxylate (120.00 mg, yield: 73.39%) as a yellow oil. ES-API: [M+H].sup.+=459.3.

[0846] Step 2: The tert-butyl (S)-2-[6-chloro-2-(1-ethyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]pyrrolidine-1-carboxylate (120 mg, 0.26 mmol) was dissolved in dioxane/water (4 mL/0.8 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (80.98 mg, 0.31 mmol), potassium carbonate (108 mg, 0.78 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (18.8 mg, 26.14 mol) were added, and the system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane:methanol=20:1) to give a product tert-butyl (S)-2-[2-(1-ethyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]pyrrolidine-1-carboxylate (100.00 mg, yield: 62.06%) as a yellow oil. ES-API: [M+H].sup.+=555.4.

[0847] Step 3: The tert-butyl (S)-2-[2-(1-ethyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]pyrrolidine-1-carboxylate (100.0 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane:methanol=10:1) to give (S)-(1-ethyl-1H-pyrazol-4-yl)-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone (Z335, 23.90 mg, yield: 29.16%) as a red solid. ES-API: [M+H].sup.+=455.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.00 (s, 1H), 8.49 (s, 1H), 8.01 (s, 1H), 7.87 (s, 1H), 7.75 (s, 2H), 7.29 (s, 1H), 7.11 (s, 1H), 5.12-4.98 (m, 1H), 4.96-4.75 (m, 1H), 4.51-4.29 (m, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.04-3.81 (m, 2H), 3.36-3.24 (m, 1H), 3.16-2.96 (m, 3H), 2.34 (s, 3H), 2.30-2.14 (m, 1H), 2.05-1.85 (m, 2H), 1.73-1.61 (m, 1H), 1.51 (t, J=7.2 Hz, 3H).

Example 133. Synthesis of Compound Z356

##STR00401##

[0848] Step 1: tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.18 mmol) and triethylamine (54 mg, 0.53 mmol) were dissolved in dichloroethane (5 mL). 4-Morpholinecarbonyl chloride (53 mg, 0.36 mmol) was added under an ice bath condition and stirred at room temperature for 2 h. The obtained mixture was diluted with dichloromethane (15 mL), washed with saturated sodium bicarbonate solution (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (methanol/dichloromethane: 0-5%) to give a desired product tert-butyl (S)-2-(6-chloro-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (65 mg, yield: 81.1%) as a pale pink solid. ES-API: [M+Na].sup.+=473.2.

[0849] Step 2: The tert-butyl (S)-2-(6-chloro-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (65 mg, 0.14 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (56 mg, 0.22 mmol), 2-dicyclohexylphosphine-2,6-dimethoxy-biphenyl (6 mg, 0.014 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (11 mg, 0.014 mmol), potassium carbonate (60 mg, 0.43 mmol), 1,4-dioxane (5 mL) and water (1 mL) were added to a 25 mL round-bottom flask. The system was replaced with nitrogen three times and reacted at 110 C. for 2 h. The reaction was cooled to room temperature, and ethyl acetate (50 mL) was added. The obtained mixture was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (methanol/dichloromethane: 0-5%) to give a desired product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (65 mg, yield: 82.5%) as a pale yellow solid. ES-API: [M+H].sup.+=546.4.

[0850] Step 3: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (65 mg, 0.12 mmol) was dissolved in methanol (1 mL). 4.0M Hydrogen chloride-dioxane solution (4 mL, 16.0 mmol) was added, and the system reacted at room temperature for 2 h. The reaction mixture was concentrated. 7.0M Ammonia-methanol solution (5 mL) was added, and a solvent was spun to dryness. The crude product was purified by prep-HPLC (formic acid method) to give a desired product (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(morpholino)methanone (Z356, formate, 36 mg, yield: 61.5%) as a white solid. ES-API: [M+H].sup.+=446.3 (free base). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.37 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.77 (s, 1H), 7.47 (s, 1H), 7.27 (s, 1H), 4.54 (d, J=16.5 Hz, 1H), 4.48-4.36 (m, 2H), 3.68-3.54 (m, 4H), 3.50-3.39 (m, 2H), 3.34-3.08 (m, 6H), 3.02-2.89 (m, 2H), 2.36-2.23 (m, 4H), 2.04-1.87 (m, 2H), 1.81-1.68 (m, 1H).

Example 134. Synthesis of Compound Z256

##STR00402##

[0851] Step 1: 1-Bromo-5-chloro-2-methyl-3-nitrobenzene (4.64 g, 18.524 mmol), N-bromosuccinimide (3.63 g, 20.377 mmol) and benzoyl peroxide (0.45 g, 1.852 mmol) were added to carbon tetrachloride (50 mL), and the system was heated to reflux in an oil bath overnight. After the reaction mixture was spun to dryness to remove a solvent, the obtained mixture was diluted with ethyl acetate (30 mL), washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1-bromo-2-(bromomethyl)-5-chloro-3-nitrobenzene (6.1 g, 18.520 mmol, crude product) which was directly used in the next step without purification. ES-API: [M+H].sup.+=329.8.

[0852] Step 2: The 1-bromo-2-(bromomethyl)-5-chloro-3-nitrobenzene (6.1 g, 18.520 mmol) in tetrahydrofuran (30 mL) was added to a 70% ethylamine in water (11.5 mL, 185.202 mmol) and stirred at room temperature for 1 h. The obtained mixture was poured into water (50 mL), and extracted with ethyl acetate (50 mL3). The organic phase layers were combined, washed with saturated brine solution (100 mL1), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=20/80) to give N-(2-bromo-4-chloro-6-nitrophenyl)ethanamine (2.5 g, yield: 45.98%.) ES-API: [M+H].sup.+=292.9.

[0853] Step 3: The N-(2-bromo-4-chloro-6-nitrophenyl)ethanamine (2.5 g, 8.516 mmol) was dissolved in a solution of ethanol (100 mL) and water (20 mL). Iron (2.38 g, 42.582 mmol) and ammonium chloride (4.56 g, 85.164 mmol) were added. The mixture was stirred at 90 C. for 1 h. The reaction mixture was filtered with diatomaceous earth, and concentrated to give 3-bromo-5-chloro-2-[(ethylamino)methyl]aniline (2.3 g, crude product) which was directly used in the next step without purification. ES-API: [M+H].sup.+=263.1.

[0854] Step 4: The 3-bromo-5-chloro-2-[(ethylamino)methyl]aniline (2.1 g, 7.968 mmol) was dissolved in tetrahydrofuran solution (30 mL). Lithium bis-trimethylsilylamide (39.839 mL, 39.839 mmol) was added under an ice-water bath condition and stirred at 0 C. for 10 min. N,N-Carbonyldiimidazole (1.68 g, 10.358 mmol) was slowly added, and the mixture was stirred at 0 C. for 1 h. The reaction was quenched with IM hydrochloric acid (50 mL). The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (100 mL3). The organic layers were combined, washed with saturated brine solution (100 mL1), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=40/60) to give 5-bromo-7-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline (850 mg, yield: 36.84%). ES-API: M+H]+=288.9.

[0855] Step 5: The 5-bromo-7-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline (850 mg, 2.935 mmol) and potassium vinyltrifluoroborate (786.58 mg, 5.87 mmol) were dissolved in ethanol (20 mL). [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (239 mg, 0.293 mmol) and triethylamine (592.8 mg, 5.87 mmol) were added. The mixture was degassed with nitrogen and stirred at 85 C. for 3 h. The obtained mixture was poured into water (30 mL), and extracted with ethyl acetate (30 mL3). The organic layers were combined, washed with saturated brine solution (30 mL1), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=50/50) to give 7-chloro-3-ethyl-2-oxo-5-vinyl-1,2,3,4-tetrahydroquinazoline (556 mg, yield: 80%). ES-API: M+H]+=237.0.

[0856] Step 6: The 7-chloro-3-ethyl-2-oxo-5-vinyl-1,2,3,4-tetrahydroquinazoline (450 mg, 1.901 mmol) was dissolved in tetrahydrofuran (30 mL) and water (15 mL). Sodium periodate (2439.81 mg, 11.407 mmol) and potassium osmate dihydrate (70.05 mg, 0.190 mmol) were added and stirred at room temperature for 1 h. The obtained mixture was poured into water (30 mL), and extracted with ethyl acetate (30 mL3). The organic layers were combined, washed with saturated sodium chloride solution (30 mL1), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE/EA=50/50) to give 7-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-5-carbaldehyde (250 mg, yield: 55.10%). ES-API: [M+H].sup.+=239.0.

[0857] Step 7: The 7-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-5-carbaldehyde (250 mg, 1.047 mmol) and (S)-2-methylpropane-2-sulfinamide (253.91 mg, 2.095 mmol) were dissolved in dichloromethane (20 mL). Tetraethyl titanate (955.75 mg, 4.190 mmol) was added. The mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was poured into saturated brine (10 mL) and washed. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=70/30) to give (S)N-((7-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl)methylene)-2-methylpropane-2-sulfinamide (350 mg, yield: 97.8%). ES-API: [M+H].sup.+=342.1.

[0858] Step 8: (1,3-Dioxane-2-ethyl)magnesium bromide (16.381 mL, 8.191 mmol) was added to a solution of the (S)N-((7-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl)methylene)-2-methylpropane-2-sulfinamide (350 mg, 1.024 mmol) in tetrahydrofuran at 78 C. The mixture was stirred at 78 C. for 10 min. The reaction was quenched with aqueous ammonium chloride solution (20 mL), and the reaction mixture was extracted with ethyl acetate (50 mL3). The organic layers were combined, washed with saturated sodium chloride solution (100 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/tetrahydrofuran=10/90) to give (S)N((S)-1-(7-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl)-3-(1,3-dioxo-2-yl)propyl)-2-methylpropane-2-sulfinamide (320 mg, yield: 68.24%). ES-API: [M+H].sup.+=342.1.

[0859] Step 9: A solution of trifluoroacetic acid (8 mL) and water (0.5 mL) was added to the (S)N((S)-1-(7-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl)-3-(1,3-dioxo-2-yl)propyl)-2-methylpropane-2-sulfinamide (300 mg, 0.655 mmol) and stirred at room temperature for 0.5 h. Triethylsilane (2.092 mL, 13.100 mmol) was then added, and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to give (S)-7-chloro-3-ethyl-5-(pyrrolidin-2-yl)-3,4-dihydroquinazolin-2(1H)-one (400 mg, crude product) which was directly used in the next reaction without purification. ES-API: [M+H].sup.+=280.1.

[0860] Step 10: The (S)-7-chloro-3-ethyl-5-(pyrrolidin-2-yl)-3,4-dihydroquinazolin-2(1H)-one (400 mg, crude product) was dissolved in dichloromethane (10 mL). N,N-Diisopropylethyl amine (923.90 mg, 7.149 mmol) and di-tert-butyl dicarbonate (624.08 mg, 2.859 mmol) were added and stirred at room temperature for 1 h. The obtained mixture was poured into water (10 mL) and extracted with dichloromethane (10 mL). The organic layers were combined, washed with saturated sodium chloride solution (20 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=50/50) to give (2S)-tert-butyl 2-(7-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl)-tetrahydropyran-1-carboxylate (220 mg, yield of the 2 steps: 88.39%). ES-API: [M+H].sup.+=380.2.

[0861] Step 11: The (2S)-tert-butyl 2-(7-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl)-tetrahydropyran-1-carboxylate (50 mg, 0.132 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (50.96 mg, 0.197 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.48 mg, 0.013 mmol) and potassium carbonate (54.57 mg, 0.395 mmol) were added to 1,4-dioxane (3 mL) and water (0.5 mL). the system was replaced with nitrogen and reacted under microwave at 115 C. for 0.5 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-(3-ethyl-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl) pyrrolidine-1-carboxylate (30 mg, yield: 47.92%). ES-API: [M+H].sup.+=476.3.

[0862] Step 12: The tert-butyl (S)-2-(3-ethyl-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl) pyrrolidine-1-carboxylate (30 mg, 0.063 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (1 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again to give a crude product. The crude product was purified by prep-HPLC alkaline process (ammonia water) to give (S)-3-ethyl-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-3,4-dihydroquinazolin-2(1H)-one (Z256, 3 mg, yield: 12.7%). ES-API: [M+H].sup.+=376.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.41-11.28 (m, 1H), 9.20-9.13 (m, 1H), 8.39-8.30 (m, 1H), 8.03-7.91 (m, 1H), 7.39 (s, 1H), 7.31-7.22 (m, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.51 (q, J=15.0 Hz, 2H), 4.17 (s, 1H), 3.40 (q, J=6.9 Hz, 2H), 3.10-3.01 (m, 2H), 2.30 (t, J=1.8 Hz, 3H), 2.18 (s, 2H), 1.80-1.71 (m, 2H), 1.50 (s, 1H), 1.13 (td, J=7.1, 3.2 Hz, 3H).

Example 135. Synthesis of Compound Z402

##STR00403##

[0863] Step 1: tert-butyl (S)-2-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (210 mg, 0.623 mmol) was dissolved in 1,2-dichloroethane (2 mL). Tetrahydropyran-4-carbaldehyde (142.31 mg, 1.247 mmol) was added with stirring. After the reaction mixture was stirred at room temperature for 0.5 h, sodium triacetylborohydride (525.98 mg, 2.494 mmol) was added and stirred at room temperature overnight. The reaction was quenched by the addition of water (5 mL), and the aqueous phase was adjusted to pH 9-10. The reaction mixture was extracted with dichloromethane (10 mL2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-100% ethyl acetate/petroleum ether followed by 0-10% methanol/dichloromethane+0.1% ammonia water) to give tert-butyl (S)-2-[7-chloro-2-(3,4,5,6-tetrahydro-2H-pyran-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]pyrrolidine-1-carboxylate (290 mg, crude product) which was directly used in the next reaction. LCMS: ES-API [M+H].sup.+=435.3.

[0864] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (166.15 mg, 0.644 mmol) and the tert-butyl (S)-2-[7-chloro-2-(3,4,5,6-tetrahydro-2H-pyran-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]pyrrolidine-1-carboxylate (140 mg, 0.322 mmol) were dissolved in 1,4-dioxane (3 mL). Potassium carbonate (133.44 mg, 0.966 mmol) and water (0.75 mL) followed by chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (46.38 mg, 0.064 mmol) were added. The system was heated at 120 C. for 3 h in the presence of protective nitrogen. Ethyl acetate (10 mL) and saturated brine were added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (10 mL2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% ethyl acetate/petroleum ether followed by 0-10% methanol/dichloromethane+0.1% ammonia water) to give tert-butyl (S)-2-[7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3,4,5,6-tetrahydro)-2H-pyran-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]pyrrolidine-1-carboxylate (100 mg, yield: 58.55%). LCMS: ES-API [M+H].sup.+=531.4.

[0865] Step 3: The tert-butyl (S)-2-[7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3,4,5,6-tetrahydro)-2H-pyran-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]pyrrolidine-1-carboxylate (100 mg, 0.188 mmol) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (2 mL) was added with stirring. The system reacted at room temperature for 2 h. The reaction mixture was concentrated, and then purified by prep-HPLC (formic acid method) to give 7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3,4,5,6-tetrahydro-2H-pyran-4-ylmethyl)-5-[(2S)-tetrahydro-1H-pyrrol-2-yl]-1,2,3,4-tetrahydroisoquinoline (Z402, formate, 54 mg, yield: 59.40%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.37 (s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.24-8.15 (m, 2H), 7.75 (s, 1H), 7.50 (s, 1H), 7.27 (s, 1H), 4.81-4.66 (m, 1H), 3.91-3.79 (m, 2H), 3.71-3.60 (m, 2H), 3.52-3.41 (m, 1H), 3.33 (q, J=11.2, 9.8 Hz, 3H), 3.00-2.79 (m, 2H), 2.79-2.66 (m, 2H), 2.42-2.33 (m, 3H), 2.32 (s, 3H), 2.19-2.00 (m, 3H), 1.97-1.82 (m, 1H), 1.65 (d, J=12.0 Hz, 2H), 1.22-1.10 (m, 2H). LCMS: ES-API [M+H].sup.+=431.3.

Example 136. Synthesis of Compound Z337

##STR00404##

[0866] Step 1: tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (120 mg, 0.356 mmol), 1-methyl-3-(trifluoromethyl)pyrazole-4-carboxylic acid (82.98 mg, 0.427 mmol) and 1-propylphosphonic anhydride (452.8 mg, 0.712 mmol, 50% in ethyl acetate) were dissolved in triethylamine (108.14 mg, 1.07 mmol) and dichloromethane (5 mL), and the system reacted at room temperature for 2 h. The reaction was quenched by the addition of water, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a preparative thin layer chromatographic column (ethyl acetate/petroleum ether=2/1) to give a product tert-butyl (S)-2-[6-chloro-2-[1-methyl-3-(trifluoromethyl)pyrazole-4-carbonyl]-3,4-dihydro-1H-isoquinolin-8-yl]pyrrolidine-1-carboxylate (160 mg, yield: 87.56%). ES-API: [M+H].sup.+=513.9.

[0867] Step 2: The (S)-2-[6-chloro-2-[1-methyl-3-(trifluoromethyl)pyrazole-4-carbonyl]-3,4-dihydro-1H-isoquinolin-8-yl]pyrrolidine-1-carboxylate (160 mg, 0.311 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (85.13 mg, 0.329 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (19.78 mg, 0.027 mmol) and potassium carbonate (75.97 mg, 0.549 mmol) were dissolved in 1,4-dioxane solution (1 mL) and water (0.1 mL), and the system was warmed to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was quenched by the addition of water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[1-methyl-3-(trifluoromethyl)pyrazole-4-carbonyl]-3,4-dihydro-1H-isoquinolin-8-yl]pyrrolidine-1-carboxylate (120 mg, yield: 63.21%). ES-API: [M+H].sup.+=609.7.

[0868] Step 3: The tert-butyl (S)-2-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[1-methyl-3-(trifluoromethyl)pyrazole-4-carbonyl]-3,4-dihydro-1H-isoquinolin-8-yl]pyrrolidine-1-carboxylate (120 mg, 0.197 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid solution (2 mL) and stirred at room temperature for 1 h. The reaction mixture was spun to dryness to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water); B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give a product [6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[(2S)-pyrrolidin-2-yl]-3,4-dihydro-1H-isoquinolin-2-yl]-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methanone (Z337, 22.7 mg, yield: 22.64%). ES-API: [M+H].sup.+=509.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.58-8.32 (m, 1H), 7.99-7.72 (m, 2H), 7.63-7.42 (m, 1H), 7.06-6.88 (m, 2H), 5.08-4.53 (m, 3H), 4.11-3.90 (m, 4H), 3.84-3.72 (m, 1H), 3.64-3.27 (m, 3H), 2.81-2.65 (m, 1H), 2.44-2.35 (m, 1H), 2.27 (s, 3H), 2.22-2.02 (m, 3H).

Example 137. Synthesis of Compound Z401

##STR00405##

[0869] Step 1: tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.30 mmol) and tetrahydropyran-4-one (89 mg, 0.89 mmol) were dissolved in 1,2-dichloroethane (3 mL). Sodium triacetyl borohydride (188 mg, 0.89 mmol) was added and stirred at room temperature for 4 h. The obtained mixture was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (15 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (7M ammonia-methanol/dichloromethane: 0-5%) to give a desired product tert-butyl (S)-2-(7-chloro-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (90 mg, yield: 72.0%) as a colorless liquid. ES-API: [M+H].sup.+=421.3.

[0870] Step 2: The tert-butyl (S)-2-(7-chloro-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (90 mg, 0.21 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (83 mg, 0.32 mmol), 2-dicyclohexylphosphine-2,6-dimethoxy-biphenyl (9 mg, 0.02 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (15 mg, 0.02 mmol), potassium carbonate (89 mg, 0.64 mmol), 1,4-dioxane (5 mL) and water (1 mL) were added to a 25 mL round-bottom flask. The system was replaced with nitrogen three times and reacted at 110 C. for 2 h. The reaction was cooled to room temperature. Ethyl acetate (50 mL) was added. The obtained mixture was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by a flash silica gel column (7M ammonia-methanol/dichloromethane: 0-3%) to give a desired product tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (90 mg, yield: 81.5%) as a pale yellow solid. ES-API: [M+H].sup.+=517.3.

[0871] Step 3: The tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (90 mg, 0.17 mmol) was dissolved in methanol (1 mL). 4.0M Hydrogen chloride-dioxane solution (4 mL, 16.0 mmol) was added, and the system reacted at room temperature for 18 h. The reaction mixture was concentrated. 7.0M Ammonia-methanol solution (5 mL) was added, and a solvent was spun to dryness. The crude product was purified by prep-HPLC (formic acid) to give a desired product (S)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinoline (Z401, formate, 51 mg, yield: 63.4%) as a white solid. ES-API: [M+H].sup.+=417.3 (free base). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.35 (s, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.29 (s, 2H), 8.17 (d, J=2.0 Hz, 1H), 7.73 (s, 1H), 7.43 (s, 1H), 7.26 (s, 1H), 4.62-4.51 (m, 1H), 3.93 (d, J=9.5 Hz, 2H), 3.85-3.72 (m, 2H), 3.41-3.28 (m, 3H), 3.23-3.16 (m, 1H), 2.98-2.74 (m, 4H), 2.66-2.56 (m, 1H), 2.35-2.26 (m, 4H), 2.09-1.73 (m, 5H), 1.58-1.44 (m, 2H).

Example 138. Synthesis of Compound Z239

##STR00406##

[0872] Step 1: In the presence of protective nitrogen, sodium carbonate (72.24 mg, 681.59 mol), 2-bromo-1,3,4-thiadiazole (89.98 mg, 545.27 mol) and 1,1-bis(diphenylphosphino)ferrocene dichloride (133.05 mg, 181.76 mol) were added to a solution of (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (600 mg, 2.72 mmol) in 1,4-dioxane (20 mL) and water (2 mL). The reaction mixture was stirred at 100 C. under microwave for 1 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give a product 3-(1,3,4-thiadiazol-2-yl)pyridin-2-amine (250.00 mg, yield: 51.64%) as a yellow solid. ES-API: [M+H].sup.+=179.10.

[0873] Step 2: In the presence of protective nitrogen, N-bromosuccinimide (299.61 mg, 1.68 mmol) was added to a solution of the 3-(1,3,4-thiadiazol-2-yl)pyridin-2-amine (0.25 g, 1.40 mmol) in tetrahydrofuran (20 mL) at 0 C. The reaction mixture was stirred at 0 C. for 1 h. The reaction was monitored by LCMS for completion, and quenched by the addition of sodium thiosulfate solution. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to give a product 5-bromo-3-(1,3,4-thiadiazol-2-yl)pyridin-2-amine (250.00 mg, yield: 69.31%) as a yellow solid. ES-API: [M+H].sup.+=256.90/258.90.

[0874] Step 3: Potassium acetate (154.03 mg, 1.57 mol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (199.28 mg, 784.74 mol) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (38.30 mg, 52.32 mol) were added to a solution of tert-butyl (S)-2-(6-bromoisochroman-8-yl)pyrrolidine-1-carboxylate (0.2 g, 523.16 mol) in 1,4-dioxane (3.0 mL). The reaction mixture was stirred at 100 C. for 16 h. The reaction was monitored by LCMS for completion and quenched with water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (S)-2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl]pyrrolidine-1-carboxylate as a crude product which was directly used in the next step without purification. ES-API: [M+H].sup.+=374.20

[0875] Step 4: The tert-butyl (S)-2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl]pyrrolidine-1-carboxylate (200.39 mg, 466.73 mol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (113.88 mg, 155.58 mol) and cesium carbonate (380.17 mg, 1.17 mmol) were added to a solution of the 5-bromo-3-(1,3,4-thiadiazol-2-yl)pyridin-2-amine (0.1 g, 388.94 mol) in 1,4-dioxane (3 mL) and water (0.3 mL). The reaction mixture was stirred at 100 C. under microwave for 1 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give a product tert-butyl (S)-2-[6-[6-amino-5-(1,3,4-thiadiazol-2-yl)-3-pyridyl]isochroman-8-yl]pyrrolidine-1-carboxylate (100.00 mg, yield: 42.89%) as a yellow oil. ES-API: [M+H].sup.+=480.30.

[0876] Step 5: Trifluoroacetic acid (1.0 mL) was added to a solution of the tert-butyl (S)-2-[6-[6-amino-5-(1,3,4-thiadiazol-2-yl)-3-pyridyl]isochroman-8-yl]pyrrolidine-1-carboxylate (0.1 g, 208.51 mol) in dichloromethane (1.0 mL) and stirred at 30 C. for 1 h. A saturated aqueous sodium bicarbonate solution was added to the reaction, and the obtained mixture was then extracted with ethyl acetate (150 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane:methanol=10:1) and beating (ethyl acetate) to give 5-[8-[(S)-pyrrolidin-2-yl]isochroman-6-yl]-3-(1,3,4-thiadiazol-2-yl)pyridin-2-amine (Z239, 20.00 mg, yield: 24.01%) as a yellow solid. ES-API: [M+H].sup.+=380.1.

Example 139. Synthesis of Compound Z285

##STR00407##

[0877] Step 1: tert-butyl (S)-5-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (15 mg, 0.028 mmol) was dissolved in dichloromethane (3 mL). (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (8.90 mg, 0.056 mmol), N,N-diisopropylethyl amine (0.014 mL, 0.084 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (10.92 mg, 0.084 mmol) were added successively, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was diluted with dichloromethane (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl 5-(5-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (6 mg, yield: 32%). ES-API: [M+H].sup.+=673.3.

[0878] Step 2: The tert-butyl 5-(5-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (6 mg, 0.009 mmol) was dissolved in dichloromethane (3 mL) and added to trifluoroacetic acid (2 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia water-methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC alkaline process (ammonia water) to give (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z285, 1.8 mg, yield: 44%). ES-API: [M+H].sup.+=473.2.

Example 140. Synthesis of Compound Z284

##STR00408## ##STR00409##

[0879] Step 1: 5-Bromo-7-chloro-1,2,3,4-tetrahydroisoquinoline (11.37 g, 46.120 mmol) was dissolved in tetrahydrofuran (100 mL) and water (30 mL). Potassium carbonate (19.12 g, 138.360 mmol) was added, and the system was cooled to 0 C. Benzyl chloroformate (16.334 mL, 115.300 mmol) was then added. The mixture was stirred at room temperature for 2 h. The obtained mixture was diluted with water, and extracted with ethyl acetate (100 mL). The ethyl acetate layers were combined, washed with saturated sodium chloride solution (100 mL1), dried anhydrous sodium sulfate, filtered, and concentrated. Dichloromethane (50 ml) was added. The obtained mixture was stirred and beaten, filtered, washed with petroleum ether (100 mL), and filtered. The filter cake was dried to give benzyl 5-bromo-7-chloro-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (15 g, yield: 85.4%) as a white solid. ES-API: [M+H].sup.+=380.0.

[0880] Step 2: A solution of the benzyl 5-bromo-7-chloro-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (15 g, 39.404 mmol) and potassium vinyltrifluoroborate (10.56 g, 78.808 mmol) was added to anhydrous ethanol (300 mL). Triethylamine (5.477 mL, 39.404 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.61 g, 1.970 mmol) were added. The mixture was degassed with nitrogen, heated to 100 C. in an oil bath and stirred for 3 h, and then stirred at 90 C. for 15 h. The obtained mixture was poured into water (100 mL), and extracted with ethyl acetate (100 mL3). The organic layers were combined, washed with saturated sodium chloride solution (100 mL1), dried over anhydrous sulfuric acid, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20/80) to give benzyl 7-chloro-5-vinyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (12 g, yield: 92.90%). ES-API: [M+H].sup.+=328.1.

[0881] Step 3: Sodium periodate (46.98 g, 219.639 mmol), potassium osmate dihydrate (0.30 g, 0.805 mmol) and water (200 mL) were added to a solution of the benzyl 7-chloro-5-vinyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (12 g, 36.607 mmol) in tetrahydrofuran (400 mL) and stirred at room temperature for 2 h. The obtained mixture was diluted with ethyl acetate (100 mL) and filtered. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20/80) to give a compound benzyl 7-chloro-5-formyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (9 g, yield: 74.55%). ES-API: [M+H].sup.+=330.1.

[0882] Step 4: The benzyl 7-chloro-5-formyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (9 g, 27.291 mmol) and (S)-2-methylpropyl-2-sulfinamide were dissolved in dichloromethane (180 mL). Tetraethyl titanate (24.90 g, 109.164 mmol) was slowly added and stirred at room temperature for 18 h. The reaction mixture was diluted with dichloromethane and saturated sodium chloride solution. The organic layer was separated, washed with saturated sodium chloride solution, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=80/20) to give a compound (S)-benzyl 5-(((tert-butylsulfinyl)amino)methyl)-7-chloro-3,4-tetrahydroisoquinoline-2(1H)-carboxylate (10.5 g, yield: 88.83%). ES-API: [M+H].sup.+=433.1.

[0883] Step 5: The (S)-benzyl 5-(((tert-butylsulfinyl)amino)methyl)-7-chloro-3,4-tetrahydroisoquinoline-2(1H)-carboxylate (10 g, 23.096 mmol) was dissolved in tetrahydrofuran (100 mL), and the system was cooled to 78 C. (1,3-Dioxane-2-ethyl)magnesium bromide (184.770 mL, 92.385 mmol) was added, and the mixture was stirred at 78 C. for 1 h. The reaction was quenched by the addition of saturated ammonium chloride (50 mL). The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (100 mL3). The organic layers were combined, washed with saturated sodium chloride solution (100 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=60/40) to give benzyl 5-((S)-1-(((S)-tert-butylsulfinyl)amino)-3-(1,3-dioxan-2-yl)propyl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (11.67 g, yield: 92%). ES-API: [M+H].sup.+=549.2.

[0884] Step 6: A solution of trifluoroacetic acid (100 mL) and water (5 mL) was added to the benzyl 5-((S)-1-(((S)-tert-butylsulfinyl)amino)-3-(1,3-dioxan-2-yl)propyl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (11.67 g, 21.252 mmol) and stirred at room temperature for 0.5 h. Triethylsilane (33.851 mL, 212.518 mmol) was then added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give (S)-benzyl 7-chloro-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (15 g, crude product) which was directly used in the next reaction without purification. ES-API: [M+H].sup.+=371.1.

[0885] Step 7: The (S)-benzyl 7-chloro-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (15 g, crude product) was dissolved in dichloromethane (150 mL). N,N-Diisopropylethyl amine (26.737 mL, 161.777 mmol) and di-tert-butyl dicarbonate (11.150 mL, 48.533 mmol) were added and stirred at room temperature for 1 h. The obtained mixture was poured into water (100 mL). The organic layer was separated, washed with saturated sodium chloride solution (20 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=50/50) to give (S)-benzyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (10 g, yield of the 2 steps: 100%). ES-API: [M+H].sup.+=471.1.

[0886] Step 8: The (S)-benzyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.00 g, 2.123 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.66 g, 2.548 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (0.08 g, 0.106 mmol) and potassium carbonate (0.88 g, 6.369 mmol) were added to 1,4-dioxane (10 ml) and water (2 ml). The system was replaced with nitrogen and reacted at 120 C. for 1 h. Upon completion of the reaction, ethyl acetate (100 mL) was added. The obtained mixture was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/95) to give (S)-benzyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (774 mg, yield: 64.50%). ES-API: [M+H].sup.+=567.3.

[0887] Step 9: The (S)-benzyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (774 mg, 1.366 mmol) was dissolved in dichloromethane (50 mL). N,N-Diisopropylethyl amine (528.6 mg, 4.098 mmol), di-tert-butyl dicarbonate (0.471 mL, 2.049 mmol) and 4-dimethylamino pyridine (16.45 mg, 0.136 mmol) were added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/95) to give (S)-benzyl 7-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (540 mg, yield: 59.3%). ES-API: [M+H].sup.+=667.3.

[0888] Step 10: The (S)-benzyl 7-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (540 mg, 0.810 mmol) was dissolved in dichloromethane (15 mL). Palladium chloride (159.56 mg, 0.090 mmol), triethylamine (0.250 mL, 1.800 mmol) and triethylsilane (418.51 mg, 3.599 mmol) were then added, and the mixture was stirred at room temperature for 0.5 h. The obtained mixture was diluted with water (30 mL) and extracted with dichloromethane (30 mL3). The organic layers were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=0%-10%) to give tert-butyl (S)-5-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolidin[2,3-b]pyridine-1-carboxylate (400 mg, yield: 92.6%). ES-API: [M+H].sup.+=533.3.

[0889] Step 11: The tert-butyl (S)-5-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolidin[2,3-b]pyridine-1-carboxylate (150 mg, 0.282 mmol) was dissolved in dried dichloromethane (10 mL). Triethylamine (67.2 mg, 0.666 mmol) and methoxyacetyl chloride (45.84 mg, 0.422 mmol) were added successively under an ice-water bath condition and stirred for 1 h. Upon completion of the reaction, the reaction mixture was diluted with dichloromethane (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-5-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (110 mg, yield: 64.71%). ES-API: [M+H].sup.+=605.3.

[0890] Step 12: The tert-butyl (S)-5-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (110 mg, 0.182 mmol) was dissolved in dichloromethane (5 mL) and added to trifluoroacetic acid (3 mL), and the system reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC alkaline process (ammonia water) to give (S)-2-methoxy-1-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Z284, 32 mg, yield: 43.43%). ES-API: [M+H].sup.+=405.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.34 (d, J=14.0 Hz, 1H), 8.49-8.40 (m, 1H), 8.13-8.02 (m, 1H), 7.81-7.71 (m, 1H), 7.41 (d, J=14.2 Hz, 1H), 7.26 (s, 1H), 4.76-4.63 (m, 2H), 4.21 (d, J=5.5 Hz, 3H), 3.90-3.52 (m, 3H), 3.35-3.25 (m, 3H), 3.15-3.05 (m, 1H), 3.00-2.72 (m, 3H), 2.31 (d, J=1.1 Hz, 3H), 2.25-2.10 (m, 1H), 1.88-1.70 (m, 2H), 1.48-1.38 (m, 1H).

Example 141. Synthesis of Compound Z283

##STR00410##

[0891] Step 1: 4-Methylpyrimidine-5-carboxylic acid (11.5 mg, 0.083 mmol), 1-propylphosphonic anhydride (132.3 mg, 0.21 mmol, 50% in ethyl acetate) and triethylamine (21.01 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in dichloromethane (1 mL) and stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-methylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (35 mg, crude product). ES-API: [M+H].sup.+=553.4.

[0892] Step 2: Trifluoroacetic acid (0.5 mL) was added to a solution of the compound tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-methylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (35 mg, 0.063 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give a product (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-methylpyrimidin-5-yl)methanone (Z283, 7.3 mg, yield: 25%) as a white powder. ES-API: [M+H].sup.+=453.3.

[0893] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.16-9.12 (m, 1H), 8.99-8.80 (m, 1H), 8.56 (s, 1H), 8.50-8.45 (m, 1H), 8.03-7.98 (m, 1H), 7.85-7.57 (m, 1H), 7.32 (s, 1H), 7.08 (s, 1H), 5.41-4.90 (m, 1H), 4.82-4.36 (m, 1H), 4.19-3.85 (m, 1H), 3.57-3.31 (m, 2H), 3.19-2.98 (m, 2H), 2.95-2.82 (m, 2H), 2.60-2.45 (m, 3H), 2.43-2.34 (m, 1H), 2.34 (s, 3H), 2.13-1.90 (m, 3H).

Example 142. Synthesis of Compound Z282

##STR00411##

[0894] Step 1: 1,3-Dimethyl-1H-pyrazole-4-carboxylic acid (11.7 mg, 0.083 mmol), 1-propylphosphonic anhydride (132.3 mg, 0.21 mmol, 50% in ethyl acetate) and triethylamine (21.01 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in dichloromethane (1 mL) and stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a product tert-butyl (S)-2-(2-(1,3-dimethyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (35 mg, crude product). ES-API: [M+H].sup.+=555.4.

[0895] Step 2: Trifluoroacetic acid (0.5 mL) was added to a solution of the compound tert-butyl (S)-2-(2-(1,3-dimethyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (35 mg, 0.063 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 mL/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(1,3-dimethyl-1H-pyrazol-4-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z282, 1.7 mg, yield: 6%) as a white powder. ES-API: [M+H].sup.+=455.3.

Example 143. Synthesis of Compound Z281

##STR00412##

[0896] Step 1: 1-(2-Hydroxyethyl)-1H-pyrazole-4-carboxylic acid (11.7 mg, 0.083 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39.89 mg, 0.21 mmol), triethylamine (21.01, 0.21 mmol) and 1-hydroxybenzotriazole (14.06 mg, 0.11 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in N,N-dimethylformamide (1 ml), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a product tert-butyl (S)-2-(2-(1-(2-hydroxyethyl)-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, crude product). ES-API: [M+H].sup.+=571.4.

[0897] Step 2: Trifluoroacetic acid (0.5 mL) was added to a solution of the compound tert-butyl (S)-2-(2-(1-(2-hydroxyethyl)-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, 0.07 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 mL/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z281, 4.8 mg, yield: 14.6%) as a white powder. ES-API: [M+H].sup.+=471.3.

Example 144. Synthesis of Compound Z280

##STR00413##

[0898] Step 1: Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (13.58 mg, 0.083 mmol), 1-propylphosphonic anhydride (132.3 mg, 0.21 mmol, 50% in ethyl acetate) and triethylamine (21.01 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in dichloromethane (1 mL), and the reaction mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, crude products). ES-API: [M+H].sup.+=578.3.

[0899] Step 2: Trifluoroacetic acid (0.5 mL) was added to a solution of the compound tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, 0.069 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyrazolo[1,5-a]pyrimidin-3-yl)methanone (Z280, 5.4 mg, yield: 16.33%) as a white powder. ES-API: [M+H].sup.+=478.2.

Example 145. Synthesis of Compound Z271-1 and Compound Z271-2

##STR00414##

[0900] Step 1: (S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (46.93 mg, 0.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (85.36 mg, 0.45 mmol), triethylamine (44.97 mg, 0.45 mmol) and 1-hydroxy-benzotriazole (60.17 mg, 0.45 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a product tert-butyl (S)-2-(6-chloro-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, crude product). ES-API: [M+H-100].sup.+=377.1.

[0901] Step 2: Sodium hydride (14.09 mg, 0.59 mmol) was added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.15 mmol) in N,N-dimethylformamide (1.5 mL) and stirred at 0 C. for 0.5 h. Iodomethane (84.54 mg, 0.59 mmol) was then added to the mixture, and the mixture was stirred at 25 C. for 1 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography ((mobile phase 0-25% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/5, Rf=0.6) to give a product tert-butyl (S)-2-(6-chloro-2-((S)-3,3,3-trifluoro-2-methoxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, yield: 69.39%). ES-API: [M+H-100].sup.+=391.1.

[0902] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (31.55 mg, 0.12 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.33 mg, 0.01 mmol) and potassium carbonate (42.16 mg, 0.31 mmol) were added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-((S)-3,3,3-trifluoro-2-methoxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.10 mmol) in dioxane/water (2 mL/0.5 mL), and the mixture was heated to 110 C. and stirred for 2 h in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3,3,3-trifluoro-2-methoxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (37 mg, yield: 61.93%). ES-API: [M+H-100].sup.+=587.4.

[0903] Step 4: Trifluoroacetic acid (0.5 mL) was added to a solution of the compound tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3,3,3-trifluoro-2-methoxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (37 mg, 0.06 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 mL/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-3,3,3-trifluoro-2-methoxy-2-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z271-1, 6.3 mg, 20.53%) as a white powder. ES-API: [M+H].sup.+=487.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.73 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.74 (d, J=12.1 Hz, 1H), 7.28 (s, 1H), 7.08 (s, 1H), 5.41-4.69 (m, 2H), 4.48-3.57 (m, 3H), 3.49- 3.32 (m, 3H), 3.30-3.21 (m, 1H), 3.10-2.97 (m, 3H), 2.35 (s, 3H), 2.33-2.19 (m, 1H), 2.06-1.75 (m, 3H), 1.70 (s, 3H).

##STR00415##

[0904] Step 1: (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (37.54 mg, 0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (68.29 mg, 0.36 mmol), triethylamine 35.98 mg, 0.36 mmol) and 1-hydroxy-benzotriazole (48.13 mg, 0.36 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, 0.12 mmol) in N,N-dimethylformamide (1 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to a product tert-butyl (S)-2-(6-chloro-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, crude product). ES-API: [M+H-100].sup.+=377.1.

[0905] Step 2: Sodium hydride (12.08 mg, 0.50 mmol) was added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.13 mmol) in N,N-dimethylformamide (1.5 mL) and stirred at 0 C. for 0.5 h. Iodomethane (72.74 mg, 0.50 mmol) was then added to the mixture, and the mixture was stirred at 25 C. for 1 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to a product tert-butyl (S)-2-(6-chloro-2-((R)-3,3,3-trifluoro-2-methoxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, crude product). ES-API: [M+H-100].sup.+=391.1.

[0906] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (37.86 mg, 0.15 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.79 mg, 0.012 mmol) and potassium carbonate (50.60 mg, 0.37 mmol) were added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-((R)-3,3,3-trifluoro-2-methoxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.12 mmol) in dioxane/water (2 mL/0.5 mL), and the mixture was heated to 110 C. and stirred for 2 h in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-3,3,3-trifluoro-2-methoxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (18 mg, yield: 25.11%). ES-API: [M+H-100].sup.+=587.4.

[0907] Step 4: Trifluoroacetic acid (0.5 mL) was added to a solution of the compound tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-3,3,3-trifluoro-2-methoxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (18 mg, 0.03 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 mL/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (R)-3,3,3-trifluoro-2-methoxy-2-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z271-2, 1.1 mg, 7.37%) as a white powder. ES-API: [M+H].sup.+=487.3.

Example 146. Synthesis of Compound Z279

##STR00416##

[0908] Step 1: tert-butyl (S)-5-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolidin[2,3-b]pyridine-1-carboxylate (30 mg) was dissolved in dichloromethane (1 mL). 2,6-Dimethylisonicotinic acid (13 mg, 0.08 mmol), triethylamine (0.04 mL, 0.28 mmol) and 50% 1-propylphosphonic anhydride in ethyl acetate (107 mg, 0.17 mmol) were added successively and stirred at room temperature for 2 h. The mixture was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (10 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-7% methanol/dichloromethane) to give tert-butyl (S)-5-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(2,6-dimethylisonicotinoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (15 mg, yield: 40%). ES-API: [M+H].sup.+=666.3.

[0909] Step 2: Trifluoroacetic acid (0.1 mL) was added dropwise to a solution of the tert-butyl (S)-5-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(2,6-dimethylisonicotinoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (15 mg, 23 mol) in dichloromethane (0.2 mL) under an ice bath condition and stirred at room temperature for 1 h. The reaction mixture was concentrated, and purified by prep-HPLC (ammonium bicarbonate) to give (S)-(2,6-dimethylpyridin-4-yl)(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z279, 2.5 mg, purity: 100%, yield: 24%) as a white solid. ES-API: [M+H].sup.+=466.3.

Example 147. Synthesis of Compound Z240-1

##STR00417##

[0910] Step 1: Magnesium sulfate (330 mg, 2.74 mmol) and compound 6-bromoisochroman-8-carbaldehyde (300 mg, 1.24 mmol) were added successively to a solution of benzhydrylamine (228 mg, 1.24 mmol) in dichloromethane (10 mL) and stirred at room temperature overnight. The reaction mixture was filtered and concentrated to give (Z)N-benzoyl-1-(6-bromoisochroman-8-yl)toluidine (505 mg, crude product) which was directly used in the next reaction without purification.

[0911] Step 2: In the presence of protective nitrogen, 1 M potassium tert-butoxide in tetrahydrofuran (0.148 mL) was slowly added to a solution of the (Z)N-benzoyl-1-(6-bromoisochroman-8-yl)toluidine (50 mg, 0.12 mmol) in tetrahydrofuran (1 mL) at 65 C. and stirred for 0.5 h. 1,1-Bis(iodomethyl)cyclopropane (119 mg, 0.37 mmol) was then quickly added to the reaction mixture and stirred for 1 h. The reaction mixture was then slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched with water (10 mL), and extracted with dichloromethane (10 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was dissolved in acetone (1 mL). 3 M Hydrochloric acid solution (0.21 mL) was added and stirred at room temperature for 2 h. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (10 mL3), and concentrated to give 6-(6-bromoisochroman-8-yl)-5-azaspiro[2.4]heptane (40 mg) as a yellow oil. ES-API: [M+H].sup.+=308.0, 310.1.

[0912] Step 3: In the presence of protective nitrogen, a mixed solution of the 6-(6-bromoisochroman-8-yl)-5-azaspiro[2.4]heptane (40 mg, 0.13 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg, 0.12 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10 mg, 14 mol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (5 mg, 12 mol) and potassium carbonate (54 mg, 0.39 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 120 C. for 2 h. Ethyl acetate (10 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (ammonium bicarbonate) to give 5-(8-(5-azaspiro[2.4]heptan-6-yl)isochroman-6-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine (Z240-1, 0.7 mg, purity: 93%, yield: 1.4%) as a white solid. ES-API: [M+H].sup.+=360.2.

Example 148. Synthesis of Compound Z219-1 and Compound Z219-2

##STR00418##

[0913] Step 1: (S)-Tetrahydrofuran-3-carboxylic acid (34.47 mg, 0.3 mmol), 1-propylphosphonic anhydride (566 mg, 0.89 mmol, 50% in ethyl acetate) and triethylamine (89.95 mg, 0.89 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.29 mmol) in dichloromethane (3 mL) and stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a product tert-butyl (S)-2-(6-chloro-2-((S)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (125 mg, crude product). ES-API: [M+H-100].sup.+=335.1.

[0914] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (89.02 mg, 0.34 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (20.68 mg, 0.029 mmol) and potassium carbonate (118.98 mg, 0.86 mmol) were added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-((S)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (125 mg, 0.28 mmol) in dioxane/water (2 mL/0.5 mL), and the mixture was heated to 110 C. and stirred for 2 h in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (120 mg, yield: 78.7%) as a yellow powder. ES-API: [M+H-100].sup.+=531.4.

[0915] Step 3: Trifluoroacetic acid (0.5 mL) was added to a solution of the compound tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (130 mg, 0.24 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-tetrahydrofuran-3-yl)methanone (Z219-2, 30.3 mg, yield: 28.7%) as a white powder. ES-API: [M+H].sup.+=431.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.11 (s, 1H), 8.50-8.47 (m, 1H), 8.04-8.00 (m, 1H), 7.77-7.63 (m, 1H), 7.33-7.27 (m, 1H), 7.10 (s, 1H), 5.11-4.60 (m, 2H), 4.39-4.21 (m, 1H), 4.15-4.04 (m, 1H), 4.00-3.80 (m, 4H), 3.80-3.74 (m, 1H), 3.47-3.20 (m, 2H), 3.11-2.92 (m, 3H), 2.35 (s, 3H), 2.33-2.08 (m, 2H), 2.17-2.07 (m, 1H), 2.02-1.83 (m, 2H), 1.69-1.54 (m, 1H).

##STR00419##

[0916] Step 1: (R)-Tetrahydrofuran-3-carboxylic acid (34.47 mg, 0.3 mmol), 1-propylphosphonic anhydride (566.4 mg, 0.9 mmol, 50% in ethyl acetate) and triethylamine (89.95 mg, 0.9 mmol) was added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.3 mmol) in dichloromethane (3 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a product tert-butyl (S)-2-(6-chloro-2-((R)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (130 mg, crude product). ES-API: [M+H-100].sup.+=335.1.

[0917] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (92.58 mg, 0.36 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (21.51 mg, 0.03 mmol) and potassium carbonate (123.74 mg, 0.9 mmol) were added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-((R)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (130 mg, 0.3 mmol) in dioxane/water (3 mL/0.6 mL), and the mixture was heated to 110 C. and stirred in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (130 mg, yield: 81.97%). ES-API: [M+H].sup.+=531.3.

[0918] Step 3: Trifluoroacetic acid (1.5 mL) was added to a solution of the compound tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (130 mg, 0.24 mmol) in dichloromethane (3 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-tetrahydrofuran-3-yl)methanone (Z219-1, 38.5 mg, yield: 36.5%) as a white powder. ES-API: [M+H].sup.+=431.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.48 (s, 1H), 8.50 (s, 1H), 8.04 (s, 1H), 7.81-7.64 (m, 1H), 7.31 (d, J=11.3 Hz, 1H), 7.15-7.04 (m, 1H), 5.01-4.72 (m, 2H), 4.42-4.23 (m, 1H), 4.09 (t, J=8.3 Hz, 1H), 3.99-3.72 (m, 5H), 3.49-3.21 (m, 2H), 3.12-2.94 (m, 3H), 2.36 (s, 3H), 2.34-2.09 (m, 4H), 1.86-1.54 (m, 2H).

Example 149. Synthesis of Compound Z243

##STR00420##

[0919] Step 1: Trimethylsilyl cyanide (2.04 g, 20.53 mmol) was added to a solution of 6-bromoisochroman-8-carbaldehyde (3.3 g, 13.69 mmol) in ammonia-methanol (7M, 80 mL) at 0 C. and stirred for 1 h. The ice bath was then removed, and the mixture was stirred at 40 C. for 16 h. The reaction was checked by LCMS for completion. A solvent was spun to dryness in vacuum, and the obtained mixture was purified by a flash silica gel column (dichloromethane:methanol=10:1) to give 2-amino-2-(6-bromoisochroman-8-yl)acetonitrile (2.80 g, yield: 76.58%) as a yellow solid. ES-API: [M+H].sup.+=267.0/269.0.

[0920] Step 2: The 2-amino-2-(6-bromoisochroman-8-yl)acetonitrile (2.8 g, 10.48 mmol) in 25% hydrochloric acid (80 mL) was stirred at 100 C. for 16 h. The solution was cooled to room temperature and then stirred at 0 C. for 1 h. The reaction was checked by LCMS for completion, and the reaction mixture was filtered. The obtained solid was collected and dried to give 2-amino-2-(6-bromoisochroman-8-yl)acetic acid (2.50 g, crude product) as a brown solid. ES-API: [M+H].sup.+=286.0/288.1.

[0921] Step 3: In the presence of protective nitrogen, lithium borohydride (251.24 mg, 11.53 mmol) was dissolved in tetrahydrofuran (10 mL). Trimethylsilyl chloride (2.85 g, 26.21 mmol) and the 2-amino-2-(6-bromoisochroman-8-yl)acetic acid (1.5 g, 5.24 mmol) were added, and the mixture was stirred at 30 C. for 16 h. The reaction was checked by LCMS for completion, and methanol was slowly added under an ice bath condition. The obtained yellow solution was concentrated and purified by a flash silica gel column (dichloromethane:methanol=10:1) to give 2-amino-2-(6-bromoisochroman-8-yl)ethanol (900.00 mg, yield: 63.08%) as a yellow oil. ES-API: [M+H].sup.+=272.1/274.0.

[0922] Step 4: Anhydrous potassium carbonate (243.77 mg, 1.76 mmol) was added to a solution of the 2-amino-2-(6-bromoisochroman-8-yl)ethanol (0.4 g, 1.47 mmol) in tetrahydrofuran (15 mL) at 0 C., and then cyanogen bromide (155.69 mg, 1.47 mmol) in tetrahydrofuran (5 mL) was added. The ice bath was removed, and the system continued to be stirred at 30 C. for 16 h. The reaction was checked by LCMS for completion. The mixture was diluted with ethyl acetate (50 mL) and washed with water (100 mL). The aqueous phase was back extracted with ethyl acetate (100 mL). The combined organic layer was washed with water (50 mL) and saturated brine (100 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give 4-(6-bromoisochroman-8-yl)-4,5-dihydrooxazol-2-amine (300.00 mg, yield: 54.95%) as a yellow oil. ES-API: [M+H].sup.+=297.0/298.9.

[0923] Step 5: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (62.54 mg, 242.30 mol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14.53 mg, 20.19 mol) and potassium carbonate (83.72 mg, 605.76 mol) were added to a solution of the 4-(6-bromoisochroman-8-yl)-4,5-dihydrooxazol-2-amine (0.06 g, 201.92 mol) in 1,4-dioxane (2.5 mL) and water (0.5 mL) and stirred at 100 C. for 2 h. The reaction was checked by LCMS for completion, and the reaction mixture was concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 mL/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give 4-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl]-4,5-dihydrooxazol-2-amine (Z243, 5.17 mg, yield: 7.28%) as a white solid. ES-API: [M+H].sup.+=349.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.09 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.54 (s, 1H), 7.29 (s, 1H), 7.04 (s, 1H), 5.22-5.16 (m, 1H), 4.93 (d, J=15.0 Hz, 1H), 4.72-4.62 (m, 2H), 4.08-3.95 (m, 3H), 3.00-2.93 (m, 2H), 2.29 (s, 3H).

Example 150. Synthesis of Compound Z250

##STR00421##

[0924] Step 1: Isocyanatocyclopropane (6.92 mg, 0.083 mmol) and triethylamine (21.01 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in tetrahydrofuran (1 mL) and stirred at 0 C. for 0.2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a product tert-butyl (S)-2-(2-(cyclopropylcarbamoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, crude product). ES-API: [M+H].sup.+=516.3.

[0925] Step 2: Trifluoroacetic acid (0.5 mL) was added to a solution of the compound tert-butyl (S)-2-(2-(cyclopropylcarbamoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.058 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sulfuric acid, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give a product (S)N-cyclopropyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Z250, 4.4 mg, yield: 18.2%) as a white powder. ES-API: [M+H].sup.+=416.2.

Example 151. Synthesis of Compound Z251

##STR00422##

[0926] Step 1: Cyclopropanesulfonyl chloride (11.7 mg, 0.083 mmol) and triethylamine (21.01 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in tetrahydrofuran (1 mL) and stirred at 0 C. for 0.2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a product tert-butyl (S)-2-(2-(cyclopropylsulfonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, crude product). ES-API: [M+H].sup.+=537.3.

[0927] Step 2: Trifluoroacetic acid (0.5 mL) was added to a solution of the compound tert-butyl (S)-2-(2-(cyclopropylsulfonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.056 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give a product (S)-2-(cyclopropylsulfonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z251, 2.1 mg, yield: 8.61%) as a white powder. ES-API: [M+H].sup.+=437.2.

Example 152. Synthesis of Compound Z249

##STR00423##

[0928] Step 1: 2,2-Dimethyl-5-oxotetrahydrofuran-3-carboxylic acid (13.16 mg, 0.083 mmol), 1-propylphosphonic anhydride (132.3 mg, 0.21 mmol, 50% solution in ethyl acetate) and triethylamine (21.01 mg, 0.21 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in dichloromethane (1 mL) and stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-6% methanol/dichloromethane) to give a product (2S)-tert-butyl 2-(2-(2,2-dimethyl-5-oxotetrahydrofuran-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, yield: 75.53%). ES-API: [M+H].sup.+=573.4.

[0929] Step 2: Trifluoroacetic acid (0.5 mL) was added to a solution of the compound (2S)-tert-butyl 2-(2-(2,2-dimethyl-5-oxotetrahydrofuran-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.052 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 mL/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give a product 5,5-dimethyl-4-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-2(3H)-one (Z249, 8.3 mg, yield: 33.53%) as a white powder. ES-API: [M+H].sup.+=473.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.83 (s, 1H), 8.49-8.46 (m, 1H), 8.04-7.99 (m, 1H), 7.79-7.58 (m, 1H), 7.31 (d, J=13.8 Hz, 1H), 7.09 (s, 1H), 5.20-4.78 (m, 2H), 4.65-4.31 (m, 1H), 4.21-3.74 (m, 2H), 3.73-3.57 (m, 1H), 3.35-3.20 (m, 2H), 3.09-2.96 (m, 3H), 2.75-2.63 (m, 1H), 2.35 (s, 3H), 2.32-2.16 (m, 1H), 2.03-1.81 (m, 3H), 1.62-1.57 (m, 3H), 1.38-1.29 (m, 3H).

Example 153. Synthesis of Compound Z139

##STR00424## ##STR00425## ##STR00426##

[0930] Step 1: 2-(2-Bromo-4-chlorophenyl)acetic acid (10 g, 40.1 mmol), N,N-dimethylformamide (1 mL) and tetrahydrofuran (70 mL) were added to a 250 mL three-neck flask. Oxalyl chloride (6 g, 47.24 mmol) was slowly added dropwise at 0 C. in the presence of protective nitrogen, and the system reacted at 0 C. for 1 h. The reaction mixture was spun to dryness, dissolved in dichloromethane (30 mL), added dropwise to a solution of ammonia water (50 mL) in dichloromethane (50 mL), stirred for 30 min, and slowly poured into ice water (500 mL). As a result, a large amount of solid was precipitated, filtered, and spun to dryness to give a desired product 2-(2-bromo-4-chlorophenyl)acetamide (8.5 g, yield: 85%). ES-API: [M+H].sup.+=247.8.

[0931] Step 2: The 2-(2-bromo-4-chlorophenyl)acetamide (9 g, 36.3 mmol) and tetrahydrofuran (80 mL) were added to a 250 mL single-neck round-bottom flask. 1M borane in tetrahydrofuran (220 mL) was slowly added dropwise at 0 C. in the presence of protective nitrogen, and the system was warmed to 75 C. overnight. The reaction mixture was spun to dryness, dissolved in dichloromethane (30 mL), added dropwise to a solution of ammonia water (50 mL) in dichloromethane (50 mL), stirred for 30 min, and cooled to 0 C. 1M Hydrochloric acid solution (20 mL) was slowly added and stirred at 75 C. for 1 h. Ethyl acetate (200 mL) was added. The obtained mixture was washed with saturated brine (200 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product 2-(2-bromo-4-chlorophenyl)ethan-1-amine (7.7 g, yield: 90%). ES-API: [M+H].sup.+=239.9.

[0932] Step 3: The 2-(2-bromo-4-chlorophenyl)ethan-1-amine (8.1 g, 34.6 mmol), triethylamine (10.4 g, 103 mmol), trifluoroacetic anhydride (7.23 g, 34.4 mmol) and dichloromethane (80 mL) were added to a 250 mL single-neck round-bottom flask, and the system reacted at room temperature for 2 h. Dichloromethane (200 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (200 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product N-(2-bromo-4-chlorophenethyl)-2,2,2-trifluoroacetamide (9.2 g, yield: 81%). ES-API: [M+H].sup.+=330.

[0933] Step 4: N-(2-Bromo-4-chlorophenethyl)-2,2,2-trifluoroacetamide (4 g, 12.1 mmol) and acetic acid (50 mL) were added to a 250 mL single-neck round-bottom flask. Concentrated sulfuric acid (40 mL) was slowly added at 0 C. and stirred at room temperature for 48 h. The reaction mixture was slowly poured into water (200 mL), extracted with dichloromethane (200 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=30:100) to give a desired product 1-(5-bromo-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (1.2 g, yield: 31%). ES-API: [M+H].sup.+=341.9.

[0934] Step 5: The 1-(5-bromo-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (1.2 g, 3.5 mmol), potassium carbonate (485 mg, 3.5 mmol), ethanol (15 mL) and water (3 mL) were added to a 50 mL single-neck round-bottom flask and stirred at 80 C. for 2 h. The reaction mixture was slowly poured into water (20 mL), extracted with dichloromethane (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=30:100) to give a desired product 5-bromo-7-chloro-1,2,3,4-tetrahydroisoquinoline (860 mg, yield: 99%). ES-API: [M+H].sup.+=245.9.

[0935] Step 6: The 5-bromo-7-chloro-1,2,3,4-tetrahydroisoquinoline (492 mg, 2 mmol), triethylamine (606 mg, 6 mmol), and dichloromethane (10 mL) were added to a 50 mL single-neck round-bottom flask. Acetic anhydride (310 mg, 3 mmol) was slowly added at 0 C., and the system reacted at 0 C. for 1 h. Dichloromethane (20 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product 1-(5-bromo-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (582 mg, yield: 100%). ES-API: [M+H].sup.+=288.0.

[0936] Step 7: The 1-(5-bromo-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (540 mg, 1.88 mmol), potassium vinylfluoroborate (251 mg, 1.89 mmol), tetrakis(triphenylphosphine)palladium (216 mg, 0.18 mmol), potassium carbonate (776 mg, 5.6 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL three-neck round-bottom flask. The system was replaced with nitrogen three times, protected with a nitrogen balloon, and then reacted at 110 C. for 4 h. Ethyl acetate (100 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (50 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=40:100) to give a desired product 1-(7-chloro-5-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (470 mg, crude product). ES-API: [M+H].sup.+=236.1.

[0937] Step 8: The 1-(7-chloro-5-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (470 mg, 2 mmol), sodium periodate (2.14 g, 10 mmol), tetrahydrofuran (10 mL) and water (5 mL) were added to a 25 mL single-neck round-bottom flask. Potassium osmate dihydrate (147 mg, 0.4 mmol) was added in batches under an ice-water bath condition and then stirred at 0 C. for 1 h. Ethyl acetate (30 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=30:100) to give a desired product 2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinoline-5-carbaldehyde (200 mg, yield: 42%). ES-API: [M+H].sup.+=238.0.

[0938] Step 9: The 2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinoline-5-carbaldehyde (200 mg, 0.84 mmol) and dichloromethane (10 mL) were added to a 50 mL single-neck round-bottom flask. (S)-2-Methylpropane-2-sulfinamide (203 mg, 1.68 mmol) and tetraethyl titanate (1 mL) were added under an ice-water bath condition and stirred at room temperature for 3 h. Ethyl acetate (30 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=20:100) to give a desired product (S,E)-N-((2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)methylene)-2-methylpropane-2-sulfinamide (350 mg, yield: 83%). ES-API: [M+H].sup.+=341.1.

[0939] Step 10: The (S,E)-N-((2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)methylene)-2-methylpropane-2-sulfinamide (200 mg, 0.56 mmol) and anhydrous tetrahydrofuran (3 mL) were added to a 5 mL three-neck round-bottom flask. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide in tetrahydrofuran (3.5 mL, 0.5M) was added at 78 C. and continued to be stirred for 2 h. The reaction mixture was quenched by the addition of saturated ammonium chloride (5 mL) solution. Ethyl acetate (30 mL) was added. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=20:100) to give a desired product (S)N-(1-(2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (210 mg, yield: 78%). ES-API: [M+H].sup.+=457.2.

[0940] Step 11: The (S)N-(1-(2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (270 mg, 0.59 mmol), trifluoroacetic acid (3 mL) and water (0.15 mL) were added to a 25 mL single-neck round-bottom flask. Trimethylsilane (687 mg, 5.9 mmol) was added at 0 C. and stirred for 18 h. After the reaction mixture was spun to dryness, ethyl acetate (30 mL) was added. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a desired product (S)-1-(7-chloro-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl) ethan-1-one (160 mg, yield: 97%) as a crude product. ES-API: [M+H].sup.+=279.1.

[0941] Step 12: The (S)-1-(7-chloro-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (160 mg, 0.574 mmol), di-tert-butyl dicarbonate (1 mL), triethylamine (174 mg, 1.7 mmol) and dichloromethane (5 mL) were added to a 25 mL single-neck round-bottom flask and stirred at room temperature for 1 h. Dichloromethane (20 mL) was added to the reaction. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a desired product tert-butyl (S)-2-(2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (80 mg, yield: 37%). ES-API: [M+H].sup.+=379.2.

[0942] Step 13: The tert-butyl (S)-2-(2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (80 mg, 0.21 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (81 mg, 0.32 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (15 mg, 0.02 mmol), potassium carbonate (88 mg, 0.63 mmol), dioxane (30 ml) and water (4 mL) were added to a 25 mL single-neck round-bottom flask. The system was replaced with nitrogen three times, protected with a nitrogen balloon, and then reacted under microwave at 110 C. for 50 min. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with 5 mL of saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (S)-2-(2-acetyl-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (70 mg, yield: 70%). ES-API: [M+H].sup.+=475.3.

[0943] Step 14: The tert-butyl (S)-2-(2-acetyl-7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)pyrrolidine-1-carboxylate (70 mg, 0.15 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness, and the crude product was purified by prep-HPLC (ammonium bicarbonate) to give (S)-1-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Z139, 20 mg, yield: 36%). ES-API: [M+H].sup.+=375.2.

Example 154. Synthesis of Compound Z252

##STR00427## ##STR00428##

[0944] Step 1: 6-Bromoisochroman-8-carbaldehyde (1.6 g, 6.67 mmol) was dissolved in methanol (20 mL). Sodium borohydride (760 mg, 19.99 mmol) was slowly added under an ice-water bath condition and stirred for 1 h. Upon completion of the reaction, the reaction was quenched by the addition of water (20 mL). The reaction mixture was extracted with ethyl acetate (20 ml3), washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give (6-bromoisochroman-8-yl)methanol (1.61 g, crude product). ES-API: [M+H].sup.+=243.0.

[0945] Step 2: The (6-bromoisochroman-8-yl)methanol (1.61 g, crude product) was dissolved in tetrahydrofuran (30 mL). Triethylamine (2.02 g, 20.0 mmol) and methanesulfonyl chloride (1.14 g, 10 mmol) were added successively under an ice-water bath condition, and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction was quenched by the addition of water (20 mL). The reaction mixture was extracted with ethyl acetate (20 ml3), washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give methyl (6-bromoisochroman-8-yl)methanesulfonate (1.8 g, crude product). ES-API: [M+H].sup.+=321.1.

[0946] Step 3: The methyl (6-bromoisochroman-8-yl)methanesulfonate (1.5 g, crude product) was dissolved in acetonitrile (30 mL). Trimethylsilyl cyanide (696 mg, 7.03 mmol) and tetrabutylammonium fluoride (1.83 g, 7.03 mmol) were added successively, and the system reacted at room temperature for 2 h. The reaction was quenched by the addition of water (20 mL). The reaction mixture was extracted with ethyl acetate (20 ml3), washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/5) to give 2-(6-bromoisochroman-8-yl)acetonitrile (0.96 g, yield of the 3 steps: 57.3%). ES-API: [M+H].sup.+=252.2.

[0947] Step 4: The 2-(6-bromoisochroman-8-yl)acetonitrile (250 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (8 ml), and placed in an ice-water bath. 60% sodium hydride (200 mg, 5 mmol) was added, and the system reacted under the ice-water bath condition for 0.5 h. 1,2-Dibromoethane (188 mg, 1 mmol) was then added and stirred for 2 h. The reaction was quenched by the addition of aqueous ammonium chloride solution (20 mL). The reaction mixture was extracted with ethyl acetate (20 ml3), washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/5) to give 1-(6-bromoisochroman-8-yl)cyclopropane-1-carbonitrile (200 mg, yield: 72.2%). ES-API: [M+H].sup.+=278.

[0948] Step 5: The 1-(6-bromoisochroman-8-yl)cyclopropane-1-carbonitrile (200 mg, 0.722 mmol) was dissolved in ethanol (4 mL) and water (4 mL). Sodium hydroxide (144.4 mg, 3.61 mmol) was added, and the system reacted under microwave at 100 C. for 15 h. The reaction was cooled to room temperature, and quenched by the addition of diluted hydrochloric acid. The reaction mixture was extracted with ethyl acetate (20 ml3), washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/1) to give 1-(6-bromoisochroman-8-yl)cyclopropane-1-carboxylic acid (160 mg, yield: 74.8%). ES-API: [M+H].sup.+=297.

[0949] Step 6: Toluene (5 mL) and benzyl alcohol (982.59 mg, 9.086 mmol) were added to a flask charged with the 1-(6-bromoisochroman-8-yl)cyclopropane-1-carboxylic acid (90 mg, 0.303 mmol). Diphenylphosphoryl azide (125.03 mg, 0.454 mmol) and triethylamine (0.084 mL, 0.606 mmol) were then added, and the mixture was stirred at 110 C. for 15 h. The reaction mixture was diluted with water, extracted with ethyl acetate (30 mL3), washed with saturated sodium chloride solution (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/1) to give benzyl (1-(6-bromoisochroman-8-yl)cyclopropyl)carbamate (110 mg, yield: 90.5%). ES-API: [M+H].sup.+=402.0.

[0950] Step 7: The benzyl (1-(6-bromoisochroman-8-yl)cyclopropyl)carbamate (100 mg, 0.249 mmol) was added dropwise to a suspension of sodium hydride (29.83 mg, 0.746 mmol) in tetrahydrofuran (5 mL) under an ice-water bath condition, and the mixture was stirred for 10 min. Iodomethane (176.42 mg, 1.243 mmol) was then added, and the reaction mixture was warmed to room temperature and stirred for 3 h. The obtained mixture was poured into a saturated ammonium chloride ice water solution, extracted with ethyl acetate (30 mL3), washed with saturated sodium chloride solution (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/1) to give benzyl N-methyl-(1-(6-bromoisochroman-8-yl)cyclopropyl)carbamate (90 mg, yield: 87%). ES-API: [M+H].sup.+=416.0.

[0951] Step 8: The benzyl N-methyl-(1-(6-bromoisochroman-8-yl)cyclopropyl)carbamate (90 mg, 0.216 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (111.51 mg, 0.432 mmol), (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (15.57 mg, 0.022 mmol) and potassium carbonate (89.64 mg, 0.649 mmol) were added to 1,4-dioxane (3 mL) and water (0.5 mL). The system was replaced with nitrogen and reacted under microwave at 120 C. for 0.5 h. Upon completion of the reaction, ethyl acetate (20 mL) was added. The obtained mixture was washed with water (10 mL) and saturated brine (10 mL) successively, and dried over anhydrous sodium sulfate to give a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give benzyl N-methyl-(1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)cyclopropyl)carbamate (77 mg, yield: 76.3%). ES-API: [M+H].sup.+=468.2.

[0952] Step 9: The benzyl N-methyl-(1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)cyclopropyl)carbamate (77 mg, 0.164 mmol) was dissolved in dichloromethane (5 mL). Palladium chloride (5.08 mg, 0.01 mmol), triethylamine (16.5 mg, 0.164 mmol) and triethylsilane (76 mg, 0.656 mmol) were then added at 0 C., and the mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and concentrated to give a crude product. The crude product was purified by prep-HPLC alkaline process (ammonia water) to give N-methyl-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-8-yl)cyclopropane-1-amine (Z252, 2.8 mg, yield: 5.1%). ES-API: [M+H].sup.+=334.1.

Example 155. Synthesis of Compound Z238

##STR00429##

[0953] Step 1: 3-(4,4,5,5-Tetramethyl-1,3,2-dioxobenzofuran-2-yl)pyridin-2-amine (402 mg, 1.83 mmol), 2-bromo-1,3-thiazole (250 mg, 1.52 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (111 mg, 0.15 mmol), potassium carbonate (632 mg, 4.57 mmol), 1,4-dioxane (6 mL) and water (1.5 mL) were added to a 20 mL microwave tube. The system was purged with nitrogen for 1 min and reacted in a microwave reactor at 110 C. for 1 h. The reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0-10%) to give a desired product 3-(thiazol-2-yl)pyridin-2-amine (210 mg, yield: 77.7%) as an off-white solid. ES-API: [M+H].sup.+=178.1.

[0954] Step 2: The 3-(thiazol-2-yl)pyridin-2-amine (185 mg, 1.04 mmol) was dissolved in tetrahydrofuran (15 mL). N-Bromosuccinimide (204 mg, 1.15 mmol) was added under an ice bath condition and stirred under the ice bath for 1 h. Ethyl acetate (50 mL) was added to the reaction mixture. The obtained mixture was washed with saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0-5%) to give a desired product 5-bromo-3-(thiazol-2-yl)pyridin-2-amine (230 mg, yield: 86.0%) as a pale yellow solid. ES-API: [M+H].sup.+=256.0, 258.0. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.15 (d, J=2.5 Hz, 1H), 8.10 (d, J=2.5 Hz, 1H), 7.97 (d, J=3.5 Hz, 1H), 7.84 (d, J=3.5 Hz, 1H), 7.78 (s, 2H).

[0955] Step 3: The 5-bromo-3-(thiazol-2-yl)pyridin-2-amine (50 mg, 0.20 mmol), tert-butyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (101 mg, 0.24 mmol), 2-dicyclohexylphosphine-2,6-dimethoxy-biphenyl (4 mg, 0.01 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.02 mmol), potassium carbonate (81 mg, 0.59 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL) were added to a 5 mL microwave tube. The mixture was purged with nitrogen for 30 sec, and the system reacted in a microwave reactor at 110 C. for 45 min. The reaction was cooled to room temperature. The reaction mixture was poured into water (8 mL), and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0-4%) to give a desired product tert-butyl (S)-2-(6-(6-amino-5-(thiazol-2-yl)pyridin-3-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (55 mg, yield: 58.9%) as a pale yellow solid. ES-API: [M+H].sup.+=479.3.

[0956] Step 4: The tert-butyl (S)-2-(6-(6-amino-5-(thiazol-2-yl)pyridin-3-yl)isochroman-8-yl)pyrrolidine-1-carboxylate (55 mg, 0.11 mmol) was dissolved in methanol (1 mL). 4.0M Hydrogen chloride-dioxane solution (2 mL, 8.0 mmol) was added, and the system reacted at room temperature for 1.5 h. The reaction mixture was concentrated. 7.0M Ammonia-methanol solution (5 mL) was added, and a solvent was spun to dryness to give a crude product. The crude product was purified by prep-HPLC (formic acid) to give a desired product (S)-5-(8-(pyrrolidin-2-yl)isochroman-6-yl)-3-(thiazol-2-yl)pyridin-2-amine (Z238, formate, 31 mg, yield: 63.5%) as a pale yellow solid. ES-API: [M+H].sup.+=379.2 (free base). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.43 (d, J=2.5 Hz, 1H), 8.29 (s, 1H), 8.14 (d, J=2.5 Hz, 1H), 7.97 (d, J=3.5 Hz, 1H), 7.81 (d, J=3.5 Hz, 1H), 7.76-7.68 (m, 2H), 7.65 (s, 1H), 7.36 (s, 1H), 4.88 (d, J=15.5 Hz, 1H), 4.76 (d, J=15.5 Hz, 1H), 4.20 (t, J=8.0 Hz, 1H), 3.91-3.83 (m, 2H), 3.24-3.18 (m, 1H), 3.07-2.98 (m, 1H), 2.96-2.82 (m, 2H), 2.25-2.14 (m, 1H), 1.98-1.79 (m, 2H), 1.69-1.57 (m, 1H).

Example 156. Synthesis of Compound Z245

##STR00430##

[0957] Step 1: 1-Methoxycyclopropane carboxylic acid (9.66 mg, 0.083 mmol), 1-propylphosphonic anhydride (133.6 mg, 208.07 mol, 50% in ethyl acetate) and triethylamine (21.01 mg, 208.07 mol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in dichloromethane (1 mL) and stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-6% methanol/dichloromethane) to give a product tert-butyl (S)-2-(2-(1-methoxycyclopropanecarbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, yield: 80%). ES-API: [M+H].sup.+=531.4.

[0958] Step 2: Trifluoroacetic acid (0.5 mL) was added to a solution of the compound tert-butyl (S)-2-(2-(1-methoxycyclopropanecarbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.056 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 mL/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give a product (S)-(1-methoxycyclopropyl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z245, 8.2 mg, yield: 34%) as a white powder. ES-API: [M+H].sup.+=431.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.87 (s, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.75 (s, 1H), 7.30 (s, 1H), 7.09 (s, 1H), 5.37-4.50 (m, 2H), 4.39-4.31 (m, 1H), 4.13-3.71 (m, 2H), 3.33 (s, 3H), 3.29-3.23 (m, 1H), 3.10-2.94 (m, 3H), 2.35 (s, 3H), 2.33-2.25 (m, 1H), 2.05-1.81 (m, 3H), 1.19-1.10 (m, 2H), 1.04-0.94 (m, 2H).

Example 157. Synthesis of Compound Z75-1

##STR00431##

[0959] Step 1: 2-(Carboxymethyl)-4-nitrobenzoic acid (9 g, 40 mmol), sodium borohydride (4.6 g, 121 mmol) and tetrahydrofuran (100 mL) were added to a 500 mL single-neck round-bottom flask. 1M boron trifluoride in tetrahydrofuran (19 mL) was slowly added dropwise at 0 C. in the presence of protective nitrogen, and the system reacted at 0 C. for 3 h. Ethyl acetate (200 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (200 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product 2-(2-(hydroxymethyl)-5-nitrophenyl)ethan-1-ol (6.6 g, yield: 83%). ES-API: [M+H-18].sup.+=180.0.

[0960] Step 2: The 2-(2-(hydroxymethyl)-5-nitrophenyl)ethan-1-ol (198 g, 1 mmol), p-toluenesulfonic acid (384 mg, 2 mmol) and toluene (10 mL) were added to a 25 mL single-neck round-bottom flask, and the system reacted at 120 C. overnight. Ethyl acetate (50 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (50 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product 6-nitroisochromane (170 g, yield: 94%). ES-API: [M+H].sup.+=180.0.

[0961] Step 3: The 6-nitroisochromane (680 mg, 3.78 mmol), palladium on carbon (70 mg) and methanol (10 mL) were added to a 50 mL single-neck round-bottom flask, and the system reacted overnight in the presence of hydrogen. The reaction mixture was filtered and spun to dryness to give a desired product 6-aminoisochromane (550 mg, yield: 97%). ES-API: [M+H].sup.+=150.0.

[0962] Step 4: The 6-aminoisochromane (550 mg, 3.67 mmol), N-bromosuccinimide (594 mg, 3.3 mmol) and acetonitrile (20 mL) were added to a 50 mL single-neck round-bottom flask and stirred at 0 C. for 1 h. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=30:100) to give a desired product 5-bromoisochroman-6-amine (600 mg, yield: 71%). ES-API: [M+H].sup.+=228.0.

[0963] Step 5: The 5-bromoisochroman-6-amine (600 mg, 2.63 mmol), N-chlorosuccinimide (351 mg, 2.63 mmol) and N,N-dimethylformamide (10 mL) were added to a 50 mL single-neck round-bottom flask and stirred at 80 C. for 1 h. The reaction mixture was poured into water (30 mL), extracted with 30 mL of ethyl acetate 3 times, dried, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=30:100) to give a desired product 5-bromo-7-chloroisochroman-6-amine (420 mg, yield: 61%). ES-API: [M+H].sup.+=262.0.

[0964] Step 6: The 5-bromo-7-chloroisochroman-6-amine (400 mg, 1.52 mmol) and aqueous hypophosphorous acid solution (40 mL) were added to a 50 mL single-neck round-bottom flask. Sodium nitrite (316 mg, 4.58 mmol) was slowly added at 0 C., and the system reacted at 0 C. for 2 h. The reaction mixture was added to water (20 mL), adjusted to pH 9-10 with sodium bicarbonate solution, extracted with ethyl acetate (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product 5-bromo-7-chloroisochromane (320 mg, yield: 85%). ES-API: [M+H].sup.+=247.0.

[0965] Step 7: The 5-bromo-7-chloroisochromane (320 mg, 1.35 mmol), potassium vinylfluoroborate (180 mg, 1.35 mmol), tetrakis(triphenylphosphine)palladium (156 mg, 0.4 mmol), potassium carbonate (558 mg, 4.1 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL three-neck round-bottom flask. The system was replaced with nitrogen three times, protected with a nitrogen balloon, and then reacted at 110 C. for 4 h. Ethyl acetate (100 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (50 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=40:100) to give a desired product 7-chloro-5-vinylisochromane (250 mg, yield: 93%). ES-API: [M+H].sup.+=195.1.

[0966] Step 8: The 7-chloro-5-vinylisochromane (270 mg, 1.39 mmol), sodium periodate (1.78 g, 8.3 mmol), tetrahydrofuran (10 mL) and water (5 mL) were added to a 25 mL single-neck round-bottom flask. Potassium osmate dihydrate (102 mg, 0.27 mmol) was added in batches under an ice-water bath condition and then stirred at 0 C. for 1 h. Ethyl acetate (30 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=30:100) to give a desired product 7-chloroisochromane-5-carbaldehyde (110 mg, yield: 40%). ES-API: [M+H].sup.+=197.0.

[0967] Step 9: The 7-chloroisochromane-5-carbaldehyde (110 mg, 0.56 mmol) and dichloromethane (10 mL) were added to a 50 mL single-neck round-bottom flask. (S)-2-methylpropane-2-sulfinamide (135.6 mg, 1.12 mmol) and tetraethyl titanate (1 mL) were added under an ice-water bath condition and stirred at room temperature for 3 h. Ethyl acetate (30 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=20:100) to give a desired product (S,E)-N-((7-chloroisochroman-5-yl)methylene)propane-2-sulfinamide (155 mg, yield: 92%). ES-API: [M+H].sup.+=286.1.

[0968] Step 10: The (S,E)-N-((7-chloroisochroman-5-yl)methylene)propane-2-sulfinamide (155 mg, 0.56 mmol) and anhydrous tetrahydrofuran (3 mL) were added to a 5 mL three-neck round-bottom flask. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide in tetrahydrofuran (0.5M, 3.1 mL) was added at 78 C. and continued to be stirred for 2 h. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (5 mL), and ethyl acetate (30 mL) was added to the mixed solution. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=20:100) to give a desired product (S)N-(1-(7-chloroisochroman-5-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (180 mg, yield: 84%). ES-API: [M+H].sup.+=416.2.

[0969] Step 11: The (S)N-(1-(7-chloroisochroman-5-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (180 mg, 0.43 mmol), trifluoroacetic acid (3 mL) and water (0.15 mL) were added to a 25 mL single-neck round-bottom flask. Trimethylsilane (503 mg, 4.3 mmol) was added at 0 C. and stirred for 18 h. After the reaction mixture was spun to dryness, ethyl acetate (30 mL) was added. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a desired product (S)-2-(7-chloroisochroman-5-yl)pyrrolidine (100 mg, yield: 97%). ES-API: [M+H].sup.+=238.1.

[0970] Step 12: The (S)-2-(7-chloroisochroman-5-yl)pyrrolidine (130 mg, 0.42 mmol), di-tert-butyl dicarbonate (1 mL), triethylamine (174 mg, 1.7 mmol) and dichloromethane (5 mL) were added to a 25 mL single-neck round-bottom flask and stirred for 1 h. Dichloromethane (20 mL) was added to the reaction. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a desired product tert-butyl (S)-2-(7-chloroisochroman-5-yl)pyrrolidine-1-carboxylate (130 mg, yield: 91%). ES-API: [M+H].sup.+=338.2.

[0971] Step 13: The tert-butyl (S)-2-(7-chloroisochroman-5-yl)pyrrolidine-1-carboxylate (130 mg, 0.38 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (149 mg, 0.57 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (28 mg, 0.04 mmol), potassium carbonate (160 mg, 1.15 mmol), dioxane (20 mL) and water (3 mL) were added to a 25 mL single-neck round-bottom flask. The system was replaced with nitrogen three times, protected with a nitrogen balloon, and then reacted under microwave at 110 C. for 50 min. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 ml3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-5-yl)pyrrolidine-1-carboxylate (150 mg, yield: 90%). ES-API: [M+H].sup.+=434.3.

[0972] Step 14: The tert-butyl (S)-2-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochroman-5-yl)pyrrolidine-1-carboxylate (150 mg, 0.15 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness to give a crude product. The crude product was purified by prep-HPLC (ammonium bicarbonate) to give (S)-3-methyl-5-(5-(pyrrol-2-yl)isochroman-7-yl)-1H-pyrrolo[2,3-b]pyridine (Z75-1, 100 mg, yield: 65%). ES-API: [M+H].sup.+=334.2.

Example 158. Synthesis of Compound Z244

##STR00432##

[0973] Step 1: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39.89 mg, 0.21 mmol), 4-hydroxytetrahydropyran-4-carboxylic acid (12.16 mg, 0.083 mmol) and 1-hydroxybenzotriazole (14.06 mg, 0.1 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.069 mmol) in N,N-dimethylformamide (1 mL) and stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-6% methanol/dichloromethane) to give a product tert-butyl (S)-2-(2-(2-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (20 mg, 51%). ES-API: [M+H].sup.+=561.4

[0974] Step 2: Trifluoroacetic acid (0.5 mL) was added to a solution of the compound tert-butyl (S)-2-(2-(2-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (20 mg, 0.036 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 ml/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give a product (S)-(4-hydroxytetrahydro-2H-pyran-4-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z244, 3.6 mg, yield: 22%) as a white powder. ES-API: [M+H].sup.+=461.3.

Example 159. Synthesis of Compound Z242

##STR00433##

[0975] Step 1: 1-Hydroxycyclopropane carboxylic acid (5.66 mg, 0.055 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.59 mg, 0.14 mmol) and 1-hydroxybenzotriazole (18.74 mg, 0.14 mmol) were added to a solution of tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (20 mg, 0.0646 mmol) in N,N-dimethylformamide (1 mL) and stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-6% methanol/dichloromethane) to give a product tert-butyl (S)-2-(2-(1-hydroxycyclopropanecarbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, crude product). ES-API: [M+H].sup.+=517.3.

[0976] Step 2: Trifluoroacetic acid (0.5 mL) was added to a solution of the compound tert-butyl (S)-2-(2-(1-hydroxycyclopropanecarbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (30 mg, 0.058 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase system: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 mL/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give a product (S)-(1-hydroxycyclopropyl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z242, 6.5 mg, yield: 27%) as a white powder. ES-API: [M+H].sup.+=417.2.

Example 160. Synthesis of Compound Z436

##STR00434##

[0977] Step 1: N-Iodosuccinimide (879 mg, 3.91 mmol) was slowly added to a solution of 3-chloro-7H-pyrrolo[2,3-c]pyridazine (500 mg, 3.26 mmol) in acetonitrile (20 mL) and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction was quenched with sodium thiosulfate (20 mL) solution, and the reaction mixture was extracted with ethyl acetate (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-8% methanol/dichloromethane) to give 3-chloro-5-iodo-7H-pyrrolo[2,3-c]pyridazine (750 mg, yield: 82%) as a yellow solid. ES-API: [M+H].sup.+=280.0.

[0978] Step 2: In the presence of protective nitrogen, trimethylaluminum in tetrahydrofuran (5.37 mL, 1 M) was added to a mixed solution of the 3-chloro-5-iodo-7H-pyrrolo[2,3-c]pyridazine (750 mg, 2.68 mmol) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II) (98 mg, 0.13 mmol) in tetrahydrofuran (20 mL) and stirred at 80 C. overnight. The reaction mixture was quenched with 1 M hydrochloric acid (20 mL) and spun to dryness. The residue was dissolved in dichloromethane (20 mL), filtered, concentrated, and purified by a flash silica gel column (0-8% methanol/dichloromethane) to give 3-chloro-5-methyl-7H-pyrrolo[2,3-c]pyridazine (250 mg, yield: 56%) as a yellow solid. ES-API: [M+H].sup.+=168.1.

[0979] Step 3: N,N-diisopropylethyl amine (1.29 mL, 7.42 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (847 mg, 2.23 mmol) were added successively to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (500 mg, 1.48 mmol) and (S)-2-trifluoromethyl-2-hydroxypropanoic acid (469 mg, 2.97 mmol) in dichloromethane (20 mL) and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated and purified by a flash silica gel column (1-100% tetrahydrofuran/petroleum ether) to give tert-butyl (S)-2-(6-chloro-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (650 mg, yield: 92%) as a clear oil. ES-API: [M+H-Boc].sup.+=377.2.

[0980] Step 4: In the presence of protective nitrogen, a mixture of the tert-butyl (S)-2-(6-chloro-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (215 mg, 0.45 mmol), bis(pinacolato)diboron (343 mg, 1.35 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (32 mg, 0.04 mmol) and potassium acetate (133 mg, 1.35 mmol) in 1,4-dioxane (5 mL) was stirred at 120 C. for 2 h. Upon completion of the reaction, the reaction mixture was filtered, concentrated, and purified by a flash silica gel column (0-100% tetrahydrofuran/petroleum ether) to give tert-butyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (220 mg, yield: 86%) as a clear oil. ES-API: [M+H-Boc].sup.+=469.2.

[0981] Step 5: In the presence of protective nitrogen, a mixed solution of the tert-butyl (S)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.18 mmol), 3-chloro-5-methyl-7H-pyrrolo[2,3-c]pyridazine (60 mg, 0.36 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (13 mg, 0.02 mmol) and potassium carbonate (73 mg, 0.53 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 100 C. for 2 h. The reaction mixture was poured into ethyl acetate (10 mL) and washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-10% methanol/dichloromethane) to give tert-butyl (S)-2-(6-(5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, yield: 50%). ES-API: [M+H-Boc].sup.+=474.2.

[0982] Step 6: Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of the tert-butyl (S)-2-(6-(5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 87 mol) in dichloromethane (1 mL) under an ice bath condition and stirred at room temperature for 1 h. The reaction mixture was concentrated, neutralized with 7M amine-methanol (5 mL), concentrated, and purified by prep-HPLC (trifluoroacetic acid) to give (S)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-(6-(5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one trifluoroacetate (Z436, 2.5 mg, purity: 100%, yield: 5%) as a white solid. ES-API: [M+H].sup.+=474.2.

Example 161 Synthesis of Compound 7405

##STR00435##

[0983] Step 1: tert-butyl (S)-2-(6-chloro-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (55 mg, 0.116 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (96 mg, 0.34 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8 mg, 0.012 mmol) and potassium carbonate (48 mg, 0.34 mmol) were dissolved in 1,4-dioxane (5 ml) and stirred at 110 C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (S)-2-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (35 mg, yield: 51%). ES-API: [M+H].sup.+=593.

[0984] Step 2: The tert-butyl (S)-2-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (35 mg, 0.06 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again to give a crude product. The crude product was purified by prep-HPLC acid process (formic acid) to give (S)-1-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3,3-trifluoro-2-hydroxy-2-methylpropan-1-one (Z405, 18.6 mg, yield: 58%). ES-API: [M+H].sup.+=493. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.07 (s, 1H), 8.61 (d, J=1.6 Hz, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 7.79 (s, 1H), 7.73 (s, 1H), 7.48 (s, 1H), 5.25-5.15 (m, 1H), 4.87-4.75 (m, 1H), 4.32 (s, 1H), 4.17-4.07 (m, 1H), 3.87-3.83 (m, 1H), 3.63-3.60 (m, 1H), 3.20 (s, 2H), 3.01-2.93 (m, 3H), 2.27-2.17 (m, 1H), 1.89-1.88 (m, 2H), 1.59 (s, 3H).

Example 162. Synthesis of Compound Z367-1

##STR00436##

[0985] Step 1: (S)-Tert-butylsulfinamide (337 mg, 2.78 mmol) was added to a solution of 6-bromoisochromene-8-carbaldehyde (670 mg, 2.78 mmol) in tetrahydrofuran (20 mL). Tetraisopropyl titanate (2.34 g, 8.34 mmol) was added under an ice bath condition and stirred at room temperature for 3 h. The reaction was monitored by LCMS for completion, and saturated brine (20 mL) was added. The obtained mixture was filtered by suction, and the phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S,E)-N-((6-bromoisochromen-8-yl)methylene)-2-methylpropane-2-sulfonamide (850 mg, yield: 88%). ES-API: [M+H].sup.+=344.

[0986] Step 2: The (S,E)-N-((6-bromoisochromen-8-yl)methylene)-2-methylpropane-2-sulfonamide (500 mg, 1.4 mmol) was dissolved in tetrahydrofuran (15 mL). Allylmagnesium bromide (4.3 mL, 4.3 mmol) was added at 78 C., and the system reacted at room temperature for 2 h. A saturated ammonium chloride solution (10 mL) was added, and the obtained mixture was extracted with ethyl acetate (10 mL3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give (S)N-(1-(6-bromoisochromen-8-yl)but-3-en-1-yl)-2-methylpropane-2-sulfonamide (400 mg, yield: 71%). ES-API: [M+H].sup.+=386.

[0987] Step 3: The (S)N-(1-(6-bromoisochromen-8-yl)but-3-en-1-yl)-2-methylpropane-2-sulfonamide (400 mg, 1 mmol) was dissolved in methanol (10 mL). Hydrochloric acid/1,4-dioxane (0.7 ml, 3 mmol) was added, and the system reacted at room temperature for 16 h. Upon completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and water (10 mL) was added. The obtained mixture was adjusted to pH 9 with saturated sodium carbonate solution, and extracted with ethyl acetate (10 mL3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-(6-bromoisochromen-8-yl)but-3-en-1-amine (230 mg, yield: 78%). ES-API: [M+H].sup.+=282.

[0988] Step 4: The 1-(6-bromoisochromen-8-yl)but-3-en-1-amine (230 mg, 0.8 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (123 mg, 1.2 mmol) was added, followed by acetic anhydride (91 mg, 0.9 mmol), and the system reacted at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (10 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure to give N-(1-(6-bromoisochromen-8-yl)but-3-en-1-yl)acetamide (230 mg, yield: 88%). ES-API: [M+H].sup.+=324.

[0989] Step 5: The N-(1-(6-bromoisochromen-8-yl)but-3-en-1-yl)acetamide (170 mg, 0.5 mmol) was dissolved in tetrahydrofuran/water (15 mL). Iodine (333 mg, 1.3 mmol) was added, and the system reacted at room temperature for 16 h. Saturated sodium sulfite solution (5 mL) and saturated sodium bicarbonate solution (5 mL) were added to the reaction mixture. The obtained mixture was extracted with ethyl acetate (10 mL33), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give 5-(6-bromoisochromen-8-yl)pyrrolidin-3-yl acetate (140 mg, yield: 78%). ES-API: [M+H].sup.+=340.

[0990] Step 6: The 5-(6-bromoisochromen-8-yl)pyrrolidin-3-yl acetate (556 mg, 1.6 mmol) was dissolved in dichloromethane (15 mL). Triethylamine (247 mg, 2.4 mmol) was added, followed by di-tert-butyl carbonate (356 mg, 1.6 mmol), and the system reacted at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (10 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure to give tert-butyl 4-acetoxy-2-(6-bromoisochromen-8-yl)pyrrolidine-1-carboxylate (633 mg, yield: 88%). ES-API: [M+H].sup.+=440.

[0991] Step 7: The tert-butyl 4-acetoxy-2-(6-bromoisochromen-8-yl)pyrrolidine-1-carboxylate (600 mg, 1.3 mmol) was dissolved in methanol (5 mL). 1N Sodium hydroxide solution (1.5 ml, 1.5 mmol) was added, and the system reacted at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane (10 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give tert-butyl 2-(6-bromoisochromen-8-yl)-4-hydroxypyrrolidine-1-carboxylate (440 mg, yield: 81%). ES-API: [M+H].sup.+=398.

[0992] Step 8: The tert-butyl 2-(6-bromoisochromen-8-yl)-4-hydroxypyrrolidine-1-carboxylate (200 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL). Diethylaminosulfur trifluoride (161 mg, 1.0 mmol) was added at 78 C., and the system reacted at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and diluted with dichloromethane (10 mL). A saturated sodium bicarbonate solution (5 mL) was added, and the phase was separated. The organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=80/20) to give tert-butyl 2-(6-bromoisochromen-8-yl)-4-fluoropyrrolidine-1-carboxylate (160 mg, yield: 80%). ES-API: [M+H].sup.+=400.

[0993] Step 9: The tert-butyl 2-(6-bromoisochromen-8-yl)-4-fluoropyrrolidine-1-carboxylate (110 mg, 0.27 mmol), 3-methyl-7-azaindole-5-boronic acid pinacol ester (212 mg, 0.82 mmol) and potassium carbonate (114 mg, 0.82 mmol) were dissolved in 1,4-dioxane/water (3 mL). 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (10 mg) was added, and the system reacted at 110 C. in the presence of protective nitrogen for 2 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl 4-fluoro-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochromen-8-yl)pyrrolidine-1-carboxylate (90 mg, yield: 72%). ES-API: [M+H].sup.+=452.

[0994] Step 10: The tert-butyl 4-fluoro-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isochromen-8-yl)pyrrolidine-1-carboxylate (20 mg, 0.044 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again to give a crude product. The crude product was purified by prep-HPLC acid process (formic acid) to give 5-(8-(4-fluoropyrrolidin-2-yl)isochromen-6-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine (Z367-1, 10.6 mg, yield: 56%, formate). ES-API: [M+H].sup.+=352. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.32 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.69 (s, 1H), 7.37 (s, 1H), 7.25 (s, 1H), 5.42-5.39 (m, 1H), 5.27 (s, 1H), 4.91-4.87 (m, 1H), 4.78-4.74 (m, 1H), 4.32 (dd, J=10.0, 6.0 Hz, 1H), 3.95-3.81 (m, 3H), 3.40-3.36 (m, 1H), 3.15-3.07 (m, 1H), 2.96-2.83 (m, 2H), 2.31 (s, 3H), 1.82-1.66 (m, 1H).

Example 163. Synthesis of Compound Z362

##STR00437##

[0995] Step 1: In the presence of protective nitrogen, triethylamine (350 mg, 3.47 mmol) and (4-nitrophenyl)carbonyl chloride (480 mg, 2.08 mmol) were added to a solution of 2,2-dimethylmorpholine (200 mg, 1.74 mmol) in anhydrous dichloromethane (10 mL) at 0 C., and the mixture was warmed to 20 C. and stirred for 3 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:90) to give 4-nitrophenyl 2,2-dimethylmorpholine-4-carboxylate (480 mg, yield: 98.62%) as a yellow solid. ES-API: [M+1].sup.+=281.1.

[0996] Step 2: The 4-nitrophenyl 2,2-dimethylmorpholine-4-carboxylate (87.36 mg, 0.31 mmol) and potassium carbonate (57.44 mg, 0.42 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in N,N-dimethylacetamide (1 mL), and the mixture was warmed to 130 C. and stirred for 3 h. The reaction was monitored by LCMS for completion. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether:ethyl acetate=1:1) to give tert-butyl (S)-2-(6-chloro-2-(2,2-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70.00 mg, yield: 70.47%) as a yellow oil. ES-API: [M+1].sup.+=478.3.

[0997] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (45.36 mg, 0.18 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.54 mg, 14.64 mol) and potassium carbonate (60.62 mg, 0.44 mmol) were added to a solution of the tert-butyl (S)-2-(6-chloro-2-(2,2-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.15 mmol) in dioxane/water (2 mL/0.4 mL), and the system was heated to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-(2-(2,2-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60.00 mg, yield: 71.42%) as a yellow oil. ES-API: [M+1].sup.+=574.4.

[0998] Step 4: The tert-butyl (S)-2-(2-(2,2-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (2.0 mL). Trifluoroacetic acid (1.0 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give a product (S)-(2,2-dimethylmorpholine)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z362, 14.5 mg, yield: 29.28%) as a white solid. ES-API: [M+1].sup.+=474.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.36 (s, 1H), 8.50 (s, 1H), 7.98 (s, 1H), 7.76 (s, 1H), 7.29 (s, 1H), 7.08 (s, 1H), 4.64 (d, J=16.3 Hz, 1H), 4.55-4.38 (m, 2H), 3.84-3.73 (m, 2H), 3.61-3.33 (m, 3H), 3.32-3.25 (m, 2H), 3.21-310 (m, 3H), 3.05-2.90 (m, 2H), 2.34 (s, 3H), 2.32-2.26 (m, 1H), 2.12-1.78 (m, 3H), 1.27 (s, 6H).

Example 164. Synthesis of Compound Z345

##STR00438##

[0999] Step 1: Diisopropylethyl amine (115.12 mg, 890.59 mol) and 4-chloro-2-(trifluoromethyl)pyridine (161.69 mg, 890.59 mol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 296.86 mol) in N-methylpyrrolidinone (1 mL), and the system reacted at 130 C. for 15 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-5% methanol in dichloromethane) to give a product tert-butyl (S)-2-(6-chloro-2-(2-(trifluoromethyl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, yield: 70%). ES-API: [M+H].sup.+=483.2.

[1000] Step 2: The compound tert-butyl (S)-2-(6-chloro-2-(2-(trifluoromethyl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 207.58 mol) was dissolved in dioxane/water (2 mL/0.4 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (69.77 mg, 270.29 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14.94 mg, 20.76 mol) and potassium carbonate (85.94 mg, 622.74 mol) were added. The system was heated to 100 C. for 2 h. The reaction mixture was extracted with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-(trifluoromethyl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (79 mg, yield: 66.6%). ES-API: [M+H].sup.+=578.3.

[1001] Step 3: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-(trifluoromethyl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (79 mg, 136.76 mol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness, extracted with dichloromethane and saturated aqueous sodium bicarbonate solution, dried over anhydrous sulfuric acid, filtered, and spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-2-(2-(trifluoromethyl)pyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline (Z345, 20.12 mg, yield: 31%). ES-API: [M+1].sup.+=478.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.32 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.29 (d, J=6.0 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.46-7.41 (m, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.25- 7.22 (m, 1H), 7.13-7.10 (m, 1H), 4.78-4.59 (m, 2H), 4.47-4.33 (m, 1H), 3.82-3.59 (m, 2H), 3.17-3.10 (m, 1H), 3.04-2.94 (m, 3H), 2.28 (s, 3H), 2.26-2.20 (m, 1H), 1.90-1.77 (m, 2H), 1.60-1.50 (m, 1H).

Example 165. Synthesis of Compound Z359-1 and Compound Z359-2

##STR00439##

[1002] Step 1: In the presence of protective nitrogen, triethylamine (0.4 g, 3.95 mmol) and (4-nitrophenyl)carbonyl chloride (0.48 g, 2.37 mmol) were added to a solution of (S)-2-methylmorpholine (0.2 g, 1.98 mmol) in anhydrous dichloromethane (5 mL) at 0 C., and the mixture was warmed to 20 C. and stirred for 3 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:90) to give (4-nitrophenyl)(S)-2-methylmorpholine-4-carboxylate (0.45 g, yield: 85.48%) as a yellow solid. ES-API: [M+1].sup.+=267.1.

[1003] Step 2: The (4-nitrophenyl)(S)-2-methylmorpholine-4-carboxylate (82.99 mg, 0.31 mmol) and potassium carbonate (57.44 mg, 0.42 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in N,N-dimethylacetamide (1 mL), and the mixture was warmed to 150 C. and stirred for 3 h. The reaction was monitored by LCMS for completion. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether:ethyl acetate=1:1) to give tert-butyl (S)-2-[6-chloro-2-[(S)-2-methylmorpholine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (67.00 mg, yield: 69.49%) as a yellow oil. ES-API: [M+1].sup.+=464.3.

[1004] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (44.73 mg, 0.17 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.4 mg, 14.44 mol) and potassium carbonate (59.78 mg, 0.43 mmol) were added to a solution of the tert-butyl (S)-2-[6-chloro-2-[(S)-2-methylmorpholine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (67 mg, 0.14 mmol) in dioxane/water (4 mL/0.8 mL), and the system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[2-[(S)-2-methylmorpholine-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (64.50 mg, yield: 79.81%) as yellow oil. ES-API: [M+1].sup.+=560.3.

[1005] Step 4: Tert-butyl (S)-2-[2-[(S)-2-methylmorpholine-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydro-1H-isoquinolin-8-yl]pyrrolidine-1-carboxylate (64.5 mg, 0.12 mmol) was dissolved in dichloromethane (2.0 mL). Trifluoroacetic acid (2.0 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-2-methylmorpholin)methanone (Z359-1, 23.40 mg, yield: 44.18%) as a yellow solid. ES-API: [M+1].sup.+=460.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.28 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.73 (d, J=1.4 Hz, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 4.61 (d, J=16.3 Hz, 1H), 4.53-4.40 (m, 2H), 3.88-3.83 (m, 1H), 3.67-3.51 (m, 5H), 3.49-3.31 (m, 2H), 3.21-2.84 (m, 4H), 2.73-2.66 (m, 1H), 2.33-2.25 (m, 4H), 2.08-2.01 (m, 1H), 1.97-1.88 (m, 1H), 1.84-1.76 (m, 1H), 1.17 (d, J=6.0 Hz, 3H).

##STR00440##

[1006] Step 1: A solution of (R)-2-methylmorpholine (200.00 mg, 1.98 mmol) in dichloromethane (10 mL) was cooled in an ice bath. Triethylamine (400.17 mg, 3.95 mmol) and (4-nitrophenyl)carbonyl chloride (478.27 mg, 2.37 mmol) were then added successively, and the mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was spun to dryness to remove a solvent and obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give (4-nitrophenyl)(R)-2-methylmorpholine-4-carboxylate (380 mg, yield: 72.74%). ES-API: [M+H].sup.+=267.10.

[1007] Step 2: Diisopropylethyl amine (97.08 mg, 751.18 mol) and tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (63.26 mg, 187.79 mol) were added to a solution of the (4-nitrophenyl)(R)-2-methylmorpholine-4-carboxylate (50 mg, 187.79 mol) in toluene (2 mL), and the obtained mixture was warmed to 100 C. and stirred for 48 h. The reaction mixture was spun to dryness to remove a solvent and obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-[6-chloro-2-[(R)-2-methylmorpholine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (35 mg, yield: 36.15%) as a yellow oil. ES-API: [M+H].sup.+=464.23.

[1008] Step 3: Tert-butyl (S)-2-[6-chloro-2-[(2)-2-methylmorpholine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (35.00 mg, 75.43 mol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (44.06 mg, 170.69 mol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.24 mg, 14.22 mol) and potassium carbonate (39.32 mg, 0.28 mmol) were dissolved in 1,4-dioxane solution (1 mL) and water (0.1 mL), and the system was warmed to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was quenched by the addition of water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=10/1) to give tert-butyl (S)-2-[2-[(R)-2-methylmorpholine-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (40.00 mg, yield: 46.22%) as a white solid. ES-API: [M+H].sup.+=560.32.

[1009] Step 4: The tert-butyl (S)-2-[2-[(R)-2-methylmorpholine-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (25 mg, 44.67 mol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid solution (2 mL) and stirred at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=5/1) to give a product (6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-2-methylmorpholin)methanone (Z359-2, 5.00 mg, yield: 23.87%) as a white solid. ES-API: [M+H].sup.+=460.27.

Example 166. Synthesis of Compound Z437

##STR00441##

[1010] Step 1: tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.15 mmol) was dissolved in ethanol (0.5 mL), 1,6-Dioxaspiro[2.5]octane (34 mg, 0.30 mmol) and triethylamine (45 mg, 0.44 mmol) were added, and the system was heated to 75 C. for 16 h. The reaction mixture was spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether/ethyl acetate=1/1) to give a product (87 mg, crude product). ES-API: [M+H].sup.+=451.3.

[1011] Step 2: tert-butyl (S)-2-(6-chloro-2-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (87 mg, 0.19 mmol) was dissolved in dioxane/water (2 mL/0.4 mL), 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (60 mg, 0.23 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.019 mmol) and potassium carbonate (53 mg, 0.38 mmol) were added, and the system was heated to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was Spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=20/1) to give a product (90 mg, yield: 85%). ES-API: [M+1].sup.+=547.3.

[1012] Step 3: tert-butyl (S)-2-(2-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (90 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness, extracted with dichloromethane and saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, filtered, and spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give a product (S)-4-((6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrol-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)tetrahydro-2H-pyran-4-ol (Z437, 25.2 mg, yield: 34%). ES-API: [M+1].sup.+=447.3. .sup.1H NMR (400 MHz, DMSO-d6) 11.33-11.27 (m, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.29-7.25 (m, 1H), 7.24-7.20 (m, 1H), 4.32-4.21 (m, 1H), 4.17-4.10 (m, 1H), 3.88-3.81 (m, 1H), 3.72-3.55 (m, 6H), 3.14-3.09 (m, 1H), 2.92-2.82 (m, 4H), 2.80-2.74 (m, 1H), 2.28 (s, 3H), 2.21-2.09 (m, 1H), 1.87-1.71 (m, 2H), 1.65-1.56 (m, 2H), 1.47-1.39 (m, 3H).

Example 167. Synthesis of Compound Z339

##STR00442##

[1013] Step 1: 2-Dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (595.63 mg, 1.40 mmol), tris(dibenzylideneacetone)dipalladium (321.11 mg, 350.67 mol), zinc cyanide (494.10 mg, 4.21 mmol) and zinc dust (91.17 mg, 1.40 mmol) were added to a solution of 4-chloro-2,6-dimethyl-pyrimidine (1 g, 7.01 mmol) in N,N-dimethylacetamide (2 mL), and the mixture was stirred at 25 C. for 0.5 h and then at 90 C. for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-20% ethyl acetate in petroleum ether) to give a product 2,6-dimethylpyrimidine-4-carbonitrile (450.00 mg, yield: 48.19%) as a yellow solid. ES-API: [M+1].sup.+=134.1.

[1014] Step 2: Sodium hydroxide (1.05 g, 26.29 mmol) was added to a solution of the 2,6-dimethylpyrimidine-4-carbonitrile (350 mg, 2.63 mmol) in ethanol (4 mL)/water (2 mL), and the mixture was stirred at 90 C. for 2 h. The reaction was monitored by LCMS for completion, and the reaction mixture was treated with ethyl acetate/water. Water was then removed, and the obtained mixture was freeze-dried to give a product 2,6-dimethylpyrimidine-4-carboxylic acid (400.00 mg, crude product) as a yellow solid. ES-API: [M+1].sup.+=153.1.

[1015] Step 3: The 2,6-dimethylpyrimidine-4-carboxylic acid (400 mg, 2.63 mmol) in (4M) hydrochloric acid/methanol (10 mL) was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion. The reaction mixture was spun to dryness to remove a solvent, and treated with ethyl acetate/water. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-40% ethyl acetate in petroleum ether) to give a product methyl 2,6-dimethylpyrimidine-4-carboxylate (280.00 mg, yield: 64.09%) as a yellow solid. ES-API: [M+1].sup.+=167.1.

[1016] Step 4: The methyl 2,6-dimethylpyrimidine-4-carboxylate (280 mg, 1.68 mmol) was dissolved in tetrahydrofuran (2 mL)/methanol (1 mL)/water (2 mL). Lithium hydroxide monohydrate (353.6 mg, 8.42 mmol) was added and stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion. The reaction mixture was spun to dryness to remove a solvent and treated with ethyl acetate/water. Water was then removed, and the obtained mixture was freeze-dried to give a product 2,6-dimethylpyrimidine-4-carboxylic acid (256.00 mg, crude product) as a yellow oil. The crude product was purified by prep-HPLC (ammonia water) (37 mg, yield: 14.45%), ES-API: [M+1].sup.+=153.1.

[1017] Step 5: The 2,6-dimethylpyrimidine-4-carboxylic acid (36.13 mg, 0.24 mmol), 1-propylphosphonic anhydride (229 mg, 0.36 mmol, 50% in ethyl acetate) and triethylamine (36.05 mg, 0.36 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, 0.12 mmol) in dichloromethane (1 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/1, Rf=0.3) to give a product tert-butyl (S)-2-(6-chloro-2-(2,6-dimethylpyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (34 mg, yield: 60.79%). ES-API: [M+H-100].sup.+=471.3.

[1018] Step 6: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (22.36 mg, 0.087 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (5.19 mg, 0.007 mmol) and potassium carbonate (29.89 mg, 0.22 mmol) were added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-(2,6-dimethylpyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (34 mg, 0.072 mmol) in dioxane/water (2 mL/0.4 mL), and the mixture was heated to 110 C. and stirred in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(2-(2,6-dimethylpyrimidine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (33 mg, yield: 80.67%). ES-API: [M+H].sup.+=567.4.

[1019] Step 7: Trifluoroacetic acid (1 ml) was added to a solution of the compound tert-butyl (S)-2-(2-(2,6-dimethylpyrimidine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (33 mg, 0.06 mmol) in dichloromethane (2 ml) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 mL/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(2,6-dimethylpyrimidin-4-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z339, 15.1 mg, 55.58%) as a white powder. ES-API: [M+H].sup.+=467.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.55-8.50 (m, 1H), 8.01-7.74 (m, 2H), 7.25-7.24 (m, 1H), 7.16-7.11 (m, 1H), 7.05 (s, 1H), 5.11-4.83 (m, 2H), 4.74-4.01 (m, 1H), 3.86-3.08 (m, 4H), 3.07-2.80 (m, 2H), 2.76-2.72 (m, 3H), 2.59-2.54 (m, 3H), 2.31 (s, 3H), 2.25-1.93 (m, 4H).

Example 168. Synthesis of Compound Z368

##STR00443##

[1020] Step 1: 1-Methyl-1H-pyrazole-5-carboxylic acid (47 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (1 mL), N,N-Diisopropylethyl amine (0.2 mL) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (353 mg, 0.93 mmol) were then added and stirred for 1 min. tert-butyl (S)-2-(6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate (0.1 g, 0.31 mol) was added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5 mL), and extracted with ethyl acetate (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (S)-2-(6-chloro-2-(1-methyl-1H-pyrazole-4-carbonyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.12 g) as a yellow oil. ES-API: [M+H].sup.+=431.1.

[1021] Step 2: The tert-butyl (S)-2-(6-chloro-2-(1-methyl-1H-pyrazole-4-carbonyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.12 g, 0.23 mmol) was dissolved in dioxane (1 mL), 3-Methyl-5-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (72 mg, 0.28 mmol) was added, followed by water (0.1 mL) and potassium carbonate (64 mg, 0.46 mmol), Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (17 mg, 0.02 mmol) was finally added, and the system was heated and stirred for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5 mL), and extracted with ethyl acetate (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl (S)-2-(2-(1-methyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.09 g) as yellow oil. ES-API: [M+H].sup.+=527.3.

[1022] Step 3: The tert-butyl (S)-2-(2-(1-methyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.1 g) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was concentrated to give a crude product. The crude product was purified by prep-HPLC (hydrochloric acid) to give (S)-(1-methyl-1H-pyrazol-4-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(pyrrolidin-2-yl)isoindolin-2-yl)methanone hydrochloride (Z368, 25.76 mg, yield: 31.8%) as a white solid. ES-API: [M+H].sup.+=427.3. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.46-8.50 (m, 1H), 8.29-8.22 (m, 2H), 8.04-8.03 (m, 1H), 7.72-7.71 (m, 1H), 7.61-7.58 (m, 1H), 7.19 (s, 1H), 5.28-5.21 (m, 2H), 5.05-5.02 (m, 2H), 4.27-4.23 (m, 1H), 4.00-3.98 (m, 3H), 3.29-3.27 (m, 1H), 3.24-3.05 (m, 1H), 2.37 (s, 3H), 2.35-2.33 (m, 1H), 2.04-1.98 (m, 3H).

Example 169. Synthesis of Compound Z388

##STR00444##

[1023] Step 1: In the presence of protective nitrogen, triethylamine (0.55 g, 5.42 mmol) and (4-nitrophenyl)carbonyl chloride (0.33 g, 1.63 mmol) were added to a solution of 3-oxa-8-azabicyclo[3.2.1]octane (0.2 g, 1.35 mmol) in anhydrous dichloromethane (10 mL) at 0 C., and the mixture was warmed to 20 C. and stirred for 3 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:90) to give (4-nitrophenyl) 3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (0.3 g, yield: 75.59%) as a yellow solid. ES-API: [M+1].sup.+=279.1.

[1024] Step 2: The (4-nitrophenyl) 3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (86.74 mg, 0.31 mmol) and potassium carbonate (57.44 mg, 0.42 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in N,N-dimethylacetamide (1 mL), and the mixture was warmed to 150 C. and stirred for 3 h. The reaction was monitored by LCMS for completion. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether:ethyl acetate=1:1) to give tert-butyl (S)-2-[6-chloro-2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.00 mg, yield: 70.77%) as a yellow oil. ES-API: [M+1].sup.+=476.3.

[1025] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (45.55 mg, 0.18 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.6 mg, 14.71 mol) and potassium carbonate (60.88 mg, 0.44 mmol) were added to a solution of the tert-butyl (S)-2-[6-chloro-2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70 mg, 0.15 mmol) in dioxane/water (4 mL/0.8 mL), and the system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.00 mg, yield: 83.26%) as yellow oil. ES-API: [M+1].sup.+=572.4.

[1026] Step 4: The tert-butyl (S)-2-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70 mg, 0.12 mmol) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (2.0 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give a product (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z388, 16.30 mg, yield: 28.23%) as a white solid. ES-API: [M+1].sup.+=472.4 .sup.1H NMR (400 MHz, CDCl.sub.3) 10.28 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.72 (d, J=1.4 Hz, 1H), 7.27 (s, 1H), 7.11 (s, 1H), 4.72 (d, J=16.4 Hz, 1H), 4.60 (d, J=16.4 Hz, 1H), 4.46-4.32 (m, 1H), 3.95 (s, 2H), 3.81 (d, J=10.7 Hz, 2H), 3.71-3.54 (m, 4H), 3.38-3.27 (m, 1H), 3.14-2.94 (m, 4H), 2.34 (s, 3H), 2.31-2.25 (m, 1H), 2.05-1.85 (m, 7H), 1.81-1.64 (m, 1H).

Example 170. Synthesis of Compound Z389

##STR00445##

[1027] Step 1: In the presence of protective nitrogen, triethylamine (0.55 g, 5.42 mmol) and (4-nitrophenyl)carbonyl chloride (0.33 g, 1.63 mmol) were added to a solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.2 g, 1.35 mmol) in anhydrous dichloromethane (6 mL) at 0 C., and the mixture was warmed to 20 C. and stirred for 3 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:90) to give (4-nitrophenyl) 8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate (0.3 g, yield: 79.57%) as a yellow solid. ES-API: [M+1].sup.+=279.1.

[1028] Step 2: The (4-nitrophenyl) 8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate (86.74 mg, 0.31 mmol) and potassium carbonate (57.44 mg, 0.42 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in N,N-dimethylacetamide (1 mL), and the mixture was warmed to 150 C. and stirred for 3 h. The reaction was monitored by LCMS for completion. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether:ethyl acetate=1:1) to give tert-butyl (2S)-2-[6-chloro-2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.00 mg, yield: 70.77%) as a yellow oil. ES-API: [M+1].sup.+=476.3.

[1029] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (45.55 mg, 0.18 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.6 mg, 14.71 mol) and potassium carbonate (60.88 mg, 0.44 mmol) were added to a solution of the tert-butyl (2S)-2-[6-chloro-2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70 mg, 0.15 mmol) in dioxane/water (4 mL/0.8 mL), and the system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.00 mg, yield: 83.26%) as yellow oil. ES-API: [M+1].sup.+=572.5.

[1030] Step 4: The tert-butyl (S)-2-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70 mg, 0.12 mmol) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (2.0 mL) was added. The system reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give a product (8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z389, 27.10 mg, yield: 46.93%) as a white solid. ES-API: [M+1].sup.+=472.4. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.77 (s, 1H), 8.42 (s, 1H), 7.78 (s, 2H), 7.00 (s, 2H), 4.93-4.86 (m, 1H), 4.53-4.25 (m, 4H), 3.79-3.72 (m, 1H), 3.63-3.37 (m, 4H), 3.32-3.20 (m, 2H), 3.12-3.04 (m, 1H), 2.92-2.76 (m, 1H), 2.64-2.55 (m, 1H), 2.50-2.29 (m, 3H), 2.24 (s, 3H), 2.22-2.10 (m, 1H), 1.99-1.75 (m, 4H).

Example 171. Synthesis of Compound Z357-1 and Compound Z357-2

##STR00446##

[1031] Step 1: In the presence of protective nitrogen, triethylamine (0.4 g, 3.64 mmol) and (4-nitrophenyl)carbonyl chloride (0.48 g, 2.18 mmol) were added to a solution of (S)-3-methoxypyrrolidine hydrochloride (0.25 g, 1.82 mmol) in anhydrous dichloromethane (10 mL) at 0 C., and the mixture was warmed to 20 C. and stirred for 3 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:90) to give (4-nitrophenyl)(S)-3-methoxypyrrolidine-1-carboxylate (0.4 g, yield: 82.59%) as a yellow solid. ES-API: [M+1].sup.+=267.0.

[1032] Step 2: The (4-nitrophenyl)(S)-3-methoxypyrrolidine-1-carboxylate (82.99 mg, 0.31 mmol) and potassium carbonate (57.44 mg, 0.42 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in N,N-dimethylacetamide (1 mL), and the mixture was warmed to 150 C. and stirred for 3 h. The reaction was monitored by LCMS for completion. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether:ethyl acetate=1:1) to give tert-butyl (S)-2-(6-chloro-2-((S)-3-methoxypyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70.00 mg, yield: 72.6%) as a yellow oil. ES-API: [M+1].sup.+=464.3.

[1033] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (46.73 mg, 0.18 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.9 mg, 15.09 mol) and potassium carbonate (62.46 mg, 0.45 mmol) were added to a solution of the tert-butyl (S)-2-(6-chloro-2-((S)-3-methoxypyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.15 mmol) in dioxane/water (4 mL/0.8 mL), and the system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[2-[(S)-3-methoxypyrrolidine-1-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (45.00 mg, yield: 53.29%) as a yellow oil. ES-API: [M+1].sup.+=560.5.

[1034] Step 4: The tert-butyl (S)-2-[2-[(S)-3-methoxypyrrolidine-1-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (45 mg, 80.40 mol) was dissolved in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give a product ((S)-3-methoxypyrrole-1-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z357-1, 10.30 mg, yield: 27.88%) as a white solid. ES-API: [M+1].sup.+=460.3

##STR00447##

[1035] Step 1: In the presence of protective nitrogen, triethylamine (0.4 g, 3.95 mmol) and (4-nitrophenyl)carbonyl chloride (0.48 g, 2.37 mmol) were added to a solution of (R)-3-methoxypyrrolidine (0.2 g, 1.98 mmol) in anhydrous dichloromethane (10 mL) at 0 C. The mixture was warmed to 20 C. and stirred for 3 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:90) to give (R)-4-nitrophenyl 3-methoxypyrrolidine-1-carboxylate (0.4 g, yield: 75.98%) as a yellow solid. ES-API: [M+1].sup.+=267.0.

[1036] Step 2: The (R)-4-nitrophenyl 3-methoxypyrrolidine-1-carboxylate (82.99 mg, 0.31 mmol) and potassium carbonate (57.44 mg, 0.42 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in N,N-dimethylacetamide (1 mL), and the mixture was warmed to 150 C. and stirred for 3 h. The reaction was monitored by LCMS for completion. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether:ethyl acetate=1:1) to give tert-butyl (S)-2-(6-chloro-2-((R)-3-methoxypyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70.00 mg, yield: 72.6%) as a yellow oil. ES-API: [M+1].sup.+=464.4.

[1037] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (46.73 mg, 0.18 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.86 mg, 15.09 mol) and potassium carbonate (62.46 mg, 0.45 mmol) were added to a solution of the tert-butyl (S)-2-(6-chloro-2-((R)-3-methoxypyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.15 mmol) in dioxane/water (2 mL/0.4 mL), and the system was heated to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-(2-((R)-3-methoxypyrrolidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (55.00 mg, yield: 65.14%) as yellow oil. ES-API: [M+1].sup.+=560.5.

[1038] Step 4: The tert-butyl (S)-2-(2-((R)-3-methoxypyrrolidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (55 mg, 0.10 mmol) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (1.0 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give a product ((R)-3-methoxypyrrolidin-1-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z357-2, 13.20 mg, yield: 30.15%) as a white solid. ES-API: [M+1].sup.+=460.4. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.09 (s, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.73 (s, 1H), 7.28 (s, 1H), 7.09 (s, 1H), 4.63 (d, J=16.3 Hz, 1H), 4.51-4.37 (m, 2H), 3.99-3.94 (m, 1H), 3.67-3.54 (m, 3H), 3.53-3.42 (m, 3H), 3.34 (s, 3H), 3.32-3.25 (m, 1H), 3.15-2.92 (m, 3H), 2.35 (s, 3H), 2.34-2.24 (m, 1H), 2.07-1.85 (m, 5H), 1.77-1.66 (m, 1H).

Example 172. Synthesis of Compound Z358-2 and Compound Z358-1

##STR00448##

[1039] Step 1: In the presence of protective nitrogen, triethylamine (0.4 g, 3.95 mmol) and (4-nitrophenyl)carbonyl chloride (0.48 g, 2.37 mmol) were added to a solution of (R)-3-methylmorpholine (0.2 g, 1.98 mmol) in anhydrous dichloromethane (10 mL) at 0 C., and the mixture was warmed to 20 C. and stirred for 3 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:90) to give (4-nitrophenyl)(R)-3-methylmorpholine-4-carboxylate (0.47 g, yield: 89.28%) as a yellow solid. ES-API: [M+1].sup.+=267.0.

[1040] Step 2: The (4-nitrophenyl)(R)-3-methylmorpholine-4-carboxylate (82.99 mg, 0.31 mmol) and potassium carbonate (57.44 mg, 0.42 mmol) were added to a solution of (tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in N,N-dimethylacetamide (1 mL), and the mixture was warmed to 130 C. and stirred for 3 h. The reaction was monitored by LCMS for completion. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether:ethyl acetate=1:1) to give tert-butyl (S)-2-[6-chloro-2-[(R)-3-methylmorpholine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.00 mg, yield: 72.6%) as a yellow oil. ES-API: [M+1].sup.+=464.4.

[1041] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (46.73 mg, 0.18 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.86 mg, 15.09 mol) and potassium carbonate (62.46 mg, 0.45 mmol) were added to a solution of the tert-butyl (S)-2-[6-chloro-2-[(R)-3-methylmorpholine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70 mg, 0.15 mmol) in dioxane/water (2 mL/0.4 mL), and the system was heated to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[2-[(R)-3-methylmorpholine-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60.00 mg, yield: 71.06%) as yellow oil. ES-API: [M+1].sup.+=560.5.

[1042] Step 4: The tert-butyl (S)-2-[2-[(R)-3-methylmorpholine-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (1.0 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give a product (6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-3-methylmorpholin)methanone (Z358-2, 18.9 mg, yield: 38.36%) as a white solid. ES-API: [M+1].sup.+=460.4. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.55 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.72 (s, 1H), 7.28 (s, 1H), 7.10 (s, 1H), 4.67-4.43 (m, 2H), 4.44-4.33 (m, 1H), 3.87-3.78 (m, 2H), 3.73-3.67 (m, 1H), 3.67-3.52 (m, 3H), 3.49-3.39 (m, 1H), 3.39-3.26 (m, 3H), 3.13-2.94 (m, 3H), 2.35 (s, 3H), 2.33-2.24 (m, 1H), 2.05-1.84 (m, 2H), 1.79-1.68 (m, 1H), 1.32 (d, J=6.8 Hz, 3H).

##STR00449##

[1043] Step 1: In the presence of protective nitrogen, triethylamine (0.4 g, 3.95 mmol) and (4-nitrophenyl)carbonyl chloride (0.48 g, 2.37 mmol) were added to a solution of (S)-3-methylmorpholine (0.2 g, 1.98 mmol) in anhydrous dichloromethane (10 mL) at 0 C., and the mixture was warmed to 20 C. and stirred for 3 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:90) to give (4-nitrophenyl)(S)-3-methylmorpholine-4-carboxylate (0.45 g, yield: 85.48%) as a yellow solid. ES-API: [M+1].sup.+=267.0.

[1044] Step 2: The (4-nitrophenyl)(S)-3-methylmorpholine-4-carboxylate (82.99 mg, 0.31 mmol) and potassium carbonate (57.44 mg, 0.42 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in N,N-dimethylacetamide (1 mL), and the mixture was warmed to 150 C. and stirred for 3 h. The reaction was monitored by LCMS for completion. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether:ethyl acetate=1:1) to give tert-butyl (S)-2-[6-chloro-2-[(S)-3-methylmorpholine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60.00 mg, yield: 62.23%) as a yellow oil. ES-API: [M+1].sup.+=464.4.

[1045] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (40.05 mg, 0.16 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.31 mg, 12.93 mol) and potassium carbonate (53.53 mg, 0.39 mmol) were added to a solution of the tert-butyl (S)-2-[6-chloro-2-[(S)-3-methylmorpholine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60 mg, 0.13 mmol) in dioxane/water (4 mL/0.8 mL), and the system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[2-[(S)-3-methylmorpholine-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60.00 mg, yield: 82.90%) as a yellow oil. ES-API: [M+1].sup.+=560.5.

[1046] Step 4: The tert-butyl (S)-2-[2-[(S)-3-methylmorpholine-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (2.0 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give a product (6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrol-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-3-methylmorpholin)methanone (Z358-1, 13.50 mg, yield: 27.40%) as a white solid. ES-API: [M+1].sup.+=460.4. H NMR (400 MHz, CDCl.sub.3) 9.96 (s, 1H), 8.48 (d, J=2.1 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.28 (d, J=1.4 Hz, 1H), 7.12 (s, 1H), 4.61 (d, J=16.4 Hz, 1H), 4.49 (d, J=16.4 Hz, 1H), 4.38 (t, J=7.6 Hz, 1H), 3.86-3.78 (m, 2H), 3.73-3.69 (m, 1H), 3.66-3.48 (m, 4H), 3.41-3.26 (m, 3H), 3.13-2.98 (m, 3H), 2.35 (s, 3H), 2.32-2.25 (m, 1H), 2.04-1.86 (m, 2H), 1.78-1.67 (m, 1H), 1.32 (d, J=6.8 Hz, 3H).

Example 173. Synthesis of Compound Z361

##STR00450##

[1047] Step 1: A solution of (4-nitrophenyl)carbonyl chloride (350.02 mg, 1.74 mmol) in dichloromethane (10 mL) was cooled in an ice bath, triethylamine (351.43 mg, 3.47 mmol) and 3,3-dimethylmorpholine (200 mg, 1.74 mmol) were then added successively, and the obtained mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was spun to dryness to remove a solvent and obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give 4-nitrophenyl 3,3-dimethylmorpholine-4-carboxylate (280 mg, yield: 56.38%). ES-API: [M+H].sup.+=281.11.

[1048] Step 2: Diisopropylethyl amine (97.07 mg, 751.12 mol) and tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (63.25 mg, 187.78 mol) were added to a solution of (4-nitrophenyl) 3,3-dimethylmorpholine-4-carboxylate (52.63 mg, 187.78 mol) in anhydrous N,N-dimethylformamide (2 mL), and the obtained mixture was warmed to 130 C. and stirred for 5 h. The reaction mixture was spun to dryness to remove a solvent and obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/) to give tert-butyl 2-[6-chloro-2-(3,3-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (33 mg, yield: 33%) as a yellow oil. ES-API: [M+H].sup.+=478.25.

[1049] Step 3: The tert-butyl 2-[6-chloro-2-(3,3-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (36.06 mg, 75.43 mol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (44.06 mg, 170.69 mol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.24 mg, 14.22 mol) and potassium carbonate (39.32 mg, 0.28 mmol) were dissolved in 1,4-dioxane solution (1 mL) and water (0.1 mL), and the system was warmed to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[2-(3,3-dimethylmorpholine-4-carbonyl)-6-(3-methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (30.00 mg, yield: 34.92%). ES-API: [M+H].sup.+=574.34.

[1050] Step 4: The tert-butyl (S)-2-[2-(3,3-dimethylmorpholine-4-carbonyl)-6-(3-methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (30 mg, 49.68 mol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid solution (2 mL) and stirred at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=5/1) to give a product (S)-(3,3-dimethylmorpholino[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone (Z361, 8.20 mg, 16.97 mol, yield: 38.94%) as a white solid. ES-API: [M+H]+=474.29.

Example 174. Synthesis of Compound Z343

##STR00451##

[1051] Step 1: 2-Dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (27.12 mg, 59.37 mol), (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (49.72 mg, 59.37 mol), potassium carbonate (123.12 mg, 890.59 mol) and 4-bromo-2,6-lutidine (165.69 mg, 890.59 mol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 296.86 mol) in dioxane (1 mL), and the system reacted at 130 C. for 15 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-5% methanol in dichloromethane) to give a product tert-butyl (S)-2-(6-chloro-2-(2,6-dimethylpyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (95 mg, yield: 65.2%). ES-API: [M+H].sup.+=442.2.

[1052] Step 2: The compound tert-butyl (S)-2-(6-chloro-2-(2,6-dimethylpyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 226.24 mol) was dissolved in dioxane/water (2 mL/0.4 mL), 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (69.77 mg, 270.29 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (16.28 mg, 22.62 mol) and potassium carbonate (93.67 mg, 678 mol) were added, and the system was heated to 100 C. for 2 h. The reaction mixture was extracted with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-(2-(2,6-dimethylpyridin-4-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (90 mg, yield: 66.6%). ES-API: [M+H].sup.+=538.4.

[1053] Step 3: The tert-butyl (S)-2-(2-(2,6-dimethylpyridin-4-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (55 mg, 102.9 mol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness, extracted with dichloromethane and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-2-(2,6-dimethylpyridin-4-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z343, 12 mg, yield: 21.95%). (Rf=0.4, dichloromethane/methanol=10/1). ES-API: [M+1].sup.+=438.2.

Example 175. Synthesis of Compound Z261

##STR00452##

[1054] Step 1: Methoxyacetic acid (26.79 mg, 297.37 umol) was dissolved in N,N-dimethylformamide (1 mL). N,N-Diisopropylethyl amine and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (306.23 mg, 805.38 umol) were added and stirred for 1 min, tert-butyl(S)-2-(6-chloroisoindolin-4-yl) pyrrolidine-1-carboxylate (0.08 g, 247.81 umol) was then added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5 mL) and extracted with ethyl acetate (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (S)-2-(6-chloro-2-(2-methoxyacetyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.09 g) as a yellow oil. ES-API: [M+H].sup.+=395.2.

[1055] Step 2: The tert-butyl (S)-2-(6-chloro-2-(2-methoxyacetyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.09 g, 227.91 umol) was dissolved in dioxane (1 mL), 3-Methyl-5-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (64.71 mg, 250.70 umol) was added, followed by water (0.1 mL) and potassium carbonate (94.50 mg, 683.73 umol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (16.42 mg, 22.79 umol) was finally added, and the system was heated and stirred for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5 mL), and then extracted with ethyl acetate (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl tert-butyl (S)-2-(2-(2-methoxyacetyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.1 g) as a yellow oil. ES-API: [M+H].sup.+=491.3.

[1056] Step 3: The tert-butyl (S)-2-(2-(2-methoxyacetyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.1 g) was dissolved in ethyl acetate (1 mL), hydrochloric acid-ethyl acetate (4.0 M, 1.0 mL) was added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was concentrated to give a crude product. The crude product was purified by prep-HPLC (hydrochloric acid) to give (S)-2-methoxy-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(pyrrolidin-2-yl)isoindolin-2-yl)ethan-1-one hydrochloride (Z261, 17.8 mg, yield: 22.4%) as a white solid. ES-API: [M+H].sup.+=391.2.

Example 176. Synthesis of Compound Z262

##STR00453## ##STR00454## ##STR00455##

[1057] Step 1: 5-Aminoisoindoline-1,3-dione (200 g, 1.23 mmol) was dissolved in N,N-dimethylformamide (350 mL) and dioxane (1000 mL), N-Chlorosuccinimide (164.12 g, 1.23 mol) was slowly added and stirred at room temperature for 16 h. Upon completion of the reaction, the reaction mixture was slowly poured into ice water and filtered to give 5-amino-6-chloroisoindoline-1,3-dione (230 g) as a yellow solid. ES-API: [M+H.sup.+]=197.1.

[1058] Step 2: The 5-amino-6-chloroisoindoline-1,3-dione (230 g, 1.17 mol) was dissolved in N,N-dimethylformamide (1200 mL), N-Bromosuccinimide (249.88 g, 1.40 mol) was slowly added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was slowly poured into ice water and filtered to give 5-amino-4-bromo-6-chloroisoindoline-1,3-dione (280 g) as a yellow solid. ES-API: [M+H.sup.+]=275.0, 277.0.

[1059] Step 3: The 5-amino-4-bromo-6-chloroisoindoline-1,3-dione (285 g, 1.03 mol) was added to sulfuric acid (57.47 mL) at a controlled temperature of 0-5 C., sodium nitrite (214.13 g, 3.1 mmol) was added in batches and stirred at a controlled temperature of 0-5 C. for 0.5 h. Phosphorous acid (132.38 g, 50% in water, 1.03 mol) was slowly added dropwise and stirred at 0-5 C. for 2 h. Upon completion of the reaction, the reaction mixture was slowly poured into ice water and filtered to give 4-bromo-6-chloroisoindoline-1,3-dione (170 g) as a yellow solid. ES-API: [M+H.sup.+]=259.9.

[1060] Step 4: In the presence of protective nitrogen, the 4-bromo-6-chloroisoindoline-1,3-dione (66 g, 253.39 mmol) was added to tetrahydrofuran (350 mL), 1M borane in tetrahydrofuran (1.52 L) was added dropwise at 0-10 C., and the system was heated to 80 C. and stirred for 36 h. Upon completion of the reaction, methanol (500 mL) was added, and the obtained mixture was concentrated to give 4-bromo-6-chloro-isoindoline (40 g). ES-API: [M+H].sup.+=231.8, 233.

[1061] Step 5: The 4-bromo-6-chloro-isoindoline (80 g, 344.08 mmol) was added to a tetrahydrofuran (560 mL) solution, and potassium carbonate (237.77 g, 1.72 mol) was added. After the system was cooled to 0 C., acetyl chloride (36.83 mL, 516.12 mmol) was slowly added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was slowly added to ice water (800 mL) and extracted with ethyl acetate (100 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 1-(4-bromo-6-chloro-isoindoline)-2-ethanone (50 g). ES-API: [M+H]+=276.0, 274.0.

[1062] Step 6: The 1-(4-bromo-6-chloro-isoindoline)-2-ethanone (50 g, 182.12 mmol) and potassium vinyltrifluoroborate (48.79 g, 364.21 mmol) were added to an ethanol (350 mL) solution, triethylamine (25.35 mL, 182.12 mmol) was then added, and the system was replaced with nitrogen three times, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (7.44 g, 9.11 mmol) was finally added, and the system was heated to 80 C. for 16 h. Upon completion of the reaction, the reaction mixture was slowly poured into ice water (800 mL) and extracted with ethyl acetate (200 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (0-100% ethyl acetate/petroleum ether) to give 1-(6-chloro-4-vinyl-isoindoline)-2-ethanone (30 g, yield: 74%) as a yellow oil. ES-API: [M+H].sup.+=222.1.

[1063] Step 7: The 1-(6-chloro-4-vinyl-isoindoline)-2-ethanone (30 g, 135.33 mmol) was added to tetrahydrofuran (90 mL) and water (40 mL), sodium periodate (173.67 g, 811.97 mmol) and potassium osmate dihydrate (997.25 mg, 2.71 mmol) were added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was filtered. The obtained liquid was slowly poured into ice water (400 mL) and extracted with ethyl acetate (200 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-100% ethyl acetate/petroleum ether) to give 2-acetyl-6-chloro-isoindoline-4-carbaldehyde (20 g, yield: 66%) as a yellow solid. ES-API: [M+H].sup.+=224.1.

[1064] Step 8: The 2-acetyl-6-chloro-isoindoline-4-carbaldehyde (20 g, 135.33 mmol) was dissolved in dichloromethane (140 mL), S()-2-Methyl-2-propanesulfinamide (13.01 g, 103.71 mmol) and tetraethyl titanate (61.19 g, 2.68 mmol) were then added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was filtered, slowly added to ice water (100 mL), and extracted with dichloromethane (500 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give (E,S)N-[(2-acetyl-6-chloroisoindolin-4-yl)methylene]-2-methylpropane-2-sulfinamide (21 g) as a yellow solid. ES-API: [M+H].sup.+=327.1.

[1065] Step 9: The (E,S)N-[(2-acetyl-6-chloroisoindolin-4-yl)methylene]-2-methylpropane-2-sulfinamide (11 g, 33.66 mmol) was dissolved in tetrahydrofuran (75 mL), the system was replaced with nitrogen three times and cooled to 70 C., (1,3-Dioxane-2-ethyl)magnesium bromide (0.5 M, 134.62 mL) was added and stirred for 2 h. Upon completion of the reaction, the reaction mixture was filtered, slowly added to aqueous ammonium chloride solution (100 mL), and extracted with ethyl acetate (80 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give (S)N((S)-1-(2-acetyl-6-chloroisoindolin-4-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (12.5 g) as a yellow solid. ES-API: [M+H].sup.+=443.1.

[1066] Step 10: The (S)N((S)-1-(2-acetyl-6-chloroisoindolin-4-yl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (12 g, 27.09 mmol) was dissolved in trifluoroacetic acid (60 mL), water (3 mL) was added and stirred at room temperature for 0.5 h, triethylsilane (31.50 g, 270.88 mmol) was then added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was directly concentrated to give (S)-1-(6-chloro-4-(pyrrolidin-2-yl)isoindol-2-yl)ethan-1-one (7.0 g) as a yellow oil. ES-API: [M+H].sup.+=265.1.

[1067] Step 11: The (S)-1-(6-chloro-4-(pyrrolidin-2-yl)isoindol-2-yl)ethan-1-one (7.0 g, 27.09 mmol) was dissolved in tetrahydrofuran (14 mL), triethylamine (11 mL) and di-tert-butyl dicarbonate (9.11 mL) was then added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was slowly added to ice water (50 mL) and extracted with ethyl acetate (30 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-100% ethyl acetate/petroleum ether) to give tert-butyl (S)-2-(2-acetyl-6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate (6.0 g, yield: 62%) as a yellow oil. ES-API: [M+H].sup.+=365.0.

[1068] Step 12: The tert-butyl (S)-2-(2-acetyl-6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate (2.0 g, 5.48 mmol) was dissolved in ethanol (14 mL), 10% sodium hydroxide (3 mL) was added, and the system was heated to 95 C. and stirred for 12 h. Upon completion of the reaction, the reaction mixture was concentrated, added to ice water (20 mL), and extracted with ethyl acetate (15 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-100% ethyl acetate/petroleum ether) to give tert-butyl (S)-2-(6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate (1.5 g) as a yellow foamy solid. ES-API: [M+H].sup.+=322.9.

[1069] Step 13: 2,6-Dimethylisonicotinic acid (93 mg, 0.60 mmol) was dissolved in N,N-dimethylformamide (1 mL), N,N-diisopropylethyl amine and 2-(7-azobenzotriazol)-N,N,N,N-tetramethylurea hexafluorophosphate (306 mg, 0.8 mmol) were added and stirred for 1 min. The tert-butyl (S)-2-(6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate (0.13 g, 0.4 mmol) was added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5 mL) and extracted with ethyl acetate (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (S)-2-(6-chloro-2-(2,6-dimethylisonicotinoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.18 g) as a yellow oil. ES-API: [M+H].sup.+=456.2.

[1070] Step 14: The tert-butyl (S)-2-(6-chloro-2-(2,6-dimethylisonicotinoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.18 g, 0.39 mmol) was dissolved in dioxane (1 mL), 3-methyl-5-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (112 mg, 0.4 mmol) was added, followed by water (0.1 mL) and potassium carbonate (164 mg, 1.18 mmol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (28.45 mg, 0.04 mmol) was finally added, and the system was heated and stirred for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5 mL) and extracted with ethyl acetate (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl (S)-2-(2-(2,6-dimethylisonicotinoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.2 g) as a yellow oil. ES-API: [M+H].sup.+=552.3.

[1071] Step 15: The tert-butyl (S)-2-(2-(2,6-dimethylisonicotinoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.2 g) was dissolved in ethyl acetate (1 mL), hydrochloric acid-ethyl acetate (4.0 M, 1.0 mL) was added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was concentrated to give a crude product. The crude product was purified by prep-HPLC (hydrochloric acid) to give (S)-(2,6-dimethylpyridin-4-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(pyrrolidin-2-yl)isoindolin-2-yl)methanone hydrochloride (Z262, 59.48 mg, yield: 36.3%) as a white solid. ES-API: [M+H].sup.+=452.1. .sup.1H NMR (400 MHz, CD.sub.3OD) 9.08-9.06 (m, 1H), 8.82 (s, 1H), 8.12-8.06 (m, 1H), 7.96-7.80 (m, 3H), 7.55-7.54 (m, 1H), 5.28-5.14 (m, 2H), 5.02-4.99 (m, 1H), 4.87-4.83 (m, 1H), 4.65-4.64 (m, 1H), 3.71-3.47 (m, 2H), 2.87-2.86 (6H), 2.53-2.51 (m, 1H), 2.49-2.48 (m, 3H), 2.46-2.13 (m, 3H).

Example 177. Synthesis of Compound Z438

##STR00456##

[1072] Step 1: Ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1.0 g, 4.80 mmol) was dissolved in acetonitrile (10 mL) and stirred at room temperature. 2-Iodopropane (1.23 g, 7.21 mmol) was added to this solution, followed by potassium carbonate (1.0 g, 7.21 mmol), and the reaction mixture was stirred at 80 C. for 6 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (petroleum ether/ethyl acetate=10/1) to give ethyl 1-isopropyl-5-(trifluoromethyl)pyrazole-4-carboxylate (0.1 g, yield: 8%) as a yellow oil. ES-API: [M+1].sup.+=251.1.

[1073] Step 2: Sodium hydroxide (79.92 mg, 2.00 mmol) was added to a solution of the ethyl 1-isopropyl-5-(trifluoromethyl)pyrazole-4-carboxylate (0.1 g, 0.4 mmol) in methanol/water (6 mL/1 mL), and the mixture was stirred at 20 C. for 3 h. The reaction mixture was concentrated, diluted with water, and then adjusted to pH 3 with 1N hydrochloric acid to form a precipitate. The precipitate was filtered, and the obtained solid was dried to give 1-isopropyl-5-(trifluoromethyl)pyrazole-4-carboxylic acid (70.00 mg, crude product) as a white solid. ES-API: [M+1].sup.+=223.0.

[1074] Step 3: The 1-isopropyl-5-(trifluoromethyl)pyrazole-4-carboxylic acid (69.25 mg, 311.71 mol), 1-propylphosphonic anhydride (197 mg, 0.31 mmol, 50% in ethyl acetate) and triethylamine (63.08 mg, 623.41 mol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in dichloromethane (6 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether/ethyl acetate=1/1) to give a product tert-butyl (S)-2-[6-chloro-2-[1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60.00 mg, yield: 53.37%) as a yellow oil. ES-API: [M+1-100].sup.+=441.2.

[1075] Step 4: The tert-butyl (S)-2-[6-chloro-2-[1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dioxane/water (4 mL/0.8 mL), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (34.35 mg, 133.09 mol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.99 mg, 11.09 mol) and potassium carbonate (45.91 mg, 332.71 mol) were added, and the system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[2-[1-isopropyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (55.00 mg, yield: 77.89%) as yellow oil. ES-API: [M+1].sup.+=637.4.

[1076] Step 5: The tert-butyl (S)-2-[2-[1-isopropyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl]-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (55 mg, 86.38 mol) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (2.0 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-[1-isopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone (Z438, 18.00 mg, yield: 38.83%) as a yellow solid. ES-API: [M+1].sup.+=537.3 .sup.1H NMR (400 MHz, CDCl.sub.3) 9.61-9.38 (m, 1H), 8.55-8.49 (m, 1H), 8.02-7.98 (m, 1H), 7.84 (s, 1H), 7.61-7.59 (m, 1H), 7.23 (s, 1H), 7.09 (s, 1H), 5.05 (d, J=17.6 Hz, 1H), 4.89 (d, J=17.5 Hz, 1H), 4.73-4.65 (m, 2H), 4.45 (t, J=5.0 Hz, 1H), 4.19-3.98 (m, 1H), 3.63-3.53 (m, 1H), 3.41-3.33 (m, 1H), 3.21-2.85 (m, 3H), 2.34 (s, 3H), 2.12-1.98 (m, 1H), 1.94-1.87 (m, 1H), 1.81-1.68 (m, 1H), 1.55 (d, J=5.8 Hz, 6H).

Example 178. Synthesis of Compound Z344

##STR00457##

[1077] Step 1: 2-Dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (27.12 mg, 59.37 mol), (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (49.72 mg, 59.37 mol), potassium carbonate (123.12 mg, 890.59 mol) and 4-iodo-2-methoxypyridine (209.31 mg, 890.59 mol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 296.86 mol) in dioxane (1 mL), and the system reacted at 130 C. for 15 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-5% methanol in dichloromethane) to give a product tert-butyl (S)-2-(6-chloro-2-(2-methoxypyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (90 mg, yield: 61.5%). ES-API: [M+H].sup.+=444.3.

[1078] Step 2: The compound tert-butyl (S)-2-(6-chloro-2-(2-methoxypyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 225.24 mol) was dissolved in dioxane/water (2 mL/0.4 mL), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (69.77 mg, 270.29 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (16.21 mg, 22.5 mol) and potassium carbonate (96.7 mg, 675 mol) were added, and the system was heated to 100 C. for 2 h. The obtained mixture was extracted with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-(2-(2-methoxypyridin-4-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (90 mg, yield: 68.1%). ES-API: [M+H].sup.+=539.5.

[1079] Step 3: The tert-butyl (S)-2-(2-(2-methoxypyridin-4-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (75 mg, 139 mol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness, extracted with dichloromethane and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-2-(2-methoxypyridin-4-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline (Z344, 20 mg, yield: 40.95%). ES-API: [M+1].sup.+=440.3.

Example 179. Synthesis of Compound Z348

##STR00458##

[1080] Step 1: Ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1.0 g, 4.80 mmol) was dissolved in acetonitrile (10 mL) and stirred at room temperature. 2-Iodopropane (1.23 g, 7.21 mmol) was added to this solution, followed by potassium carbonate (1.0 g, 7.21 mmol), and the reaction mixture was stirred at 80 C. for 6 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give ethyl 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.9 g, yield: 75%) as a white solid. ES-API: [M+1].sup.+=251.1.

[1081] Step 2: Sodium hydroxide (0.72 mg, 17.98 mmol) was added to a solution of the ethyl 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.9 g, 3.60 mmol) in methanol/water (6 mL/1 mL), and the mixture was stirred at 20 C. for 3 h. The reaction mixture was concentrated, diluted with water, and then adjusted to pH 3 with 1N hydrochloric acid to form a precipitate. The precipitate was filtered, and the obtained solid was dried to give 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.6 g, crude product) as a white solid. ES-API: [M+1].sup.+=223.1.

[1082] Step 3: The 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (92.33 mg, 0.42 mmol), 1-propylphosphonic anhydride (197 mg, 0.31 mmol, 50% in ethyl acetate) and triethylamine (63.08 mg, 0.62 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in dichloromethane (6 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether/ethyl acetate=1/1) to give a product tert-butyl (S)-2-[6-chloro-2-[1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (90 mg, yield: 80.05%) as a yellow oil. ES-API: [M+1-100].sup.+=441.2.

[1083] Step 4: The tert-butyl (S)-2-[6-chloro-2-[1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (90 mg, 0.17 mmol) was dissolved in dioxane/water (4 mL/0.8 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (51.53 mg, 0.2 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (11.98 mg, 16.64 mol) and potassium carbonate (68.87 mg, 0.5 mmol) were added, and the system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[2-[1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonyl]-6-(3-methyl-H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (90 mg, yield: 84.97%) as yellow oil. ES-API: [M+1].sup.+=637.5.

[1084] Step 5: The tert-butyl (S)-2-[2-[1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonyl]-6-(3-methyl-H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (90 mg, 0.14 mmol) was dissolved in dichloromethane (2.0 mL). Trifluoroacetic acid (2.0 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-[1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone (Z348, 27.6 mg, yield: 36.39%) as a yellow solid. ES-API: [M+1].sup.+=537.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.32 (s, 1H), 8.48 (s, 1H), 8.02 (s, 1H), 7.84-7.59 (m, 2H), 7.27 (s, 1H), 7.12 (s, 1H), 5.21-4.61 (m, 2H), 4.61-4.51 (m, 1H), 4.46-3.46 (m, 3H), 3.36-2.45 (m, 6H), 2.34 (s, 3H), 2.04-1.60 (m, 3H), 1.53 (d, J=5.9 Hz, 6H).

Example 180. Synthesis of Compound Z350

##STR00459##

[1085] Step 1: 2-(Trifluoromethyl)-pyrimidine-5-carboxylic acid (41.06 mg, 213.74 mol), 1-propylphosphonic anhydride (52.63 mg, 267.18 mol) and triethylamine (0.05 mL) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 178.12 mol) in dichloromethane (2 mL), and the mixture was stirred at 20 C. for 2 h. The reaction mixture was spun to dryness to remove a solvent and obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-[6-chloro-2-[2-(trifluoromethyl)pyrimidine-5-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate as a yellow oil (65.00 mg, yield: 67.85%). ES-API: [M+H].sup.+=511.17.

[1086] Step 2: The tert-butyl (S)-2-[6-chloro-2-[2-(trifluoromethyl)pyrimidine-5-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (55.00 mg, 0.11 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (44.06 mg, 0.17 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.24 mg, 0.014 mmol) and potassium carbonate (39.32 mg, 0.28 mmol) were dissolved in 1,4-dioxane solution (1 mL) and water (0.1 mL), and the system was warmed to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=10/1) to give tert-butyl (S)-2-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[2-(trifluoromethyl)pyrimidine-5-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60.00 mg, yield: 66.06%) as a white solid. ES-API: [M+H].sup.+=607.26.

[1087] Step 3: The tert-butyl (S)-2-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[2-(trifluoromethyl)pyrimidine-5-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60.00 mg, 93.96 mol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid solution (2 mL) and stirred at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=5/1) to give a product (S)-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-[2-(trifluoromethyl)pyrimidin-5-yl]methanone (Z350, 18.80 mg, yield: 44.13%) as a pale yellow solid. ES-API: [M+H].sup.+=507.21. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.83-9.49 (m, 1H), 9.09-8.95 (m, 2H), 8.52-8.33 (m, 1H), 8.04-7.56 (m, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 5.18-4.84 (m, 2H), 4.22-3.97 (m, 1H), 3.65-3.44 (m, 2H), 3.35-3.23 (m, 1H), 3.15-2.75 (m, 3H), 2.44-2.35 (m, 1H), 2.32 (s, 3H), 2.22-2.12 (m, 1H), 2.07-2.01 (m, 1H), 1.94-1.81 (m, 1H).

Example 181. Synthesis of Compound Z354

##STR00460##

[1088] Step 1: 1,5-Dimethyl-1H-pyrazole-3-carboxylic acid (29.95 mg, 213.74 mol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 178.12 mol) in dichloromethane (2 mL), 1-propylphosphonic anhydride (169.8 mg, 267.18 mol, 50% in ethyl acetate), triethylamine (0.05 mL) and the mixture was stirred at 20 C. for 2 h. The reaction mixture was spun to dryness to remove a solvent and obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-[6-chloro-2-(1,5-dimethyl-1H-pyrazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60.00 mg, yield: 69.72%) as a yellow oil. ES-API: [M+H].sup.+=459.2.

[1089] Step 2: The tert-butyl (S)-2-[6-chloro-2-(1,5-dimethyl-1H-pyrazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (50.00 mg, 0.1 1 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (28.12 mg, 0.11 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.84 mg, 0.011 mmol) and potassium carbonate (30.11 mg, 0.22 mmol) were dissolved in 1,4-dioxane solution (1 mL) and water (0.1 mL), and the system was warmed to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=10/1) to give tert-butyl (2)-2-[2-(1,5-dimethyl-1H-pyrazole-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (45.00 mg, 65.75 mol, yield: 70.75%) as a white solid. ES-API: [M+H].sup.+=555.31.

[1090] Step 3: The tert-butyl (2)-2-[2-(1,5-dimethyl-1H-pyrazole-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (45.00 mg, 65.75 mol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid solution (2 mL) and stirred at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a thin layer chromatographic column (dichloromethane/methanol=5/1) to give a product (S)-(1,5-dimethyl-1H-pyrazol-3-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-methanone (Z354, 22.80 mg, yield: 54.53%) as a pale yellow solid. ES-API: [M+H].sup.+=455.26. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.71 (s, 1H), 8.52 (s, 1H), 8.09-7.71 (m, 2H), 7.14 (s, 1H), 7.06-6.96 (m, 1H), 6.55-6.39 (m, 1H), 5.50-4.51 (m, 2H), 4.68-4.50 (m, 1H), 4.20-3.95 (m, 1H), 3.82 (s, 3H), 3.77-3.48 (m, 2H), 3.43-3.17 (m, 1H), 3.02-2.78 (m, 2H), 2.41-2.33 (m, 1H), 2.32-2.27 (m, 6H), 2.21-2.08 (m, 1H), 2.05-1.80 (m, 2H).

Example 182. Synthesis of Compound Z349

##STR00461##

[1091] Step 1: 2-Methyl-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (73.43 mg, 0.36 mmol), 1-propylphosphonic anhydride (337 mg, 0.53 mmol, 50% in ethyl acetate) and triethylamine (54.07 mg, 0.53 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.18 mmol) in dichloromethane (2 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/1) to give a product tert-butyl (S)-2-(6-chloro-2-(2-methyl-4-(trifluoromethyl)pyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, yield: 42.78%). ES-API: [M+H-100].sup.+=425.2.

[1092] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (23.60 mg, 0.09 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (5.48 mg, 0.008 mmol) and potassium carbonate (31.55 mg, 0.23 mmol) were added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-(2-methyl-4-(trifluoromethyl)pyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, 0.076 mmol) in dioxane/water (2 mL/0.4 mL), and the mixture was heated to 110 C. and stirred in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methyl-4-(trifluoromethyl)pyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, yield: 84.58%). ES-API: [M+H].sup.+=621.4.

[1093] Step 3: Trifluoroacetic acid (1 mL) was added to a solution of the compound tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methyl-4-(trifluoromethyl)pyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, 0.06 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 mL/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-methyl-4-(trifluoromethyl)pyrimidin-5-yl)methanone (Z349, 17.9 mg, yield: 53.36%) as a white powder. ES-API: [M+H].sup.+=521.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.90 (s, 1H), 8.83-8.75 (m, 1H), 8.51-8.46 (m, 1H), 8.04-7.98 (m, 1H), 7.84 (s, 1H), 7.32 (s, 1H), 7.09 (s, 1H), 5.44-4.44 (m, 2H), 4.44-4.36 (m, 1H), 4.20-3.86 (m, 1H), 3.56-3.42 (m, 1H), 3.38-3.27 (m, 1H), 3.20-2.89 (m, 3H), 2.88 (s, 3H), 2.35 (s, 3H), 2.12-1.81 (m, 4H).

Example 183. Synthesis of Compound Z351

##STR00462##

[1094] Step 1: 2-Cyclopropylpyrimidine-5-carboxylic acid (58.48 mg, 0.36 mmol), 1-propylphosphonic anhydride (337.1 mg, 0.53 mmol, 50% in ethyl acetate) and triethylamine (54.07 mg, 0.53 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.18 mmol) in dichloromethane (2 ml), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/1, Rf=0.4) to give a product tert-butyl (S)-2-(6-chloro-2-(2-cyclopropylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (45 mg, yield: 52.31%). ES-API: [M+H].sup.+=483.3.

[1095] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (28.86 mg, 0.11 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.7 mg, 0.009 mmol) and potassium carbonate (38.57 mg, 0.238 mmol) were added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-(2-cyclopropylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (45 mg, 0.093 mmol) in dioxane/water (2 mL/0.4 mL), and the mixture was heated to 110 C. and stirred in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(2-(2-cyclopropylpyrimidine-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (45 mg, yield: 83.46%). ES-API: [M+H].sup.+=579.5.

[1096] Step 3: Trifluoroacetic acid (1 mL) was added to a solution of the compound tert-butyl (S)-2-(2-(2-cyclopropylpyrimidine-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (45 mg, 0.08 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Ultimate XB-C18, 50*250 mm, 10 um, mobile phase: A: purified water (0.05% ammonia water) B: pure acetonitrile, flow rate: 80 mL/min, gradient: B/A=20%-90% over 50 min, wavelength: 214 nm, column temperature: room temperature) to give (S)-(2-cyclopropylpyrimidin-5-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z351, 17.6 mg, yield: 47.29%) as a white powder. ES-API: [M+H].sup.+=479.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.58 (s, 1H), 8.70 (s, 2H), 8.48 (s, 1H), 8.01 (s, 1H), 7.86-7.59 (m, 1H), 7.10 (s, 1H), 5.12- 4.82 (m, 2H), 4.53-3.94 (m, 1H), 3.94-3.59 (m, 2H), 3.41-2.92 (m, 4H), 2.34 (s, 3H), 2.11-1.59 (m, 4H), 1.35-1.07 (m, 5H).

Example 184. Synthesis of Compound Z376

##STR00463##

[1097] Step 1: The tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 90 mg, 255 umol) and ethyl isocyanate (22 mg, 306 umol, 24 uL) were dissolved in dichloromethane (1 mL), N,N-diisopropylethyl amine (66 mg, 510 umol, 89 uL) was then added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with dichloromethane (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-[6-chloro-2-(ethylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (100 mg) as a brown oil. ES-API: [M+H]+=424.2.

[1098] Step 2: The tert-butyl (R)-3-[6-chloro-2-(ethylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (100 mg, 236 umol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (73 mg, 283 umol) were dissolved in dioxane (1 mL) and water (0.2 mL), and potassium carbonate (65 mg, 472 umol) was then added. [2-(2-Aminophenyl)phenyl]-chloropalladium; dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphorus (17.00 mg, 24 umol) was added in the presence of protective nitrogen and stirred at 120 C. for 3 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-[2-(ethylcarbamoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morphinme-4-carboxylate (104 mg) as a brown oil. ES-API: [M+H].sup.+=520.2.

[1099] Step 3: The tert-butyl (R)-3-[2-(ethylcarbamoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morphinme-4-carboxylate (104 mg, 200 umol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid-ethyl acetate (4 M, 1 mL) was then added and stirred at room temperature for 4 h. Upon completion of the reaction, the reaction mixture was filtered and purified by prep-HPLC (formic acid method) to give (R)N-ethyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide formate (Z376, 26.68 mg, yield: 31.8%) as a gray solid. ES-API: [M+H].sup.+=420.1. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.45 (br s, 1H), 8.43-8.38 (m, 1H), 8.22 (d, J=1.9 Hz, 1H), 7.73 (s, 1H), 7.55 (s, 1H), 7.20 (s, 1H), 4.82 (s, 1H), 4.60 (d, J=16.3 Hz, 2H), 4.05 (br d, J=12.1 Hz, 2H), 3.74 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 3.42-3.34 (m, 1H), 3.26 (d, J=7.1 Hz, 3H), 3.01 (br t, J=5.9 Hz, 2H), 2.38 (s, 3H), 1.16 (t, J=7.2 Hz, 3H).

Example 185. Synthesis of Compound Z375

##STR00464##

[1100] Step 1: Tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (0.09 g, 255 umol) and tetrahydropyran-4-carboxylic acid (66 mg, 0.51 mmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethyl amine (98.9 mg, 765 umol, 133 uL) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphate (194 mg, 510 umol) were added, and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with ethyl acetate (1 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-[6-chloro-2-(tetrahydropyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (105 mg) as a brown solid. ES-API: [M+H].sup.+=465.1.

[1101] Step 2: The tert-butyl (R)-3-[6-chloro-2-(tetrahydropyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (105 mg, 226 umol) was dissolved in dioxane (1 mL), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (70 mg, 271 umol) was added, followed by water (0.2 mL) and potassium carbonate (62 mg, 452 umol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (163 mg, 226 umol) was added, and the system was heated to 120 C. and stirred for 12 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydropyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg) as a yellow oil. ES-API: [M+H].sup.+=561.3.

[1102] Step 3: The tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydropyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 178 umol) was dissolved in ethyl acetate (1 mL), hydrochloric acid-ethyl acetate (4.0 M, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness, and purified by prep-HPLC (formic acid method) to give (R)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8 [morpholin-3-yl)-3,4-dihydro-1H-isoquinolin-2(1H)-yl)-tetrahydropyran-4-yl]methanone (Z375, formate, 29.2 mg, yield: 35.6%) as a black solid. ES-API: [M+H].sup.+=461.1. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.45 (s, 1H), 8.22 (s, 1H), 7.75 (s, 1H), 7.57-7.53 (d, J=18.0 Hz, 1H), 7.21 (s, 1H), 5.02-4.98 (d, J=16.8 Hz, 2H), 4.79-4.74 (d, J=16.8 Hz, 1H), 4.47-4.45 (d, J=8.8 Hz, 1H), 4.05-3.98 (m, 4H), 3.90-3.89 (d, J=4.0 Hz, 2H), 3.85-3.78 (m, 1H), 3.73-3.67 (m, 1H), 3.59-3.56 (d, J=11.6 Hz, 2H), 3.35 (s, 2H), 3.13-3.09 (m, 2H), 2.38 (s, 3H), 1.86-1.80 (m, 2H), 1.70-1.67 (d, J=12.0 Hz, 2H).

Example 186. Synthesis of Compound Z372

##STR00465##

[1103] Step 1: tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morphinme-4-carboxylate (90 mg, 255 umol) and 2-hydroxy-2-methylpropanoic acid (27 mg, 255 umol) were dissolved in N,N-dimethylformamide (1 mL), N,N-diisopropylethyl amine (66 mg, 510 umol, 89 uL) and tetramethylurea hexafluorophosphate (97 mg, 255 umol) were then added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-[6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morphinme-4-carboxylate (100 mg) as a brown oil. ES-API: [M+H].sup.+=439.2.

[1104] Step 2: The tert-butyl (R)-3-[6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morphinme-4-carboxylate (100 mg, 228 umol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (71 mg, 273 umol) were dissolved in dioxane (1 mL) and water (0.2 mL), and potassium carbonate (63 mg, 456 umol) was added. Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl]palladium (II) (16 mg, 23 umol) was added in the presence of protective nitrogen and stirred at 120 C. for 3 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-[2-(2-hydroxy-2-methylpropanoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morphinme-4-carboxylate (110 mg) as a brown oil. ES-API: [M+H].sup.+=535.3.

[1105] Step 3: The tert-butyl (R)-3-[2-(2-hydroxy-2-methylpropanoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morphinme-4-carboxylate (110 mg, 206 umol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid-ethyl acetate solution (4 M, 1 mL) was then added and stirred at room temperature for 4 h. Upon completion of the reaction, the reaction mixture was filtered and purified by prep-HPLC (formic acid method) to give (R)-2-hydroxy-2-methyl-1-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[morphin-3-yl]-3,4-dihydroisoquinolin-2(1H)-yl]propan-1-one (Z372, formate, 21.64 mg, yield: 24.1%) as a white solid. ES-API: [M+H].sup.+=435.1. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.45 (d, J=1.9 Hz, 1H), 8.39 (br s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.55 (s, 1H), 7.20 (d, J=0.9 Hz, 1H), 5.05-4.93 (m, 1H), 4.80 (br d, J=5.3 Hz, 1H), 4.51-4.41 (m, 1H), 4.36-4.16 (m, 1H), 4.05 (br dd, J=2.8, 12.3 Hz, 2H), 3.83 (br d, J=1.6 Hz, 2H), 3.50-3.32 (m, 2H), 3.30-3.23 (m, 1H), 3.07 (br s, 2H), 2.38 (d, J=1.0 Hz, 3H), 1.56-1.43 (m, 6H).

Example 187. Synthesis of Compound Z382

##STR00466##

[1106] Step 1: Lactic acid (25 mg, 0.28 mmol) and tert-butyl (S)-2-(6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate were dissolved in anhydrous dichloromethane (1.0 mL), N,N-diisopropylethyl amine and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (306 mg, 0.81 mmol) were added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5.0 mL) and extracted with ethyl acetate (5.0 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give rac-(2R)-tert-butyl 2-(6-chloro-2-(2-hydroxypropanoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (70 mg) as a yellow oil. ES-API: [M+H].sup.+=395.1.

[1107] Step 2: The rac-(2R)-tert-butyl 2-(6-chloro-2-(2-hydroxypropanoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (70 mg, 0.18 mmol) was dissolved in dioxane (1.0 mL), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (69 mg, 0.27 mmol) was added, followed by water (1.0 mL) and potassium carbonate (73.5 mg, 0.68 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)palladium (II) (13 mg, 0.018 mmol) was finally added, and the system was heated to 120 C. and stirred for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5.0 mL) and then extracted with ethyl acetate (5.0 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give rac-(2R)-tert-butyl 2-(2-(2-hydroxypropanoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-4-yl)pyrrolidine-1-carboxylate (80 mg) as a yellow oil. ES-API: [M+H]+=491.2.

[1108] Step 3: The rac-(2R)-tert-butyl 2-(2-(2-hydroxypropanoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-4-yl)pyrrolidine-1-carboxylate (80 mg) was dissolved in ethyl acetate (1.0 mL). Hydrochloric acid-ethyl acetate (4.0 M, 1.0 mL) was added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was concentrated and purified by prep-HPLC (formic acid method) to give rac-2-hydroxy-1-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-((R)-pyrrolidin-2-yl)isoindolin-2-yl)propan-1-one (Z382, formate, 1.38 mg, yield: 2.2%). ES-API: [M+H].sup.+=391.2.

Example 188. Synthesis of Compound Z443

##STR00467##

[1109] Step 1: 5-Methylpyrazine-2-carboxylic acid (57.41 mg, 0.42 mmol), 1-propylphosphonic anhydride (394.3 mg, 0.62 mmol, 50% in ethyl acetate) and triethylamine (63.08 mg, 0.62 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in dichloromethane (2 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-50% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/1, Rf=0.3) to give a product tert-butyl (S)-2-(6-chloro-2-(5-methylpyrazine-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, yield: 52.65%). ES-API: [M+H-100].sup.+=357.2.

[1110] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (33.89 mg, 0.13 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.87 mg, 0.011 mmol) and potassium carbonate (45.30 mg, 0.33 mmol) were added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-(5-methylpyrazine-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.11 mmol) in dioxane/water (2 mL/0.4 mL), and the mixture was heated to 110 C. and stirred for 2 h in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(5-methylpyrazine-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (35 mg, yield: 57.88%). ES-API: [M+H].sup.+=553.4.

[1111] Step 3: Trifluoroacetic acid (1 mL) was added to a solution of the compound tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(5-methylpyrazine-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (35 mg, 0.063 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give a product (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(5-methylpyrazin-2-yl)methanone (Z443, 15.5 mg, yield: 53.38%) as a white solid. ES-API: [M+H].sup.+=453.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.99 (s, 1H), 8.92-8.86 (m, 1H), 8.55-8.42 (m, 2H), 8.02-7.95 (m, 1H), 7.83-7.65 (m, 1H), 7.28-7.26 (m, 1H), 7.07 (s, 1H), 5.21-4.87 (m, 2H), 4.55-4.11 (m, 1H), 4.03-3.78 (m, 2H), 3.44-2.98 (m, 4H), 2.67-2.61 (m, 3H), 2.40-2.30 (m, 4H), 2.17-1.93 (m, 3H).

Example 189. Synthesis of Compound Z404

##STR00468## ##STR00469##

[1112] Step 1: In the presence of protective nitrogen, 5-bromo-1H-pyrrolo[2,3-b]pyridine (2 g, 10.15 mmol) was added to a stirred solution of aluminum trichloride (6.77 g, 50.77 mmol) suspended in anhydrous dichloromethane (100 mL), and the reaction mixture was stirred at 25 C. for 1 h. Acetyl chloride (3.98 g, 50.75 mmol) was then added dropwise, and the reaction mixture was stirred for 5 h. The reaction was cooled to 0 C. in an ice bath and carefully quenched with methanol until the solution became clear. The reaction mixture was concentrated, and water was added. 1N Sodium hydroxide was added dropwise to adjust pH to 4, and the obtained product was extracted into ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum to give a product 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (1.80 g, crude product) as a yellow solid. ES-API: [M+1].sup.+=239.0.

[1113] Step 2: Sodium hydride (1.29 g, 32.21 mmol, purity: 60%) was added to a solution of the 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (7 g, 29.28 mmol) in tetrahydrofuran (60 mL) under ice bath cooling. After 1 h, p-toluenesulfonyl chloride (6.70 g, 35.14 mmol) in tetrahydrofuran (4 mL) was added dropwise, and the mixture was stirred at 25 C. for 32 h. The reaction was monitored by LCMS for completion. The mixture was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was beaten with petroleum ether/ethyl acetate (5/1) to give 1-[5-bromo-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridin-3-yl]ethanone (9.00 g, yield: 78.16%) as a yellow solid. ES-API: [M+1].sup.+=395.1.

[1114] Step 3: Methylmagnesium bromide (1M, 11.44 mmol, 11.44 mL) was added dropwise to a solution of the 1-[5-bromo-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridin-3-yl]ethanone (900 mg, 2.29 mmol) in tetrahydrofuran (30 mL) under an ice bath condition, and the obtained mixture was stirred at 0 C. for 2 h. The mixture was poured into ice water and extracted with ethyl acetate (10 mL3). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to dryness. The obtained residue was purified by silica gel column chromatography (0-30% ethyl acetate in petroleum ether) to give a product 2-[5-bromo-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridin-3-yl]propan-2-ol (560.00 mg, yield: 59.78%) as a yellow solid. ES-API: [M+1].sup.+=411.0.

[1115] Step 4: The 2-[5-bromo-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridin-3-yl]propan-2-ol (500 mg, 1.22 mmol) was dissolved in anhydrous dichloromethane (10 mL). Triethylsilane (354.27 mg, 3.05 mmol) and trifluoroacetic acid (696.44 mg, 6.11 mmol) were added dropwise at 0 C. The obtained mixture was warmed to 25 C. and stirred for 16 h. The mixture was poured into ice water, adjusted to pH 4-5 with saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (310 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to dryness. The obtained residue was purified by silica gel column chromatography (0-30% ethyl acetate in petroleum ether) to give a product 5-bromo-3-isopropyl-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridine (380.00 mg, yield: 79.09%) as a white solid. ES-API: [M+1].sup.+=395.0.

[1116] Step 5: 6N Sodium hydroxide (7.5 ml) was added to a solution of the 5-bromo-3-isopropyl-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridine (380 mg, 0.97 mmol) in methanol, and the system heated to reflux and stirred for 2 h. The reaction mixture was concentrated, and the residue was poured into ice water. The mixture was adjusted to pH 5 with saturated citric acid solution and filtered. The filter cake was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to dryness to give 5-bromo-3-isopropyl-1H-pyrrolo[2,3-b]pyridine (225.00 mg, yield: 97.39%) as a yellow solid. ES-API: [M+1].sup.+=239.0.

[1117] Step 6: Bis(pinacolato)diboron (165.67 mg, 652.42 mol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (36.42 mg, 50.19 mol) and potassium acetate (246.26 mg, 2.51 mmol) were added to a solution of the 5-bromo-3-isopropyl-1H-pyrrolo[2,3-b]pyridine (120 mg, 501.86 mol) in acetonitrile (1 mL), and the mixture was heated to 90 C. under a nitrogen atmosphere and stirred overnight. The reaction mixture was filtered. The filter cake was washed with ethyl acetate, and the filtrate was concentrated in vacuum to dryness. The obtained residue was purified by silica gel column chromatography (5%-30% ethyl acetate in petroleum ether) to give (3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (60.00 mg, yield: 41.78%) as a yellow solid. ES-API: [M+H].sup.+=205.1.

[1118] Step 7: 2-Methoxyacetic acid (37.44 mg, 0.42 mmol), 1-propylphosphonic anhydride (389.3 mg, 0.62 mmol, 50% in ethyl acetate) and triethylamine (63.08 mg, 0.62 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in dichloromethane (2 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-50% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/1, Rf=0.3) to give a product tert-butyl (S)-2-(6-chloro-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, yield: 70.61%). ES-API: [M+H-100].sup.+=309.2.

[1119] Step 8: The (3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (35.92 mg, 0.18 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.56 mg, 0.015 mmol) and potassium carbonate (60.75 mg, 0.45 mmol) were added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.15 mmol) in dioxane/water (2 mL/0.4 mL), and the mixture was heated to 110 C. and stirred for 2 h in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (25 mg, yield: 31.99%). ES-API: [M+H].sup.+=533.4.

[1120] Step 9: Trifluoroacetic acid (1 mL) was added to a solution of the compound tert-butyl (S)-2-(6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (20 mg, 0.05 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give (S)-1-(6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H))-yl)-2-methoxyethan-1-one (Z404, 2.4 mg, yield: 11.82%) as a white powder. ES-API: [M+H].sup.+=433.3.

Example 190. Synthesis of Compound Z387

##STR00470##

[1121] Step 1: 3-Aminopyridine (0.15 g, 1.59 mmol) was dissolved in anhydrous dichloromethane (1.0 mL), N,N-diisopropylethyl amine (830 uL) was then added, and the system was cooled to 0 C. Triphosgene (0.39 g, 1.31 mmol) was added and stirred at room temperature for 2 h. Upon completion of the reaction, tert-butyl (S)-2-(6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate (0.15 g, 0.46 mmol) was added directly, and the system was heated to 25 C. and stirred for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5 mL) and extracted with ethyl acetate (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (S)-2-(6-chloro-2-(pyridin-3-ylcarbamoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.1 g) as a yellow oil. ES-API: [M+H].sup.+=443.3.

[1122] Step 2: The tert-butyl (S)-2-(6-chloro-2-(pyridin-3-ylcarbamoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.1 g, 0.23 mmol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (64 mg, 0.27 mmol) was added, followed by water (0.1 mL) and potassium carbonate (95 mg, 0.69 mmol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)palladium ((II) (16 mg, 0.02 mmol) was finally added, and the system was heated to 120 C. and stirred for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5 mL) and extracted with ethyl acetate (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-3-ylcarbamoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.05 g) as a yellow oil. ES-API: [M+H].sup.+=539.2.

[1123] Step 3: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(pyridin-3-ylcarbamoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.05 g) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 M, 1.0 mL) was added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was concentrated to give a crude product. The crude product was purified by prep-HPLC (formic acid method) to give (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(pyridin-3-yl)-4-(pyrrolidin-2-yl)isoindoline-2-carboxamide (Z387, formate, 1.38 mg, yield: 3.4%) as a white solid. ES-API: [M+H].sup.+=439.2.

Example 191. Synthesis of Compound Z385

##STR00471##

[1124] Step 1: 4-Nitropyrazole (5.0 g, 44.22 mmol) and di-tert-butyl dicarbonate (10.62 g, 48.64 mmol) were dissolved in tetrahydrofuran (35 mL), N,N-diisopropylethyl amine (8.47 mL) and 4-dimethylamino pyridine (540.21 mg, 4.42 mmol) were then added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (50 mL) and extracted with ethyl acetate (30 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was beaten with petroleum ether (20 mL) to give tert-butyl 4-nitro-1H-pyrazole-1-carboxylate (9.0 g) as a yellow solid. ES-API: [M+H].sup.+=214.9.

[1125] Step 2: The tert-butyl 4-nitro-1H-pyrazole-1-carboxylate (9.0 g, 44.22 mmol) was dissolved in ethanol (60 mL). Wet palladium on carbon (0.9 g, 10%) was then added, and the system was heated to 30 C. and stirred for 12 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was rinsed with ethyl acetate (50 mL) 3 to 5 times and concentrated. The obtained mixture was then beaten with methyl tert-butyl ether (20 mL) to give tert-butyl 4-amino-1H-pyrazole-1-carboxylate (5.0 g) as a yellow solid. ES-API: [M+H.sup.+-56]=128.0.

[1126] Step 3: The tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.2 g, 1.36 mmol) and 4-nitrophenol chloroformate (302.55 mg, 1.50 mmol) were dissolved in anhydrous dichloromethane (1.0 mL). N,N-Diisopropylethyl amine (1.19 mL) was then added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated directly to give tert-butyl 4-(((4-nitrophenoxy) carbonyl)amino)-1H-pyrazole-1-carboxylate (0.3 g) as a yellow solid.

[1127] Step 4: The tert-butyl 4-(((4-nitrophenoxy) carbonyl)amino)-1H-pyrazole-1-carboxylate (309.76 ug, 371.71 umol) was dissolved in N,N-dimethylacetamide (1.0 mL), N,N-diisopropylethyl amine (404.65 uL) was added and stirred for 1 min. Tert-butyl (S)-2-(6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate (0.15 g, 464.64 umol) was then added, and the system was heated to 80 C. and stirred for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5 mL) and then extracted with ethyl acetate (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (S)-4-(4-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-chloroisoindoline-2-carboxamido)-1H-pyrazole-1-carboxylate (0.1 g) as a yellow oil. ES-API: [M+H.sup.+-200]=331.9.

[1128] Step 5: The tert-butyl (S)-4-(4-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-chloroisoindoline-2-carboxamido)-1H-pyrazole-1-carboxylate (0.1 g, 187.96 umol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (48.52 mg, 187.96 umol) was added, followed by water (0.1 mL) and potassium carbonate (25.98 mg, 187.96 umol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (13.55 mg, 18.80 umol) was finally added, and the system was heated to 120 C. and stirred for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5 mL) and then extracted with ethyl acetate (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (S)-4-(4-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindoline-2-carboxamide)-1H-pyrazole-1-carboxylate (0.1 g) as a yellow oil.

[1129] Step 6: The (S)-tert-butyl 4-(4-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindoline-2-carboxamide)-1H-pyrazole-1-carboxylate (0.1 g) was dissolved in ethyl acetate (1 mL), hydrochloric acid-ethyl acetate (4.0 M, 1.0 mL) was added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was concentrated to give a crude product. The crude product was purified by prep-HPLC (formic acid method) to give (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(1H-pyrazol-4-yl)-4-(pyrrolidin-2-yl))isoindoline-2-carboxamide (Z385, formate, 2.28 g, yield: 3%) as a white solid. ES-API: [M+H].sup.+=428.2.

Example 192. Synthesis of Compound Z386

##STR00472##

[1130] Step 1: 2-Aminothiazole (0.1 g, 1.36 mmol) and 4-nitrophenol chloroformate (201 mg, 1 mmol) were dissolved in anhydrous dichloromethane (1.0 mL), N,N-diisopropylethyl amine (870 uL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated directly to give 4-nitrophenylthiazol-2-ylcarbamate (0.15 g) as a yellow solid.

[1131] Step 2: The 4-nitrophenylthiazol-2-ylcarbamate (0.2 g, 0.75 mmol) was dissolved in N,N-dimethylacetamide (1.0 mL). N,N-Diisopropylethyl amine (240 uL) was added and stirred for 1 min. Tert-butyl (S)-2-(6-chloroisoindolin-4-yl)pyrrolidine-1-carboxylate (221 mg, 0.69 mmol) was then added, and the system was heated to 80 C. and stirred for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5 mL) and then extracted with ethyl acetate (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (S)-2-(6-chloro-2-(thiazol-2-ylcarbamoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.1 g) as a yellow oil. ES-API: [M-200]+=449.1.

[1132] Step 3: The tert-butyl (S)-2-(6-chloro-2-(thiazol-2-ylcarbamoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (107 mg, 0.24 mmol) was dissolved in dioxane (1 mL), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (74 mg, 0.29 mmol) was added, followed by water (0.1 mL) and potassium carbonate (99 mg, 0.72 mmol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)palladium ((II) (17 mg, 0.02 mmol) was finally added, and the system was heated to 120 C. and stirred for 12 h. Upon completion of the reaction, the reaction mixture was added to ice water (5 mL) and then extracted with ethyl acetate (5 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(thiazol-2-ylcarbamoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.05 g) as a yellow oil. ES-API: [M+H].sup.+=545.2.

[1133] Step 4: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(thiazol-2-ylcarbamoyl)isoindolin-4-yl)pyrrolidine-1-carboxylate (0.1 g) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 M, 1.0 mL) was added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was concentrated to give a crude product. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(pyrrolidin-2-yl)-N-(thiazol-2-yl)isoindoline-2-carboxamide (Z386, 8.45 mg, yield: 10.3%) as a white solid. ES-API: [M+H].sup.+=445.1.

Example 193. Synthesis of Compound Z439

##STR00473##

[1134] Step 1: Tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) was dissolved in dichloromethane (2 ml). 5-Methylpicolinic acid (57 mg, 0.42 mmol), 1-propylphosphonic anhydride (396 mg, 0.62 mmol, 50% in ethyl acetate) and triethylamine (63 mg, 0.62 mmol) were added, and the system reacted at room temperature for 16 h. Upon completion of the reaction, the reaction was quenched by the addition of water. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (petroleum ether/ethyl acetate=2/1) to give a product tert-butyl (S)-2-(6-chloro-2-(5-methylpicolinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (90 mg, yield: 95%). ES-API: [M+H].sup.+=456.2.

[1135] Step 2: The tert-butyl (S)-2-(6-chloro-2-(5-methylpicolinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (90 mg, 0.20 mmol) was dissolved in dioxane/water (2 mL/0.4 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (61 mg, 0.24 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.020 mmol) and potassium carbonate (54 mg, 0.39 mmol) were added, and the system was heated to 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=20/1) to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(5-methylpicolinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, yield: 92%). ES-API: [M+1].sup.+=552.3.

[1136] Step 3: The tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(5-methylpicolinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added, and the system reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness, extracted with dichloromethane and saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, filtered, and spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give a product (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(5-methylpyridin-2-yl)methanone (Z439, 31.4 mg, yield: 38%). ES-API: [M+1].sup.+=452.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.69 (s, 1H), 8.47 (d, J=14.4 Hz, 2H), 7.98 (d, J=14.7 Hz, 1H), 7.83-7.60 (m, 3H), 7.25-7.2 (m, 1H), 7.08 (s, 1H), 5.20-4.84 (m, 2H), 4.57-3.75 (m, 3H), 3.42-2.99 (m, 4H), 2.65-2.57 (m, 1H), 2.41-2.33 (m, 6H), 2.05-1.73 (m, 3H).

Example 194. Synthesis of Compound Z440

##STR00474##

[1137] Step 1: In the presence of protective nitrogen, triethylamine (0.5 g, 4.95 mmol) and (4-nitrophenyl)carbonyl chloride (0.49 g, 2.48 mmol) were added to a solution of 4,4-difluoropiperidine hydrochloride (0.2 g, 1.65 mmol) in anhydrous dichloromethane (5 mL) at 0 C. The mixture was warmed to 20 C. and stirred for 3 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:90) to give 4-nitrophenyl-4,4-difluoropiperidine-1-carboxylate (300.00 mg, yield: 63.48%) as a yellow solid. ES-API: [M+1].sup.+=287.1.

[1138] Step 2: The 4-nitrophenyl-4,4-difluoropiperidine-1-carboxylate (71.38 mg, 0.25 mmol) and potassium carbonate (86.16 mg, 0.62 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in N,N-dimethylacetamide (1 mL), and the mixture was warmed to 150 C. and stirred for 3 h. The reaction was monitored by LCMS for completion. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (ethyl acetate:petroleum ether=1:1) to give tert-butyl (S)-2-(6-chloro-2-(4,4-difluoropiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (77.00 mg, yield: 76.56%) as a yellow oil. ES-API: [M+1-100].sup.+=384.2.

[1139] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (49.28 mg, 0.19 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (11.46 mg, 15.91 mol) and potassium carbonate (65.87 mg, 0.48 mmol) were added to a solution of the (S)-2-[6-chloro-2-(4,4-difluoropiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (77.00 mg, 0.16 mmol) in dioxane/water (4 mL/0.8 mL), and the system was heated to 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-(2-(4,4-difluoropiperidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70.00 mg, yield: 75.90%) as a yellow oil. ES-API: [M+1].sup.+=580.4.

[1140] Step 4: The tert-butyl (S)-2-[2-(4,4-difluoropiperidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70 mg, 0.12 mmol) was dissolved in dichloromethane (2.0 mL). Trifluoroacetic acid (2.0 mL) was added, and the system reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-(4,4-difluoropiperidin-1-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z440, 17.90 mg, yield: 30.91%) as a white solid. ES-API: [M+1].sup.+=480.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.63 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.28 (s, 1H), 7.11 (s, 1H), 4.64 (d, J=16.4 Hz, 1H), 4.50 (d, J=16.4 Hz, 1H), 4.34 (t, J=6.0 Hz, 1H), 3.57-3.50 (m, 2H), 3.46-3.39 (m, 4H), 3.36-3.25 (m, 1H), 3.13-3.05 (m, 1H), 3.04-2.99 (m, 2H), 2.35 (s, 3H), 2.31-2.24 (m, 1H), 2.08-1.95 (m, 5H), 1.94-1.85 (m, 1H), 1.81-1.65 (m, 1H).

Example 195. Synthesis of Compound Z414

##STR00475##

[1141] Step 1: 2-Hydrazino-5-bromopyridine (5.61 g, 30.00 mmol) was dissolved in ethanol (100 mL). 2-Butanone (2.16 g, 30.00 mmol) was added at room temperature and stirred at reflux for 2 h. The reaction was checked by LC-MS for completion, and the above mixture was spun to dryness. Polyphosphoric acid (50.00 g) was added, and the system reacted in an oil bath at 170 C. for 1 h. The reaction was checked by LC-MS for completion and cooled to 30 C. Water (100 mL) was added. The mixture was cooled to 0 C. and adjusted to pH 7-8 with 4 mol/L of sodium hydroxide solution. A solid was precipitated and filtered to give a filter cake. The filter cake was then rinsed with ice water (100 mL) and a mixed solution (150 mL) (methanol:water=1:5), air-dried, extracted with a mixed solution (dichloromethane:methanol=10:1) (150 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a product 5-bromo-2,3-dimethyl-1H-pyrrolo[2,3-b]pyridine (4.21 g, yield: 62%) as a white solid. ES-API: [M+H].sup.+=225.2.

[1142] Step 2: The 5-bromo-2,3-dimethyl-1H-pyrrolo[2,3-b]pyridine (300.0 mg, 1.33 mmol) was dissolved in dioxane (4 mL). Bis(pinacolato)diboron (372.5 mg, 1.47 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (93.7 mg, 0.13 mmol) and potassium acetate (260.7 mg, 2.66 mmol) were added at room temperature. The system was replaced with nitrogen for protection and stirred in an oil bath at 100 C. for 16 h. The reaction was checked by LC-MS for completion, and water (10 mL) was added. The obtained mixture was extracted with a mixed solution (dichloromethane:methanol=10:1) (50 mL2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol=3%-6%) to give a product (2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (210.3 mg, yield: 83%). ES-API: [M+H].sup.+=191.2.

[1143] Step 3: Tert-butyl (S)-2-(6-chloro-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.21 mmol) was dissolved in dioxane (2 mL) and water (0.5 mL). The (2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (47.9 mg, 0.25 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14.4 mg, 0.02 mmol) and potassium carbonate (57.9 mg, 0.42 mmol) were added at room temperature and stirred under microwave irradiation at 110 C. for 2 h in the presence of protective nitrogen. The reaction mixture was extracted with a mixed solution (dichloromethane:methanol=10:1) (10 mL), washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol=3%-7%) to give a product tert-butyl (S)-2-(6-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin 5-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (112.1 mg, yield: 91%). ES-API: [M+H].sup.+=587.2.

[1144] Step 4: The (S)-2-(6-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (112.1 mg, 0.19 mmol) was dissolved in dichloromethane (4.0 mL). Trifluoroacetic acid (2.0 mL) was added, and the system reacted at room temperature for 2 h. The reaction mixture was concentrated. 7.0 M Ammonia-methanol solution (5.0 mL) was added, and a solvent was spun to dryness to a crude product. The crude product was purified by prep-HPLC (hydrochloric acid) to give a desired product (S)-1-(6-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3,3-trifluoro-2-hydroxy-2-methylpropan-1-one (Z414, 45.3 mg, yield: 49%) as a white solid. ES-API: [M+H].sup.+=487.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.97 (s, 1H), 10.00-9.70 (m, 1H), 9.60-9.20 (m, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 8.03 (s, 1H), 7.68 (s, 1H), 7.50-6.90 (m, 1H), 5.02-4.80 (m, 1H), 4.79-4.68 (m, 2H), 4.24-4.14 (s, 2H), 4.12-4.00 (m, 2H), 3.60-3.30 (m, 2H), 3.02 (s, 2H), 2.39 (s, 3H), 2.27 (s, 3H), 2.21-1.97 (m, 3H), 1.61 (s, 3H).

Example 196. Synthesis of Compound Z441

##STR00476##

[1145] Step 1: 6-Methylnicotinic acid (56.99 mg, 0.42 mmol), 1-propylphosphonic anhydride (394.3 mg, 0.62 mmol, 50% in ethyl acetate) and triethylamine (63.08 mg, 0.62 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in dichloromethane (2 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-50% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/1, Rf=0.3) to give a product tert-butyl (S)-2-(6-chloro-2-(6-methylnicotinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (65 mg, yield: 68.60%). ES-API: [M+H].sup.+=456.3.

[1146] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (44.15 mg, 0.17 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.26 mg, 0.014 mmol) and potassium carbonate (59.02 mg, 0.43 mmol) were added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-(6-methylnicotinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (65 mg, 0.14 mmol) in dioxane/water (2 mL/0.4 mL), and the mixture was heated to 110 C. and stirred for 2 h in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(6-methylnicotinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, yield: 76.29%). ES-API: [M+H].sup.+=552.4.

[1147] Step 3: Trifluoroacetic acid (1 mL) was added to a solution of the compound tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(6-methylnicotinoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.06 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give a product (S)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(6-methylpyridin-3-yl)methanone (15.5 mg, yield: 31.56%) as a white solid. ES-API: [M+H].sup.+=452.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.34 (s, 1H), 8.63 (d, J=1.8 Hz, 1H), 8.49 (s, 1H), 8.02 (s, 1H), 7.88-7.61 (m, 2H), 7.31-7.26 (m, 1H), 7.24-7.21 (m, 1H), 7.10 (s, 1H), 5.14-4.73 (m, 2H), 4.54-3.60 (m, 3H), 3.42-2.82 (m, 4H), 2.62 (s, 3H), 2.35 (s, 3H), 2.18-1.98 (m, 4H).

Example 197. Synthesis of Compound Z442

##STR00477##

[1148] Step 1: Tetrahydro-2H-pyran-4-carbaldehyde (18.64 mg, 0.16 mmol) and sodium triacetoxyborohydride (29 mg, 0.24 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.18 mmol) in dichloromethane (2 mL), and the mixture was stirred at 25 C. for 2 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/1, Rf=0.4) to give a product tert-butyl (S)-2-(6-chloro-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, yield: 82%). ES-API: [M+H].sup.+=435.3.

[1149] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (35.6 mg, 0.14 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.27 mg, 0.011 mmol) and potassium carbonate (47.57 mg, 0.344 mmol) were added to a solution of the compound tert-butyl (S)-2-(6-chloro-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.16 mmol) in dioxane/water (2 mL/0.4 mL), and the mixture was heated to 110 C. and stirred for 2 h in the presence of protective nitrogen. The reaction was monitored by LCMS for completion. The reaction mixture was extracted with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (65 mg, yield: 100%). ES-API: [M+H].sup.+=531.3.

[1150] Step 3: Trifluoroacetic acid (1 mL) was added to a solution of the compound tert-butyl (S)-2-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.09 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane/methanol=8/1) to give (S)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (10.5 mg, yield: 25.88%) as a yellow powder. ES-API: [M+H].sup.+=431.3. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.47 (s, 1H), 8.42 (s, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.63 (s, 1H), 7.21 (s, 1H), 7.08 (s, 1H), 4.37 (t, J=5.3 Hz, 1H), 4.02-3.95 (m, 2H), 3.79 (d, J=15.2 Hz, 1H), 3.62 (d, J=15.1 Hz, 1H), 3.47-3.38 (m, 2H), 3.38-3.28 (m, 1H), 3.19-3.09 (m, 1H), 3.00- 2.93 (m, 2H), 2.73-2.63 (m, 2H), 2.43 (d, J=6.4 Hz, 2H), 2.34-2.31 (m, 3H), 2.28-2.21 (m, 1H), 2.05-1.88 (m, 3H), 1.78-1.69 (m, 3H), 1.47-1.11 (m, 2H).

Example 198. Synthesis of Compound Z433

##STR00478##

[1151] Step 1: 5-Bromo-3-isopropyl-1H-pyrrolo[2,3-b]pyridine (94 mg, 0.4 mmol), bis(pinacolato)diboron (200 mg, 0.8 mmol) and potassium acetate (120 mg, 1.2 mmol) were dissolved in 1,4-dioxane (3 mL). [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (20 mg) was added, and the system reacted at 110 C. for 2 h in the presence of protective nitrogen. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50%-60%) to give 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (80 mg, yield: 70%). ES-API: [M+H].sup.+=287.2.

[1152] Step 2: In the presence of protective nitrogen, a mixture of tert-butyl (R)-3-(2-acetyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 0.17 mmol), the 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.28 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (13 mg, 0.02 mmol) and potassium carbonate (74 mg, 0.54 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 120 C. for 2 h. Upon completion of the reaction, ethyl acetate (20 mL) was poured into the reaction mixture, and the obtained mixture was washed with saturated brine (10 mL) and water (10 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-10% methanol/dichloromethane) to give tert-butyl (R)-3-(2-acetyl-6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, yield: 76%) as a colorless oil. ES-API: [M+H].sup.+=519.2.

[1153] Step 3: The tert-butyl (R)-3-(2-acetyl-6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 0.14 mmol) was dissolved in ethanol (3.5 mL). 5.0 mol/L Sodium hydroxide (2 mL) was added at room temperature, and the system was stirred at 85 C. in a sealed tube for 6 h. The reaction was checked by LC-MS for completion. The reaction mixture was extracted with a mixed solution of dichloromethane:methanol (10:1, 10 mL), washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol containing 5% c ammonia=3%-5%) to give a product tert-butyl (R)-3-(6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)-morpholine-4-carboxylate (55.3 mg, yield: 83%). ES-API: [M+H].sup.+=477.2.

[1154] Step 4: 1-Hydroxycyclopropane-1-carboxylic acid (11.9 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.1 mg, 0.11 mmol) and 1-hydroxybenzotriazole (14.9 mg, 0.11 mmol) were added at room temperature and stirred at room temperature for 3 min. The tert-butyl (R)-3-(6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)-morpholine-4-carboxylate (55.3 mg, 0.11 mol) was then added and stirred at room temperature for 2 h. The reaction was checked by LC-MS for completion, and water (5 mL) was added. The obtained mixture was extracted with a mixed solution of dichloromethane:methanol (10:1, 10 mL2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol=3%-6%) to give a product tert-butyl (R)-3-(2-(1-hydroxycyclopropane-1-carbonyl)-6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl-morpholine-4-carboxylate (43.2 mg, yield: 70%). ES-API: [M+H].sup.+=561.2.

[1155] Step 5: The tert-butyl (R)-3-(2-(1-hydroxycyclopropane-1-carbonyl)-6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl-morpholine-4-carboxylate (43.2 mg, 0.08 mmol) was dissolved in dichloromethane (4.0 mL). Trifluoroacetic acid (2.0 mL) was added, and the system reacted at room temperature for 2 h. The reaction mixture was concentrated. 7.0 M Ammonia-methanol solution (5.0 mL) was added, and a solvent was spun to dryness to give a crude product. The crude product was purified by prep-HPLC (ammonia water) to give (R)-(1-hydroxycyclopropyl)(6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z433, 15.6 mg, yield: 44%) as a white solid. ES-API: [M+H].sup.+=461.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.37 (s, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.13 (s, 1H), 7.77 (s, 1H), 7.44 (s, 1H), 7.24 (s, 1H), 6.43 (s, 1H), 4.93-4.64 (m, 2H), 3.98 (d, J=8.4 Hz, 2H), 3.78 (d, J=10.0 Hz, 2H), 3.57-3.49 (m, 1H), 3.33-3.29 (m, 1H), 3.28-3.16 (m, 2H), 3.06-2.88 (m, 4H), 1.33 (d, J=6.8 Hz, 6H), 1.01-0.91 (m, 2H), 0.85-0.78 (m, 2H).

Example 199. Synthesis of Compound Z424-1

##STR00479##

[1156] Step 1: N,N-Diisopropylethyl amine (476 mg, 3.68 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (210 mg, 0.55 mmol) were added successively to a solution of tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (130 mg, 0.37 mmol) and methoxyacetic acid (66 mg, 0.73 mmol) in N,N-dimethylformamide (1 mL) and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-80% tetrahydrofuran/petroleum ether) to give tert-butyl (R)-3-(6-chloro-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (130 mg, yield: 83%) as an oil. ES-API: [M+H].sup.+=425.1.

[1157] Step 2: In the presence of protective nitrogen, a mixture of the tert-butyl (R)-3-(6-chloro-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.19 mmol), bis(pinacolato)diboron (96 mg, 0.38 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.02 mmol) and potassium acetate (55 mg, 0.57 mmol) in 1,4-dioxane (2 mL) was stirred at 110 C. for 2 h. Upon completion of the reaction, the reaction mixture was filtered, concentrated, and purified by a flash silica gel column (0-100% tetrahydrofuran/petroleum ether) to give tert-butyl (R)-3-(2-(2-methoxyacetyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, yield: 72%) as a colorless oil. ES-API: [M+H]+=517.3.

[1158] Step 3: In the presence of protective nitrogen, a mixture of the tert-butyl (R)-3-(2-(2-methoxyacetyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 0.14 mmol), 5-bromo-3-isopropyl-1H-pyrrolo[2,3-b]pyridine (32 mg, 0.14 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10 mg, 0.01 mmol) and potassium carbonate (56 mg, 0.41 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 110 C. for 2 h. Upon completion of the reaction, the reaction mixture was dissolved in ethyl acetate (20 mL) and washed with saturated brine (10 mL) and water (10 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-10% methanol/dichloromethane) to give tert-butyl (R)-3-(6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (55 mg, yield: 74%) as a colorless oil. ES-API: [M+H].sup.+=549.3.

[1159] Step 4: Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of the tert-butyl (R)-3-(6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 34 mol) in dichloromethane (1 mL) under an ice bath condition and stirred at room temperature for 1 h. The reaction mixture was concentrated, neutralized with 7M amine-methanol (5 mL), concentrated, and then purified by prep-HPLC (ammonium bicarbonate) to give (R)-1-(6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H))-yl)-2-methoxyethan-1-one (Z424-1, 27.32 mg, purity: 100%, yield: 61%) as a white solid. ES-API: [M+H].sup.+=449.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.42 (s, 1H), 8.62 (d, J=1.6 Hz, 1H), 8.37 (s, 1H), 8.21-8.11 (m, 1H), 7.67 (s, 1H), 7.25 (d, J=1.6 Hz, 1H), 5.02-4.83 (m, 1H), 4.74-4.53 (m, 2H), 4.41-4.26 (m, 1H), 4.23 (s, 1H), 4.11-3.98 (m, 3H), 3.97-3.67 (m, 2H), 3.67-3.45 (m, 3H), 3.34 (s, 3H), 3.27-3.18 (m, 1H), 3.06-2.85 (m, 2H), 1.35 (d, J=3.2 Hz, 3H), 1.33 (d, J=3.2 Hz, 3H).

Example 200. Synthesis of Compound Z418-1

##STR00480##

[1160] Step 1: Tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (35 mg, 0.1 mmol) and 2-hydroxy-2-methylpropanoic acid (10 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (1 mL). 2-(7-Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (57 mg, 0.15 mmol) and N,N-diisopropylethyl amine (40 mg, 0.3 mmol) were added, and the system reacted at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (35 mg, yield: 79%). ES-API: [M+H].sup.+=439.

[1161] Step 2: The tert-butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (35 mg, 0.08 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (68 mg, 0.24 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8 mg, 0.012 mmol) and potassium carbonate (48 mg, 0.34 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL) and stirred at 110 C. for 2 h. The obtained mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (22 mg, yield: 51%). ES-API: [M+H].sup.+=555.

[1162] Step 3: The tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (22 mg, 0.04 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia-methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonium bicarbonate) to give (R)-1-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H))-yl)-2-methyl-2-hydroxy-propan-1-one (Z418-1, 8.8 mg, yield: 45%) ES-API: [M+H].sup.+=455.1. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.33 (s, 1H), 8.45-8.24 (m, 1H), 8.08 (s, 1H), 7.79-7.72 (m, 1H), 7.36 (s, 1H), 5.31-5.26 (m, 1H), 4.91-4.72 (m, 1H), 4.25-4.18 (m, 1H), 4.09-4.04 (m, 1H), 3.97-3.85 (m, 2H), 3.75-3.71 (m, 1H), 3.53-3.48 (m, 1H), 3.28-3.22 (m, 1H), 3.11-2.93 (m, 2H), 1.77-1.67 (m, 2H), 1.63 (s, 6H).

Example 201. Synthesis of Compound Z374

##STR00481##

[1163] Step 1: Tert-butyl (R)-3-(2-acetyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (32.1 mg, 0.08 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (23.4 mg, 0.09 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.2 mg, 0.01 mmol) and potassium carbonate (22.1 mg, 0.16 mmol) were added at room temperature, and in the presence of protective nitrogen, the system was stirred at 100 C. for 3 h. The reaction was checked by LC-MS for completion. The reaction mixture was extracted with a mixed solution of dichloromethane:methanol (=10:1, 10 mL), washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol containing 5 ammonia=2%-5%) to give a product tert-butyl (R)-3-(2-acetyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (23.1 mg, yield: 59%). ES-API: [M+H].sup.+=491.2.

[1164] Step 2: Tert-butyl (R)-3-(2-acetyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (23.1 mg, 0.05 mmol) was dissolved in ethanol (2.0 mL). 5 M sodium hydroxide solution (0.5 mL) was added at room temperature, and stirred at 90 C. in a sealed tube for 18 h. The reaction was checked by LC-MS for completion. The reaction mixture was extracted with a mixed solution of dichloromethane:methanol (=10:1, 10 mL), washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol containing 5% c ammonia=3%-5%) to give a product tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (19.2 mg, yield: 91%). ES-API: [M+H].sup.+=449.2.

[1165] Step 3: 1-Hydroxycyclopropane-1-carboxylic acid (4.4 mg, 0.04 mmol) was dissolved in dichloromethane (1.0 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.6 mg, 0.04 mmol) and 1-hydroxybenzotriazole (5.4 mg, 0.04 mmol) were added at room temperature and stirred at room temperature for 3 min. tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (19.2 mg, 0.04 mol) was then added and stirred at room temperature for 2 h. The reaction was checked by LC-MS for completion. Water (5 mL) was added. The obtained mixture was extracted with a mixed solution of dichloromethane:methanol (=10:1, 10 mL2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol=3%-6%) to give a product tert-butyl (R)-3-(2-(1-hydroxycyclopropane-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (21.2 mg, yield: 93%). ES-API: [M+H].sup.+=533.2.

[1166] Step 4: Tert-butyl (R)-3-(2-(1-hydroxycyclopropane-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (21.2 mg, 0.04 mmol) was dissolved in dichloromethane (4.0 mL). Trifluoroacetic acid (2.0 mL) was added, and the system was reacted at room temperature for 2 h. The reaction mixture was concentrated. 7.0 M Ammonia/methanol solution (5.0 mL) was added, and the solvent was spun to dryness. The crude product was purified by prep-HPLC (formic acid method) to give a desired product (R)-(1-hydroxycyclopropyl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z374, formate, 6.85 mg, yield: 40%) as a white solid. ES-API: [M+H].sup.+=433.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.35 (s, 1H), 8.46 (s, 1H), 8.11 (s, 1H), 7.79 (s, 1H), 7.45 (s, 1H), 7.27 (s, 1H), 4.97-4.68 (m, 2H), 3.99 (d, J=8.4 Hz, 1H), 3.81-3.76 (m, 2H), 3.58-3.54 (m, 2H), 3.30-3.20 (m, 2H), 2.99-2.92 (m, 4H), 2.31 (s, 3H), 1.04-0.90 (m, 2H), 0.88-0.78 (m, 2H).

Example 202. Synthesis of Compound Z419

##STR00482##

[1167] Step 1: 2-Hydroxy-2-methylpropanoic acid (18.7 mg, 0.18 mmol) was dissolved in dichloromethane (1.0 mL). 2-(7-Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (68.4 mg, 0.18 mmol) and N,N-diisopropylethyl amine (46.5 mg, 0.36 mmol) were added at room temperature, and stirred at room temperature for 3 min. (R)-tert-Butyl 3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 65 mg, 0.18 mol) was then added and stirred at room temperature for 2 h. The reaction was checked by LC-MS for completion. Water (5 mL) was added. The obtained mixture was extracted with a mixed solution of dichloromethane:methanol (dichloromethane:methanol=10:1, 10 mL2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol=3%-6%) to give a product tert-butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (51.1 mg, yield: 64%). ES-API: [M+H].sup.+=439.2.

[1168] Step 2: tert-Butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (51.1 mg, 0.12 mmol) was dissolved in 1,4-dioxane (2.0 mL). Bis(pinacolato)diboron (60.9 mg, 0.24 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.2 mg, 0.01 mmol) and potassium phosphate (50.9 mg, 0.24 mmol) were added at room temperature, and in the presence of protective nitrogen, the system was stirred at 100 C. for 2 h. Upon completion of the reaction checked by LC-MS, a crude product tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate was obtained and directly used in the next step without posttreatment. ES-API: [M+H].sup.+=531.2.

[1169] Step 3: Water (0.5 mL), 5-bromo-3-isopropyl-1H-pyrrolo[2,3-b]pyridine (57.2 mg, 0.24 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.2 mg, 0.01 mmol) and potassium phosphate (50.9 mg, 0.24 mmol) were added to the above mixture, and in the presence of protective nitrogen, the system was stirred at 100 C. for 2 h. Upon completion of the reaction checked by LC-MS, the reaction mixture was dissolved in ethyl acetate (20.0 mL), and washed with saturated brine (10.0 mL) and water (10.0 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-10% methanol/dichloromethane) to give a product tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (56.8 mg, yield: 84%). ES-API: [M+H].sup.+=563.2.

[1170] Step 4: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (56.8 mg, 0.10 mmol) was dissolved in dichloromethane (4.0 mL). Trifluoroacetic acid (2.0 mL) was added, and the system was reacted at room temperature for 2 h. The reaction mixture was concentrated. 7.0 M Ammonia-methanol solution (5.0 mL) was added, and the solvent was spun to dryness. The crude product was purified by prep-HPLC (ammonia water method) to give a desired product (R)-2-hydroxy-1-(6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-methylpropan-1-one (Z419, 13.5 mg, yield: 29%) as a white solid. ES-API: [M+H].sup.+=463.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.37 (s, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H), 7.76 (s, 1H), 7.42 (s, 1H), 7.24 (d, J=2.0 Hz, 1H), 5.55-5.27 (m, 2H), 4.86-4.62 (m, 2H), 4.14 (s, 1H), 3.99-3.94 (m, 1H), 3.81-3.74 (m, 2H), 3.56-3.48 (m, 1H), 3.27-3.17 (m, 2H), 3.05-2.85 (m, 4H), 1.45-1.06 (m, 12H).

Example 203. Synthesis of Compound Z422

##STR00483##

[1171] Step 1: tert-Butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.114 mmol) and bis(pinacolato)diboron (87 mg, 0.341 mmol) were dissolved in 1,4-dioxane (10 mL). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.92 mg, 0.0114 mmol) and potassium acetate (39 mg, 0.341 mmol) were added, and the system was reacted at 120 C. for 1 h. Upon completion of the reaction, a solution of tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate in 1,4-dioxane (10 mL of the reaction mixture) was obtained, which was directly used in the next step. ES-API: [M+H].sup.+=531.1.

[1172] Step 2: Water (1 mL), 5-bromo-2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (30 mg, 0.114 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (8.3 mg, 0.0114 mmol) and potassium carbonate (31 mg, 0.228 mmol) were added to a solution of tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate in 1,4-dioxane (10 mL of the reaction mixture). In the presence of protective nitrogen, the system was warmed to 100 C. and stirred for 1 h. Monitored by LCMS, the reaction mixture was diluted with water and extracted with ethyl acetate (20 mL1). The organic phase was washed with saturated brine (20 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give tert-butyl (R)-3-(6-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, yield of the 2 steps: 29.8%) as a yellow oil. ES-API: [M+1].sup.+=583.2.

[1173] Step 3: tert-Butyl (R)-3-(6-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.034 mmol) was dissolved in dichloromethane (2.0 mL). Trifluoroacetic acid (2.0 mL) was added. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated. Ammonia water (0.5 mL) was added, and the obtained mixture was concentrated again. The crude product was purified by prep-HPLC (ammonia water method) to give a product (R)-1-(6-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropan-1-one (Z422, 2.8 mg, yield: 16.90%) ES-API: [M+H].sup.+=483.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.29 (s, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.12 (d, J=2.2 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.47-7.41 (m, 1H), 5.52 (s, 1H), 5.32 (t, J=4.8 Hz, 1H), 4.13 (s, 1H), 3.98 (d, J=9.5 Hz, 1H), 3.78 (d, J=11.1 Hz, 2H), 3.52 (d, J=12.0 Hz, 1H), 3.25 (d, J=11.1 Hz, 2H), 3.01-2.87 (m, 4H), 2.75 (q, J=7.5 Hz, 2H), 2.00 (q, J=7.2 Hz, 2H), 1.36 (s, 3H), 1.24 (s, 3H), 1.21 (d, J=7.5 Hz, 3H).

Example 204. Synthesis of Compound Z425

##STR00484##

[1174] Referring to the synthesis procedure of compound Z424-1, except replacing 5-bromo-3-isopropyl-1H-pyrrolo[2,3-b]pyridine in step 3 with 5-bromo-2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine, compound Z425 was finally obtained. ES-API: [M+H]+=469.2.

Example 205. Synthesis of Compound Z428

##STR00485##

[1175] Referring to the synthesis procedure of compound Z376, except replacing 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine in step 4 with 2-chloro-3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine, compound Z428 was finally obtained. ES-API: [M+H].sup.+=468.2.

Example 206. Synthesis of Compound Z429

##STR00486##

[1176] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 35 mg, 0.1 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). Ethyl isocyanate (7 mg, 0.1 mmol) was added, and the system was reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to give tert-butyl (R)-3-(6-chloro-2-(ethylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (42 mg, yield: 100%), which was directly used in the next step without purification. ES-API: [M+H].sup.+=424.1.

[1177] Step 2: tert-Butyl (R)-3-(6-chloro-2-(ethylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (42 mg, 0.1 mmol), 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (57 mg, 0.2 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8 mg, 0.012 mmol) and potassium carbonate (42 mg, 0.3 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and stirred at 110 C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (R)-3-(2-(ethylcarbamoyl)-6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (15 mg, yield: 30%). ES-API: [M+H].sup.+=548.2.

[1178] Step 3: tert-Butyl (R)-3-(2-(ethylcarbamoyl)-6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (15 mg, 0.03 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion. The reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonium bicarbonate method) to give (R)N-ethyl-6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Z429, 2.98 mg, yield: 25%). ES-API: [M+H].sup.+=448.2.

Example 207. Synthesis of Compound Z430

##STR00487##

[1179] Referring to the synthesis procedure of compound Z376, except replacing 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine in step 4 with 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine, compound Z430 was finally obtained. ES-API: [M+H].sup.+=440.2.

Example 208. Synthesis of Compound Z435

##STR00488##

[1180] Step 1: In the presence of protective nitrogen, a mixture of (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (52 mg, 0.27 mmol), tert-butyl (R)-3-(2-acetyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (95 mg, 0.28 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (17 mg, 0.02 mmol) and potassium carbonate (66 mg, 0.48 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was dissolved in ethyl acetate (10 mL), and washed with saturated brine (5 mL) and water (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-10% methanol/dichloromethane) to give tert-butyl (R)-3-(2-acetyl-6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (65 mg, 0.13 mmol, yield: 52.9%). ES-API: [M+H].sup.+=511.1.

[1181] Step 2: tert-Butyl (R)-3-(2-acetyl-6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (65 mg, 0.13 mmol) was dissolved in ethanol (3 mL). 5.0 mol/L sodium hydroxide (2 mL) solution was added at room temperature, and stirred at 90 C. in a sealed tube for 10 h. The reaction was checked by LC-MS for completion. The reaction mixture was extracted with a mixed solution of dichloromethane:methanol=10:1 (10 mL), washed with water (5 mL) and saturated brine (5 mL) successively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol containing 5 ammonia=2%-5%) to give a product tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine4-carboxylate (45 mg, 0.10 mmol, yield: 73.9%). ES-API: [M+H].sup.+=469.1.

[1182] Step 3: 1-Hydroxycyclopropane-1-carboxylic acid (11 mg, 0.11 mmol) was dissolved in dichloromethane (1.0 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18 mg, 0.10 mmol) and 1-hydroxybenzotriazole (13 mg, 0.10 mmol) were added at room temperature and stirred at room temperature for 3 min. tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (45 mg, 0.10 mmol) was then added and stirred at room temperature for 2 h. The reaction was checked by LC-MS for completion. Water (5 mL) was added. The obtained mixture was extracted with a mixed solution of dichloromethane:methanol=10:1 (5 mL2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol=3%-6%) to give a product tert-butyl 3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(1-hydroxycyclopropane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (45 mg, 0.08 mmol, yield: 81.5%). ES-API: [M+H].sup.+=553.2.

[1183] Step 4: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(1-hydroxycyclopropane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (45 mg, 0.08 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (5 mL) was added, and the system was reacted at room temperature for 2 h. The reaction mixture was concentrated. 7.0 M Ammonia-methanol solution (5.0 mL) was added, and the solvent was spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give a desired product (R)-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-hydroxycyclopropyl)methanone (Z435, 10.4 mg, 0.02 mmol, yield: 28.4%). ES-API: [M+H].sup.+=453.1. .sup.1HNMR: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.07 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.50 (s, 1H), 6.43 (s, 1H), 4.10-3.92 (m, 2H), 3.82-3.75 (m, 2H), 3.58-3.49 (m, 1H), 3.43-3.36 (m, 1H), 3.31-3.22 (m, 2H), 3.07-2.86 (m, 4H), 1.03-0.90 (m, 2H), 0.88-0.76 (m, 2H).

Example 209. Synthesis of Compound Z410

##STR00489##

[1184] Referring to the synthesis procedure of compound Z424-1, except replacing methoxyacetic acid in step 1 with (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid, compound Z410 was finally obtained. ES-API: [M+H].sup.+=517.2.

Example 210. Synthesis of Compound Z413

##STR00490##

[1185] Referring to the synthesis procedure of compound Z424-1, except replacing 5-bromo-3-isopropyl-1H-pyrrolo[2,3-b]pyridine in step 3 with 5-bromo-2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine, compound Z413 was finally obtained. ES-API: [M+H].sup.+=537.2.

Example 211. Synthesis of Compound Z406

##STR00491##

[1186] Referring to the synthesis procedure of compound Z418-1, except replacing 2-hydroxy-2-methylpropanoic acid in step 1 with (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid, compound Z406 was finally obtained. ES-API: [M+H].sup.+=509.2.

Example 212. Synthesis of Compound Z373

##STR00492##

[1187] Step 1: tert-Butyl (R)-3-(2-acetyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (90 mg, 228 mol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (71 mg, 273 mol) were dissolved in dioxane (1 mL) and water (0.2 mL). Potassium carbonate (63 mg, 456 mol) was then added. In the presence of protective nitrogen, chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (16 mg, 23 mol) was then added, and stirred at 120 C. for 3 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(2-acetyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg) as a brown oil. ES-API: [M+H]+=491.3.

[1188] Step 2: tert-Butyl (R)-3-(2-acetyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 204 mol) was dissolved in ethanol (2 mL). 10% Sodium hydroxide solution (0.5 mL) was then added and stirred at 85 C. for 12 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (0.1 g) as a brown oil. ES-API: [M+H].sup.+=449.3.

[1189] Step 3: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 223 mol) and 1-methoxycyclopropanecarboxylic acid (31 mg, 268 mol) were dissolved in N,N-dimethylformamide (1 mL). N,N-Diisopropylethyl amine (58 mg, 446 mol, 78 L) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (85 mg, 223 mol) were then added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(2-(1-methoxycyclopropane-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (0.1 g) as a brown oil. ES-API: [M+H].sup.+=547.3.

[1190] Step 4: tert-Butyl (R)-3-(2-(1-methoxycyclopropane-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 183 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4 mol/L, 1 mL) was then added and stirred at room temperature for 4 h. Upon completion of the reaction, the reaction mixture was filtered and purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(1-methoxycyclopropyl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z373, 10.16 mg) as a white solid. ES-API: [M+H].sup.+=447.3. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.45 (d, J=2.0 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 7.78 (d, J=1.4 Hz, 1H), 7.47 (s, 1H), 7.19 (s, 1H), 5.27-5.06 (m, 1H), 4.90 (br s, 1H), 4.82-4.68 (m, 1H), 4.19-4.04 (m, 2H), 4.01-3.82 (m, 3H), 3.78-3.61 (m, 2H), 3.55-3.42 (m, 1H), 3.35 (s, 1H), 3.20-2.91 (m, 4H), 2.37 (s, 3H), 1.16-0.93 (m, 4H).

Example 213. Synthesis of Compound Z444

##STR00493##

[1191] Step 1: Sodium hydride (313.42 mg, 13.06 mmol) was added to a solution of methyl 5-(hydroxymethyl)nicotinate (1.0 g, 6.53 mmol) in N,N-dimethylformamide (10 mL) at 0 C. and stirred for 1 h. Iodomethane (813 L, 13.06 mmol) was then added and stirred for 1 h. The reaction was monitored by LCMS for completion, and quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=9:1-1:1) to give a product methyl 5-(methoxymethyl)nicotinate (700 mg, yield: 64.13%). ES-API: [M+H].sup.+=182.1.

[1192] Step 2: Sodium hydroxide (334.98 mg, 8.38 mmol) was added to a solution of the methyl 5-(methoxymethyl)nicotinate (0.7 g, 4.19 mmol) in methanol (12 mL) and water (8 mL). The mixture was stirred at 50 C. for 2 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated. 1N aqueous hydrochloric acid solution was added to give a solid. The obtained mixture was filtered to give 5-(methoxymethyl)pyridine-3-carboxylic acid (0.5 g, crude product) as a white solid. ES-API: [M+H].sup.+=168.0.

[1193] Step 3: The 5-(methoxymethyl)pyridine-3-carboxylic acid (17.39 mg, 104.03 mol), 1-propylphosphonic anhydride (133.5 mg, 208.07 mol, 50% in ethyl acetate) and triethylamine (21.01 mg, 208.07 mol) were added to a solution of tert-butyl (S)-2-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (0.03 g, 69.36 mol) in dichloromethane (1.5 mL) and stirred at room temperature for 2 h. The reaction was monitored by LCMS for completion. The reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane:methanol=20:1) to give a product tert-butyl (S)-2-(2-(2-(methoxymethyl)isonicotinoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (17 mg, yield: 42.14%) as a yellow oil. ES-API: [M+H].sup.+=582.3.

[1194] Step 4: Trifluoroacetic acid (1 mL) was added to a solution of the tert-butyl (S)-2-(2-(2-(methoxymethyl)isonicotinoyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (0.014 g, 24.07 mol) in dichloromethane (1 mL) and stirred at 30 C. for 2 h. The reaction was monitored by LCMS for completion, and the reaction mixture was concentrated to give a crude product. The crude product was purified by a preparative thin layer chromatographic column (dichloromethane:methanol=10:1) to give (S)-[2-(methoxymethyl)pyridyl-4-yl]-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-2-yl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone (5.00 mg, yield: 42.41%) as a white solid. ES-API: [M+H].sup.+=482.2.

Example 214. Synthesis of Compound Z452

##STR00494##

[1195] Step 1: (S)-2-Methyl-morpholine (90 mg, 890 mol) was dissolved in anhydrous dichloromethane (0.5 mL). N,N-Diisopropylethyl amine (345 mg, 465 L) was added, and triphosgene (290 mg, 981 mol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give (S)-2-methyl-morpholine-4-carbonyl chloride (135 mg) as a crude product which was directly used in the next step.

[1196] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 90 mg, 255 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (98.9 mg, 133 L) and (S)-2-methyl-morpholine-4-carbonyl chloride (41.7 mg, 255 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-chloro-2-((S)-2-methyl-morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (122 mg) as a yellow oil. ES-API: [M+H].sup.+=480.3.

[1197] Step 3: tert-Butyl (R)-3-(6-chloro-2-((S)-2-methyl-morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (122 mg, 254 mol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (78.7 mg, 305 mol) was added, followed by water (0.2 mL) and potassium carbonate (70.3 mg, 508 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (183 mg, 254 mol) was finally added, and the system was heated to 120 C. and stirred for 12 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-2-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (146 mg) as a yellow oil. ES-API: [M+H].sup.+=576.3.

[1198] Step 4: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-2-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (146 mg, 254 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness and purified by prep-HPLC (ammonium bicarbonate method) to give (6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-2-methylmorpholine)methanone (Z452, 21.58 mg) as a white solid. ES-API: [M+H].sup.+=476.3. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.43 (d, J=1.5 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 7.74 (s, 1H), 7.43 (s, 1H), 7.18 (s, 1H), 4.74-4.67 (m, 1H), 4.61-4.50 (m, 1H), 4.12 (dd, J=2.6, 10.0 Hz, 1H), 3.94-3.85 (m, 3H), 3.76-4.48 (m, 8H), 3.19-3.08 (m, 1H), 3.07-2.97 (m, 4H), 2.71 (s, 1H), 2.37 (s, 3H), 1.17 (d, J=6.3 Hz, 3H).

Example 215. Synthesis of Compound Z453

##STR00495##

[1199] Step 1: 2,2-Dimethylmorpholine (90 mg, 781 mol) was dissolved in anhydrous dichloromethane (0.5 mL). N,N-Diisopropylethyl amine (302 mg, 408 L) was added, and triphosgene (292 mg, 985 mol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was directly concentrated to give 2,2-dimethylmorpholine-4-carbonyl chloride (140 mg) as a crude product which was directly used in the next step.

[1200] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 0.09 g, 255 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (98.9 mg, 133 L) and 2,2-dimethylmorpholine-4-carbonyl chloride (45.31 mg, 255 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-chloro-2-(2,2-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (126 mg) as a yellow oil. ES-API: [M+H].sup.+=494.4.

[1201] Step 3: tert-Butyl (R)-3-(6-chloro-2-(2,2-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (126 mg, 255 mol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (79 mg, 306 mol) was added, followed by water (0.2 mL) and potassium carbonate (70.2 mg, 510 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (184 mg, 255 mol) was finally added, and the system was heated to 120 C. and stirred for 12 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2.0 mL) and extracted with ethyl acetate (5.0 mL). The organic phase was washed with saturated brine (1.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(2-(2,2-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (167 mg) as a yellow oil. ES-API: [M+H].sup.+=590.4.

[1202] Step 4: tert-Butyl (R)-3-(2-(2,2-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (167 mg, 283 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness and purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(2,2-dimethylmorpholine)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z453, 32.46 mg) as a white solid. ES-API: [M+H].sup.+=490.4. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.44-8.43 (d, J=2.00 Hz, 1H), 8.20 (s, 1H), 7.75 (s, 1H), 7.44 (s, 1H), 7.18 (s, 1H), 4.74-4.70 (d, J=16.0 Hz, 1H), 4.57-4.53 (d, J=16.0 Hz 1H), 4.14-4.12 (m, 1H), 3.91-3.86 (m, 2H), 3.81-3.78 (m, 2H), 3.73-3.69 (m, 1H), 3.59-3.56 (t, J=6.00 Hz, 2H), 3.53-3.47 (t, J=10.8 Hz, 2H), 3.32-3.29 (m, 2H), 3.18-3.01 (m, 6H), 2.37 (s, 3H), 1.28-1.27 (d, J=2.40 Hz, 6H).

Example 216. Synthesis of Compound Z454

##STR00496##

[1203] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 60 mg, 170 mol) and tetrahydropyran-4-one (26 mg, 255 mol) were dissolved in methanol (1 mL). Sodium cyanoborohydride (21 mg, 340 mol), acetic acid (10 mg, 170 mol, 9.73 L) and tetraisopropyltitanium (72 mg, 255 mol) were then added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was poured into ice water (5 mL), stirred, and then extracted with ethyl acetate (3 mL) 3 times. The organic phase was washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-chloro-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg) as a yellow oil. ES-API: [M+H].sup.+=437.3.

[1204] Step 2: tert-Butyl (R)-3-(6-chloro-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 160 mol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 192 mol) were dissolved in dioxane (1 mL) and water (0.2 mL). Potassium carbonate (44 mg, 320 mol) was then added. In the presence of protective nitrogen, chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (12 mg, 16 mol) was added and stirred at 120 C. for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL) 3 times. The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg) as a brown oil. ES-API: [M+H].sup.+=533.4.

[1205] Step 3: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 131 mol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid-ethyl acetate (4 mol/L, 1 mL) was then added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered and purified by prep-HPLC (ammonium bicarbonate method) to give (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine (Z454, 7.88 mg) as a white solid. ES-API: [M+H].sup.+=433.3. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.43 (d, J=1.6 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 7.72 (s, 1H), 7.40 (s, 1H), 7.18 (s, 1H), 4.13-3.99 (m, 4H), 3.93-3.78 (m, 3H), 3.69 (br d, J=2.1 Hz, 1H), 3.49 (br s, 3H), 3.18-3.07 (m, 1H), 3.03 (br s, 3H), 2.91 (br d, J=5.6 Hz, 2H), 2.85-2.72 (m, 1H), 2.37 (s, 3H), 1.96 (br s, 2H), 1.72 (br d, J=11.8 Hz, 2H)

Example 217. Synthesis of Compound Z455

##STR00497##

[1206] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 100 mg, 283 mol) and 2-hydroxy-2-methylpropanoic acid (36 mg, 340 mol) were dissolved in N,N-dimethylformamide (1 mL). N,N-Diisopropylethyl amine (220 mg, 1.70 mmol) and tetramethylurea hexafluorophosphate (323 mg, 850 mol) were then added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL) 3 times. The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-[6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (100 mg) as a brown oil. ES-API: [M+H].sup.+=439.2.

[1207] Step 2: tert-Butyl (R)-3-[6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (90 mg, 205 mol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (64 mg, 246 mol) were dissolved in dioxane (1 mL) and water (0.2 mL). Potassium carbonate (57 mg, 410 mol) was then added. In the presence of protective nitrogen, chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (15 mg, 20.5 mol) was then added and stirred at 120 C. for 3 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL) 3 times. The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (110 mg) as a brown oil. ES-API: [M+H].sup.+=536.4.

[1208] Step 3: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (110 mg, 205 mol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid-ethyl acetate (4 mol/L, 1 mL) was then added and stirred at room temperature for 4 h. Upon completion of the reaction, the reaction mixture was filtered and purified by prep-HPLC (formic acid method) to give (R)-2-hydroxy-2-methyl-1-(6-(3-methyl-1H-pyrazolo [3,4-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z455, 13.84 mg, formate) as a white solid. ES-API: [M+H].sup.+=436.2. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.80 (d, J=2.0 Hz, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.36 (s, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.58 (s, 1H), 4.76-4.60 (m, 2H), 4.45 (d, J=8.8 Hz, 1H), 4.41-4.18 (m, 1H), 4.15-4.02 (m, 2H), 3.88-3.77 (m, 1H), 3.82-3.51 (m, 2H), 3.51-3.36 (m, 1H), 3.29-3.18 (m, 1H), 3.15-3.00 m, 2H), 2.63 (s, 3H), 1.54-1.44 (m, 6H).

Example 218. Synthesis of Compound Z456

##STR00498##

[1209] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 0.09 g, 255 mol) was dissolved in N,N-dimethylformamide (2 mL). N,N-Diisopropylethyl amine (98.9 mg, 765 mol, 133 L), 1-cyclopropyl-1H-pyrazole-4-carboxylic acid (38.8 mg, 255 L), and a tri-n-propyl phosphonic acid cyclic anhydride 50% ethyl acetate solution (8.12 mg, 25.5 mol, 7.58 L) were added, and the system was reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with ethyl acetate (1.0 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-[6-chloro-2-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (124 mg) as a brown solid. ES-API: [M+H].sup.+=487.2.

[1210] Step 2: tert-Butyl (R)-3-[6-chloro-2-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (124 mg, 255 mol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (78.9 mg, 306 mol) was added, followed by water (0.2 mL) and potassium carbonate (70.4 mg, 509 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (183 mg, 255 mol) was finally added, and the system was heated to 120 C. and stirred for 12 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2.0 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(2-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (107 mg) as a yellow oil. ES-API: [M+H].sup.+=583.3.

[1211] Step 3: tert-Butyl (R)-3-(2-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (107 mg, 184 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1.0 mL), spun to dryness and purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(1-cyclopropyl-1H-pyrazol-4-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl))-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z456, 7.37 mg) as a white solid. ES-API: [M+H].sup.+=483.3. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.45 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.83-7.80 (d, J=13.2 Hz, 2H), 7.49 (s, 1H), 7.19 (s, 1H), 4.59 (s, 1H), 3.95 (s, 1H), 3.90-3.88 (m, 4H), 3.76-3.72 (m, 2H), 3.48 (s, 1H), 3.35 (s, 1H), 3.13-2.97 (m, 4H), 2.37 (s, 3H), 1.19-1.08 (m, 4H).

Example 219. Synthesis of Compound Z457

##STR00499##

[1212] Step 1: 2-Oxa-5-azabicyclo[2.2.2]octane (90 mg, 255 mol) was dissolved in anhydrous dichloromethane (0.5 mL). Triethylamine (241 mg, 332 L) was added, and triphosgene (300 mg, 1.01 mmol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was directly concentrated to give 2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl chloride (140 mg) as a crude product which was directly used in the next step.

[1213] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 0.09 g, 255 mol) was dissolved in anhydrous dichloromethane (2 mL). Triethylamine (98.9 mg, 106 L) and 2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl chloride (44.8 mg, 255 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-(2-(2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (126 mg) as a yellow oily liquid. ES-API: [M+H].sup.+=492.2.

[1214] Step 3: tert-Butyl (3R)-3-(2-(2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (125 mg, 254 mol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (78.8 mg, 206 mol) was added, followed by water (0.2 mL) and potassium carbonate (70.3 mg, 508 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (183 mg, 254 mol) was finally added, and the system was heated to 120 C. and stirred for 12 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2 mL) and extracted with ethyl acetate (5.0 mL). The organic phase was washed with saturated brine (1.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-(2-(2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (167 mg) as a yellow oil. ES-API: [M+H].sup.+=588.3.

[1215] Step 4: tert-Butyl (3R)-3-(2-(2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (167 mg, 283 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness and purified by prep-HPLC (formic acid method) to give (2-oxa-5-azabicyclo[2.2.2]octan-5-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z457, 21.35 mg, formate) as a white solid. ES-API: [M+H].sup.+=488.3. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.51-8.37 (m, 2H), 8.22 (d, J=1.60 Hz, 1H), 7.72 (s, 1H), 7.54 (d, J=3.20 Hz, 1H), 7.20 (s, 1H), 4.82-4.68 (m, 1H), 4.59-4.36 (m, 2H), 4.28-4.17 (m, 1H), 4.05-3.54 (m, 13H), 3.08-3.05 (m, 2H), 2.38 (s, 3H), 2.23-2.10 (m, 2H), 1.95-1.75 (m, 2H).

Example 220. Synthesis of Compound Z458

##STR00500##

[1216] Step 1: 2,5-Dimethylmorpholine (90 mg, 781 mol) was dissolved in anhydrous dichloromethane (0.5 mL). N,N-Diisopropylethyl amine (302 mg, 408 L) was added, and triphosgene (292 mg, 985 mol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 2,5-dimethylmorpholine-4-carbonyl chloride (140 mg) as a crude product which was directly used in the next step.

[1217] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 0.09 g, 255 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (98.9 mg, 133 L) and 2,5-dimethylmorpholine-4-carbonyl chloride (45.31 mg, 255 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2.0 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-[6-chloro-2-(2,5-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (126 mg) as a yellow oily liquid. ES-API: [M+H].sup.+=494.3.

[1218] Step 3: tert-Butyl (3R)-3-[6-chloro-2-(2,5-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (126 mg, 255 mol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (79 mg, 306 mol) was added, followed by water (0.2 mL) and potassium carbonate (70.2 mg, 510 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (184 mg, 255 mol) was finally added, and the system was heated to 120 C. and stirred for 12 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2.0 mL) and extracted with ethyl acetate (5.0 mL). The organic phase was washed with saturated brine (1.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-(2-(2,5-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (167 mg) as a yellow oil. ES-API: [M+H].sup.+=590.3.

[1219] Step 4: tert-Butyl (3R)-3-(2-(2,5-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (167 mg, 283 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness and purified by prep-HPLC (formic acid method) to give (2,5-dimethylmorpholine)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z458, 30.92 mg, formate) as a white solid. ES-API: [M+H].sup.+=490.3. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.52-8.40 (m, 2H), 8.22-8.21 (m, 1H), 7.75-7.72 (m, 1H), 7.51 (s, 1H), 7.2 (s, 1H), 4.75-4.66 (m, 1H), 4.50-4.44 (m, 1H), 4.37-4.26 (m, 1H), 4.02-3.97 (m, 2H), 3.91-3.46 (m, 6H), 3.41-3.35 (m, 3H), 3.20-3.13 (s, 2H), 3.13-3.09 (m, 1H), 3.05-2.95 (m, 2H), 2.38 (s, 3H), 1.35-1.33 (m, 2H), 1.25-1.18 (m, 3H), 1.07-1.30 (m, 1H).

Example 221. Synthesis of Compound Z459

##STR00501##

[1220] Step 1: 2,6-Dimethylmorpholine (90 mg, 781 mol) was dissolved in anhydrous dichloromethane (0.5 mL). N,N-Diisopropylethyl amine (302 mg, 408 L) was added, and triphosgene (292 mg, 985 mol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 2,6-dimethylmorpholine-4-carbonyl chloride (140 mg) as a crude product which was directly used in the next step.

[1221] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 0.09 g, 255 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (98.9 mg, 133 L) and 2,6-dimethylmorpholine-4-carbonyl chloride (45.31 mg, 255 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2.0 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-[6-chloro-2-(2,6-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (126 mg) as a yellow oily liquid. ES-API: [M+H].sup.+=494.3.

[1222] Step 3: tert-Butyl (3R)-3-[6-chloro-2-(2,6-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (126 mg, 255 mol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (79 mg, 306 mol) was added, followed by water (0.2 mL) and potassium carbonate (70.2 mg, 510 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (184 mg, 255 mol) was finally added, and the system was heated to 120 C. and stirred for 12 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2.0 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-(2-(2,6-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (167 mg) as a yellow oil. ES-API: [M+H].sup.+=590.3.

[1223] Step 4: tert-Butyl (3R)-3-(2-(2,6-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (167 mg, 283 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness and purified by prep-HPLC (formic acid method) to give (2,6-dimethylmorpholine)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z459, 23.93 mg, formate) as a white solid. ES-API: [M+H].sup.+=490.3. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.57-8.38 (m, 2H), 8.21-8.20 (d, J=1.60 Hz, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 7.20 (s, 1H), 4.70-4.66 (d, J=21.9 Hz, 1H), 4.50-4.46 (d, J=16.4 Hz, 1H), 4.41-4.38 (m, 1H), 4.04-4.00 (m, 2H), 3.81-3.55 (m, 8H), 3.32-3.30 (m, 1H), 3.24-3.21 (d, J=12.4 Hz, 1H), 3.05-3.02 (t, J=6.00 Hz, 2H), 3.68-2.62 (m, 2H), 2.37 (s, 3H), 1.18-1.16 (d, J=6.00 Hz, 6H).

Example 222. Synthesis of Compound Z460

##STR00502##

[1224] Step 1: 3,5-Dimethylmorpholine (90 mg, 781 mol) was dissolved in anhydrous dichloromethane (0.5 mL). N,N-Diisopropylethyl amine (302 mg, 2.34 mmol, 408 L) was added, and triphosgene (292 mg, 985 mol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 3,5-dimethylmorpholine-4-carbonyl chloride (140 mg) as a crude product which was directly used in the next step.

[1225] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 0.09 g, 255 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (99 mg, 765 mol, 133 L) and 3,5-dimethylmorpholine-4-carbonyl chloride (45.31 mg, 255 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (3R)-3-[6-chloro-2-(3,5-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (126 mg) as a yellow oil. ES-API: [M+H].sup.+=494.3.

[1226] Step 3: tert-Butyl (3R)-3-[6-chloro-2-(3,5-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (126 mg, 255 mol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (79 mg, 306 mol) was added, followed by water (0.2 mL) and potassium carbonate (70.2 mg, 510 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (184 mg, 255 mol) was finally added, and the system was heated to 120 C. and stirred for 12 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2.0 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1.0 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (3R)-3-(2-(3,5-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (167 mg) as a yellow oil. ES-API: [M+H].sup.+=590.3.

[1227] Step 4: tert-Butyl (3R)-3-(2-(3,5-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (167 mg, 283 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1.00 mL), spun to dryness and purified by prep-HPLC (formic acid method) to give (3,5-dimethylmorpholine)(6-(methyl-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z460, 16.14 mg, formate) as a white solid. ES-API: [M+H].sup.+=490.3. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.49-8.37 (s, 2H), 8.22 (s, 1H), 7.75-7.33 (m, 1H), 7.52 (s, 1H), 7.20 (s, 1H), 4.83 (s, 1H), 4.77-4.66 (m, 1H), 4.40-4.32 (m, 1H), 4.03-4.00 (m, 2H), 3.85-3.67 (m, 4H), 3.68-3.54 (m, 2H), 3.53-3.52 (m, 2H), 3.48-3.43 (m, 2H), 3.32-3.31 (m, 1H), 3.23-3.20 (m, 1H), 3.09-3.06 (m, 1H), 3.00-2.94 (m, 1H), 2.38 (s, 3H), 1.11-1.08 (t, J=6.00 Hz, 6H).

Example 223. Synthesis of Compound Z445

##STR00503##

[1228] Step 1: tert-Butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (44 mg, 0.1 mmol), bis(pinacolato)diboron (0.055 g, 0.22 mmol), potassium acetate (21 mg, 0.22 mmol), and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8 mg, 0.012 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 110 C. for 2 h. 5-Bromo-3-fluoro-1H-pyrrolo[2,3-b]pyridine (47 mg, 0.22 mmol) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (10 mg, 0.014 mmol) were added and stirred at 110 C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (R)-3-(6-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, yield: 38%). ES-API: [M+H].sup.+=539.2.

[1229] Step 2: tert-Butyl (R)-3-(6-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.038 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion. The reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (R)-1-(6-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropan-1-one (Z445, 10.5 mg, yield: 63%). ES-API: [M+H].sup.+=439.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.56 (s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.79 (s, 1H), 7.51 (s, 1H), 7.46 (s, 1H), 5.53-5.30 (m, 2H), 4.94-4.55 (m, 1H), 4.03-3.96 (m, 2H), 3.79-3.77 (m, 2H), 3.55-3.51 (m, 1H), 3.30-3.16 (m, 3H), 2.96-2.94 (m, 4H), 1.36 (s, 6H).

Example 224. Synthesis of Compound Z446

##STR00504##

[1230] Step 1: (S)-Tetrahydrofuran-3-carboxylic acid (23 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (1 mL). 2-(7-Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (98 mg, 0.26 mmol) was added, tert-butyl (R)-3-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (70 mg, 0.2 mmol) and N,N-diisopropyl ethylenediamine (52 mg, 0.4 mmol) were added, and the system was reacted at room temperature for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL3). The organic phase was washed with saturated sodium chloride (10 mL) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/tetrahydrofuran=50/50) to give tert-butyl (R)-3-(7-chloro-2-((S)-tetrahydrofuran-3-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (74 mg, yield: 80%). ES-API: [M+H].sup.+=451.2.

[1231] Step 2: tert-Butyl (R)-3-(7-chloro-2-((S)-tetrahydrofuran-3-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (45 mg, 0.1 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (52 mg, 0.2 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8 mg, 0.012 mmol) and potassium carbonate (42 mg, 0.3 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and stirred at 110 C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (R)-3-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-tetrahydrofuran-3-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (38 mg, yield: 70%). ES-API: [M+H].sup.+=547.3.

[1232] Step 3: tert-Butyl (R)-3-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-tetrahydrofuran-3-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (38 mg, 0.07 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion. The reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-tetrahydrofuran-3-yl)methanone (Z446, 25.0 mg, yield: 80%). ES-API: [M+H].sup.+=447.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.47-11.34 (m, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.27-8.19 (m, 1H), 7.98-7.87 (m, 1H), 7.73 (s, 1H), 7.29 (s, 1H), 4.92-4.81 (m, 1H), 4.81-4.74 (m, 1H), 4.72-4.60 (m, 1H), 4.12-4.01 (m, 2H), 4.00-3.78 (m, 4H), 3.78-3.66 (m, 4H), 3.60-3.33 (m, 3H), 3.14-2.99 (m, 1H), 2.98-2.76 (m, 1H), 2.32 (s, 3H), 2.14-1.88 (m, 2H).

Example 225. Synthesis of Compound Z447

##STR00505##

[1233] Step 1: 4-Nitrophenyl 8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate (111 mg, 0.4 mmol), tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 70 mg, 0.2 mmol), and potassium carbonate (55 mg, 0.4 mmol) were dissolved in DMA (2 mL), and the system was reacted at 130 C. overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL3). The organic phase was washed with saturated sodium chloride (10 mL), filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/tetrahydrofuran=50/50) to give tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (68 mg, yield: 70%). ES-API: [M+H].sup.+=492.2.

[1234] Step 2: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (68 mg, 0.14 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (78 mg, 0.28 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8 mg, 0.012 mmol) and potassium carbonate (58 mg, 0.42 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and stirred at 110 C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (33 mg, yield: 40%). ES-API: [M+H].sup.+=608.2.

[1235] Step 3: tert-Butyl (R)-3-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (33 mg, 0.055 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion. The reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z447, 10.0 mg, yield: 37%). ES-API: [M+H].sup.+=508.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.07 (s, 1H), 8.58 (d, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.47 (s, 1H), 4.60-4.50 (m, 1H), 4.44-4.35 (m, 1H), 4.28 (s, 2H), 4.04-3.95 (m, 1H), 3.78 (t, J=10.0 Hz, 2H), 3.60-3.49 (m, 1H), 3.49-3.27 (m, 4H), 3.16-3.04 (m, 3H), 3.01-2.87 (m, 4H), 1.87-1.75 (m, 4H).

Example 226. Synthesis of Compound Z448

##STR00506##

[1236] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 70 mg, 0.198 mmol) and N,N-diisopropylethyl amine (0.098 mL, 0.595 mmol) were dissolved in dichloromethane (5 mL), and the system was cooled in an ice-water bath. 1,4-Oxazinane-4-carbonyl chloride (59.34 mg, 0.397 mmol) was added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, water (10 mL) was added, and the reaction mixture was extracted with dichloromethane (10 mL3). The organic phases were combined, washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give tert-butyl (R)-3-(6-chloro-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (78.57 mg, yield: 85%). ES-API: [M+H].sup.+=466.3.

[1237] Step 2: tert-Butyl (R)-3-(6-chloro-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (78.57 mg, 0.169 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (127.52 mg, 0.502 mmol) were dissolved in dioxane (10 mL). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (13.15 mg, 0.017 mmol) and potassium acetate (49.28 mg, 0.502 mmol) were added successively, and the system was reacted at 120 C. for 1 h. The system was cooled to 100 C., and water (3 mL), potassium carbonate (69.2 mg, 0.502 mmol) and 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine (76 mg, 0.338 mmol) were added successively. The system was reacted for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL1). The organic phase was washed with saturated brine (20 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give tert-butyl (R)-3-(6-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (57.55 mg, yield: 60%). ES-API: [M+H].sup.+=576.2.

[1238] Step 3: tert-Butyl (R)-3-(6-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (57.55 mg, 0.100 mmol) was dissolved in dichloromethane (2.0 mL). Trifluoroacetic acid (2.0 mL) was added. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated. Ammonia water (0.5 mL) was added, and the obtained mixture was concentrated again. The crude product was purified by prep-HPLC (ammonia water method) to give a product (R)-(6-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(morpholine)methanone (Z448, 8 mg, yield: 16.65%). ES-API: [M+H].sup.+=476.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.37 (s, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.11 (d, J=2.2 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.43 (s, 1H), 7.27 (d, J=2.3 Hz, 1H), 4.59 (d, J=16.4 Hz, 1H), 4.45 (d, J=16.4 Hz, 1H), 3.99 (s, 1H), 3.79 (t, J=9.7 Hz, 2H), 3.62 (t, J=4.7 Hz, 4H), 3.45 (q, J=6.0 Hz, 2H), 3.32 (s, 4H), 3.20 (q, J=4.1 Hz, 3H), 2.96 (d, J=7.3 Hz, 4H), 2.76 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H).

Example 227. Synthesis of Compound Z377

##STR00507##

[1239] Step 1: tert-Butyl (R)-3-(2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (78 mg, 0.2 mmol) was dissolved in ethanol (5 mL) and water (1 mL), Sodium hydroxide (32 mg, 0.8 mmol) was added, and the system was reacted at 80 C. overnight. The reaction mixture was concentrated under reduced pressure, diluted with water (10 mL), and extracted with dichloromethane (15 mL3). The organic phase was washed with saturated sodium chloride (10 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/tetrahydrofuran=50/50) to give tert-butyl (R)-3-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (56 mg, yield: 80%). ES-API: [M+H].sup.+=353.2.

[1240] Step 2: Tetrahydropyran-4-carboxylic acid (26 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (1 mL). 2-(7-Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (98 mg, 0.26 mmol) was added, tert-butyl (R)-3-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (70 mg, 0.2 mmol) and N,N-diisopropylethyl amine (52 mg, 0.4 mmol) were added, and the system was reacted at room temperature for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL3). The organic phase was washed with saturated sodium chloride (10 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/tetrahydrofuran=50/50) to give tert-butyl (R)-3-(7-chloro-2-(tetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (74 mg, yield: 80%). ES-API: [M+H].sup.+=465.2.

[1241] Step 3: tert-Butyl (R)-3-(7-chloro-2-(tetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (46 mg, 0.1 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (52 mg, 0.2 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8 mg, 0.012 mmol) and potassium carbonate (42 mg, 0.3 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and stirred at 110 C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (R)-3-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (31 mg, yield: 55%). ES-API: [M+H].sup.+=561.2.

[1242] Step 4: tert-Butyl (R)-3-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (31 mg, 0.055 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion. The reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (R)-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (Z377, 22.0 mg, yield: 88%). ES-API: [M+H].sup.+=461.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.35 (s, 1H), 8.48 (s, 1H), 8.13 (s, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 7.27 (s, 1H), 4.83 (s, 1H), 4.71 (d, J=6.0 Hz, 1H), 4.08-4.06 (m, 1H), 3.78-3.66 (m, 6H), 3.56-3.42 (m, 3H), 3.25-3.22 (m, 1H) 3.08-2.69 (m, 6H), 2.32 (s, 3H), 1.60 (s, 4H).

Example 228. Synthesis of Compound Z449

##STR00508##

[1243] Step 1: tert-Butyl (S)-3-(2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (78 mg, 0.2 mmol) was dissolved in ethanol (5 mL) and water (1 mL), Sodium hydroxide (32 mg, 0.8 mmol) was added, and the system was reacted at 80 C. overnight. The reaction mixture was concentrated under reduced pressure, diluted with water (10 mL), and extracted with dichloromethane (15 mL3). The organic phase was washed with saturated sodium chloride (10 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/tetrahydrofuran=50/50) to give tert-butyl (S)-3-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (56 mg, yield: 80%). ES-API: [M+H].sup.+=353.2.

[1244] Step 2: Tetrahydropyran-4-carboxylic acid (26 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (1 mL). 2-(7-Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (98 mg, 0.26 mmol) was added, tert-butyl (S)-3-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (70 mg, 0.2 mmol) and N,N-diisopropylethyl amine (52 mg, 0.4 mmol) were added, and the system was reacted at room temperature for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL3). The organic phase was washed with saturated sodium chloride (10 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/tetrahydrofuran=50/50) to give tert-butyl (S)-3-(7-chloro-2-(tetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (74 mg, yield: 80%). ES-API: [M+H].sup.+=465.2.

[1245] Step 3: tert-Butyl (S)-3-(7-chloro-2-(tetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (46 mg, 0.1 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (52 mg, 0.2 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8 mg, 0.012 mmol) and potassium carbonate (42 mg, 0.3 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and stirred at 110 C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (S)-3-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (28 mg, yield: 50%). ES-API: [M+H].sup.+=561.3.

[1246] Step 4: tert-Butyl (S)-3-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (28 mg, 0.05 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion. The reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (S)-(7-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (Z449, 18.5 mg, yield: 78%). ES-API: [M+H].sup.+=461.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.47 (s, 1H), 8.12 (s, 1H), 7.77 (s, 1H), 7.51 (s, 1H), 7.27 (s, 1H), 4.82 (s, 1H), 4.70 (d, J=6.0 Hz, 1H), 4.02 (d, J=10.0 Hz, 1H), 3.88-3.76 (m, 6H), 3.54-3.42 (m, 3H), 3.25- 3.22 (m, 1H), 3.09-2.71 (m, 6H), 2.32 (s, 3H), 1.65-1.58 (m, 4H).

Example 229. Synthesis of Compound Z450

##STR00509##

[1247] Step 1: 4-Hydroxytetrahydro-2H-pyran-4-carboxylic acid (26.3 mg, 0.18 mmol) was dissolved in dichloromethane (1.0 mL). 2-(7-Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (68.4 mg, 0.18 mmol) and N,N-diisopropylethyl amine (46.5 mg, 0.36 mmol) were added at room temperature, and stirred at room temperature for 3 min. (R)-tert-Butyl 3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 65 mg, 0.18 mol) was then added and stirred at room temperature for 2 h. The reaction was checked by LC-MS for completion. Water (5 mL) was added. The obtained mixture was extracted with a mixed solution of dichloromethane:methanol (10:1, 10 mL2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol=3%-6%) to give a product tert-butyl (R)-3-(6-chloro-2-(4-hydroxytetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (54 mg, yield: 93%). ES-API: [M+H].sup.+=481.2.

[1248] Step 2: tert-Butyl (R)-3-(6-chloro-2-(4-hydroxytetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (54 mg, 0.11 mmol) was dissolved in 1,4-dioxane (2.0 mL) and water (0.5 mL). (3-Methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (23.1 mg, 0.13 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.2 mg, 0.01 mmol) and potassium carbonate (30.4 mg, 0.22 mmol) were added at room temperature, and in the presence of protective nitrogen, the system was stirred at 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was dissolved in ethyl acetate (20.0 mL), and washed with saturated brine (10.0 mL) and water (10.0 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-10% methanol/dichloromethane) to give a product tert-butyl (R)-3-(2-(4-hydroxytetrahydro-2H-pyran-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (57.2 mg, yield: 88%). ES-API: [M+H].sup.+=577.2.

[1249] Step 3: tert-Butyl (R)-3-(2-(4-hydroxytetrahydro-2H-pyran-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (57.2 mg, 0.10 mmol) was dissolved in dichloromethane (4.0 mL). Trifluoroacetic acid (2.0 mL) was added, and the system was reacted at room temperature for 2 h. The reaction mixture was concentrated. 7.0 M Ammonia-methanol solution (5.0 mL) was added, and the solvent was spun to dryness. The crude product was purified by prep-HPLC (ammonia water method) to give a desired product (R)-(4-hydroxytetrahydro-2H-pyran-4-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl))-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z450, 27.3 mg, yield: 57%) as a white solid. ES-API: [M+H].sup.+=477.2.

Example 230. Synthesis of Compound Z451

##STR00510##

[1250] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 0.14 mmol) and triethylamine (29 mg, 0.28 mmol) were dissolved in dichloroethane (5 mL). p-Nitrophenyl chloroformate (37 mg, 0.18 mmol) was added under an ice bath condition, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated. The crude product was purified by a flash silica gel column (tetrahydrofuran/petroleum ether: 0-25%) to give a desired product tert-butyl (R)-3-(6-chloro-2-((4-nitrophenoxy)carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, yield: 95.4%) as a colorless liquid. ES-API: [M+Na]+=518.2.

[1251] Step 2: tert-Butyl (R)-3-(6-chloro-2-((4-nitrophenoxy)carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.077 mmol) was dissolved in N,N-dimethylacetamide (2 mL). Potassium carbonate (43 mg, 0.31 mmol) and 8-oxo-3-azabicyclo[3,2,1]octane hydrochloride (23 mg, 0.15 mmol) were added at room temperature and stirred at 135 C. for 6 h. The reaction mixture was cooled to room temperature. Water (6 mL) was added, and the precipitated solid was filtered. The filter cake was dried in vacuum, and then purified by a flash silica gel column (methanol/dichloromethane: 0-3%) to give a desired product tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, yield: 65.8%) as a pale yellow solid. ES-API: [M+H].sup.+=492.3.

[1252] Step 3: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, 0.05 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (26 mg, 0.10 mmol), 2-dicyclohexylphosphino-2,6-dimethoxy-biphenyl (4 mg, 0.005 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (2 mg, 0.005 mmol), potassium carbonate (21 mg, 0.15 mmol), 1,4-dioxane (2 mL) and water (0.4 mL) were added to a 25 mL round-bottom flask. The system was replaced with nitrogen 3 times and reacted at 120 C. for 2 h. The reaction was cooled to room temperature, and ethyl acetate (50 mL) was added. The obtained mixture was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0-3%) to give a desired product tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (18 mg, yield: 60.3%) as a pale yellow solid. ES-API: [M+H].sup.+=588.2.

[1253] Step 4: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (18 mg, 0.03 mmol) was dissolved in methanol (1 mL). 4.0 M hydrogen chloride/dioxane solution (4 mL, 16.0 mmol) was added, and the system was reacted at room temperature for 2 h. The reaction mixture was concentrated. 7.0 M Ammonia-methanol solution (5 mL) was added, and the solvent was spun to dryness. The crude product was purified by prep-HPLC (formic acid method) to give a desired product (8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z451, formate, 8 mg, yield: 53.6%) as a white solid. ES-API: [M+H].sup.+=488.2.

Example 231. Synthesis of Compound Z461

##STR00511##

[1254] Step 1: tert-Butyl (3R)-3-(6-chloro-2-(4-hydroxy-2,2-dimethylpyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (22 mg, 0.445 mmol) and tetrahydrofuran (10 mL) were added to a 25 mL round-bottom flask. Sodium hydride (53 mg, 2.2 mmol) was added in batches at 0 C. and stirred at the temperature for 20 min, and iodomethane (316 mg, 2.2 mmol) was added. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (10 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (3R)-3-(6-chloro-2-(4-methoxy-2,2-dimethylpyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, yield: 35%). ES-API: [M+H].sup.+=508.3.

[1255] Step 2: tert-Butyl (3R)-3-(6-chloro-2-(4-methoxy-2,2-dimethylpyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (90 mg, 0.17 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (137.2 mg, 0.53 mmol), potassium carbonate (73.5 mg, 0.53 mmol), (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (12.7 mg, 0.01 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 120 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (3R)-3-(2-(4-methoxy-2,2-dimethylpyrrolidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, yield: 46%). ES-API: [M+H].sup.+=604.3.

[1256] Step 3: tert-Butyl (3R)-3-(2-(4-methoxy-2,2-dimethylpyrrolidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.08 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude produce was purified by prep-HPLC (ammonium bicarbonate method) to give (4-methoxy-2,2-dimethylpyrrolidin-1-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z461, 10 mg, yield: 24%). ES-API: [M+H].sup.+=504.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.09 (d, J=1.9 Hz, 1H), 7.75 (s, 1H), 7.42 (s, 1H), 7.26 (s, 1H), 4.43 (dd, J=16.4, 5.4 Hz, 1H), 4.30-4.19 (m, 1H), 3.90-4.05 (m, 2H), 3.85-3.66 (m, 3H), 3.59-3.34 (m, 3H), 3.31-3.28 (m, 2H), 3.27-3.20 (m, 4H), 3.0-2.88 (m, 4H), 2.31 (s, 3H), 2.03-1.77 (m, 2H), 1.44 (d, J=5.4 Hz, 3H), 1.37 (s, 3H).

Example 232. Synthesis of Compound Z462

##STR00512##

[1257] Step 1: tert-Butyl (3R)-3-(6-chloro-2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.06 mmol), 5-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (66 mg, 0.24 mmol), potassium carbonate (25 mg, 0.18 mmol), (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (5.80 mg, 0.01 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted under microwave at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (3R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, yield: 84%). ES-API: [M+H].sup.+=601.3.

[1258] Step 2: tert-Butyl (3R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.03 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude produce was purified by prep-HPLC (ammonium bicarbonate method) to give 6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (Z462, 0.5 mg, yield: 2%). ES-API: [M+H].sup.+=501.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.36 (s, 1H), 8.47 (d, J=1.7 Hz, 1H), 8.11 (d, J=1.7 Hz, 1H), 7.78 (s, 1H), 7.45 (s, 1H), 7.27 (s, 1H), 4.53 (d, J=16.3 Hz, 1H), 4.38 (d, J=16.4 Hz, 1H), 4.05 (d, J=7.7 Hz, 1H), 3.84 (s, 1H), 3.56-2.89 (m, 16H), 2.32 (d, J=5.6 Hz, 6H), 1.95 (s, 2H), 1.77-1.66 (m, 2H).

Example 233. Synthesis of Compound Z463

##STR00513##

[1259] Step 1: (1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane hydrochloride (272 mg, 2.018 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (0.701 mL, 5.044 mmol) and p-nitrophenyl chloroformate (447.32 mg, 2.219 mmol) were added under an ice bath condition, and the system was reacted at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate=80/20) to give (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid 4-nitrophenyl ester (380 mg, 1.438 mmol, yield: 71.28%). ES-API: [M+H].sup.+=265.0.

[1260] Step 2: (1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid 4-nitrophenyl ester (89.86 mg, 0.340 mmol) was dissolved in N,N-dimethylacetamide (1 mL). tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 60 mg, 0.170 mmol) and potassium carbonate (47.00 mg, 0.340 mmol) were added, and the system was reacted at 130 C. for 3 h. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl (R)-3-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (56 mg, 0.117 mmol, yield: 68.90%). ES-API: [M+H].sup.+=478.1.

[1261] Step 3: tert-Butyl (R)-3-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (55 mg, 0.115 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (59.40 mg, 0.230 mmol), (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (8.28 mg, 0.012 mmol) and potassium carbonate (47.71 mg, 0.345 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). In the presence of protective nitrogen, the reaction mixture was stirred at 110 C. for 2 h and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to give tert-butyl (R)-3-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.052 mmol, yield: 45.45%). ES-API: [M+H].sup.+=574.3.

[1262] Step 4: tert-Butyl (R)-3-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (22 mg, 0.038 mmol) was dissolved in methanol (1 mL). Hydrochloric acid/dioxane (2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give ((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z463, 9.8 mg, 0.021 mmol, yield: 51.58%). ES-API: [M+H].sup.+=474.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.46 (s, 1H), 8.10 (s, 1H), 7.76 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 4.67-4.42 (m, 3H), 4.34 (s, 1H), 3.97-3.91 (m, 2H), 3.79-3.71 (m, 3H), 3.58-3.51 (m, 4H), 3.28-3.18 (m, 3H), 3.02-2.85 (m, 4H), 2.32 (s, 3H), 1.78-1.73 (m, 2H).

Example 234. Synthesis of Compound Z464

##STR00514##

[1263] Step 1: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 0.189 mmol), 5-bromo-3-ethyl-2-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.378 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (13.59 mg, 0.019 mmol) and potassium carbonate (78.27 mg, 0.566 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). In the presence of protective nitrogen, the reaction mixture was stirred at 100 C. for 1 h. Upon completion of the reaction, water (30 mL) was added, and the reaction mixture was extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/5) to give tert-butyl (R)-3-(6-(3-ethyl-2-fluoro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (95 mg, 0.132 mmol, yield: 69.80%). ES-API: [M+H].sup.+=721.2.

[1264] Step 2: tert-Butyl (R)-3-(6-(3-ethyl-2-fluoro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (95 mg, 0.132 mmol) was dissolved in tetrahydrofuran (5 mL). Tetrabutylammonium fluoride (0.416 mL, 1 M tetrahydrofuran solution) was added. After 6 h at room temperature, the reaction mixture was treated with saturated sodium bicarbonate solution, and extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/5) to give tert-butyl (R)-3-(6-(3-ethyl-2-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (35 mg, 0.062 mmol, yield: 44.52%). ES-API: [M+H].sup.+=567.2.

[1265] Step 3: tert-Butyl (R)-3-(6-(3-ethyl-2-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (35 mg, 0.062 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added, and the system was reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (R)-3-(6-(3-ethyl-2-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine (Z464, 4.81 mg, 0.010 mmol, yield: 16.69%). ES-API: [M+H].sup.+=467.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.72 (s, 1H), 8.74 (s, 1H), 8.18 (s, 1H), 7.82 (s, 1H), 7.67 (s, 1H), 5.54 (s, 1H), 5.32 (t, J=4.9 Hz, 1H), 4.14 (d, J=8.4 Hz, 1H), 3.99 (d, J=10.0 Hz, 1H), 3.79 (d, J=10.5 Hz, 2H), 3.55 (s, 1H), 3.36-3.34 (m, 2H), 2.99-2.89 (m, 4H), 2.36-2.34 (s, 2H), 2.00 (q, J=7.1 Hz, 2H), 1.24 (s, 6H), 1.16 (t, J=7.2 Hz, 3H).

Example 235. Synthesis of Compound Z465

##STR00515##

[1266] Step 1: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.151 mmol), 2-bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine (105.18 mg, 0.452 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (21.72 mg, 0.030 mmol) and potassium carbonate (62.44 mg, 0.452 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). In the presence of protective nitrogen, the reaction mixture was stirred at 115 C. for 6 h. Upon completion of the reaction, water (30 mL) was added, and the reaction mixture was extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/5) to give tert-butyl (R)-3-(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (55 mg, 0.099 mmol, yield: 65.59%). ES-API: [M+H].sup.+=556.2.

[1267] Step 2: tert-Butyl (R)-3-(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (55 mg, 0.099 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added, and the system was reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (R)-3-(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine (Z465, 5.28 mg, 0.012 mmol, yield: 11.71%). ES-API: [M+H].sup.+=456.1.

Example 236. Synthesis of Compound Z466

##STR00516##

[1268] Step 1: 2-Methoxyacetyl chloride (23.07 mg, 0.21 mmol) and triethylamine (43.02 mg, 0.43 mmol) were added to a solution of tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 0.14 mmol) in dichloromethane (2 mL). The mixture was stirred at 0 C. for half an hour. The reaction was monitored by LCMS for completion, and the reaction was quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-60% ethyl acetate/petroleum ether, petroleum ether/ethyl acetate=1/1, Rf=0.4) to give a product tert-butyl (R)-3-(6-chloro-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, yield: 66.43%). ES-API: [M+H].sup.+=425.2.

[1269] Step 2: 3-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (31.46 mg, 0.11 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.25 mg, 0.013 mmol), and potassium carbonate (38.97 mg, 0.28 mmol) were added to a solution of compound tert-butyl (R)-3-(6-chloro-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.09 mmol) in dioxane/water (2 mL/0.4 mL). In the presence of protective nitrogen, the mixture was heated to 100 C. and stirred for 2 h. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (18 mg, yield: 35.34%). ES-API: [M+H].sup.+=541.2.

[1270] Step 3: Trifluoroacetic acid (1 mL) was added to a solution of compound tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (18 mg, 0.03 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. Monitored by LCMS, the reaction mixture was neutralized and adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (ammonia water method-A) to give (R)-1-[6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-morpholin-3-yl-3,4-dihydroisoquinolin-2(1H)-yl]-2-methoxyethan-1-one (Z466, 2.54 mg, yield: 17.32%) as a white powder. ES-API: [M+H].sup.+=441.1.

Example 237. Synthesis of Compound Z467

##STR00517##

[1271] Step 1: Triethylamine (43.02 mg, 0.43 mmol) and cyclopropanesulfonyl chloride (23.91 mg, 0.17 mmol) were added to a solution of tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 0.14 mmol) in dichloromethane (2 mL), and the reaction mixture was stirred at 0 C. for 2 h. Water was added to the mixture. The obtained mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give tert-butyl (R)-3-(6-chloro-2-cyclopropylsulfonyl-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60.00 mg, yield: 92.66%) as a colorless oil. ES-API: [M+1-100].sup.+=357.1.

[1272] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (40.68 mg, 0.16 mmol), potassium carbonate (54.36 mg, 0.39 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.45 mg, 13.13 mol) were added to a solution of tert-butyl (R)-3-(6-chloro-2-cyclopropylsulfonyl-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.13 mmol) in dioxane/water (4 mL/1.0 mL), and the system was heated to 100 C. and reacted for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give a product tert-butyl (R)-3-[2-cyclopropylsulfonyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (57.00 mg, yield: 78.55%) as a yellow oil. ES-API: [M+1].sup.+=553.2.

[1273] Step 3: tert-Butyl (R)-3-[2-cyclopropylsulfonyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (57.00 mg, 0.1 mmol) was dissolved in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give a product (R)-3-[2-cyclopropylsulfonyl-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine (Z467, 15.3 mg, yield: 32.14%) as a yellow solid. ES-API: [M+1].sup.+=453.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.35 (s, 1H), 8.58-8.53 (m, 1H), 8.29-8.25 (m, 1H), 8.08-8.02 (m, 1H), 7.58 (s, 1H), 7.25- 7.21 (m, 1H), 4.73 (d, J=15.8 Hz, 1H), 4.48 (d, J=15.8 Hz, 1H), 4.35-4.23 (m, 1H), 3.95-3.79 (m, 3H), 3.68-3.36 (m, 6H), 3.04-2.96 (m, 2H), 2.81-2.73 (m, 1H), 2.29 (s, 3H), 1.06-0.94 (m, 4H).

Example 238. Synthesis of Compound Z468

##STR00518##

[1274] Step 1: 2-Methylpyrimidine-5-carboxylic acid (29.36 mg, 0.21 mmol), triethylamine (43.02 mg, 0.43 mmol), and 1-propylphosphonic anhydride (133.6 mg, 0.21 mmol, 50% ethyl acetate solution) were added to a solution of tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 0.14 mmol) in dichloromethane (2 mL), and the reaction mixture was stirred at 25 C. for 2 h. Water was added to the mixture. The obtained mixture was extracted with ethyl acetate (10 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (R)-3-[6-chloro-2-(2-methylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (60.00 mg, yield: 89.53%) as a yellow oil. ES-API: [M+1].sup.+=473.2.

[1275] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (39.29 mg, 0.15 mmol), potassium carbonate (52.52 mg, 0.38 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.26 mg, 12.69 mol) were added to a solution of tert-butyl (R)-3-[6-chloro-2-(2-methylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (60 mg, 0.13 mmol) in dioxane/water (4 mL/1.0 mL), and the system was heated to 100 C. and reacted for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give a product tert-butyl (R)-3-[2-(2-methylpyrimidine-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (60.00 mg, yield: 83.17%) as a yellow oil. ES-API: [M+1].sup.+=569.3.

[1276] Step 3: tert-Butyl (R)-3-[2-(2-methylpyrimidine-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (1.0 mL). Trifluoroacetic acid (1.0 mL) was added. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give a product (R)-(2-methylpyrimidin-5-yl)-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[morpholin-3-yl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone (Z468, 20.00 mg, yield: 40.46%) as a yellow solid. ES-API: [M+1].sup.+=469.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.36 (s, 1H), 8.83 (s, 2H), 8.64 (d, J=1.6 Hz, 1H), 8.45 (d, J=1.2 Hz, 1H), 8.41-8.23 (m, 1H), 7.66 (s, 1H), 7.23-7.19 (m, 1H), 5.05 (d, J=17.0 Hz, 1H), 4.90-4.52 (m, 1H), 4.27-4.07 (m, 1H), 4.04-3.90 (m, 2H), 3.91-3.51 (m, 3H), 3.34-3.12 (m, 3H), 3.02-2.94 (m, 2H), 2.66 (s, 3H), 2.31-2.24 (m, 4H).

Example 239. Synthesis of Compound Z469

##STR00519##

[1277] Step 1: (S)-Tetrahydrofuran-3-carboxylic acid (24.68 mg, 0.21 mmol), triethylamine (43.02 mg, 0.43 mmol), and 1-propylphosphonic anhydride (133.6 mg, 0.21 mmol, 50% ethyl acetate solution) were added to a solution of tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 0.14 mmol) in dichloromethane (2 mL), and the reaction mixture was stirred at 20 C. for 3 h. Water was added to the mixture. The obtained mixture was extracted with ethyl acetate (10 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (R)-3-[6-chloro-2-[(S)-tetrahydrofuran-3-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (60.00 mg, yield: 93.9%) as a yellow oil. ES-API: [M+1].sup.+=451.2.

[1278] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (41.21 mg, 0.16 mmol), potassium carbonate (55.08 mg, 0.40 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.58 mg, 13.31 mol) were added to a solution of tert-butyl (R)-3-[6-chloro-2-[(S)-tetrahydrofuran-3-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (60 mg, 0.13 mmol) in dioxane/water (4 mL/1.0 mL), and the system was heated to 100 C. and reacted for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give a product tert-butyl (R)-3-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[(S)-tetrahydrofuran-3-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (58.00 mg, yield: 79.74%) as a yellow oil. ES-API: [M+1].sup.+=547.3.

[1279] Step 3: tert-Butyl (R)-3-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[(S)-tetrahydrofuran-3-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (58 mg, 0.11 mmol) was dissolved in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated, neutralized to be basic with the addition of ammonia water (0.5 mL), and spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give a product [6-(3-methyl-1H-pyrrolidine[2,3-b]pyridin-5-yl)-8-[(R)-morpholin-3-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-[(S)-tetrahydrofuran-3-yl]methanone (Z469, 13.00 mg, yield: 27.44%) as a white solid.

[1280] ES-API: [M+1].sup.+=447.1. .sup.1H NMR (400 MHz, CD.sub.3Cl) 8.55 (s, 1H), 8.05-7.87 (m, 2H), 7.37-7.32 (m, 1H), 7.14-7.09 (m, 1H), 5.32-5.22 (m, 1H), 4.91-4.80 (m, 2H), 4.68-4.57 (m, 2H), 4.42-4.27 (m, 1H), 4.11 (t, J=8.2 Hz, 1H), 4.01-3.53 (m, 9H), 3.41-2.93 (m, 4H), 2.37 (s, 3H), 2.31-2.11 (m, 2H).

Example 240. Synthesis of Compound Z470

##STR00520##

[1281] Step 1:8-Methyl-3,8-diazabicyclo[3.2.1]octane (315 mg, 2.5 mmol), triethylamine (757 mg, 7.5 mmol), and dichloromethane (10 mL) were added to a 50 mL round-bottom flask, p-Nitrophenyl chloroformate (605 mg, 3 mmol) was slowly added at 0 C. and stirred at room temperature for 1 h. Dichloromethane (20 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product 4-nitrophenyl 8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (400 mg, yield: 55%). ES-API: [M+H].sup.+=292.2.

[1282] Step 2: 4-Nitrophenyl 8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (82.5 mg, 0.283 mmol), tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 0.14 mmol), potassium carbonate (117 mg, 0.43 mmol), and dimethylacetamide (2 mL) were added to a 5 mL microwave reactor. The reaction mixture was stirred at 130 C. overnight. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (10 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (3R)-3-(6-chloro-2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, yield: 70%). ES-API: [M+H].sup.+=405.3.

[1283] Step 3: tert-Butyl (3R)-3-(6-chloro-2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.06 mmol), 5-bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (66 mg, 0.24 mmol), potassium carbonate (25 mg, 0.18 mmol), (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (5.80 mg, 0.01 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted under microwave at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (3R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, yield: 54%). ES-API: [M+H].sup.+=621.3.

[1284] Step 4: tert-Butyl (3R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.03 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude produce was purified by prep-HPLC (ammonium bicarbonate method) to give 6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (Z470, 5 mg, yield: 20%). ES-API: [M+H].sup.+=521.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.07 (s, 1H), 8.58 (d, J=1.7 Hz, 1H), 8.07 (d, J=1.8 Hz, 1H), 7.75 (d, J=15.3 Hz, 2H), 7.45 (s, 1H), 4.51 (d, J=16.5 Hz, 1H), 4.35 (d, J=16.4 Hz, 1H), 3.96 (d, J=9.6 Hz, 1H), 3.77 (t, J=10.8 Hz, 2H), 3.60-3.39 (m, 5H), 3.25 (d, J=10.5 Hz, 2H), 3.16-2.80 (m, 8H), 2.18 (s, 3H), 1.88 (s, 2H), 1.70-1.50 (m, 2H).

Example 241. Synthesis of Compound Z471

##STR00521##

[1285] Step 1: tert-Butyl (3R)-3-(6-chloro-2-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.06 mmol), 5-bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (66 mg, 0.24 mmol), potassium carbonate (25 mg, 0.18 mmol), (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (5.80 mg, 0.01 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted under microwave at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (3R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, yield: 54%). ES-API: [M+H].sup.+=601.3.

[1286] Step 2: tert-Butyl (3R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.03 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude produce was purified by prep-HPLC (ammonium bicarbonate method) to give (6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Z471, 5 mg, yield: 20%). ES-API: [M+H].sup.+=501.3.

Example 242. Synthesis of Compound Z472

##STR00522##

[1287] Step 1: 3-Methyl-3,8-diazabicyclo[3.2.1]octane (315 mg, 2.5 mmol), triethylamine (757 mg, 7.5 mmol), and dichloromethane (10 mL) were added to a 50 mL round-bottom flask. p-Nitrophenyl chloroformate (605 mg, 3 mmol) was slowly added at 0 C. and stirred at room temperature for 1 h. Dichloromethane (20 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product 4-nitrophenyl 3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, yield: 55%). ES-API: [M+H].sup.+=292.2.

[1288] Step 2: 4-Nitrophenyl 3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (82.5 mg, 0.283 mmol), tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 0.14 mmol), potassium carbonate (117 mg, 0.43 mmol), and dimethylacetamide (2 mL) were added to a 5 mL microwave reactor. The reaction mixture was stirred at 130 C. overnight. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (10 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (3R)-3-(6-chloro-2-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, yield: 70%). ES-API: [M+H].sup.+=405.3.

[1289] Step 3: tert-Butyl (3R)-3-(6-chloro-2-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.06 mmol), 5-bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (66 mg, 0.24 mmol), potassium carbonate (25 mg, 0.18 mmol), (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (5.80 mg, 0.01 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted under microwave at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (3R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, yield: 54%). ES-API: [M+H].sup.+=621.3.

[1290] Step 4: tert-Butyl (3R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.03 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude produce was purified by prep-HPLC (ammonium bicarbonate method) to give 6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Z472, 5 mg, yield: 30%). ES-API: [M+H].sup.+=521.3.

Example 243. Synthesis of Compound Z473

##STR00523##

[1291] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 70 mg, 198 mol) and 2-hydroxy-2-methylpropanoic acid (25 mg, 238 mol) were dissolved in N,N-dimethylformamide (1 mL), N,N-Diisopropylethyl amine (154 mg, 1.19 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (220 mg, 596 mol) were then added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg) as a brown oil. ES-API: [M+H].sup.+=439.3.

[1292] Step 2: tert-Butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 189 mol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (118 mg, 377 mol) were dissolved in dioxane (1 mL) and water (0.2 mL). Potassium carbonate (78 mg, 566 mol) was then added. In the presence of protective nitrogen, chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (13 mg, 19 mol) was then added and stirred at 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg) as a brown oil. ES-API: [M+H].sup.+=589.3.

[1293] Step 3: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 170 mol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid-ethyl acetate (4 mol/L, 1 mL) was then added and stirred at room temperature for 4 h. Upon completion of the reaction, the reaction mixture was filtered and purified by prep-HPLC (ammonium bicarbonate method) to give (R)-2-hydroxy-2-methyl-1-(8-(morpholin-3-yl)-6-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z473, 10.6 mg) as a white solid. ES-API: [M+H].sup.+=489.3. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.63 (d, J=1.6 Hz, 1H), 8.29 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.47 (s, 1H), 4.58 (s, 1H), 4.23 (d, J=8.4 Hz, 1H), 4.01-3.84 (m, 3H), 3.80-3.66 (m, 2H), 3.52 (t, J=10.8 Hz, 2H), 3.18 (d, J=12 Hz, 1H), 3.14-2.95 (m, 3H), 1.49 (s, 6H).

Example 244. Synthesis of Compound Z475

##STR00524##

[1294] Step 1: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.163 mmol), bis(pinacolato)diboron (53.68 mg, 0.211 mmol), potassium acetate (47.80 mg, 0.488 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10 mg, 0.014 mmol) were dissolved in 1,4-dioxane (2.5 mL) and stirred at 110 C. for 2 h. 5-Bromo-3-fluoro-1H-pyrrolo[2,3-b]pyridine (36.85 mg, 0.171 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (6.27 mg, 0.009 mmol), potassium carbonate (35.53 mg, 0.257 mmol), and water (0.5 mL) were added and stirred at 110 C. for 2 h. The obtained mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to give tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(3-fluoro-1H-pyrrolo[2,3-b]pyridine)-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.051 mmol, yield: 59.17%). ES-API: [M+H].sup.+=592.0.

[1295] Step 2: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(3-fluoro-1H-pyrrolo[2,3-b]pyridin)-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, 0.042 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia water/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(3-fluoro-4H-pyrrolo[2,3-b]pyridine)-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z475, 14.5 mg, 0.029 mmol, yield: 69.81%). ES-API: [M+H].sup.+=492.1.

Example 245. Synthesis of Compound Z476

##STR00525## ##STR00526##

[1296] Step 1: In the presence of protective nitrogen, 5-bromo-1H-pyrrolo[2,3-b]pyridine (2 g, 10.15 mmol) was added to a solution of anhydrous aluminum chloride (6.77 g, 50.77 mmol) suspended in anhydrous dichloromethane (100 mL). The reaction mixture was stirred at 25 C. for 1 h. Acetyl chloride (3.98 g, 50.75 mmol) was then added dropwise, and the mixture was stirred at 25 C. for 5 h. The reaction mixture was cooled in an ice bath to 0 C., and the reaction was carefully quenched by the addition of methanol until the solution became clear. The reaction mixture was concentrated in vacuum. Water was added, and 1 N sodium hydroxide solution was added dropwise to pH 5. The obtained product was extracted into ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum to give compound 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (2.20 g, crude product) as a yellow solid. ES-API: [M+H].sup.+=238.9.

[1297] Step 2: Trifluoroacetic acid (15.74 g, 138.04 mmol, 10.49 mL) and triethylsilane (16.05 g, 138.04 mmol, 21.99 mL) were added to a single-neck flask of compound 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (2.2 g, 9.2 mmol), and the mixture was stirred at 15 C. for 16 h. The reaction was monitored by LCMS for completion. The reaction mixture was concentrated, neutralized with sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-30% ethyl acetate/petroleum ether, petroleum ether/ethyl acetate=1/1, Rf=0.4) to give a product 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine (390 mg, yield: 18.83%) as a white powder. ES-API: [M+H].sup.+=224.9.

[1298] Step 3: Bis(pinacolato)diboron (235.79 mg, 0.93 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (61.25 mg, 0.084 mmol), and potassium acetate (1.27 g, 2.53 mmol) were added to a solution of compound 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine (190 mg, 0.84 mmol) in dioxane (4 mL). In the presence of protective nitrogen, the mixture was heated to 100 C. and stirred. Monitored by LCMS, the reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-30% ethyl acetate/petroleum ether, petroleum ether/ethyl acetate=1/1, Rf=0.4) to give a product 3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (165 mg, yield: 71.82%). ES-API: [M+H].sup.+=191.1.

[1299] Step 4: 2-Hydroxy-2-methylpropanoic acid (177.02 mg, 1.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (325.97 mg, 1.70 mmol), 1-hydroxybenzotriazole (229.76 mg, 1.70 mmol), and triethylamine (258.10 mg, 2.55 mmol) were added to a solution of tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 300 mg, 0.85 mmol) in N,N-dimethylformamide (8 mL). The mixture was stirred at 25 C. for half an hour. The reaction was monitored by LCMS for completion, and the reaction was quenched by the addition of water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate/petroleum ether, petroleum ether/ethyl acetate=1/1, Rf=0.4) to give a product tert-butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (290 mg, yield: 77.71%). ES-API: [M+H-100].sup.+=339.1.

[1300] Step 5: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (44.64 mg, 0.16 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.84 mg, 0.014 mmol), and potassium carbonate (56.59 mg, 0.41 mmol) were added to a solution of compound tert-butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.14 mmol) in dioxane/water (2 mL/0.4 mL). In the presence of protective nitrogen, the mixture was heated and stirred to 100 C. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (R)-3-(6-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, yield: 66.67%). ES-API: [M+H].sup.+=549.3.

[1301] Step 6: Trifluoroacetic acid (1 mL) was added to a solution of compound tert-butyl (R)-3-(6-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.09 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was neutralized and adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a chromatographic column (dichloromethane/methanol=8/1, Rf=0.4) to give (R)-1-(6-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropan-1-one (Z476, 14.5 mg, yield: 35.47%) as a white powder. ES-API: [M+H].sup.+=449.0. .sup.1H NMR (400 MHz, CD.sub.3Cl) 8.81 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 7.74 (s, 1H), 7.11-7.08 (m, 1H), 5.33-5.15 (m, 1H), 4.95-4.62 (m, 1H), 4.24-3.99 (m, 2H), 3.96-3.77 (m, 4H), 3.76-3.61 (m, 1H), 3.56-3.44 (m, 1H), 3.28-3.14 (m, 1H), 3.11-2.86 (m, 3H), 2.85-2.71 (m, 3H), 1.59 (s, 6H), 1.37-1.30 (m, 3H).

Example 246. Synthesis of Compound Z477

##STR00527##

[1302] Step 1: 1-Isopropyl-1H-pyrazole-4-carboxylic acid (32.77 mg, 0.21 mmol), 1-propylphosphonic anhydride (273.5 mg, 0.43 mmol, 50% ethyl acetate solution), and triethylamine (43.02 mg, 0.43 mmol) were added to a solution of tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 0.14 mmol) in dichloromethane (2 mL). The mixture was stirred at 0 C. for half an hour. The reaction was monitored by LCMS for completion, and the reaction was quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-60% ethyl acetate/petroleum ether, petroleum ether/ethyl acetate=1/1, Rf=0.4) to give a product tert-butyl (R)-3-(6-chloro-2-(1-isopropyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, yield: 57.73%). ES-API: [M+H].sup.+=489.2.

[1303] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (25.34 mg, 0.1 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (5.89 mg, 0.008 mmol), and potassium carbonate (33.86 mg, 0.25 mmol) were added to a solution of compound tert-butyl (R)-3-(6-chloro-2-(1-isopropyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.08 mmol) in dioxane/water (2 mL/0.4 mL). In the presence of protective nitrogen, the mixture was heated and stirred to 110 C. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (R)-3-(2-(1-isopropyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 62.72%). ES-API: [M+H].sup.+=585.3.

[1304] Step 3: Trifluoroacetic acid (1 mL) was added to a solution of compound tert-butyl (R)-3-(2-(1-isopropyl-1H-pyrazole-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.05 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was neutralized and adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a chromatographic column (dichloromethane/methanol=8/1, Rf=0.4) to give (R)-(1-isopropyl-1H-pyrazole-4-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl))-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z477, 13.9 mg, yield: 55.91%) as a white powder. ES-API: [M+H].sup.+=485.2. .sup.1H NMR (400 MHz, CD.sub.3Cl) 8.71 (s, 1H), 8.35 (s, 1H), 7.88 (s, 1H), 7.73 (d, J=44.2 Hz, 1H), 7.16 (s, 1H), 7.03 (s, 2H), 5.44 (s, 1H), 5.08 (s, 1H), 4.52- 4.29 (m, 6H), 4.12 (d, J=10.6 Hz, 4H), 3.78-3.51 (m, 2H), 2.93-2.72 (m, 2H), 2.26 (s, 3H), 1.55 (d, J=7.1 Hz, 6H).

Example 247. Synthesis of Compound Z478

##STR00528##

##STR00529##

[1305] Step 1: 3,3-Dimethylmorpholine (345 mg, 3 mmol), triethylamine (607 mg, 6 mmol), and dichloromethane (10 mL) were added to a 50 mL round-bottom flask. p-Nitrophenyl chloroformate (786 mg, 3.9 mmol) was slowly added at 0 C. and stirred at room temperature for 1 h. Dichloromethane (20 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give 4-nitrophenyl 3,3-dimethylmorpholine-4-carboxylate (600 mg, yield: 72%). ES-API: [M+H].sup.+=281.1.

[1306] Step 2: 4-Nitrophenyl 3,3-dimethylmorpholine-4-carboxylate (50 mg, 0.142 mmol), tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 0.14 mmol), potassium carbonate (59 mg, 0.43 mmol), and dimethylacetamide (2 mL) were added to a 5 mL microwave reactor. The reaction mixture was stirred at 130 C. overnight. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (10 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (R)-3-(6-chloro-2-(3,3-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, yield: 57%). ES-API: [M+H].sup.+=494.2.

[1307] Step 3: tert-Butyl (R)-3-(6-chloro-2-(3,3-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.08 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (62 mg, 0.24 mmol), potassium carbonate (33 mg, 0.24 mmol), (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (5.80 mg, 0.01 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted under microwave at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (R)-3-(2-(3,3-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, yield: 63%). ES-API: [M+H].sup.+=590.3.

[1308] Step 4: tert-Butyl (R)-3-(2-(3,3-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.05 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude produce was purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(3,3-dimethylmorpholine)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z479, 10 mg, yield: 40%). ES-API: [M+H].sup.+=490.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.09 (d, J=1.9 Hz, 1H), 7.75 (s, 1H), 7.43 (s, 1H), 7.26 (s, 1H), 4.60 (dd, J=50.9, 15.7 Hz, 2H), 3.95 (d, J=8.2 Hz, 1H), 3.85-3.65 (m, 4H), 3.61-3.42 (m, 3H), 3.31-3.21 (m, 4H), 3.15-3.05 (m, 2H), 2.90-3.00 (m, 4H), 2.31 (s, 3H), 1.23 (d, J=6.1 Hz, 6H).

Example 249. Synthesis of Compound Z480

##STR00530##

[1309] Step 1: (3R)-3-Methyl-1,4-oxazinane (300 mg, 2.966 mmol) and N,N-diisopropylethyl amine (1.472 mL, 8.898 mmol) were dissolved in dichloromethane (10 mL), and the system was cooled in an ice-water bath. 4-Nitrophenyl chloroformate (896.71 mg, 4.449 mmol) was added. The system was reacted at room temperature for 1 h. Upon completion of the reaction, water (30 mL) was added, and the reaction mixture was extracted with dichloromethane (30 mL3). The organic phases were combined, washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give 4-nitrophenyl (3R)-3-methyl-1,4-oxazinane-4-carboxylate (550 mg, 2.066 mmol, yield: 69.65%). ES-API: [M+H].sup.+=267.0.

[1310] Step 2: tert-Butyl (3R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)-1,4-morpholine-4-carboxylate (5a, 50 mg, 0.142 mmol) and 4-nitrophenyl (3R)-3-methyl-1,4-oxazinane-4-carboxylate (75.61 mg, 0.284 mmol) were dissolved in DMA (2 mL). Potassium carbonate (58.87 mg, 0.426 mmol) was added, and the system was reacted at 130 C. for 18 h. Upon completion of the reaction, water (30 mL) was added, and the reaction mixture was extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (3R)-3-(6-chloro-2-{[(3R)-3-methyl-1,4-morpholin-4-yl]formyl}-1,2,3,4-tetrahydroisoquinolin-8-yl)-1,4-morpholine-4-carboxylate (60 mg, 0.125 mmol, yield: 88%). ES-API: [M+H].sup.+=480.2.

[1311] Step 3: tert-Butyl (3R)-3-(6-chloro-2-{[(3R)-3-methyl-1,4-morpholin-4-yl]formyl}-1,2,3,4-tetrahydroisoquinolin-8-yl)-1,4-morpholin-4-carboxylate (60 mg, 0.125 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (96.80 mg, 0.375 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.00 mg, 0.013 mmol) and potassium carbonate (51.82 mg, 0.375 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), and stirred at 120 C. for 2 h in the presence of protective nitrogen. Upon completion of the reaction, water (30 mL) was added, and the reaction mixture was extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/5) to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, 0.043 mmol, yield: 34.74%), ES-API: [M+H].sup.+=576.3.

[1312] Step 4: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, 0.043 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added, and the system was reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-3-methylmorpholino)methanone (Z480, 10 mg, yield: 48.9%). ES-API: [M+H].sup.+=476.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.45 (d, J=2.1 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H), 7.74 (d, J=1.9 Hz, 1H), 7.42 (s, 1H), 7.26 (s, 1H), 4.57 (d, J=16.4 Hz, 1H), 4.46 (d, J=16.4 Hz, 1H), 3.95 (d, J=9.8 Hz, 1H), 3.82-3.67 (m, 4H), 3.59-3.41 (m, 6H), 3.28 (d, J=11.3 Hz, 2H), 3.23-3.17 (m, 2H), 2.95 (d, J=8.1 Hz, 4H), 2.31 (s, 3H), 1.22 (d, J=6.7 Hz, 3H).

Example 250. Synthesis of Compound Z481

##STR00531##

[1313] Step 1: 5-Bromo-3-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.369 mmol) was dissolved in dried tetrahydrofuran (20 mL) and cooled to 78 C. At this temperature, a solution of lithium diisopropylamide in tetrahydrofuran (2 M, 0.821 mL, 1.643 mmol) was slowly added dropwise to the above solution. After the addition was completed, the reaction mixture continued to be stirred at 78 C. for 2 h. Benzenesulfonyl chloride (0.262 mL, 2.053 mmol) was then dissolved in tetrahydrofuran (5 mL) and slowly added dropwise to the reaction mixture. After the dropwise addition was completed, the reaction mixture was warmed to room temperature and continued to be stirred for 1 h. The reaction was quenched by saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (15 mL3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (dichloromethane/petroleum ether: 0%-20%) to give 5-bromo-2-chloro-3-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (400 mg, 1.001 mmol, yield: 73.11%) as a pale yellow solid. ES-API: [M+H].sup.+=399.1, 401.1.

[1314] Step 2: 5-Bromo-2-chloro-3-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (400 mg, 1.001 mmol) was dissolved in tetrahydrofuran (3 mL), and a solution of tetrabutylammonium bromide in tetrahydrofuran (1 M, 2.0 mL, 2.0 mmol) was added to the above solution. After the addition was completed, the reaction mixture was stirred at room temperature for 3 h. Upon completion of the reaction, water (10 mL) was added to the above solution, and the obtained mixture was extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (10 mL5), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (tetrahydrofuran/petroleum ether: 0%-30%) to give 5-bromo-2-chloro-3-methyl-1H-pyrrolo[2,3-b]pyridine (250 mg, 0.652 mmol, yield: 65.12%) as a yellow oily liquid, ES-API: [M+H].sup.+=245.1, 247.1.

[1315] Step 3: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.113 mmol) was dissolved in dioxane (5 mL) and water (1 mL). 5-Bromo-2-chloro-3-methyl-1H-pyrrolo[2,3-b]pyridine (55.54 mg, 0.226 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II) (8.28 mg, 0.011 mmol) and potassium carbonate (31.27 mg, 0.226 mmol) were added to the above solution at room temperature. After the addition was completed, the reaction mixture was stirred at 100 C. for 2 h under nitrogen atmosphere. Upon completion of the reaction, water (10 mL) was added to the above solution, and the obtained mixture was extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (tetrahydrofuran/petroleum ether: 5%-40%) to give tert-butyl (R)-3-(6-(2-chloro-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (8 mg, 0.014 mmol, yield: 12.43%) as a yellow solid. ES-API: [M+H].sup.+=569.1.

[1316] Step 4: tert-Butyl (R)-3-(6-(2-chloro-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (8 mg, 0.014 mmol) was dissolved in anhydrous dichloromethane (1 mL). Trifluoroacetic acid (0.5 mL) was added to the above solution, and the reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and adjusted to neutrality with a solution of ammonia in methanol (7 M). The obtained mixture was concentrated again. The crude product was purified by prep-HPLC 50 (ammonium bicarbonate method) to give (R)-1-(6-(2-chloro-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-tetrahydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropan-1-one (Z481, 2.2 mg, 0.005 mmol, yield: 33.37%) as a white solid. ES-API: [M+H].sup.+=469.1.

Example 251. Synthesis of Compound Z482

##STR00532##

[1317] Step 1: 1-Methylpiperazine (200 mg, 1.997 mmol) was dissolved in dichloromethane (8 mL). Triethylamine (0.833 mL, 5.990 mmol) and p-nitrophenyl chloroformate (442.68 mg, 2.196 mmol) were added to the above solution under an ice bath condition, and the system was reacted at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 1-12%) to give 4-nitrophenyl 4-methylpiperazine-1-carboxylate (450 mg, 1.696 mmol, yield: 84.96%) as a white solid. ES-API: [M+H].sup.+=266.0.

[1318] Step 2: 4-Nitrophenyl 4-methylpiperazine-1-carboxylate (90.21 mg, 0.340 mmol) was dissolved in N,N-dimethylacetamide (3 mL). tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 60 mg, 0.170 mmol) and potassium carbonate (70.50 mg, 0.510 mmol) were then added to the above solution. The system was reacted at 130 C. for 17 h. Upon completion of the reaction, water (30 mL) was added to the above solution, and the obtained mixture was extracted with ethyl acetate (30 mL3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0%-15%) to give tert-butyl (R)-3-(6-chloro-2-(4-methylpiperazin-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.125 mmol, yield: 73.66%) as a pale yellow solid. ES-API: [M+H].sup.+=479.1.

[1319] Step 3: tert-Butyl (R)-3-(6-chloro-2-(4-methylpiperazine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.104 mmol) was dissolved in dioxane (5 mL) and water (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (67.36 mg, 0.261 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.51 mg, 0.010 mmol) and potassium carbonate (52.04 mg, 0.377 mmol) were added to the above solution at room temperature. After the addition was completed, the reaction mixture was stirred at 110 C. for 2 h under nitrogen atmosphere. Upon completion of the reaction, water (10 mL) was added to the above solution, and the obtained mixture was extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by preparative thin layer chromatography (methanol/dichloromethane: 1/10) to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-methylpiperazine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (45 mg, 0.078 mmol, yield: 75.01%) as a yellow solid. ES-API: [M+H].sup.+=575.2.

[1320] Step 4: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-methylpiperazine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.087 mmol) was dissolved in anhydrous dichloromethane (1 mL). Trifluoroacetic acid (0.5 mL) was added to the above solution, and the reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and adjusted to neutrality with a solution of ammonia in methanol (7 M). The obtained mixture was concentrated again, and then purified by a flash silica gel column (methanol/dichloromethane: 0%-6%) to give (R)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-methylpiperazin-1-yl)methanone (Z482, 20 mg, 0.042 mmol, yield: 48.44%) as a pale yellow solid. ES-API: [M+H].sup.+=475.2.

Example 252. Synthesis of Compound Z483

##STR00533##

[1321] Step 1: In the presence of protective nitrogen, a mixture of tert-butyl (R)-3-(6-chloro-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (45 mg, 0.1 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (54 mg, 0.19 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (7 mg, 0.01 mmol) and potassium carbonate (40 mg, 0.29 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 100 C. for 2 h. Upon completion of the reaction, ethyl acetate (10 mL) was added, and the obtained mixture was washed with water (5 mL) and saturated brine (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-10% methanol/dichloromethane) to give tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (45 mg, yield: 80%) as a colorless oil. ES-API: [M+H].sup.+=582.3.

[1322] Step 2: Trifluoroacetic acid (0.5 mL) was added to a solution of compound tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (45 mg, 0.08 mmol) in dichloromethane (1 mL) under an ice bath condition, and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and then neutralized with 7 M amine/methanol solution (2 mL). The mixture was concentrated and purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(morpholine)methanone (Z483, 11 mg, purity: 100%, yield: 30%). ES-API: [M+H].sup.+=482.2.

Example 253. Synthesis of Compound Z484

##STR00534##

[1323] Step 1: tert-Butyl (R)-3-(6-chloro-2-((4-nitrophenoxy)carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.097 mmol) and (2R)-2-methyl-1,4-oxazinane (29.29 mmol, 0.290 mmol) were dissolved in N,N-dimethylacetamide (2 mL). Potassium carbonate (53.36 mg, 0.386 mmol) was added. The mixture was stirred at 135 C. for 6 h. Upon completion of the reaction, water (30 mL) was added, and the reaction mixture was extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (R)-3-(6-chloro-2-((R)-2-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.083 mmol, yield: 86.32%). ES-API: [M+H].sup.+=480.2.

[1324] Step 2: tert-Butyl (R)-3-(6-chloro-2-((R)-2-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.083 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (32.27 mg, 0.125 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (12.00 mg, 0.017 mmol) and potassium carbonate (34.50 mg, 0.250 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), and stirred at 120 C. for 2 h in the presence of protective nitrogen. Upon completion of the reaction, water (30 mL) was added, and the reaction mixture was extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/5) to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-2-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.035 mmol, yield: 41.68%), ES-API: [M+H].sup.+=576.3.

[1325] Step 3: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-2-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.035 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added, and the system was reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-2-methylmorpholino)methanone (Z484, 2.6 mg, yield: 15.7%). ES-API: [M+H].sup.+=476.3.

Example 254. Synthesis of Compound Z485

##STR00535##

[1326] Step 1: 4-Hydroxytetrahydropyran-4-carboxylic acid (17.70 mg, 0.170 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (56.90 mg, 0.150 mmol) were dissolved in N,N-dimethylacetamide (1 mL). tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 44 mg, 0.125 mmol) and N,N-diisopropylethyl amine (64.47 mg, 0.499 mmol) were added under an ice bath condition, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl (R)-3-(6-chloro-2-(4-hydroxytetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.137 mmol, yield: 80.39%). ES-API: [M+H].sup.+=481.1.

[1327] Step 2: tert-Butyl (R)-3-(6-chloro-2-(4-hydroxytetrahydro-2H-pyran-4-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (44 mg, 0.091 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (50.96 mg, 0.183 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.59 mg, 0.009 mmol) and potassium carbonate (31.50 mg, 0.228 mmol) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL). The reaction mixture was stirred at 110 C. for 2 h and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=97/3) to give tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-hydroxytetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, 0.042 mmol, yield: 46.01%). ES-API: [M+H].sup.+=597.2.

[1328] Step 3: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-hydroxytetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, 0.042 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia water/methanol solution (1 mL), the obtained mixture was concentrated again and purified by column chromatography (dichloromethane/methanol=10/1) to give (R)-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-hydroxytetrahydro-2H-pyran-4-yl)methanone (Z485, 10 mg, 0.020 mmol, yield: 48.06%). ES-API: [M+H].sup.+=497.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.06 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.48 (s, 1H), 5.76-5.65 (m, 1H), 5.38-5.22 (m, 1H), 4.88-4.62 (m, 1H), 4.18-3.95 (m, 2H), 3.86-3.51 (m, 7H), 3.30-3.27 (m, 3H) 2.95-2.88 (m, 4H), 2.14-1.87 (m, 2H), 2.14-1.58 (m, 2H).

Example 255. Synthesis of Compound Z486

##STR00536##

[1329] Step 1: 3-(R)-Fluoropyrrolidine hydrochloride (250 mg, 2.000 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (0.975 mL, 7.014 mmol) and p-nitrophenyl chloroformate (735.13 mg, 3.647 mmol) were added under an ice bath condition, and the system was reacted at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=80/20) to give (R)-3-fluoropyrrolidin-1-yl 4-nitrobenzoate (480 mg, 1.888 mmol, yield: 67.30%). ES-API: [M+H].sup.+=254.9.

[1330] Step 2: (R)-3-Fluoropyrrolidin-1-yl 4-nitrobenzoate (36.10 mg, 0.142 mmol) was dissolved in DMA (1 mL). tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 0.142 mmol) and potassium carbonate (58.75 mg, 0.425 mmol) were added, and the system was reacted at 130 C. for 3 h. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl (R)-3-(6-chloro-2-((R)-3-fluoropyrrolidin-1-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.107 mmol, yield: 75.24%). ES-API: [M+H].sup.+=468.1.

[1331] Step 3: tert-Butyl (R)-3-(6-chloro-2-((R)-3-fluoropyrrolidin-1-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.107 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (55.16 mg, 0.214 mmol), potassium carbonate (44.30 mg, 0.321 mmol), and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.03 mg, 0.008 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at 110 C. for 2 h and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to give tert-butyl (R)-3-(2-((R)-3-fluoropyrrolidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.053 mmol, yield: 49.81%). ES-API: [M+H].sup.+=564.1.

[1332] Step 4: tert-Butyl (R)-3-(2-((R)-3-fluoropyrrolidin-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.035 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia water/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give ((R)-3-fluoropyrrolidin-1-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z486, 11 mg, 0.024 mmol, yield: 66.88%). ES-API: [M+H].sup.+=464.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.45 (s, 1H), 7.27 (s, 1H), 5.36-5.25 (m, 1H), 4.59 (d, J=16.4 Hz, 1H), 4.42 (d, J=16.4 Hz, 1H), 4.01-3.96 (m, 1H), 3.82-3.68 (m, 2H), 3.66-3.43 (m, 7H), 3.30-3.27 (m, 2H), 3.02-2.85 (m, 4H), 2.32 (s, 3H), 2.15-1.92 (m, 2H).

Example 256. Synthesis of Compound Z487

##STR00537##

[1333] Step 1: Tetrahydro-2H-pyran-4-carboxylic acid (22.13 mg, 0.170 mmol) was dissolved in N,N-dimethylformamide (0.5 mL). 2-(7-Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (77.59 mg, 0.204 mmol), tert-butyl (R)-3-(7-chloro-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (60 mg, 0.170 mmol) and N,N-diisopropylethyl amine (65.81 mg, 0.510 mmol) were added, and the system was reacted at room temperature for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl (R)-3-(7-chloro-2-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (55 mg, 0.118 mmol, yield: 69.56%). ES-API: [M+H].sup.+=465.1.

[1334] Step 2: tert-Butyl (R)-3-(7-chloro-2-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (50 mg, 0.108 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (59.90 mg, 0.215 mmol), potassium carbonate (44.58 mg, 0.323 mmol), and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.74 mg, 0.011 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at 110 C. for 2 h and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to give tert-butyl (R)-3-(7-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (20 mg, 0.034 mmol, yield: 32.01%). ES-API: [M+H].sup.+=581.0.

[1335] Step 3: tert-Butyl (R)-3-(7-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)morpholine-4-carboxylate (20 mg, 0.034 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (R)-(7-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (Z487, 9 mg, 0.019 mmol, yield: 54.38%). ES-API: [M+H].sup.+=481.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.06 (s, 1H), 8.61 (s, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.80 (d, J=11.2 Hz, 1H), 7.73 (s, 1H), 7.55 (d, J=16.4 Hz, 1H), 4.96-4.61 (m, 2H), 4.03 (d, J=9.6 Hz, 1H), 3.95-3.66 (m, 6H), 3.57-3.46 (m, 4H), 3.29-3.16 (m, 1H), 3.12-2.84 (m, 5H), 1.79-1.45 (m, 4H).

Example 257. Synthesis of Compound Z488

##STR00538##

[1336] Step 1: 3-(S)-Fluoropyrrolidine hydrochloride (250 mg, 2.000 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (0.695 mL, 5.000 mmol) and p-nitrophenyl chloroformate (524.06 mg, 2.600 mmol) were added under an ice bath condition, and the system was reacted at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate=80/20) to give (S)-3-fluoropyrrolidin-1-yl 4-nitrobenzoate (370 mg, 1.455 mmol, yield: 72.77%). ES-API: [M+H].sup.+=255.0.

[1337] Step 2: (S)-3-Fluoropyrrolidin-1-yl 4-nitrobenzoate (54.03 mg, 0.213 mmol) was dissolved in DMA (1 mL). tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 0.142 mmol) and potassium carbonate (58.75 mg, 0.425 mmol) were added, and the system was reacted at 130 C. for 3 h. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl (R)-3-(6-chloro-2-((S)-3-fluoropyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.107 mmol, yield: 75.40%). ES-API: [M+H].sup.+=468.1.

[1338] Step 3: tert-Butyl (R)-3-(6-chloro-2-((S)-3-fluoropyrrolidin-1-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (45 mg, 0.096 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (49.64 mg, 0.192 mmol), potassium carbonate (34.70 mg, 0.251 mmol), and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.03 mg, 0.008 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at 110 C. for 2 h and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to give tert-butyl (R)-3-(2-((S)-3-fluoropyrrolidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.035 mmol, yield: 36.90%). ES-API: [M+H].sup.+=564.3.

[1339] Step 4: tert-Butyl (R)-3-(2-((S)-3-fluoropyrrolidin-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.035 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give ((S)-3-fluoropyrrolidin-1-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z488, 9.8 mg, 0.021 mmol, yield: 59.58%). ES-API: [M+H].sup.+=464.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.46 (d, J=1.6 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 7.77 (s, 1H), 7.45 (s, 1H), 7.27 (s, 1H), 5.36-5.27 (m, 1H), 4.58-4.41 (m, 1H), 3.82-3.73 (m, 2H), 3.71-3.44 (m, 6H), 3.23-3.16 (m, 2H), 3.10-2.82 (m, 6H), 2.55 (s, 1H), 2.32 (s, 3H), 2.18-1.84 (m, 2H)

Example 258. Synthesis of Compound Z489

##STR00539##

[1340] Step 1: tert-Butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.06 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (68 mg, 0.24 mmol), potassium carbonate (25 mg, 0.18 mmol), (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (4.40 mg, 0.006 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted under microwave at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, yield: 37%). ES-API: [M+H].sup.+=608.3.

[1341] Step 2: tert-Butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.11 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude produce was purified by prep-HPLC (ammonium bicarbonate method) to give (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z489, 7 mg, yield: 42%). ES-API: [M+H].sup.+=508.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.00 (s, 1H), 8.52 (s, 1H), 8.02 (s, 1H), 7.68 (d, J=15.5 Hz, 2H), 7.41 (s, 1H), 4.58 (dd, J=57.2, 16.3 Hz, 2H), 3.93-3.44 (m, 12H), 3.23-3.16 (m, 2H), 2.88 (s, 4H), 1.80-1.63 (m, 4H).

Example 259. Synthesis of Compounds Z491 and Z490

##STR00540##

[1342] Step 1: (6-(3-Methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-(trifluoromethyl)morpholino)methanone (20 mg) was chirally resolved by SFC (chromatographic column: ChiralpakIC 250 mm4.6 mm5 m, mobile phase: ACN-IPA-DEA=80-20-02, flow rate: 1 mL/MIN, column temperature: 30 C., 30 min) to give two isomeric compounds. One of the isomeric compounds was arbitrarily assigned as (6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-2-(trifluoromethyl)morpholino)methanone (Z491, 4.5 mg, yield: 22.5%, retention time: 9.411 min, ee value: 96.3%). ES-API: [M+H].sup.+=514.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.38 (s, 1H), 8.60 (d, J=2.1 Hz, 1H), 8.28 (d, J=2.2 Hz, 1H), 7.86 (d, J=1.7 Hz, 1H), 7.62 (d, J=1.7 Hz, 1H), 7.28 (s, 1H), 4.70 (s, 1H), 4.62 (d, J=16.5 Hz, 1H), 4.50 (d, J=16.5 Hz, 1H), 4.30 (s, 1H), 3.97 (d, J=11.4 Hz, 1H), 3.68 (t, J=13.1 Hz, 2H), 3.54-3.45 (m, 4H), 3.18-3.12 (m, 1H), 2.98 (d, J=8.9 Hz, 2H), 2.92 (d, J=13.0 Hz, 3H), 2.42 (s, 1H), 2.32 (d, J=1.1 Hz, 3H), 2.18-2.07 (m, 3H).

[1343] The other isomeric compound was arbitrarily assigned as (6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((S)-pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-2-(trifluoromethyl)morpholino)methanone (Z490, 7.5 mg, yield: 37.5%, retention time: 10.206 min, ee value: 96.84%). ES-API: [M+H].sup.+=514.2.

Example 260. Synthesis of Compound Z492

##STR00541##

[1344] Step 1: 3-Oxa-8-azabicyclo[3.2.1]octane (340 mg, 3 mmol), triethylamine (607 mg, 6 mmol), and dichloromethane (10 mL) were added to a 50 mL round-bottom flask. p-Nitrophenyl chloroformate (786 mg, 3.9 mmol) was slowly added at 0 C. and stirred at room temperature for 1 h. Dichloromethane (20 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give 4-nitrophenyl 3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (600 mg, yield: 72%). ES-API: [M+H].sup.+=279.1.

[1345] Step 2: 4-Nitrophenyl 3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.283 mmol), tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 100 mg, 0.28 mmol), potassium carbonate (117 mg, 0.86 mmol), and dimethylacetamide (2 mL) were added to a 5 mL microwave reactor. The reaction mixture was stirred at 130 C. overnight. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (10 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, yield: 72%). ES-API: [M+H].sup.+=492.2.

[1346] Step 3: tert-Butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.1 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (68 mg, 0.24 mmol), potassium carbonate (42 mg, 0.3 mmol), (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (7.30 mg, 0.01 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted under microwave at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, yield: 50%). ES-API: [M+H].sup.+=588.3.

[1347] Step 4: tert-Butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.05 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude produce was purified by prep-HPLC (ammonium bicarbonate method) to give (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z492, 15 mg, yield: 60%). ES-API: [M+H].sup.+=488.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.35 (s, 1H), 8.46 (d, J=1.9 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H), 7.76 (s, 1H), 7.45 (s, 1H), 7.27 (s, 1H), 4.72 (d, J=16.4 Hz, 1H), 4.57 (d, J=16.3 Hz, 1H), 4.08-3.50 (m, 12H), 3.31-3.25 (m, 2H), 3.05-2.85 (m, 4H), 2.31 (s, 3H), 1.87-1.70 (m, 4H).

Example 261. Synthesis of Compound Z493

##STR00542##

[1348] Step 1: Sodium hydroxide (154.45 mg, 3.86 mmol) was added to a solution of ethyl 3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylate (0.25 g, 1.29 mmol) in methanol (6 mL) and water (1 mL), and the mixture was stirred at 20 C. for 16 h. The reaction mixture was concentrated to remove methanol, then diluted with water, acidified with 1 N dilute hydrochloric acid to pH 3, extracted with ethyl acetate (10 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (0.18 g, crude product) as a white solid which was directly used in the next step without purification. ES-API: [M+1].sup.+=167.1.

[1349] Step 2: 5-Cyclopropyl-2-methyl-pyrazole-3-carboxylic acid (49.33 mg, 0.3 mmol), triethylamine (63.1 mg, 0.63 mmol), and 1-propylphosphonic anhydride (197.2 mg, 0.31 mmol, 50% ethyl acetate solution) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (0.07 g, 0.21 mmol) in dichloromethane (4 mL), and the reaction mixture was stirred at 20 C. for 3 h. Water was added to the mixture. The obtained mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S)-2-[6-chloro-2-(3-cyclopropyl-1-methyl-1H-pyrazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.00 mg, yield: 68.9%) as a yellow oil. ES-API: [M+1].sup.+=485.2.

[1350] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (44.7 mg, 0.17 mmol), potassium carbonate (59.75 mg, 0.43 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.39 mg, 14.43 mol) were added to a solution of tert-butyl (S)-2-[6-chloro-2-(3-cyclopropyl-1-methyl-1H-pyrazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70 mg, 0.14 mmol) in dioxane/water (4 mL/0.8 mL), and the system was heated to 100 C. and reacted for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[2-(3-cyclopropyl-1-methyl-1H-pyrazole-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60.00 mg, yield: 71.59%) as a yellow oil. ES-API: [M+1].sup.+=581.3.

[1351] Step 4: tert-Butyl (S)-2-[2-(3-cyclopropyl-1-methyl-1H-pyrazole-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (60 mg, 0.10 mmol) was dissolved in dichloromethane (1.0 mL). Trifluoroacetic acid (1.0 mL) was added. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a chromatographic column (dichloromethane/methanol=10/1) to give a product (S)-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[pyrrolidin-5-yl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone (Z493, 13.60 mg, yield: 27.39%). ES-API: [M+1].sup.+=481.1. .sup.1H NMR (400 MHz, CD.sub.3Cl) 10.09 (s, 1H), 8.51 (s, 1H), 8.01 (s, 1H), 7.90-7.68 (m, 1H), 7.27 (s, 1H) 7.12 (s, 1H), 6.07 (s, 1H), 5.11-4.84 (m, 2H), 4.53-4.04 (m, 1H), 3.97-3.68 (m, 5H), 3.49-2.90 (m, 5H), 2.35 (s, 3H), 2.11-1.84 (m, 5H), 0.99-0.88 (m, 2H), 0.79-0.69 (m, 2H).

Example 262. Synthesis of Compound Z494

##STR00543##

[1352] Step 1: 1-Cyclopropyl-1H-pyrazole-3-carboxylic acid (63.23 mg, 0.42 mmol), 1-propylphosphonic anhydride (394.3 mg, 0.62 mmol, 50% ethyl acetate solution), and triethylamine (63.08 mg, 0.62 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in dichloromethane (2 mL). The mixture was stirred at 25 C. for two hours. Monitored by LCMS, the reaction was quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/1, Rf=0.3) to give a product tert-butyl (S)-2-(6-chloro-2-(1-cyclopropyl-1H-pyrazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (64 mg, yield: 65.39%). ES-API: [M+H-100].sup.+=371.1.

[1353] Step 2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (42.09 mg, 0.16 mmol), (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.78 mg, 0.014 mmol), and potassium carbonate (56.26 mg, 0.41 mmol) were added to a solution of compound tert-butyl (S)-2-(6-chloro-2-(1-cyclopropyl-1H-pyrazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (64 mg, 0.14 mmol) in dioxane/water (2 mL/0.4 mL). In the presence of protective nitrogen, the mixture was heated to 110 C. and stirred. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (S)-2-(2-(1-cyclopropyl-1H-pyrazole-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (42 mg, yield: 54.54%). ES-API: [M+H].sup.+=567.3.

[1354] Step 3: Trifluoroacetic acid (1 mL) was added to compound tert-butyl (S)-2-(2-(1-cyclopropyl-1H-pyrazole-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (54 mg, 0.074 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was neutralized and adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a chromatographic column (dichloromethane/methanol=8/1) to give a product (S)-(1-cyclopropyl-1H-pyrazol-3-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z494, 9.2 mg, yield: 26.60%) as a white solid. ES-API: [M+H].sup.+=467.1. .sup.1H NMR (400 MHz, CD.sub.3Cl) 8.82-8.36 (m, 1H), 7.54 (s, 1H), 6.99-6.79 (m, 2H), 6.57-6.41 (m, 1H), 6.20-5.96 (m, 2H), 5.85-5.63 (m, 1H), 4.55-3.56 (m, 5H), 3.22-3.07 (m, 1H), 2.76-2.53 (m, 2H), 2.31-1.87 (m, 3H), 1.30 (s, 3H), 1.21-0.93 (m, 4H), 0.23-0.03 (m, 4H).

Example 263. Synthesis of Compound Z495

##STR00544##

[1355] Step 1: N,N-diisopropylethyl amine (187 mg, 1.45 mmol) and 4-morpholinecarbonyl chloride (86 mg, 0.58 mmol) were added to a solution of tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 170 mg, 0.48 mmol) in dichloromethane (2 mL) successively under an ice bath condition, and stirred for 15 min. Upon completion of the reaction, dichloromethane (10 mL) was added, and the obtained mixture was washed with water (5 mL) 3 times. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-70% tetrahydrofuran/petroleum ether) to give tert-butyl (R)-3-(6-chloro-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (200 mg, yield: 89%). ES-API[M+H.sup.+]=466.1.

[1356] Step 2: In the presence of protective nitrogen, a mixture of tert-butyl (R)-3-(6-chloro-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.13 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (43 mg, 0.17 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (9 mg, 0.01 mmol) and potassium carbonate (53 mg, 0.39 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 120 C. for 2 h. Upon completion of the reaction, ethyl acetate (10 mL) was added, and the obtained mixture was washed with water (5 mL) and saturated brine (5 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-10% methanol/dichloromethane) to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, yield: 83%) as a colorless oil. ES-API: [M+H].sup.+=562.3.

[1357] Step 3: Trifluoroacetic acid (0.5 mL) was added to a solution of compound tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.11 mmol) in dichloromethane (1 mL) under an ice bath condition, and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and then neutralized with 7 M amine/methanol solution. The mixture was concentrated and purified by a flash silica gel column (7 M amine/methanol/dichloromethane 0-10%) to give (R)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(morpholine)methanone (Z495, 20.34 mg, purity: 100%, yield: 41%). ES-API: [M+H].sup.+=462.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.35 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.76 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 4.62-4.55 (m, 1H), 4.49-4.42 (m, 1H), 4.03-3.93 (m, 1H), 3.79 (t, J=8.8 Hz, 2H), 3.68-3.57 (m, 4H), 3.58-3.51 (m, 1H), 3.50-3.40 (m, 2H), 3.31-3.29 (m, 1H), 3.29-3.16 (m, 4H), 3.04-2.88 (m, 4H), 2.31 (s, 3H).

Example 264. Synthesis of Compound Z411

##STR00545##

[1358] Step 1: 1-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (7 g, 29.28 mmol) was dissolved in trifluoroacetic acid (50 g, 439.2 mmol). Triethylsilane (51 g, 439.2 mmol) was added, and the system was reacted at room temperature for 16 h. Upon completion of the reaction, the reaction mixture was spun to dryness, neutralized with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (100 mL3), and purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give a product 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine (6.6 g, crude product). ES-API: [M+H].sup.+=225.0, 227.0.

[1359] Step 2: 5-Bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine (6.6 g, 29.32 mmol) was dissolved in acetonitrile (80 mL). N-Chlorosuccinimide (4.7 g, 35.19 mmol) was added. The system was heated to 40 C. and reacted for 24 h. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, filtered, and spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give a product 5-bromo-3-ethyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one (1.1 g, yield: 15%). ES-API: [M+1].sup.+=241.0, 243.0.

[1360] Step 3: 5-Bromo-3-ethyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one (1.1 g, 4.56 mmol) was dissolved in phosphorus oxychloride (20 mL), and the system was heated to 100 C. and reacted for 16 h. Upon completion of the reaction, the reaction mixture was spun to dryness. The reaction was quenched by the addition of ice water. The obtained mixture was neutralized with saturated aqueous sodium carbonate solution, extracted with dichloromethane (30 mL3), dried over anhydrous sodium sulfate, filtered, and spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give 5-bromo-2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (710 mg, yield: 60%). ES-API: [M+1].sup.+=258.9, 260.9.

[1361] Step 4: tert-Butyl (S)-2-[6-chloro-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70 mg, 0.17 mmol) was dissolved in dioxane (1 mL). Bis(pinacolato)diboron (87 mg, 0.34 mmol), potassium acetate (50 mg, 0.51 mmol), and chloro (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenylyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (13 mg, 0.017 mmol) were added, and the system was heated to 100 C. and reacted for 2 h. Upon completion of the reaction, the reaction mixture was extracted with dichloromethane (10 mL) and water (10 mL), dried over anhydrous sodium sulfate, filtered, and spun to dryness to give a crude product. The crude product was purified by a chromatographic column (petroleum ether/ethyl acetate=1/1) to give a product tert-butyl (S)-2-[2-(2-methoxyacetyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70 mg, yield: 82%). ES-API: [M+1-100].sup.+=401.1.

[1362] Step 5: tert-Butyl (S)-2-[2-(2-methoxyacetyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (35 mg, 0.07 mmol) was dissolved in dioxane (1 mL). 5-Bromo-2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (18 mg, 0.07 mmol), potassium carbonate (29 mg, 0.21 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (5 mg, 0.007 mmol), and water (0.2 mL) were added, and the system was heated to 100 C. and reacted for 3 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a chromatographic column (dichloromethane/methanol=10/1) to give a product tert-butyl (S)-2-[6-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (20 mg, yield: 52%). ES-API: [M+1].sup.+=553.1.

[1363] Step 6: tert-Butyl (S)-2-[6-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methoxyacetyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (40 mg, 0.072 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added. The system was reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness, extracted with dichloromethane and saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, filtered, and spun to dryness to give a crude product. The crude product was purified by a chromatographic column (dichloromethane/methanol=8/1) to give a product (S)-1-[6-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-2-methoxyethan-1-one (Z411, 7.5 mg, yield: 23%). ES-API: [M+1].sup.+=453.0. .sup.1H NMR (400 MHz, CD.sub.3Cl) 8.55 (s, 1H), 7.89 (s, 1H), 7.79 (d, 1H), 7.12 (d, 1H), 5.10-4.94 (m, 1H), 4.72-4.65 (dd, 2H), 4.37 (t, J=12.5 Hz, 1H), 4.18 (s, 2H), 3.61 (d, 2H), 3.44 (s, 3H), 3.25 (d, J=8.2 Hz, 1H), 2.88 (d, 2H), 2.72 (t, J=8.5 Hz, 2H), 2.39-2.29 (m, 1H), 2.04 (d, 3H), 1.27 (s, 3H), 1.24 (s, 1H), 0.90-0.78 (m, 1H).

Example 265. Synthesis of Compound Z496

##STR00546##

[1364] Step 1: 2-Hydroxy-2-methylpropanoic acid (139.07 mg, 1.34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (341.45 mg, 1.78 mmol), 1-hydroxybenzotriazole (240.67 mg, 1.78 mmol), and triethylamine (270.36 mg, 2.67 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (300 mg, 0.9 mmol) in N,N-dimethylformamide (3 mL). The mixture was stirred at 25 C. for two hours. The reaction was monitored by LCMS for completion, and the reaction was quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/1, Rf=0.3) to give a product tert-butyl (S)-2-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (180 mg, yield: 47.49%). ES-API: [M+H-100].sup.+=323.1.

[1365] Step 2: 4,4,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (144.10 mg, 0.57 mmol), chloro (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenylyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (22.30 mg, 28.37 mol), and potassium acetate (83.42 mg, 0.85 mmol) were added to a solution of compound tert-butyl (S)-2-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (120 mg, 0.28 mmol) in dioxane (0.5 mL). The mixture was heated and stirred to 100 C. In the presence of protective nitrogen, the system was reacted for 2 h. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/1, Rf=0.3) to give a product tert-butyl (S)-2-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (93 mg, yield: 63.71%). ES-API: [M+H-100].sup.+=415.3.

[1366] Step 3: 5-Bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (27.00 mg, 0.12 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (7.05 mg, 0.0097 mmol), and potassium carbonate (40.24 mg, 0.30 mmol) were added to a solution of compound tert-butyl (S)-2-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.097 mmol) in dioxane/water (2 mL/0.4 mL). The mixture was heated and stirred to 100 C. In the presence of protective nitrogen, the system was reacted for 2 h. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-5% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.4) to give a product tert-butyl (S)-2-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (43 mg, yield: 82.07%). ES-API: [M+H].sup.+=539.2.

[1367] Step 4: Trifluoroacetic acid (1 mL) was added to a solution of compound tert-butyl (S)-2-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (60 mg, 0.11 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was neutralized and adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a chromatographic column (dichloromethane/methanol=8/1) to give a product (S)-1-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropan-1-one (Z496, 14.1 mg, yield: 28.86%) as a white solid. ES-API: [M+H].sup.+=439.0. .sup.1H NMR (400 MHz, CD.sub.3Cl) 8.56-8.38 (m, 1H), 8.04 (s, 1H), 7.78-7.67 (m, 1H), 7.31 (s, 1H), 7.26-7.24 (m, 1H), 5.17-4.67 (m, 2H), 4.45-4.30 (m, 1H), 4.06-3.72 (m, 2H), 3.39-2.79 (m, 4H), 2.35-2.25 (m, 3H), 2.08-1.92 (m, 3H), 1.60-1.55 (m, 6H).

Example 266. Synthesis of Compound Z416

##STR00547##

[1368] Step 1: 2-Hydroxy-2-methylpropanoic acid (139.07 mg, 1.34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (341.45 mg, 1.78 mmol), 1-hydroxybenzotriazole (240.67 mg, 1.78 mmol), and triethylamine (270.36 mg, 2.67 mmol) were added to a solution of tert-butyl (S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (300 mg, 0.9 mmol) in N,N-dimethylformamide (3 mL). The mixture was stirred at 25 C. for two hours. The reaction was monitored by LCMS for completion, and the reaction was quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/1, Rf=0.3) to give a product tert-butyl (S)-2-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (180 mg, yield: 47.49%). ES-API: [M+H-100].sup.+=323.1.

[1369] Step 2: 4,4,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (144.10 mg, 0.57 mmol), chloro (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenylyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (22.30 mg, 28.37 mol), and potassium acetate (83.42 mg, 0.85 mmol) were added to a solution of compound tert-butyl (S)-2-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (120 mg, 0.28 mmol) in 50 dioxane (0.5 mL). In the presence of protective nitrogen, the mixture was heated and stirred to 100 C. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate/petroleum ether, ethyl acetate/petroleum ether=1/1, Rf=0.3) to give a product tert-butyl (S)-2-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (93 mg, yield: 63.71%). ES-API: [M+H-100].sup.+=415.3.

[1370] Step 3: 5-Bromo-3-isopropyl-1H-pyrrolo[2,3-b]pyridine (27.89 mg, 0.12 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.99 mg, 0.01 mmol), and potassium carbonate (40.24 mg, 0.30 mmol) were added to a solution of compound tert-butyl (S)-2-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (50 mg, 0.097 mmol) in dioxane/water (2 mL/0.4 mL). The mixture was heated and stirred to 100 C. In the presence of protective nitrogen, the system was reacted for 2 h. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-5% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.4) to give a product tert-butyl (S)-2-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (40 mg, yield: 75.28%). ES-API: [M+H]+=547.2.

[1371] Step 4: Trifluoroacetic acid (1 mL) was added to a solution of compound tert-butyl (S)-2-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (55 mg, 0.1 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was neutralized and adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a chromatographic column (dichloromethane/methanol=8/1, Rf=0.4) to give a product (S)-2-hydroxy-1-(6-(3-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(pyrrolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-methylpropan-1-one (Z416, 15.5 mg, yield: 34.50%) as a white solid. ES-API: [M+H].sup.+=447.1. .sup.1H NMR (400 MHz, CD.sub.3Cl) 8.48-8.26 (m, 1H), 7.97 (s, 1H), 7.70 (s, 1H), 7.23-7.17 (m, 1H), 7.07-7.05 (m, 1H), 4.81 (d, J=16.6 Hz, 1H), 4.56-4.37 (m, 1H), 4.11-3.83 (m, 1H), 3.46-3.29 (m, 1H), 3.24-3.11 (m, 2H), 3.06-2.71 (m, 2H), 2.37-2.28 (m, 1H), 2.21-1.92 (m, 5H), 1.62-1.56 (m, 6H), 1.37-1.32 (m, 6H).

Example 267. Synthesis of Compound Z497

##STR00548##

[1372] Step 1: Triethylamine (198.22 mg, 1.96 mmol) and (4-nitrophenyl)carbonyl chloride (197.42 mg, 0.98 mmol) were added to a solution of 2-(trifluoromethyl)morpholine hydrochloride (0.1 g, 0.65 mmol) in anhydrous dichloromethane (5 mL) at 0 C. In the presence of protective nitrogen, the mixture was warmed to 20 C. and stirred for 3 h. The reaction was monitored by LCMS for completion. The reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:90) to give 4-nitrophenyl2-(trifluoromethyl)morpholine-4-carboxylic acid (0.18 g, yield: 86.62%) as a yellow oil. ES-API: [M+1].sup.+=321.0.

[1373] Step 2: 4-Nitrophenyl 2-(trifluoromethyl)morpholine-4-carboxylic acid (99.81 mg, 0.31 mmol) and potassium carbonate (86.16 mg, 0.62 mmol) were added to a solution of tert-butyl (2S)-2-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidine-1-carboxylate (70 mg, 0.21 mmol) in N,N-dimethylacetamide (1 mL). The mixture was warmed to 150 C. and stirred for 3 h. The reaction was monitored by LCMS for completion. The reaction mixture was diluted with water and extracted with ethyl acetate (30 ml1). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give tert-butyl (2S)-2-[6-chloro-2-[2-(trifluoromethyl)morpholine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.00 mg, yield: 65.03%) as a yellow oil. ES-API: [M+1-100].sup.+=418.1.

[1374] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (41.86 mg, 0.16 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.73 mg, 13.51 mol) and potassium carbonate (55.95 mg, 0.41 mmol) were added to a solution of tert-butyl (2S)-2-[6-chloro-2-[2-(trifluoromethyl)morpholine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.00 mg, 0.14 mmol) in dioxane/water (4 mL/0.8 mL). The system was heated to 100 C. and reacted for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give a product tert-butyl (2S)-2-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[2-(trifluoromethyl)morpholine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70.00 mg, yield: 84.41%) as a yellow oil. ES-API: [M+1].sup.+=614.3.

[1375] Step 4: tert-Butyl (2S)-2-[6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[2-(trifluoromethyl)morpholine-4-carbonyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]pyrrolidine-1-carboxylate (70 mg, 0.11 mmol) was dissolved in dichloromethane (1.0 mL). Trifluoroacetic acid (1.0 mL) was added. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the mixture was quenched with sodium bicarbonate and extracted with dichloromethane (20 mL). The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give a product [6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-[(S)-pyrrolidin-2-yl]-3,4-dihydro-isoquinolin-2(1H)-yl]-[2-(trifluoromethyl)morpholin-4-yl]methanone (Z497, 22.10 mg, yield: 37.73%) as a white solid. ES-API: [M+1].sup.+=514.1. .sup.1H NMR (400 MHz, CD.sub.3Cl) 9.73 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.72 (d, J=1.2 Hz, 1H), 7.26 (s, 1H), 7.10 (s, 1H), 4.69 (d, J=16.4 Hz, 1H), 4.57-4.50 (m, 1H), 4.42-4.32 (m, 1H), 4.04-3.97 (m, 2H), 3.84-3.65 (m, 2H), 3.58-3.49 (m, 3H), 3.36-3.28 (m, 1H), 3.23-2.96 (m, 6H), 2.34 (s, 3H), 2.32-2.22 (m, 1H), 2.06-1.88 (m, 2H), 1.81-1.66 (m, 1H).

Example 268. Synthesis of Compound Z498

##STR00549##

[1376] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 60 mg, 170 mol) was dissolved in anhydrous methanol (2 mL). 1-Methyl-4-piperidone (100 mg, 884 mol, 103 L), sodium cyanoborohydride (21.4 mg, 340 mol), acetic acid (10.2 mg, 170 mol, 9.73 L) and tetraisopropyl titanate (72.5 mg, 255 mol, 75.3 L) were added, and the system was reacted at room temperature for 2 h. Upon completion of the reaction, methanol was removed by rotary evaporation. The obtained mixture was dissolved in ethyl acetate (1.00 mL) and filtered. Water (0.5 mL) was added to the filtrate, and the obtained mixture was extracted with ethyl acetate (2.00 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-chloro-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (76 mg) as a yellow oil. ES-API: [M+H].sup.+=450.3.

[1377] Step 2: tert-Butyl (R)-3-(6-chloro-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (76 mg, 169 mol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (52.3 mg, 203 mol) was added, followed by water (0.2 mL) and potassium carbonate (46.7 mg, 33 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (12 mg, 17 mol) was finally added, and the system was heated to 120 C. and stirred for 12 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (92.0 mg) as a yellow oil. ES-API: [M+H].sup.+=546.4.

[1378] Step 3: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (92 mg, 169 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness and purified by prep-HPLC (ammonium bicarbonate) to give (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine (Z498, 6.55 mg) as a white solid. ES-API: [M+H].sup.+=446.3. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.43 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.40 (d, J=1.2 Hz, 1H), 7.18 (d, J=0.8 Hz, 1H), 4.11-4.01 (m, 2H), 3.93-3.79 (m, 3H), 3.74-3.59 (m, 2H), 3.51-3.40 (m, 3H), 3.19-3.08 (m, 1H), 3.07-2.95 (m, 5H), 2.94-2.85 (m, 2H), 2.37 (d, J=0.8 Hz, 3H), 2.33 (s, 3H), 2.23-2.11 (m, 2H), 1.83-1.69 (m, 2H).

Example 269. Synthesis of Compound Z499

##STR00550##

[1379] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 55 mg, 155.87 mol) was dissolved in anhydrous tetrahydrofuran (2 mL). N,N-diisopropylethyl amine (40.3 mg, 312 mol, 54.3 L) and cyclopropylsulfonyl chloride (35.1 mg, 249 mol) were added, and the system was reacted at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with ethyl acetate (1 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-chloro-2-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (71 mg) as a brown solid. ES-API: [M+H].sup.+=457.2.

[1380] Step 2: tert-Butyl (R)-3-(6-chloro-2-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (71 mg, 155 mol) was dissolved in dioxane (1.00 mL). 3-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (43.3 mg, 155 mol) was added, followed by water (0.2 mL) and potassium carbonate (43.0 mg, 311 L). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (11 mg, 16 mol) was finally added, and the system was heated to 100 C. and stirred for 3 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg) as a yellow oil. ES-API: [M+H].sup.+=573.2.

[1381] Step 3: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 52.4 mol) was dissolved in ethyl acetate (1.00 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness and purified by prep-HPLC (ammonium bicarbonate) to give (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine (Z499, 5.85 mg, yield: 24%) as a white solid. ES-API: [M+H].sup.+=473.0. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.59 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.50 (d, J=1.2 Hz, 1H), 7.49 (s, 1H), 4.82-4.74 (m, 1H), 4.65-4.55 (m, 1H), 4.09 (dd, J=10.0, 2.8 Hz, 1H), 3.95-3.84 (m, 2H), 3.76-3.68 (m, 1H), 3.68-3.61 (m, 2H), 3.55-3.45 (m, 1H), 3.19-3.09 (m, 3H), 3.08-3.00 (m, 1H), 2.70-2.58 (m, 1H), 1.21-1.12 (m, 2H), 1.12-1.02 (m, 2H).

Example 270. Synthesis of Compound Z500

##STR00551##

[1382] Step 1: (R)-3-Methyl-morpholine (100 mg, 989 mol) was dissolved in anhydrous dichloromethane (0.5 mL). N,N-Diisopropylethyl amine (383 mg, 2.97 mmol, 517 L) was added, and triphosgene (0.290 g, 977 mol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to give (R)-3-methylmorpholine-4-carbonyl chloride (160 mg) as a crude product which was directly used in the next step.

[1383] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 60 mg, 170 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (89 L, 510 mol) and (R)-3-methylmorpholine-4-carbonyl chloride (28 mg, 170 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-chloro-2-((R)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (81 mg) as a yellow oil. ES-API: [M+H].sup.+=480.3.

[1384] Step 3: tert-Butyl (R)-3-(6-chloro-2-((R)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (81 mg, 169 mol) was dissolved in dioxane (1 mL). 3-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (56 mg, 202 mol) was added, followed by water (0.2 mL) and potassium carbonate (47 mg, 337 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (12 mg, 17 mol) was finally added, and the system was heated to 100 C. and stirred for 3 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg) as a yellow oil. ES-API: [M+H].sup.+=596.3.

[1385] Step 4: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 168 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), neutralized with 7 M amine/methanol solution (2 mL), spun to dryness, and purified by prep-HPLC (formic acid) to give (6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-3-methylmorpholine)methanone (Z500, 2.37 mg, yield: 2.6%, formate) as a white solid. ES-API: [M+H].sup.+=496.3. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.58 (d, J=1.6 Hz, 1H), 8.45 (s, 1H), 8.24 (d, J=1.6 Hz, 1H), 7.76 (s, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 4.77-4.70 (m, 1H), 4.55-4.47 (m, 1H), 4.45-4.37 (m, 1H), 4.08-3.99 (m, 2H), 3.93-3.79 (m, 3H), 3.79-3.49 (m, 7H), 3.48-3.35 (m, 2H), 3.26-3.20 (m, 1H), 3.12-3.01 (m, 2H), 1.34 (d, J=6.4 Hz, 3H).

Example 271. Synthesis of Compound Z501

##STR00552##

[1386] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 60 mg, 170 mol) was dissolved in dichloromethane (2 mL). Triethylamine (52 mg, 510 mol) was then added, methanesulfonyl chloride (29 mg, 255 mol) was then added at 0 C., and the reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1.00 mL) and extracted with ethyl acetate (1.00 mL) 3 times. The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-chloro-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg) as a white solid. ES-API: [M+H-Boc].sup.+=331.2.

[1387] Step 2: tert-Butyl (R)-3-(6-chloro-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 116 mol) and 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (39 mg, 139 mol) were dissolved in dioxane (1 mL) and water (0.2 mL). Potassium carbonate (48 mg, 348 mol) was then added. In the presence of protective nitrogen, chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (8 mg, 12 mol) was then added and stirred at 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL) 3 times. The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg) as a brown oil. ES-API: [M+H].sup.+=547.2.

[1388] Step 3: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 91 mol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid-ethyl acetate (4 mol/L, 1 mL) was then added and stirred at room temperature for 3 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was neutralized with 7 M amine/methanol solution (2 mL), spun to dryness, and purified by prep-HPLC (ammonium bicarbonate) to give (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine (Z501, 14.06 mg, yield: 34.42%) as a white solid. ES-API: [M+H].sup.+=447.2. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.48 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.44 (d, J=1.6 Hz, 1H), 7.38 (s, 1H), 4.66-4.59 (m, 1H), 4.50-4.38 (m, 1H), 4.18-4.10 (m, 1H), 3.92-3.81 (m, 2H), 3.70-3.61 (m, 1H), 3.56-3.47 (m, 2H), 3.48-3.36 (m, 2H), 3.07-3.00 (m, 3H), 2.89 (s, 3H).

Example 272. Synthesis of Compound Z502

##STR00553##

[1389] Step 1: (R)-2-Methylmorpholine (100 mg, 989 mol) was dissolved in anhydrous dichloromethane. N,N-Diisopropylethyl amine (128 mg, 989 mol) was added. Triphosgene (323 mg, 1.09 mmol) was added at 0 C. and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness and concentrated to give a crude product (R)-2-methylmorpholine-4-carbonyl chloride (160 mg) which was directly used in the next step.

[1390] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 60 mg, 170 mol) was dissolved in anhydrous dichloromethane. N,N-Diisopropylethyl amine (66 mg, 510 mol) was then added. (R)-2-Methylmorpholine-4-carbonyl chloride (33 mg, 204 mol) were added, and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with dichloromethane (1 mL) 3 times. The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-chloro-2-((R)-2-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg) as a brown oil. ES-API: [M+H].sup.+=480.3.

[1391] Step 3: tert-Butyl (R)-3-(6-chloro-2-((R)-2-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 125.00 mol) and 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (48 mg, 174 mol) were dissolved in dioxane (1 mL) and water (0.2 mL). Potassium carbonate (60 mg, 434 mol) was then added. In the presence of protective nitrogen, chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (10 mg, 14 mol) was then added and stirred at 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1.00 mL) 3 times. The organic phase was washed with saturated brine (1.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-2-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg) as a brown oil. ES-API: [M+H].sup.+=596.3.

[1392] Step 4: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((R)-2-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 84 mol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid-ethyl acetate (4 mol/L, 1 mL) was then added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was neutralized with 7 M amine/methanol solution (2 mL), concentrated, and purified by prep-HPLC (ammonium bicarbonate) to give (6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-2-methylmorpholino)methanone (Z502, 12.46 mg, yield: 30%) as a white solid. ES-API: [M+H].sup.+=496.3. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.57 (d, J=2.0 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.48 (s, 1H), 7.46 (s, 1H), 4.76-4.68 (m, 1H), 4.61-4.53 (m, 1H), 4.13 (dd, J=10.0, 2.8 Hz, 1H), 3.96-3.86 (m, 3H), 3.78-3.55 (m, 7H), 3.56-3.44 (m, 1H), 3.21-3.09 (m, 2H), 3.08-2.99 (m, 3H), 2.72 (dd, J=12.8, 10.4 Hz, 1H), 1.19 (d, J=6.0 Hz, 3H).

Example 273. Synthesis of Compound Z503

##STR00554##

[1393] Step 1: 3,3-Dimethylmorpholine (0.1 g, 868 mol) was dissolved in anhydrous dichloromethane (0.5 mL). N,N-Diisopropylethyl amine (112 mg, 868 mol, 151 L) was added, and triphosgene (283 mg, 955 mol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to give 3,3-dimethylmorpholine-4-carbonyl chloride (154 mg) as a crude product which was directly used in the next step.

[1394] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 60 mg, 170 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (66 mg, 510 mol, 89 L) and 3,3-dimethylmorpholine-4-carbonyl chloride (30 mg, 170 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-chloro-2-(3,3-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (84 mg) as a yellow oil. ES-API: [M+H].sup.+=494.2.

[1395] Step 3: tert-Butyl (R)-3-(6-chloro-2-(3,3-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (84 mg, 170 mol) was dissolved in dioxane (1 mL). 3-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (52 mg, 187 mol) was added, followed by water (0.2 mL) and potassium carbonate (47 mg, 340 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (12 mg, 17 mol) was finally added, and the system was heated to 100 C. and stirred for 2 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3,3-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (32 mg) as a yellow oil. ES-API: [M+H].sup.+=610.2.

[1396] Step 4: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3,3-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (32 mg, 52 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), neutralized with 7 M amine/methanol (2 mL), spun to dryness and purified by prep-HPLC (formic acid) to give (R)-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(3,3-dimethylmorpholino)methanone (Z503, 5.92 mg, yield: 20%, formate) as a white solid. ES-API: [M+H].sup.+=510.2. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.58 (d, J=1.2 Hz, 1H), 8.45 (s, 1H), 8.24 (d, J=1.6 Hz, 1H), 7.77 (s, 1H), 7.54 (s, 1H), 7.49 (s, 1H), 4.82-4.71 (m, 1H), 4.66-4.55 (m, 1H), 4.35 (dd, J=10.2, 2.8 Hz, 1H), 4.04 (d, J=2.8 Hz, 1H), 4.01 (d, J=2.5 Hz, 1H), 3.91-3.76 (m, 3H), 3.74-3.59 (m, 3H), 3.44-3.27 (m, 5H), 3.25-3.18 (m, 1H), 3.05 (t, J=6.0 Hz, 2H), 1.36 (s, 3H), 1.32 (s, 3H).

Example 274. Synthesis of Compound Z504

##STR00555##

[1397] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 60 mg, 170 mol) was dissolved in N,N-dimethylformamide (2 mL). N,N-Diisopropylethyl amine (66 mg, 510 mol, 89 L), 8-oxabicyclo[3.2.1]octane-3-carboxylic acid (29 mg, 187 mol), and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (7 mg, 17 mol) were added, and the system was reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with ethyl acetate (1 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (3R)-3-[2-(8-oxabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (50 mg) as a brown solid. ES-API: [M+H].sup.+=491.3.

[1398] Step 2: tert-Butyl (3R)-3-[2-(8-oxabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (50 mg, 102 mol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (32 mg, 122 mol) was added, followed by water (0.2 mL) and potassium carbonate (28.2 mg, 204 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (7 mg, 10 mol) was finally added, and the system was heated to 120 C. and stirred for 3 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (3R)-3-(2-(8-oxabicyclo[3.2.1]octane-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (59 mg) as a yellow oil. ES-API: [M+H].sup.+=587.4.

[1399] Step 3: tert-Butyl (3R)-3-(2-(8-oxabicyclo[3.2.1]octane-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (59 mg, 101 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric 50 acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), neutralized with 7 M amine/methanol (2 mL), spun to dryness, and purified by prep-HPLC (formic acid) to give (8-oxabicyclo[3.2.1]octan-3-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8[(R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-methanone (Z504, 7.37 mg, formate) as a white solid. ES-API: [M+H].sup.+=487.2. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.47 (s, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.22 (s, 1H), 5.05-4.96 (m, 1H), 4.81-4.72 (m, 1H), 4.46 (s, 3H), 4.09-3.94 (m, 2H), 3.93-3.76 (m, 3H), 3.75-3.64 (m, 1H), 3.46-3.20 (m, 2H), 3.11 (t, J=5.6 Hz, 2H), 3.02-2.93 (m, 1H), 2.39 (s, 3H), 2.10-1.90 (m, 6H), 1.66-1.54 (m, 2H).

Example 275. Synthesis of Compound Z505

##STR00556##

[1400] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 142 mol) was dissolved in N,N-dimethylformamide (2 mL). N,N-Diisopropylethyl amine (55 mg, 425 mol, 74 L), 3-methyl-3-carboxy-1-oxetane (33 mg, 283 mol), and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (108 mg, 283 mol) were added, and the system was reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with ethyl acetate (1 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-chloro-2-(3-methyloxetane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (63 mg) as a brown solid. ES-API: [M+H].sup.+=451.3.

[1401] Step 2: tert-Butyl (R)-3-(6-chloro-2-(3-methyloxetane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (63.0 mg, 140 mol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (39.7 mg, 154 mol) was added, followed by water (0.2 mL) and potassium carbonate (38.6 mg, 279 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (101 mg, 140 mol) was finally added, and the system was heated to 120 C. and stirred for 3 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3-methyloxetane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (76 mg) as a yellow oil. ES-API: [M+H].sup.+=547.3.

[1402] Step 3: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3-methyloxetane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (76 mg, 139 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness and purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-methyloxetan-3-yl)methanone (Z505, 5.53 mg) as a white solid. ES-API: [M+H].sup.+=447.1. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.44 (s, 1H), 8.24-8.20 (m, 1H), 7.81-7.72 (m, 1H), 7.46 (s, 1H), 7.19 (s, 1H), 5.04 (d, J=6.0 Hz, 2H), 5.00-4.93 (m, 1H), 4.83-4.73 (m, 1H), 4.63-4.50 (m, 1H), 4.49-4.42 (m, 2H), 4.22-3.96 (m, 1H), 3.94-3.81 (m, 2H), 3.76-3.64 (m, 1H), 3.60-3.45 (m, 1H), 3.41-3.33 (m, 1H), 3.20-3.08 (m, 1H), 3.07-2.95 (m, 3H), 2.37 (s, 3H), 1.77-1.67 (m, 3H).

Example 276. Synthesis of Compound Z506

##STR00557##

[1403] Step 1: 5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (2 g, 8.33 mmol) and triethylamine (8.41 g, 83.3 mmol) were dissolved in acetonitrile (14 mL). Trifluoroacetic anhydride (5.25 g, 25 mmol) was then added and stirred at room temperature for 0.5 h. Upon completion of the reaction, di-tert-butyl dicarbonate (2.73 g, 12.50 mmol) and 4-dimethylamino pyridine (102 mg, 0.83 mmol) were added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was added to water (10 mL) and extracted with dichloromethane (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-40% ethyl acetate/petroleum ether) to give tert-butyl 5-bromo-3-cyano-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.5 g, yield: 18.63%) as a white solid. ES-API: [M+H-56].sup.+=265.8, 267.8.

[1404] Step 2: N,N-Diisopropylethyl amine (154 mg, 1.19 mmol) and 2-(7-Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (220 mg, 596 mol) were added to a solution of tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 70 mg, 198 mol) and 2-hydroxy-2-methylpropanoic acid (25 mg, 238 mol) in N,N-dimethylformamide (1 mL) successively, and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg) as an oil. ES-API: [M+H].sup.+=439.3.

[1405] Step 3: In the presence of protective nitrogen, a mixture of tert-butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 228 mol), bis(pinacolato)diboron (174 mg, 683 mol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (16 mg, 23 mol) and potassium acetate (67 mg, 683 mol) in 1,4-dioxane (1 mL) was stirred at 110 C. for 2 h. Upon completion of the reaction, the reaction mixture was concentrated to give a product tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (120 mg), which was directly used in the next step without treatment. ES-API: [M+H].sup.+=531.4.

[1406] Step 4: In the presence of protective nitrogen, a mixture of tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 189 mol), tert-butyl 5-bromo-3-cyano-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (122 mg, 377 mol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (28 mg, 38 mol) and potassium carbonate (78 mg, 566 mol) in 1,4-dioxane (1 mL) and water (0.2 mL) was stirred at 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was dissolved in ethyl acetate (20 mL), and washed with saturated brine (10 mL) and water (10 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (R)-3-(6-(1-(tert-butoxycarbonyl)-3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg) as a brown oil. ES-API: [M+H].sup.+=646.3.

[1407] Step 5: tert-Butyl (R)-3-(6-(1-(tert-butoxycarbonyl)-3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 77 mol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid-ethyl acetate (4 mol/L, 1 mL) was then added and stirred at room temperature for 4 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was neutralized with 7 M amine/methanol (3 mL), concentrated, and purified by prep-HPLC (formic acid method) to give (R)-5-(2-(2-hydroxy-2-methylpropanoyl)-8-(morpholin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Z506, 5.16 mg, yield: 14%, formate) as a white solid. ES-API: [M+H].sup.+=446.3. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.71 (d, J=2.0 Hz, 1H), 8.51 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.20 (s, 1H), 7.81 (s, 1H), 7.55 (s, 1H), 4.61 (s, 1H), 4.36-4.23 (m, 2H), 4.05-3.87 (m, 3H), 3.80-3.47 (m, 3H), 3.28-3.17 (m, 1H), 3.16-2.99 (m, 3H), 1.51 (s, 6H).

Example 277. Synthesis of Compound Z507

##STR00558##

[1408] Step 1: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.15 mmol), 2-bromo-7-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (44 mg, 0.13 mmol), potassium carbonate (55 mg, 0.4 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.6 mg, 0.013 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(7-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, yield: 33%). ES-API: [M+H].sup.+=666.3.

[1409] Step 2: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(7-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.045 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min, spun to dryness, and then dissolved in dichloromethane (2 mL). Ammonia-methanol (7 M) (2 mL) was added, and the obtained mixture was stirred for 1 h and then spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give (R)-1-(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropan-1-one (Z507, 3 mg, yield: 15%). ES-API: [M+H].sup.+=436.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.78-11.64 (m, 1H), 8.73 (s, 1H), 8.18 (d, J=1.9 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.66 (s, 1H), 5.66-5.26 (m, 2H), 4.98-4.61 (m, 1H), 4.15 (s, 1H), 3.98 (dd, J=10.0, 2.9 Hz, 1H), 3.79 (d, J=10.7 Hz, 2H), 3.54 (td, J=10.4, 4.4 Hz, 1H), 3.25 (t, J=10.4 Hz, 1H), 3.06-2.76 (m, 6H), 2.35 (s, 3H), 1.36 (s, 6H).

Example 278. Synthesis of Compound Z508

##STR00559##

[1410] Step 1: 5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.55 mmol), potassium vinylfluoroborate (230 mg, 1.7 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (113 mg, 0.15 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL round-bottom flask. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 60 C. for 3 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give 5-bromo-3-vinyl-1H-pyrrolo[2,3-b]pyridine (200 mg, yield: 57%). ES-API: [M+H].sup.+=223.0.

[1411] Step 2: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 0.19 mmol), 5-bromo-3-vinyl-1H-pyrrolo[2,3-b]pyridine (63 mg, 0.28 mmol), potassium carbonate (78 mg, 0.57 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (27 mg, 0.04 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropyl)-6-(3-vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, yield: 29%). ES-API: [M+H].sup.+=547.3.

[1412] Step 3: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropyl)-6-(3-vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.06 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness and dissolved in dichloromethane (2 mL). Ammonia-methanol (7 M, 2 mL) was added, stirred for 1 h, and then spun to dryness to give a crude product. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give (R)-2-hydroxy-2-methyl-1-(8-(morpholin-3-yl)-6-(3-vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z508, 0.49 mg, yield: 2%). ES-API: [M+H].sup.+=447.2.

Example 279. Synthesis of Compound Z509

##STR00560##

[1413] Referring to the synthesis procedure of compound Z455, except replacing 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine in step 2 with 3-ethynyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine, compound Z509 was finally obtained. ES-API: [M+H].sup.+=445.2.

Example 280. Synthesis of Compound Z510

##STR00561##

[1414] Step 1: 5-Bromo-3-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (600 mg, 1.643 mmol) was dissolved in dried tetrahydrofuran (20 mL) and cooled to 78 C. At this temperature, a solution of lithium diisopropylamide in tetrahydrofuran (2 M, 0.986 mL, 1.971 mmol) was slowly added dropwise to the above solution. After the addition was completed, the reaction mixture continued to be stirred at 78 C. for 2 h. N-Fluorobisbenzenesulfonamide (776.99 mg, 2.464 mmol) was then dissolved in tetrahydrofuran (5 mL) and slowly added dropwise to the reaction mixture. After the dropwise addition was completed, the reaction mixture was warmed to room temperature and continued to be stirred for 1 h. The reaction was quenched by saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (15 mL3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (dichloromethane/petroleum ether: 20%-100%) to give 5-bromo-2-fluoro-3-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (400 mg, 1.044 mmol, yield: 63.54%) as a pale yellow solid. ES-API: [M+H].sup.+=383.1, 385.1.

[1415] Step 2: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (181 mg, 0.341 mmol) was dissolved in dioxane (10 mL) and water (1 mL). 5-Bromo-2-fluoro-3-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (130.76 mg, 0.341 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (12.48 mg, 0.017 mmol) and potassium carbonate (94.32 mg, 0.682 mmol) were added to the above solution at room temperature. After the addition was completed, the reaction mixture was stirred at 110 C. for 3 h under nitrogen atmosphere. Upon completion of the reaction, water (10 mL) was added to the above solution, and the obtained mixture was extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0%-2%) to give tert-butyl (R)-3-(6-(2-fluoro-3-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.057 mmol, yield: 16.59%) as a yellow solid. ES-API: [M+H].sup.+=707.1.

[1416] Step 3: tert-Butyl (R)-3-(6-(2-fluoro-3-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.057 mmol) was dissolved in tetrahydrofuran (1 mL), and a solution of tetrabutylammonium bromide in tetrahydrofuran (1 M, 0.113 mL, 0.113 mmol) was added to the above solution. After the addition was completed, the reaction mixture was stirred at room temperature for 3 h. Upon completion of the reaction, water (10 mL) was added to the above solution, and the obtained mixture was extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (10 mL5), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0%-5%) to give tert-butyl (R)-3-(6-(2-fluoro-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (15 mg, 0.027 mmol, yield: 47.96%) as a yellow solid, ES-API: [M+H].sup.+=553.1.

[1417] Step 4: tert-Butyl (R)-3-(6-(2-fluoro-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (15 mg, 0.027 mmol) was dissolved in anhydrous dichloromethane (1 mL). Trifluoroacetic acid (0.5 mL) was added to the above solution, and the reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and adjusted to neutrality with ammonia/methanol solution (7 M). The obtained mixture was concentrated again, and then purified by a flash silica gel column (methanol/dichloromethane: 0%-7%) to give (R)-1-(6-(2-fluoro-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-tetrahydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropan-1-one (Z510, 2 mg, 0.004 mmol, yield: 16.28%) as a white solid. ES-API: [M+H].sup.+=453.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.32 (s, 1H), 8.43 (s, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.79 (s, 1H), 7.45 (s, 1H), 5.53 (s, 1H), 4.84 (s, 1H), 4.65 (s, 1H), 4.14-3.99 (m, 2H), 3.88-3.75 (m, 4H), 3.59 (s, 1H), 3.02-2.88 (s, 4H), 2.33-2.28 (m, 1H), 2.19 (s, 3H), 1.37 (s, 6H).

Example 281. Synthesis of Compound Z511

##STR00562##

[1418] Referring to the synthesis procedure of compound Z377, except replacing 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine in step 3 with 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine, compound Z511 was finally obtained. ES-API: [M+H].sup.+=482.2.

Example 282. Synthesis of Compound Z512

##STR00563##

[1419] Step 1: (2S,6S)-2,6-dimethylmorpholine (0.05 g, 434 mol) was dissolved in anhydrous dichloromethane (0.5 mL). N,N-Diisopropylethyl amine (168 mg, 1.30 mmol, 227 L) was added, and triphosgene (142 mg, 478 mol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to give (2S,6S)-2,6-dimethylmorpholine-4-carbonyl chloride (77 mg) as a crude product which was directly used in the next step without purification.

[1420] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 0.06 g, 170 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (66 mg, 510 mol, 89 L) and (2S,6S)-2,6-dimethylmorpholine-4-carbonyl chloride (30 mg, 170 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-chloro-2-((2S,6S)-2,6-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (84 mg) as a yellow oily liquid. ES-API: [M+H].sup.+=494.3.

[1421] Step 3: tert-Butyl (R)-3-(6-chloro-2-((2S,6S)-2,6-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (84 mg, 170 mol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (52.7 mg, 204 mol) was added, followed by water (0.2 mL) and potassium carbonate (47.0 mg, 340 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (122 mg, 170 mol) was finally added, and the system was heated to 120 C. and stirred for 2 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(2-((2S,6S)-2,6-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg) as a yellow oil. ES-API: [M+H].sup.+=590.3.

[1422] Step 4: tert-Butyl (R)-3-(2-((2S,6S)-2,6-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 169 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness and purified by prep-HPLC (ammonium bicarbonate method) to give ((2S,6S)-2,6-dimethylmorpholine)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2-1H-yl)methanone (Z512, 28.28 mg) as a white solid. ES-API: [M+H].sup.+=490.1. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.44 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.43 (s, 1H), 7.19 (s, 1H), 4.80-4.73 (m, 1H), 4.59-4.51 (m, 1H), 4.15-4.03 (m, 3H), 3.92-3.83 (m, 2H), 3.78-3.67 (m, 1H), 3.63-3.57 (m, 2H), 3.55-3.48 (m, 1H), 3.47-3.41 (m, 2H), 3.17-2.99 (m, 6H), 2.37 (d, J=0.8 Hz, 3H), 1.26 (d, J=6.4 Hz, 6H).

Example 283. Synthesis of Compound Z513

##STR00564##

[1423] Referring to the synthesis procedure of compound Z503, except replacing 3,3-dimethylmorpholine in step 1 with 8-methyl-3,8-diazabicyclo[3.2.1]octane, compound Z513 was finally obtained. ES-API: [M+H].sup.+=521.2.

Example 284. Synthesis of Compound Z514

##STR00565##

[1424] Step 1: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (118.6 mg, 0.2 mmol), 5-bromo-2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine (105 mg, 0.4 mmol), potassium carbonate (84 mg, 0.61 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (29.7 mg, 0.04 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (3R)-3-(2-(8-oxo-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, yield: 54%). ES-API: [M+H].sup.+=636.3.

[1425] Step 2: tert-Butyl (3R)-3-(2-(8-oxo-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 0.02 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness and dissolved in dichloromethane (2 mL). Ammonia-methanol (7 M, 2 mL) was added, stirred for 1 h, and then spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give (8-oxo-3-azabicyclo[3.2.1]octane-3-yl)(6-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z514, 5 mg, yield: 8%). ES-API: [M+H].sup.+=536.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.29 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.11 (d, J=1.9 Hz, 1H), 7.73 (s, 1H), 7.42 (s, 1H), 4.55 (d, J=16.2 Hz, 1H), 4.40 (d, J=16.3 Hz, 1H), 4.28 (s, 2H), 3.97 (d, J=8.8 Hz, 1H), 3.77 (t, J=10.8 Hz, 2H), 3.61-3.38 (m, 5H), 3.16-2.71 (m, 9H), 2.05-1.72 (m, 5H), 1.22 (d, J=7.5 Hz, 3H).

Example 285. Synthesis of Compound Z515

##STR00566##

[1426] Step 1: 5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (1.33 g, 4.12 mmol), zinc cyanide (480 mg, 4.12 mmol), tetrakis(triphenylphosphine)palladium (480 mg, 0.41 mmol) and dioxane (10 mL) were added to a 25 mL round-bottom flask. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at room temperature overnight. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (300 mg, yield: 33%). ES-API: [M+H].sup.+=222.0.

[1427] Step 2: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 0.17 mmol), 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (76 mg, 0.34 mmol), potassium carbonate (71 mg, 0.51 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (25 mg, 0.03 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, yield: 39%). ES-API: [M+H].sup.+=599.3.

[1428] Step 3: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.06 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness and dissolved in dichloromethane (2 mL). Ammonia-methanol (7 M, 2 mL) was added, stirred for 1 h, and then spun to dryness to give a crude product. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give 5-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-8-((R)-morpholin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Z515, 13.7 mg, yield: 41%). ES-API: [M+H].sup.+=499.2.

Example 286. Synthesis of Compound Z516

##STR00567##

[1429] Step 1: 6-Oxa-3-azabicyclo[3.1.1]heptane hydrochloride (100 mg, 0.738 mmol) was dissolved in dichloromethane (10 ML). Triethylamine (0.526 mL, 3.783 mmol) and p-nitrophenyl chloroformate (163.52 mg, 0.811 mmol) were added under an ice bath condition, and the system was reacted at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=80/20) to give 6-oxa-3-azabicyclo[3.1.1]heptane-3-carboxylic acid 4-nitrophenyl ester (170 mg, 0.643 mmol, yield: 87.18%). ES-API: [M+H].sup.+=265.1.

[1430] Step 2: 6-Oxa-3-azabicyclo[3.1.1]heptane-3-carboxylic acid 4-nitrophenyl ester (89.86 mg, 0.340 mmol) was dissolved in DMA (1 mL). tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 60 mg, 0.170 mmol) and potassium carbonate (39.17 mg, 0.283 mmol) were added, and the system was reacted at 130 C. for 3 h. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl (3R)-3-(2-(6-oxa-3-azabicyclo[3.1.1]heptane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.126 mmol, yield: 73.84%). ES-API: [M+H].sup.+=478.1.

[1431] Step 3: tert-Butyl (3R)-3-(2-(6-oxa-3-azabicyclo[3.1.1]heptane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.126 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (81.00 mg, 0.314 mmol), potassium carbonate (52.04 mg, 0.377 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.03 mg, 0.013 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at 110 C. for 2 h and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to give tert-butyl (3R)-3-(2-(6-oxa-3-azabicyclo[3.1.1]heptane-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.047 mmol, yield: 37.49%). ES-API: [M+H].sup.+=574.3.

[1432] Step 4: tert-Butyl (3R)-3-(2-(6-oxa-3-azabicyclo[3.1.1]heptane-3-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, 0.044 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonium bicarbonate method-A) to give (6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z516, 1.07 mg, yield: 4.7%). ES-API: [M+H].sup.+=474.2.

Example 287. Synthesis of Compound Z517

##STR00568##

[1433] Referring to the synthesis procedure of compound Z457, except replacing 2-oxa-5-azabicyclo[2.2.2]octane in step 1 with 3-oxa-6-azabicyclo[3.1.1]heptane, compound Z517 was finally obtained. ES-API: [M+H].sup.+=474.2.

Example 288. Synthesis of Compound Z518

##STR00569##

[1434] Step 1: (1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptane hydrochloride (150 mg, 1.513 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (0.526 mL, 3.783 mmol) and p-nitrophenyl chloroformate (396.49 mg, 1.967 mmol) were added under an ice bath condition, and the system was reacted at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=80/20) to give (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid 4-nitrophenyl ester (280 mg, 1.060 mmol, yield: 70.03%). ES-API: [M+H].sup.+=265.0.

[1435] Step 2: (1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid 4-nitrophenyl ester (74.89 mg, 0.283 mmol) was dissolved in DMA (1 mL). tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 0.142 mmol) and potassium carbonate (39.17 mg, 0.283 mmol) were added, and the system was reacted at 130 C. for 3 h. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl (R)-3-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-formyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.084 mmol, yield: 59.70%). ES-API: [M+H].sup.+=478.1.

[1436] Step 3: tert-Butyl (R)-3-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-formyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.084 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (43.20 mg, 0.167 mmol), potassium carbonate (34.70 mg, 0.251 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.03 mg, 0.008 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at 110 C. for 2 h and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to give tert-butyl (R)-3-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, 0.044 mmol, yield: 52.07%). ES-API: [M+H].sup.+=574.3.

[1437] Step 4: tert-Butyl (R)-3-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, 0.044 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give ((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z518, 10 mg, 0.021 mmol, yield: 47.73%). ES-API: [M+H].sup.+=474.

Example 289. Synthesis of Compound Z519

##STR00570##

[1438] Step 1: cis-2,6-Dimethylmorpholine (50 mg, 434 mol) was dissolved in anhydrous dichloromethane (0.5 mL). N,N-Diisopropylethyl amine (168 mg, 1.30 mmol, 227 L) was added, and triphosgene (142 mg, 478 mol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to give (2S,6R)-2,6-dimethylmorpholine-4-carbonyl chloride (77 mg) as a crude product which was directly used in the next step without purification.

[1439] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 0.06 g, 170 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (66 mg, 510 mol, 89 L) and (2S,6R)-2,6-dimethylmorpholine-4-carbonyl chloride (30 mg, 170 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-chloro-2-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (84 mg) as a yellow oily liquid. ES-API: [M+H].sup.+=494.2.

[1440] Step 3: tert-Butyl (R)-3-(6-chloro-2-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (84 mg, 170 mol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (52.7 mg, 204 mol) was added, followed by water (0.2 mL) and potassium carbonate (47.0 mg, 340 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (122 mg, 170 mol) was finally added, and the system was heated to 120 C. and stirred for 2 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(2-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg) as a yellow oil. ES-API: [M+H].sup.+=590.3.

[1441] Step 4: tert-Butyl (R)-3-(2-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 169 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness and purified by prep-HPLC (formic acid method) to give ((2R,6S)-2,6-dimethylmorpholine)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2-1H-yl)methanone (Z519, 13.22 mg, formate) as a white solid. ES-API: [M+H].sup.+=490.1. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.44 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.43 (d, J=1.6 Hz, 1H), 7.18 (d, J=0.8 Hz, 1H), 4.72-4.65 (m, 1H), 4.58-4.51 (m, 1H), 4.11 (dd, J=2.8, 10.0 Hz, 1H), 3.93-3.84 (m, 2H), 3.74-3.45 (m, 8H), 3.18-3.08 (m, 1H), 3.06-2.99 (m, 3H), 2.71-2.60 (m, 2H), 2.37 (d, J=1.2 Hz, 3H), 1.18 (d, J=6.0 Hz, 6H).

Example 290. Synthesis of Compound Z566

##STR00571##

[1442] Step 1: A mixture of 4-fluoropiperidine hydrochloride (46 mg, 0.33 mmol) in dichloromethane (5 mL) was cooled to 0 C. Triethylamine (0.07 mL, 0.49 mmol) and triphosgene (98 mg, 0.33 mmol) were added successively and stirred for 0.5 h. The reaction mixture was concentrated and subsequently dissolved in dichloromethane (5 mL). Triethylamine (0.07 mL, 0.49 mmol) and tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 58 mg, 0.16 mol) were added and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction was quenched with saturated sodium bicarbonate (10 mL), and the reaction mixture was extracted with dichloromethane (10 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-40% tetrahydrofuran/petroleum ether) to give tert-butyl (R)-3-(6-chloro-2-(4-fluoropiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (75 mg, yield: 95%). ES-API: [M+H-56]+=482.1.

[1443] Step 2: In the presence of protective nitrogen, a mixture of tert-butyl (R)-3-(6-chloro-2-(4-fluoropiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (75 mg, 0.16 mmol), bis(pinacolato)diboron (76 mg, 0.31 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (11 mg, 0.02 mmol) and potassium acetate (46 mg, 0.47 mmol) in 1,4-dioxane (2 mL) was stirred at 110 C. for 2 h. Upon completion of the reaction, the reaction mixture was filtered and concentrated to give tert-butyl (R)-3-(2-(4-fluoropiperidine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (90 mg) as a crude product. ES-API: [M+H].sup.+=574.3.

[1444] Step 3: In the presence of protective nitrogen, a mixture of tert-butyl (R)-3-(2-(4-fluoropiperidine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (90 mg, 0.16 mmol), 2-bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine (67 mg, 0.31 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (11 mg, 0.02 mmol) and potassium carbonate (65 mg, 0.47 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 110 C. for 2 h. Upon completion of the reaction, the reaction mixture was dissolved in ethyl acetate (20 mL), and washed with saturated brine (10 mL) and water (10 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-10% methanol/dichloromethane) to give tert-butyl (R)-3-(2-(4-fluoropiperidine-1-carbonyl)-6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, yield: 33%) as a colorless oil. ES-API: [M+H].sup.+=579.3.

[1445] Step 4: Under an ice bath condition, trifluoroacetic acid (0.5 mL) was added dropwise to a solution of tert-butyl (R)-3-(2-(4-fluoropiperidine-1-carbonyl)-6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.05 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated, neutralized with 7 M amine/methanol (5 mL), concentrated, and then purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(4-fluoropiperidin-1-yl)(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z566, 14 mg, purity: 100%, yield: 56%) as a white solid. ES-API: [M+H]+=479.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.42 (s, 1H), 8.62 (d, J=1.6 Hz, 1H), 8.37 (s, 1H), 8.21-8.11 (m, 1H), 7.67 (s, 1H), 7.25 (d, J=1.6 Hz, 1H), 5.02-4.83 (m, 1H), 4.74-4.53 (m, 2H), 4.41-4.26 (m, 1H), 4.23 (s, 1H), 4.11-3.98 (m, 3H), 3.97-3.67 (m, 2H), 3.67-3.45 (m, 3H), 3.34 (s, 3H), 3.27-3.18 (m, 1H), 3.06-2.85 (m, 2H), 1.35 (d, J=3.2 Hz, 3H), 1.33 (d, J=3.2 Hz, 3H).

Example 291. Synthesis of Compound Z522

##STR00572##

[1446] Step 1: 2-Bromo-5H-pyrrolo[2,3-b]pyrazine (500 mg, 2.525 mmol) was dissolved in acetonitrile (12 mL). Acetic acid (4 mL) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (893.85 mg, 2.525 mmol) were added, and the system was reacted at 80 C. for 15 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=85/15) to give 2-bromo-7-fluoro-5H-pyrrolo[2,3-b]pyrazine (200 mg, 0.926 mmol, yield: 36.67%). ES-API: [M+H].sup.+=216.1.

[1447] Step 2: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.163 mmol), bis(pinacolato)diboron (79.36 mg, 0.313 mmol), potassium acetate (61.25 mg, 0.625 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (20.76 mg, 0.030 mmol) were dissolved in 1,4-dioxane (2.5 mL) and stirred at 110 C. for 2 h. 2-Bromo-7-fluoro-5H-pyrrolo[2,3-b]pyrazine (29.61 mg, 0.137 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.87 mg, 0.014 mmol), potassium carbonate (56.84 mg, 0.411 mmol) and water (0.5 mL) were added and stirred at 110 C. for 2 h. The obtained mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=97/3) to give tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(7-fluoro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.051 mmol, yield: 36.92%). ES-API: [M+H].sup.+=593.1.

[1448] Step 3: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(7-fluoro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (24 mg, 0.040 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(6-(7-fluoro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z522, 10 mg, 0.020 mmol, yield: 50.14%). ES-API: [M+H].sup.+=493.1. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.93 (s, 1H), 8.67 (s, 1H), 8.11 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 4.68-4.61 (m, 1H), 4.35-4.15 (m, 5H), 3.96-3.66 (m, 3H), 3.56-3.36 (m, 6H), 3.26-3.06 (m, 5H), 1.87 (s, 4H).

Example 292. Synthesis of Compound Z567

##STR00573##

[1449] Step 1: 2-Methylpyrimidine-5-carboxylic acid (27.40 mg, 0.198 mmol) was dissolved in N,N-dimethylformamide (2 mL). tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 70 mg, 0.198 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (98.06 mg, 0.258 mmol) and N,N-diisopropylethyl amine (128.20 mg, 0.992 mmol) were added, and the system was reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl (R)-3-(6-chloro-2-(2-methylpyrimidine-5-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (75 mg, 0.159 mmol, yield: 79.93%). ES-API: [M+H].sup.+=473.0.

[1450] Step 2: tert-Butyl (R)-3-(6-chloro-2-(2-methylpyrimidine-5-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 0.148 mmol), bis(pinacolato)diboron (75.17 mg, 0.296 mmol), potassium acetate (29.01 mg, 0.296 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (20.76 mg, 0.030 mmol) were dissolved in 1,4-dioxane (2.5 mL) and stirred at 110 C. for 2 h. 5-Bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine (31.90 mg, 0.142 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10 mg, 0.028 mmol), potassium carbonate (72.54 mg, 0.525 mmol) and water (0.5 mL) were added and stirred at 110 C. for 2 h. The obtained mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=97/3) to give tert-butyl (R)-3-(6-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.051 mmol, yield: 36.33%). ES-API: [M+H].sup.+=583.2.

[1451] Step 3: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(7-isopropyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.034 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (R)-(6-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-methylpyrimidin-5-yl)methanone (Z567, 8 mg, 0.017 mmol, yield: 48.31%). ES-API: [M+H].sup.+=483.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.38 (s, 1H), 8.91 (s, 2H), 8.47 (s, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.88-7.75 (m, 1H), 7.55-7.44 (m, 1H), 7.27 (s, 1H), 5.14-4.61 (m, 2H), 4.23-3.47 (m, 6H), 3.31-3.21 (m, 2H), 3.05-2.98 (m, 4H), 2.79-2.74 (m, 2H), 2.70 (s, 3H), 1.28 (t, J=7.2 Hz, 3H).

Example 293. Synthesis of Compound Z552

##STR00574##

[1452] Step 1: (2R,6R)-Dimethylmorpholine (117.48 mg, 1.02 mmol) and pyridine (0.4 mL, 4.971 mmol) were dissolved in dichloromethane (10 mL). Triphosgene (67.36 mg, 0.227 mmol) was added under an ice bath condition, and the system was reacted at room temperature for 1 h. N,N-Diisopropylethyl amine (5 mL) and tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 80 mg, 0.227 mmol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl (R)-3-(6-chloro-2-((2R,6R)-2,6-dimethylmorpholine-4-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (90 mg, 0.182 mmol, yield: 80.36%). ES-API: [M+H].sup.+=494.3.

[1453] Step 2: tert-Butyl (R)-3-(6-chloro-2-((2R,6R)-2,6-dimethylmorpholine-4-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.101 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (52.25 mg, 0.202 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.29 mg, 0.010 mmol) and potassium carbonate (41.96 mg, 0.304 mmol) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL). The reaction mixture was stirred at 110 C. for 2 h, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (dichloromethane/methanol=97/3) to give tert-butyl (R)-3-(2-((2R,6R)-2,6-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.068 mmol, yield: 67.02%). ES-API: [M+H].sup.+=590.3.

[1454] Step 3: tert-Butyl (R)-3-(2-((2R,6R)-2,6-dimethylmorpholine-4-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (21 mg, 0.036 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give ((2R,6R)-2,6-dimethylmorpholine)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z552, 11 mg, 0.022 mmol, yield: 63.11%). ES-API: [M+H].sup.+=490.1. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.16 (s, 1H), 8.42 (d, J=1.6 Hz, 1H), 7.96 (d, J=1.6 Hz, 1H), 7.71 (s, 1H), 7.26 (s, 1H), 7.06 (s, 1H), 4.63-4.58 (m, 2H), 4.43-4.48 (m, 1H), 4.12-3.94 (m, 3H), 3.88-3.76 (m, 2H), 3.65-3.58 (m, 1H), 3.53-3.26 (m, 5H), 3.13-3.06 (m, 1H), 3.03-2.86 (m, 5H), 2.29 (s, 3H), 1.18 (s, 6H).

Example 294. Synthesis of Compound Z568

##STR00575## ##STR00576##

[1455] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 150 mg, 0.425 mmol) and (2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (134.40 mg, 0.850 mmol) were dissolved in N,N-dimethylformamide (5 mL). Triethylamine (0.177 mL, 1.275 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (323.28 mg, 0.850 mmol) were added successively. The system was reacted at room temperature for 1 h. Upon completion of the reaction, water (30 mL) was added, and the reaction mixture was extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated brine (30 mL1), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give tert-butyl (R)-3-(6-chloro-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (200 mg, 0.406 mmol, yield: 95%). ES-API: [M+H].sup.+=493.2.

[1456] Step 2: tert-Butyl (R)-3-(6-chloro-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (200 mg, 0.406 mmol), bis(pinacolato)diboron (206.07 mg, 0.811 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (17.53 mg, 0.024 mmol) and potassium acetate (119.53 mg, 1.218 mmol) were dissolved in dried 1,4-dioxane (10 mL) and stirred at 110 C. for 2 h in the presence of protective nitrogen. Upon completion of the reaction, a solution of tert-butyl (R)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate was obtained without treatment, which was directly used in the next step, ES-API: [M+H]+=585.3.

[1457] Step 3: Water (3 mL), 2-bromo-5H-pyrrolo[2,3-b]pyrazine (240.90 mg, 1.217 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (29.20 mg, 0.041 mmol) and potassium carbonate (168.13 mg, 1.217 mmol) were directly added to the above reaction mixture of tert-butyl (R)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate. In the presence of protective nitrogen, the reaction mixture was stirred at 110 C. for 3 h. The reaction mixture was diluted with ethyl acetate (20 mL) and water (20 mL). The organic layer was separated, washed with saturated sodium chloride solution (20 mL3), concentrated in vacuum, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=40/60) to give tert-butyl (3R)-3-[6-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (100 mg, 0.174 mmol, yield: 42.84%). ES-API: [M+H].sup.+=576.2.

[1458] Step 4: tert-Butyl (3R)-3-[6-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (100 mg, 0.174 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N-iodosuccinimide (39.09 mg, 0.174 mmol) was added under an ice-water bath condition. The reaction mixture was stirred at room temperature for 10 min. The reaction was quenched by slowly adding aqueous sodium thiosulfate solution (2 mL). The obtained mixture was extracted with ethyl acetate (100 mL3). The organic layers were combined, washed with saturated sodium chloride solution (100 mL1), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=40/60) to give tert-butyl (R)-3-(6-(7-iodo-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (110 mg, 0.157 mmol, yield: 90.2%). ES-API: M+H].sup.+=702.0.

[1459] Step 5: Bis(tri-tert-butylphosphine)palladium (7.31 mg, 0.014 mmol) was added to a solution of tert-butyl (R)-3-(6-(7-iodo-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 0.143 mmol) in tetrahydrofuran (5 mL). The reaction mixture was cooled to 0 C. in the presence of protective nitrogen. Dimethylzinc (0.042 mL, 0.042 mmol, 1 M in toluene) was added dropwise to the above solution and stirred at room temperature for 1 h. The reaction was quenched with aqueous ammonium chloride solution (1 mL). The obtained mixture was extracted with ethyl acetate (10 mL3). The organic layers were combined, washed with saturated aqueous sodium chloride solution (20 mL1), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=40/60) to give tert-butyl (3R)-3-[6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]morpholine-4-carboxylate (30 mg, 0.051 mmol, yield: 35.6%). ES-API: [M+H].sup.+=590.2.

[1460] Step 6: tert-Butyl (3R)-3-[6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]-1,2,3,4-tetrahydroisoquinolin-8-yl]-morpholine-4-carboxylate (30 mg, 0.051 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added, and the system was reacted at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was concentrated. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by prep-HPLC (ammonia water method) to give (S)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z568, 7.7 mg, 0.0157 mmol, yield: 30.8%). ES-API: [M+H].sup.+=490.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.72 (d, J=2.6 Hz, 1H), 8.74 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.67 (dd, J=2.7, 1.3 Hz, 1H), 7.46-7.05 (m, 1H), 5.44-5.19 (m, 1H), 5.04-4.52 (m, 1H), 4.28-4.03 (m, 1H), 3.97 (dd, J=9.9, 3.0 Hz, 1H), 3.92-3.50 (m, 4H), 3.27 (t, J=10.7 Hz, 1H), 3.08-2.89 (m, 4H), 2.81 (s, 1H), 2.35 (d, J=1.1 Hz, 3H), 1.59 (s, 3H).

Example 295. Synthesis of Compound Z569

##STR00577##

[1461] Step 1: tert-Butyl (3R)-3-(6-chloro-2-(4-hydroxy-2,2-dimethylpyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (200 mg, 0.4 mmol), bis(pinacolato)diboron (102 mg, 0.4 mmol), potassium acetate (119 mg, 1.25 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (29 mg, 0.04 mmol) and dioxane (1 mL) were added to a 25 mL microwave reactor. The reaction mixture was stirred at 90 C. overnight. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (10 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (3R)-3-(2-(4-hydroxy-2,2-dimethylpyrrolidine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (160 mg, yield: 67%). ES-API: [M+H].sup.+=586.3.

[1462] Step 2: tert-Butyl (3R)-3-(2-(4-hydroxy-2,2-dimethylpyrrolidine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.1 mmol), 2-bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine (119 mg, 0.51 mmol), potassium carbonate (42 mg, 0.3 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (15 mg, 0.02 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 120 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (3R)-3-(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(4-hydroxy-2,2-dimethylpyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, yield: 40%). ES-API: [M+H].sup.+=610.3.

[1463] Step 3: tert-Butyl (3R)-3-(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(4-hydroxy-2,2-dimethylpyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg 0.04 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give (6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-hydroxy-2,2-dimethylpyrrolidin-1-yl)methanone (Z569, 7 mg, yield: 32%). ES-API: [M+H].sup.+=510.3.

Example 296. Synthesis of Compound Z570

##STR00578##

[1464] Step 1: 2-Bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine (1.5 g, 7.074 mmol) was dissolved in acetonitrile (10 mL). Di-tert-butyl dicarbonate (2.31 g, 10.611 mmol), triethylamine (2.86 g, 28.295 mmol) and 4-dimethylamino pyridine (0.86 g, 7.074 mmol) were added, and the system was reacted at room temperature overnight. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl 2-bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (366 mg, 1.172 mmol, yield: 16.57%). ES-API: [M-56]+=256.0.

[1465] Step 2: tert-Butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-formyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.163 mmol), bis(pinacolato)diboron (79.36 mg, 0.313 mmol), potassium acetate (61.25 mg, 0.625 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (20.76 mg, 0.030 mmol) were dissolved in 1,4-dioxane (2.5 mL) and stirred at 110 C. for 2 h. tert-Butyl 2-bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (48.15 mg, 0.154 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (11.10 mg, 0.015 mmol), potassium carbonate (63.95 mg, 0.463 mmol) and water (0.5 mL) were added and stirred at 110 C. for 2 h. The obtained mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=97/3) to give tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.051 mmol, yield: 61.3%). ES-API: [M+H].sup.+=589.3.

[1466] Step 3: tert-Butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.051 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z570, 10 mg, 0.02 mmol, yield: 40.8%). ES-API: [M+H].sup.+=489.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.72 (s, 1H), 8.74 (s, 1H), 8.15 (s, 1H), 7.82 (s, 1H), 7.67 (s, 1H), 4.76-4.56 (m, 2H), 4.06-3.89 (m, 3H), 3.81-3.77 (m, 2H), 3.73-3.49 (m, 8H), 3.29-3.22 (m, 1H), 2.96-2.95 (m, 4H), 2.35 (s, 3H), 10.84-1.79 (m, 4H).

Example 297. Synthesis of Compound Z571

##STR00579##

[1467] Step 1: 3-Oxa-8-azabicyclo[3.2.1]octane hydrochloride (119.95 mg, 1.06 mmol) and pyridine (0.4 mL, 4.971 mmol) were dissolved in dichloromethane (10 mL). Triphosgene (63.07 mg, 0.213 mmol) was added under an ice bath condition, and the system was reacted at room temperature for 1 h. N,N-Diisopropylethyl amine (5 mL) and tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 75 mg, 0.213 mmol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-formyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.163 mmol, yield: 76.50%). ES-API: [M+H].sup.+=492.3.

[1468] Step 2: tert-Butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-formyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.163 mmol), bis(pinacolato)diboron (79.36 mg, 0.313 mmol), potassium acetate (61.25 mg, 0.625 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (20.76 mg, 0.030 mmol) were dissolved in 1,4-dioxane (2.5 mL) and stirred at 110 C. for 2 h. 2-Bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine (48.15 mg, 0.154 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (11.10 mg, 0.015 mmol), potassium carbonate (63.95 mg, 0.463 mmol) and water (0.5 mL) were added and stirred at 110 C. for 2 h. The obtained mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=97/3) to give tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-formyl)-6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.049 mmol, yield: 30.2%). ES-API: [M+H].sup.+=609.3.

[1469] Step 3: tert-Butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-formyl)-6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.049 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h.

[1470] The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z571, 13 mg, 0.025 mmol, yield: 51.02%). ES-API: [M+H].sup.+=509.0. .sup.1H NMR (400 MHz, CDCl.sub.3) 59.83 (s, 1H), 8.64 (s, 1H), 8.06 (s, 1H), 7.77 (s, 1H), 7.51 (s, 1H), 4.48-4.41 (m, 1H), 4.35-4.15 (m, 1H), 3.89-3.76 (m, 4H), 3.74-3.67 (m, 4H), 3.64-3.58 (m, 6H), 3.16-2.86 (m, 4H), 1.91 (s, 4H).

Example 298. Synthesis of Compound Z572

##STR00580##

[1471] Step 1: 8-Oxa-3-azabicyclo[3.2.1]octane hydrochloride (119.95 mg, 1.06 mmol) and pyridine (0.4 mL, 4.971 mmol) were dissolved in dichloromethane (10 mL). Triphosgene (63.07 mg, 0.213 mmol) was added under an ice bath condition, and the system was reacted at room temperature for 1 h. N,N-Diisopropylethyl amine (5 mL) and tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 75 mg, 0.213 mmol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.163 mmol, yield: 76.50%). ES-API: [M+H].sup.+=492.3.

[1472] Step 2: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.163 mmol), bis(pinacolato)diboron (79.36 mg, 0.313 mmol), potassium acetate (61.25 mg, 0.625 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (20.76 mg, 0.030 mmol) were dissolved in 1,4-dioxane (2.5 mL) and stirred at 110 C. for 2 h. tert-Butyl 2-bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (48.15 mg, 0.154 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (11.10 mg, 0.015 mmol), potassium carbonate (63.95 mg, 0.463 mmol) and water (0.5 mL) were added and stirred at 110 C. for 2 h. The obtained mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=97/3) to give tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.044 mmol, yield: 26.9%). ES-API: [M+H].sup.+=689.2.

[1473] Step 3: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.044 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (8-oxa-3-50 azabicyclo[3.2.1]octan-3-yl)(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z572, 13 mg, 0.027 mmol, yield: 61.3%). ES-API: [M+H].sup.+=489.1. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.37 (s, 1H), 8.57 (s, 1H), 8.05 (s, 1H), 7.70 (s, 1H), 7.32 (s, 1H), 4.62-4.56 (m, 1H), 4.46-4.23 (m, 3H), 4.12-4.11 (m, 1H), 3.77-3.58 (m, 3H), 3.55-2.90 (m, 11H), 2.37 (s, 3H), 1.87 (s, 4H).

Example 299. Synthesis of Compound Z573

##STR00581##

[1474] Step 1: tert-Butyl (R)-3-(6-chloro-2-((S)-3-methylmorpholine-4-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 0.208 mmol), bis(pinacolato)diboron (79.36 mg, 0.313 mmol), potassium acetate (61.25 mg, 0.625 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (20.76 mg, 0.030 mmol) were dissolved in 1,4-dioxane (2.5 mL) and stirred at 110 C. for 2 h. 2-Bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine (40.68 mg, 0.175 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10 mg, 0.028 mmol), potassium carbonate (72.54 mg, 0.525 mmol) and water (0.5 mL) were added and stirred at 110 C. for 2 h. The obtained mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=97/3) to give tert-butyl (R)-3-(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-((S)-3-methylmorpholine-4-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.052 mmol, yield: 16.6%). ES-API: [M+H].sup.+=597.2.

[1475] Step 2: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(7-isopropyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.052 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(S)-3-methylmorpholine)methanone (Z573, 10 mg, 0.020 mmol, yield: 38.4%). ES-API: [M+H].sup.+=497.1. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.33 (s, 1H), 8.70 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.59 (s, 1H), 4.76-4.72 (m, 2H), 4.43-4.22 (m, 2H), 3.97-3.77 (m, 5H), 3.70-3.65 (m, 5H), 3.35-3.24 (m, 3H), 3.15-3.14 (m, 2H), 3.05-2.97 (m, 2H), 1.34 (s, 3H).

Example 300. Synthesis of Compound Z574

##STR00582##

[1476] Step 1: 3,5-Dibromopyrazine-2-amine (10 g, 39.541 mmol) was dissolved in tetrahydrofuran (100 mL). Potassium tert-butoxide (59.312 mL, 59.312 mmol) and tribromopropene (5.74 g, 47.450 mmol) were added, and the system was reacted at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water (100 mL), and extracted with dichloromethane (100 mL3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give N-allyl-3,5-dibromopyrazine-2-amine (3000 mg, 10.240 mmol, yield: 25.90%). ES-API: [M+H].sup.+=291.8.

[1477] Step 2: N-Allyl-3,5-dibromopyrazine-2-amine (1.8 g, 6.3 mmol) was dissolved in acetonitrile (10 mL). Palladium acetate (0.14 g, 0.631 mmol), tris(2-methylphenyl)phosphine (0.46 g, 1.516 mmol) and triethylamine (5.266 mL, 37.889 mmol) were added and stirred at 100 C. for 5 h. The reaction mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15/1) to give 2-bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine (400 mg, 1.886 mmol, yield: 30%). ES-API: [M+H].sup.+=211.9.

[1478] Step 3: tert-Butyl (R)-3-(6-chloro-2-((S)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 0.208 mmol), bis(pinacolato)diboron (79.36 mg, 0.313 mmol), potassium acetate (61.15 mg, 0.624 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14.98 mg, 0.021 mmol) were dissolved in 1,4-dioxane (2 mL) and stirred at 110 C. for 2 h. 2-Bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine (55.65 mg, 0.262 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10 mg, 0.028 mmol), potassium carbonate (117.24 mg, 0.848 mmol) and water (0.5 mL) were added and stirred at 110 C. for 2 h. The obtained mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=97/3) to give tert-butyl (R)-3-(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-((S)-3-methylmorpholine-4-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.052 mmol, yield: 25%). ES-API: [M+H].sup.+=577.3.

[1479] Step 4: tert-Butyl (R)-3-(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-((S)-3-methylmorpholine-4-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.052 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-3-methylmorpholine)methanone (Z574, 11 mg, 0.023 mmol, yield: 44.37%). ES-API: [M+H].sup.+=477.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.71 (s, 1H), 8.74 (s, 1H), 8.14 (s, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 4.61 (d, J=16.4 Hz, 1H), 4.46 (d, J=16.4 Hz, 1H), 3.97-3.95 (m, 1H), 3.78-3.71 (m, 4H), 3.66-3.40 (m, 6H), 3.26-3.18 (m, 3H), 2.95 (s, 5H), 2.35 (s, 3H), 1.20 (s, 3H).

Example 301. Synthesis of Compound Z562

##STR00583##

[1480] Step 1: 2-Oxa-5-azabicyclo[4.1.0]heptane hydrochloride (250 mg, 1.84 mmol), N,N-diisopropylethyl amine (713 mg, 5.5 mmol) and dichloromethane (10 mL) were added to a 50 mL round-bottom flask. Triphosgene (656 mg, 2.2 mmol) was slowly added at 0 C. and stirred at room temperature for 1 h. tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 181 mg, 1.5 mmol) was then added and stirred at room temperature for 1 h. Dichloromethane (20 mL) was added to the reaction mixture, and the obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (3R)-3-(2-(2-oxa-5-azabicyclo[4.1.0]heptane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (350 mg, yield: 49%). ES-API: [M+H].sup.+=478.2.

[1481] Step 2: tert-Butyl (3R)-3-(2-(2-oxa-5-azabicyclo[4.1.0]heptane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.1 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (108 mg, 0.42 mmol), potassium carbonate (43 mg, 0.31 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.50 mg, 0.01 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted under microwave at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (3R)-3-(2-(2-oxa-5-azabicyclo[4.1.0]heptane-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridine)-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, yield: 68%). ES-API: [M+H].sup.+=574.3.

[1482] Step 3: tert-Butyl (3R)-3-(2-(2-oxa-5-azabicyclo[4.1.0]heptane-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridine)-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.07 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give (2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z562, 6 mg, yield: 18%). ES-API: [M+H].sup.+=474.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.39 (s, 1H), 8.50 (d, J=20.8 Hz, 1H), 8.13 (d, J=29.9 Hz, 1H), 7.81 (d, J=29.4 Hz, 1H), 7.50 (d, J=54.8 Hz, 1H), 7.29 (s, 1H), 4.82-4.45 (m, 2H), 4.34 (s, 1H), 4.06-3.41 (m, 11H), 3.12-2.64 (m, 5H), 2.32 (s, 3H), 2.20-1.85 (m, 1H), 0.95-0.79 (m, 2H).

Example 302. Synthesis of Compound Z540

##STR00584## ##STR00585##

[1483] Step 1: 1-Iodopyrrolidine-2,5-dione (12.50 g, 55.55 mmol) was added to a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (10 g, 50.50 mmol) in N,N-dimethylformamide (60 mL) and stirred at 20 C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and spun to dryness to give 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine (16.00 g, crude product) as a yellow solid. ES-API: [M+1].sup.+=323.9.

[1484] Step 2: At 0 C., sodium hydride (2.37 g, 59.27 mmol) was added to a solution of 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine (16 g, 49.40 mmol) in N,N-dimethylformamide (80 mL) and stirred at 0 C. for 30 min. 4-Methylbenzenesulfonyl chloride (10.36 g, 54.34 mmol) was added, and the reaction mixture was stirred at 20 C. for 3 h. The reaction was quenched by the addition of ice water. The obtained mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give 2-bromo-7-iodo-5-(p-toluenesulfonyl)-5H-pyrrolo[2,3-b]pyrazine (17.80 g, yield: 75.37%) as a yellow solid. ES-API: [M+1].sup.+=477.9.

[1485] Step 3: Potassium vinyltrifluoroborate (1.68 g, 12.55 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (765.53 mg, 1.05 mmol) and potassium carbonate (4.33 g, 31.37 mmol) were added to a solution of 2-bromo-7-iodo-5-(p-toluenesulfonyl)-5H-pyrrolo[2,3-b]pyrazine (5.0 g, 10.46 mmol) in dioxane (50 mL) and water (10 mL). The reaction mixture was stirred at 40 C. for 16 h and spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give a product 2-bromo-5-(p-toluenesulfonyl)-7-vinyl-5H-pyrrolo[2,3-b]pyrazine (2.50 g, yield: 63.20%) as a yellow solid. ES-API: [M+1].sup.+=378.0.

[1486] Step 4: 2-Bromo-5-(p-toluenesulfonyl)-7-vinyl-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 2.64 mmol) was dissolved in ethyl acetate/ethanol (20 mL/10 mL). Platinum dioxide (780.19 mg, 3.44 mmol) was added, and the reaction mixture was stirred under a hydrogen balloon at 20 C. for 3 h, filtered, and spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to give a product 2-bromo-7-ethyl-5-(p-toluenesulfonyl)-5H-pyrrolo[2,3-b]pyrazine (480.00 mg, yield: 47.75%) as a white solid. ES-API: [M+1].sup.+=379.9.

[1487] Step 5: Sodium hydroxide (208 mg, 5.2 mmol) was added to a solution of 2-bromo-7-ethyl-5-(p-toluenesulfonyl)-5H-pyrrolo[2,3-b]pyrazine (200 mg, 0.52 mol) in water/methanol (0.4 mL/1 mL). The reaction mixture was stirred at 20 C. for 16 h, diluted with water (20 mL), and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give 2-bromo-7-ethyl-5H-pyrrolo[2,3-b]pyrazine (90 mg, yield: 77%) as a crude product. ES-API: [M+1].sup.+=225.9.

[1488] Step 6: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (82 mg, 0.15 mmol), 2-bromo-7-ethyl-5H-pyrrolo[2,3-b]pyrazine (12 mg, 0.15 mmol), potassium carbonate (64 mg, 0.46 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (9.6 mg, 0.01 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (R)-3-(6-(7-ethyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (12 mg, yield: 14%). ES-API: [M+H].sup.+=550.3.

[1489] Step 7: tert-Butyl (R)-3-(6-(7-ethyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (12 mg, 0.02 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min, spun to dryness, and then dissolved in dichloromethane (2 mL). Ammonia/methanol (7 M) (2 mL) was added, and the obtained mixture was stirred for 1 h and then spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give (R)-1-(6-(7-ethyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropan-1-one (Z540, 2 mg, yield: 20%). ES-API: [M+H].sup.+=450.2.

Example 303. Synthesis of Compound Z533

##STR00586##

[1490] Step 1: tert-Butyl (R)-3-(2-(2-(2-methylpyrimidine-5-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (174 mg, 0.31 mmol), 2-bromo-7-ethyl-5H-pyrrolo[2,3-b]pyrazine (35 mg, 0.153 mmol), potassium carbonate (64 mg, 0.46 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (13 mg, 0.017 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 3 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-(7-ethyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(2-methylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, yield: 66%). ES-API: [M+H].sup.+=584.2.

[1491] Step 2: tert-Butyl (R)-3-(6-(7-ethyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(2-methylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg 0.13 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(6-(7-ethyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-methylpyrimidin-5-yl)methanone (Z533, 20 mg, yield: 40%). ES-API: [M+H].sup.+=484.2.

Example 304. Synthesis of Compound Z528

##STR00587##

[1492] Step 1: tert-Butyl (R)-3-(2-(morpholine-4-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 0.179 mmol) was dissolved in dioxane (5 mL) and water (1 mL). 2-Bromo-7-ethyl-5H-pyrrolo[2,3-b]pyrazine (50 mg, 0.221 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (12.93 mg, 0.018 mmol) and potassium carbonate (24.79 mg, 0.179 mmol) were added to the above solution at room temperature. After the addition was completed, the reaction mixture was stirred at 110 C. for 5 h under nitrogen atmosphere. Upon completion of the reaction, water (10 mL) was added to the above solution, and the obtained mixture was extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0%-4%) to give tert-butyl (R)-3-(6-(7-ethyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.087 mmol, yield: 48.34%) as a yellow solid. ES-API: [M+H].sup.+=577.3.

[1493] Step 2: tert-Butyl (R)-3-(6-(7-ethyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.087 mmol) was dissolved in anhydrous dichloromethane (1 mL). Trifluoroacetic acid (0.5 mL) was added to the above solution, and the reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and adjusted to neutrality with ammonia/methanol solution (7 M). The obtained mixture was concentrated again, and then purified by a flash silica gel column (methanol/dichloromethane: 0%-7%) to give (R)-(6-(7-ethyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(morpholino)methanone (Z528, 20 mg, purity: 90%, 0.038 mmol, yield: 43.56%) as a pale yellow solid. ES-API: [M+H].sup.+=477.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.08 (s, 1H), 8.59 (s, 1H), 8.06 (s, 1H), 7.72 (s, 1H), 7.31 (s, 1H), 4.70-4.62 (m, 1H), 4.45-4.37 (m, 1H), 4.17-4.09 (m, 1H), 3.91-3.79 (m, 2H), 3.71-3.62 (m, 5H), 3.55-3.43 (m, 3H), 3.32-3.24 (m, 4H), 3.19-3.10 (m, 1H), 3.06-3.00 (m, 1H), 2.99-2.93 (m, 2H), 2.90-2.82 (m, 2H), 1.33 (t, J=7.6 Hz, 3H).

Example 305. Synthesis of Compound Z541

##STR00588##

##STR00589##

[1494] Step 1: Potassium isopropenyltrifluoroborate (1.11 g, 7.53 mmol), Pd(dppf)Cl.sub.2 (459.32 mg, 0.63 mmol) and potassium carbonate (2.6 g, 18.82 mmol) were added to a solution of 2-bromo-7-iodo-5-(p-toluenesulfonyl)-5H-pyrrolo[2,3-b]pyrazine (3.0 g, 6.27 mmol) in dioxane (50 mL) and water (10 mL). The reaction mixture was stirred at 40 C. for 16 h and spun to dryness to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to give a product 2-bromo-7-isopropenyl-5-(p-toluenesulfonyl)-5H-pyrrolo[2,3-b]pyrazine (620.00 mg, yield: 25.19%) as a yellow solid. ES-API: [M+1].sup.+=391.8.

[1495] Step 2: tert-Butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (130 mg, 0.296 mmol), bis(pinacolato)diboron (127.85 mg, 0.503 mmol), potassium acetate (72.56 mg, 0.740 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (20.76 mg, 0.030 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 110 C. for 2 h. 2-Bromo-7-isopropenyl-5-(p-toluenesulfonyl)-5H-pyrrolo[2,3-b]pyrazine (110.92 mg, 0.283 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10 mg, 0.028 mmol), potassium carbonate (117.24 mg, 0.848 mmol) and water (1 mL) were added and stirred at 110 C. for 2 h. The obtained mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=97/3) to give tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(7-(prop-1-en-2-yl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.112 mmol, yield: 37.8%). ES-API: [M+H].sup.+=716.1.

[1496] Step 3: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(7-(prop-1-en-2-yl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.07 mmol) was dissolved in dichloromethane (3 mL). Triethylsilane (162.43 mg, 1.397 mmol) and palladium acetate (31.36 mg, 0.140 mmol) were added, and the system was reacted at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(7-isopropyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.055 mmol, yield: 79.78%). ES-API: [M+H].sup.+=718.1.

[1497] Step 4: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(7-isopropyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.055 mmol) was dissolved in methanol. Sodium hydroxide (1 mL, 6.000 mmol) was added and stirred at 60 C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to give tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(7-isopropyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.053 mmol, yield: 92.9%). ES-API: [M+H].sup.+=564.3.

[1498] Step 5: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(7-isopropyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.053 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (R)-2-hydroxy-1-(6-(7-isopropyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-methylpropan-1-one (Z541, 12 mg, 0.026 mmol, yield: 58.42%). ES-API: [M+H].sup.+=464.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.72 (s, 1H), 8.72 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 5.62-5.26 (m, 2H), 4.78 (d, J=73.1 Hz, 1H), 4.15 (s, 1H), 4.02-3.98 (m, 1H), 3.80-3.76 (m, 3H), 3.59-3.56 (m, 1H), 3.30-3.26 (m, 3H), 3.01-2.96 (m, 4H), 1.47-1.32 (m, 12H).

Example 306. Synthesis of Compound Z563

##STR00590##

[1499] Step 1: 7-Oxa-2-azaspiro[3.5]nonane hydrochloride (100.93 mg, 0.794 mmol) and pyridine (0.4 mL, 4.971 mmol) were dissolved in dichloromethane (10 mL). Triphosgene (58.86 mg, 0.198 mmol) was added under an ice bath condition, and the system was reacted at room temperature for 1 h. N,N-Diisopropylethyl amine (5 mL) and tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 70 mg, 0.198 mmol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl (R)-3-(6-chloro-2-(7-oxa-2-azaspiro[3.5]nonane-2-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.158 mmol, yield: 79.69%). ES-API: [M+H].sup.+=506.2.

[1500] Step 2: tert-Butyl (R)-3-(6-chloro-2-(7-oxa-2-azaspiro[3.5]nonane-2-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.158 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (43.20 mg, 0.167 mmol), potassium carbonate (34.70 mg, 0.251 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.03 mg, 0.008 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at 110 C. for 2 h and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (35 mg, 0.058 mmol, yield: 36.79%). ES-API: [M+H].sup.+=602.2.

[1501] Step 3: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.058 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (R)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(7-oxa-2-azaspiro[3.5]nonan-2-yl)methanone (Z563, 12 mg, 0.030 mmol, yield: 49.87%). ES-API: [M+H].sup.+=502.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.75 (s, 1H), 7.44 (s, 1H), 7.26 (s, 1H), 4.66 (d, J=16.4 Hz, 1H), 4.48 (d, J=16.4 Hz, 1H), 3.96 (dd, J=10.0, 2.8 Hz, 1H), 3.89-3.69 (m, 6H), 3.57-3.43 (m, 7H), 3.29-3.26 (m, 2H), 2.99-2.87 (m, 4H), 2.31 (s, 3H), 1.73-1.64 (m, 4H).

Example 307. Synthesis of Compound Z565

##STR00591##

[1502] Step 1: 8-Oxa-2-azaspiro[4.5]decane hydrochloride (176 mg, 0.991 mmol) and pyridine (0.4 mL, 4.971 mmol) were dissolved in dichloromethane (10 mL). Triphosgene (63.07 mg, 0.213 mmol) was added under an ice bath condition, and the system was reacted at room temperature for 1 h. N,N-Diisopropylethyl amine (5 mL) and tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 70 mg, 0.198 mmol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=70/30) to give tert-butyl (R)-3-(6-chloro-2-(8-oxa-2-azaspiro[4.5]decane-2-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.096 mmol, yield: 48.46%). ES-API: [M+H].sup.+=520.1.

[1503] Step 2: tert-Butyl (R)-3-(6-chloro-2-(8-oxa-2-azaspiro[4.5]decane-2-formyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (45 mg, 0.087 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (44.67 mg, 0.173 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.23 mg, 0.009 mmol) and potassium carbonate (35.87 mg, 0.260 mmol) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL). The reaction mixture was stirred at 110 C. for 2 h. 2-Bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine (48.15 mg, 0.154 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (11.10 mg, 0.015 mmol), potassium carbonate (63.95 mg, 0.463 mmol) and water (0.5 mL). The reaction mixture was stirred at 110 C. for 2 h and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=97/3) to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.049 mmol, yield: 56.31%). ES-API: [M+H].sup.+=616.2.

[1504] Step 3: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.049 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (R)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(8-oxa-2-azaspiro[4.5]decan-2-yl)methanone (Z565, 11 mg, 0.021 mmol, yield: 43.79%). ES-API: [M+H].sup.+=516.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.35 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H), 7.43 (d, J=1.2 Hz, 1H), 7.27 (s, 1H), 4.57 (d, J=16.4 Hz, 1H), 4.40 (d, J=16.4 Hz, 1H), 3.97 (dd, J=10.0, 2.8 Hz, 1H), 3.83-3.69 (m, 2H), 3.65-3.43 (m, 9H), 3.32-3.13 (m, 4H), 3.07-2.76 (m, 4H), 2.32 (s, 3H), 1.86-1.67 (m, 2H), 1.46-1.43 (m, 2H).

Example 308. Synthesis of Compound Z544

##STR00592##

[1505] Step 1: 8-Oxa-3-azabicyclo[3.2.1]octane (0.1 g, 884 mol, 121 L) was dissolved in anhydrous dichloromethane (0.5 mL). N,N-Diisopropylethyl amine (114 mg, 884 mol, 154 L) was added, and triphosgene (288 mg, 972 mol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to give 8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl chloride (155 mg) as a crude product which was directly used in the next step without purification.

[1506] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 60 mg, 170 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (66 mg, 510 mol, 89 L) and 8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl chloride (30 mg, 170 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (83 mg) as a yellow oil. ES-API: [M+H].sup.+=492.3.

[1507] Step 3: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (83 mg, 169 mol) was dissolved in anhydrous dioxane (1 mL). Bis(pinacolato)diboron (128 mg, 506 mol), potassium acetate (49.7 mg, 506 mol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (12 mg, 17 mol) were added, and the system was heated to 110 C. and stirred for 2 h in the presence of protective nitrogen. Upon completion of the reaction, the obtained reaction mixture containing tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (98 mg) was directly used in the next step without treatment. ES-API: [M+H].sup.+=584.4.

[1508] Step 4: Water (0.2 mL) was added to the reaction mixture containing tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (98 mg) obtained in the above step, followed by potassium carbonate (70 mg, 504 mol), 3-trifluoromethyl-5-bromo-7-azaindole (89 mg, 336 mol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (25 mg, 34 mol). The reaction mixture was stirred at 100 C. for 1 h in the presence of protective nitrogen. Upon completion of the reaction, the system was cooled, and the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (0.5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(3-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (107 mg) as a brown oil. ES-API: [M+H].sup.+=642.3.

[1509] Step 5: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(3-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (107 mg, 167 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), neutralized with 7 M amine/methanol (2 mL) solution, spun to dryness, and purified by prep-HPLC (formic acid method) to give (8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(8-((R)-morpholin-3-yl)-6-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z544, 2.33 mg, yield: 2.4%, formate) as a white solid. ES-API: [M+H].sup.+=542.2. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.63 (s, 1H), 8.55-8.44 (m, 1H), 8.29 (s, 1H), 7.91 (s, 1H), 7.74 (s, 1H), 7.48 (s, 1H), 4.71-4.64 (m, 1H), 4.55-4.49 (m, 1H), 4.33 (br s, 2H), 4.31-4.24 (m, 1H), 4.04-3.95 (m, 2H), 3.80-3.71 (m, 1H), 3.65-3.55 (m, 3H), 3.52 (br t, J=6.0 Hz, 2H), 3.28-3.19 (m, 2H), 3.18-3.09 (m, 1H), 3.07-3.00 (m, 2H), 1.93 (s, 4H).

Example 309. Synthesis of Compound Z575

##STR00593##

[1510] Step 1: 8-Methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride (0 mg, 396 mol) was dissolved in anhydrous dichloromethane (0.5 mL). N,N-Diisopropylethyl amine (154 mg, 1.19 mmol, 207 L) was added, and triphosgene (0.13 g, 438 mol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to give 8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl chloride (75 mg) as a crude product which was directly used in the next step without purification.

[1511] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 0.05 g, 142 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (54.9 mg, 425 mol, 74.0 L) and 8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl chloride (26.7 mg, 142 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-(6-chloro-2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (71.0 mg) as a yellow oil. ES-API: [M+H].sup.+=505.3.

[1512] Step 3: tert-Butyl (3R)-3-(6-chloro-2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (71.0 mg, 141 mol) was dissolved in anhydrous dioxane (1 mL). Bis(pinacolato)diboron (107 mg, 422 mol) was added, followed by potassium acetate (41.3 mg, 421 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (10.1 mg, 14.1 mol) was finally added under nitrogen atmosphere, and the system was heated to 110 C. and stirred for 2 h in the presence of protective nitrogen. Upon completion of the reaction, tert-butyl (3R)-3-(2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (84 mg) obtained by concentration was directly used in the next step without treatment. ES-API: [M+H].sup.+=597.4.

[1513] Step 4: Water (0.2 mL) was added to the reaction mixture of tert-butyl (3R)-3-(2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (84 mg, 141 mol) obtained in the above step, followed by potassium carbonate (57.7 mg, 417 mol) and 2-bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine (64.7 mg, 278 mol). Tetrakis(triphenylphosphine)palladium (20.4 mg, 27.8 mol) was added under nitrogen atmosphere, and the system was heated to 100 C. and stirred for 1 h. Upon completion of the reaction, the system was cooled, and the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (0.5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (86.0 mg) as a brown oil. ES-API: [M+H].sup.+=622.4.

[1514] Step 5: tert-Butyl (3R)-3-(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (86.0 mg, 138 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness and purified by prep-HPLC (formic acid method) to give (6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (Z575, 1.24 mg, diformate) as a pale yellow solid. ES-API: [M+H].sup.+=522.3. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.84 (s, 1H), 8.43 (br s, 2H), 8.15 (s, 1H), 7.94 (s, 1H), 7.83 (s, 1H), 4.75-4.68 (m, 1H), 4.67-4.50 (m, 2H), 4.44-4.36 (m, 1H), 4.07-3.98 (m, 2H), 3.89-3.68 (m, 6H), 3.62-3.55 (m, 2H), 3.50-3.38 (m, 2H), 3.24-3.19 (m, 1H), 3.14-3.06 (m, 2H), 2.69 (br s, 3H), 2.28-2.18 (m, 2H), 2.08-1.98 (m, 2H).

Example 310. Synthesis of Compound Z551

##STR00594##

[1515] Step 1: tert-Butyl 8-hydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (150 mg, 660 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL) and spun to dryness to give a crude product 3-azabicyclo[3.2.1]octan-8-ol hydrochloride (100 mg) as a white solid. ES-API: [M+H].sup.+=128.4.

[1516] Step 2: 3-Azabicyclo[3.2.1]octan-8-ol hydrochloride (100 mg, 611 mol) and tert-butyldimethylchlorosilane (178 mg, 1.18 mmol, 144 L) were dissolved in dichloromethane (1 mL). Imidazole (161 mg, 2.36 mmol) was added and stirred at room temperature for 4 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with dichloromethane (1 mL) and spun to dryness to give a crude product 8-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octane (300 mg) as a pale yellow solid. ES-API: [M+H].sup.+=242.3.

[1517] Step 3: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 0.100 g, 283 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (110 mg, 850 mol, 148 L) was added, and triphosgene (0.120 g, 404 mol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to give tert-butyl (R)-3-(6-chloro-2-(chlorocarbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (118 mg) as a crude product which was directly used in the next step without purification.

[1518] Step 4: tert-Butyl (R)-3-(6-chloro-2-(chlorocarbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (118 mg, 282 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (109 mg, 845 mol, 147 L) and 8-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octane (68.0 mg, 282 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product tert-butyl (3R)-3-(2-(8-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg) as a yellow oily liquid. ES-API: [M+H].sup.+=620.3.

[1519] Step 5: tert-Butyl (3R)-3-(2-(8-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 161 mol) was dissolved in dioxane (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (41.6 mg, 161 mol) was added, followed by water (0.2 mL) and potassium carbonate (66.8 mg, 484 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (116 mg, 161 mol) was finally added, and the system was heated to 120 C. and stirred for 3 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was added to ice water (2 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-(2-(8-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octane-3-carbyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg) as a yellow oil. ES-API: [M+H].sup.+=716.5.

[1520] Step 6: tert-Butyl (3R)-3-(2-(8-((tert-butyldimethylsilyl)oxy)-3-azabicyclo[3.2.1]octane-3-carbyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 140 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), neutralized with 7 M amine/methanol (2 mL) solution, spun to dryness, and purified by prep-HPLC (formic acid method) to give (8-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z551, 0.44 mg, yield: 0.58%, formate) as a white solid. ES-API: [M+H].sup.+=502.2. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.51-8.36 (m, 2H), 8.21 (d, J=2.0 Hz, 1H), 7.71 (s, 1H), 7.54 (s, 1H), 7.20 (d, J=0.8 Hz, 1H), 4.70-4.55 (m, 1H), 4.51-4.46 (m, 1H), 4.45-4.36 (m, 1H), 4.09-4.02 (m, 2H), 3.93 (s, 1H), 3.88-3.72 (m, 4H), 3.61-3.46 (m, 2H), 3.45-3.35 (m, 1H), 3.29-3.19 (m, 1H), 3.15-3.00 (m, 4H), 2.38 (d, J=0.8 Hz, 3H), 2.15 (s, 2H), 1.94-1.84 (m, 2H), 1.60 (d, J=10.8 Hz, 2H).

Example 311. Synthesis of Compound Z545

##STR00595## ##STR00596##

[1521] Step 1: A solution of 5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (1.4 g, 5.03 mmol), cesium carbonate (3.28 g, 10 mmol) and p-toluenesulfonyl chloride (1.44 g, 7.54 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 4 h. Upon completion of the reaction, the reaction mixture was added to water (20 mL) and filtered to give 5-chloro-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (2.1 g, yield: 96%) as a white solid. ES-API: [M+H].sup.+=432.9.

[1522] Step 2: 5-Chloro-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.16 mmol), bis(pinacolato)diboron (352 mg, 1.39 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (94.3 mg, 115 mol) and potassium acetate (340 mg, 3.47 mmol) were dissolved in dimethylsulfoxide (5 mL) in the presence of protective nitrogen and stirred at 80 C. for 2 h. Upon completion of the reaction, the reaction mixture was added to water (10 mL) and filtered to give a crude product 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (300 mg) as a brown solid. ES-API: [M+H].sup.+=433.1.

[1523] Step 3: 5-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (300 mg, 693 mol), 4-bromo-2,5-dimethyl-pyridine (154 mg, 831 mol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (56.6 mg, 69.3 mol) and cesium carbonate (677 mg, 2.08 mmol) were dissolved in N,N-dimethylformamide (1 mL) and water (0.1 mL) in the presence of protective nitrogen and stirred at 90 C. for 3 h. Upon completion of the reaction, the reaction mixture was added to water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (0-100% ethyl acetate/petroleum ether) to give 5-chloro-3-(2,5-dimethylpyridin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, yield: 35%) as a yellow solid. ES-API: [M+H].sup.+=412.0.

[1524] Step 4: A solution of 5-chloro-3-(2,5-dimethylpyridin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (60 mg, 145 mol) and sodium hydroxide (5 mol/L, 145 L) in tetrahydrofuran (1 mL) was stirred at 60 C. for 6 h. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate (2 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product 5-chloro-3-(2,5-dimethylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (37 mg) as a yellow solid. ES-API: [M+H].sup.+=258.0.

[1525] Step 5: 5-Chloro-3-(2,5-dimethylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg, 116 mol), bis(pinacolato)diboron (35.4 mg, 139 mol), (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (19.7 mg, 23.2 mol) and potassium acetate (22.8 mg, 232 mol) were dissolved in 1,4-dioxane (1 mL) in the presence of protective nitrogen and stirred at 115 C. for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to give 3-(2,5-dimethylpyridin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (40 mg), which was directly used in the next step without treatment. ES-API: [M+H].sup.+=350.1.

[1526] Step 6: tert-Butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (75.4 mg, 171 mol), potassium carbonate (71.2 mg, 515 mol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (12.3 mg, 17.1 mol) and water (0.2 mL) were added to the above reaction mixture of 3-(2,5-dimethylpyridin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (40 mg) in the presence of protective nitrogen and stirred at 120 C. for 2 h. Upon completion of the reaction, the reaction mixture was added to water (20 mL) and extracted with ethyl acetate (2 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-(3-(2,5-dimethylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy)-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, yield: 42%) as a brown solid. ES-API: [M+H].sup.+=626.3.

[1527] Step 7: tert-Butyl (R)-3-(6-(3-(2,5-dimethylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy)-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 47.9 mol) was dissolved in hydrochloric acid-ethyl acetate (4 mol/L, 1 mL) and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was neutralized with 7 M amine/methanol (3 mL), concentrated, and purified by prep-HPLC (formic acid method) to give (R)-1-(6-(3-(2,5-dimethylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropan-1-one (Z545, 21.64 mg, yield: 79%, formate) as a white solid. ES-API: [M+H].sup.+=526.2. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.60 (d, J=2.0 Hz, 1H), 8.41-8.33 (m, 2H), 8.18 (d, J=2.0 Hz, 1H), 7.73-7.68 (m, 2H), 7.55 (s, 1H), 7.43 (s, 1H), 4.76-4.57 (m, 1H), 4.52-4.41 (m, 1H), 4.39-4.15 (m, 1H), 4.10-3.96 (m, 2H), 3.86-3.74 (m, 1H), 3.73-3.59 (m, 1H), 3.48-3.34 (m, 3H), 3.29-3.21 (m, 1H), 3.14-2.98 (m, 2H), 2.58 (s, 3H), 2.38 (s, 3H), 1.51 (s, 3H), 1.50 (s, 3H).

Example 312. Synthesis of Compound Z546

##STR00597##

[1528] Step 1: 5-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (280 mg, 647 mol), 5-bromo-1,4-dimethyl-imidazole (135 mg, 776 mol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (52.8 mg, 64.7 mol) and cesium carbonate (632 mg, 1.94 mmol) were dissolved in N,N-dimethylformamide (1 mL) and water (0.1 mL) in the presence of protective nitrogen and stirred at 90 C. for 3 h. Upon completion of the reaction, the reaction mixture was added to water (3 mL) and extracted with ethyl acetate (3 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (0-100% ethyl acetate/petroleum ether) to give 5-chloro-3-(1,4-dimethyl-1H-imidazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, yield: 39%) as a yellow solid. ES-API: [M+H].sup.+=401.1.

[1529] Step 2: A solution of 5-chloro-3-(1,4-dimethyl-1H-imidazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.25 mmol) and sodium hydroxide (498 mg, 2.49 mmol) in tetrahydrofuran (2 mL) was stirred at 60 C. for 6 h. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate (2 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-chloro-3-(1,4-dimethyl-1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (50 mg, yield: 81%) as a yellow solid. ES-API: [M+H].sup.+=247.0.

[1530] Step 3: 5-Chloro-3-(1,4-dimethyl-1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.2 mmol), bis(pinacolato)diboron (62 mg, 0.24 mmol), (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) mesylate (17 mg, 0.02 mmol) and potassium acetate (40 mg, 0.41 mmol) were dissolved in 1,4-dioxane (1 mL) in the presence of protective nitrogen and stirred at 115 C. for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to give a product 3-(1,4-dimethyl-1H-imidazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (69 mg), which was directly used in the next step without treatment. ES-API: [M+H].sup.+=339.1.

[1531] Step 4: tert-Butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (89 mg, 0.2 mmol), potassium carbonate (71 mg, 0.52 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (12 mg, 0.02 mmol) and water (0.2 mL) were added to the above reaction mixture of 3-(1,4-dimethyl-1H-imidazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (69 mg) in the presence of protective nitrogen and stirred at 120 C. for 2 h. Upon completion of the reaction, the reaction mixture was added to water (20 mL) and extracted with ethyl acetate (2 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-(3-(1,4-dimethyl-1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, yield of the two steps: 40%) as a brown solid. ES-API: [M+H].sup.+=615.3.

[1532] Step 5: tert-Butyl (R)-3-(6-(3-(1,4-dimethyl-1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.08 mmol) was dissolved in hydrochloric acid-ethyl acetate (4 mol/L, 1 mL) and stirred at room temperature for 0.5 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was neutralized with 7 M amine/methanol (3 mL), concentrated, and purified by prep-HPLC (formic acid method) to give (R)-1-[6-[3-(1,4-dimethyl-1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-8-[morpholin-3-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-2-hydroxy-2-methylpropan-1-one (Z546, 24.6 mg, yield: 54%, formate) as a green solid. ES-API: [M+H].sup.+=515.3. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.55 (d, J=1.6 Hz, 1H), 8.45 (d, J=1.6 Hz, 1H), 8.41 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.56 (s, 1H), 4.84-4.64 (m, 1H), 4.53-4.42 (m, 1H), 4.38-4.15 (m, 1H), 4.14-4.02 (m, 2H), 3.90-3.79 (m, 1H), 3.79-3.66 (m, 4H), 3.47-3.34 (m, 3H), 3.31-3.23 (m, 1H), 3.12-2.93 (m, 2H), 2.38 (s, 3H), 1.52 (s, 3H), 1.51 (s, 3H).

Example 313. Synthesis of Compound Z555

##STR00598## ##STR00599##

[1533] Step 1: 5-Bromo-1H-pyrrolo[2,3-b]pyridine (30 g, 152 mmol) was dissolved in 1,1,1,3,3,3-hexafluoropropan-2-ol (26 g, 152 mmol). N-Chlorosuccinimide (20 g, 344 mmol) was then added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered, it was filtered and beaten with 30% ethyl acetate-cyclohexane (50.0 mL) to give 5-bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (25 g, yield: 71%) as a white solid. ES-API: [M+H].sup.+=231, 233.0.

[1534] Step 2: 5-Bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (10 g, 43.20 mmol) and bis(pinacolato)diboron (22 g, 86.40 mmol) were dissolved in 1,4-dioxane (77 mL) in the presence of protective nitrogen. Anhydrous potassium acetate (13 g, 133 mmol) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (3.13 g, 4.32 mmol) were then added and stirred at 100 C. for 12 h. Upon completion of the reaction, the reaction mixture was filtered, concentrated, and purified by a flash silica gel column (0-100% ethyl acetate/petroleum ether) to give 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (8 g, yield: 66%) as a white solid. ES-API: [M+H].sup.+=279.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.12 (br s, 1H), 8.52 (s, 1H), 8.14 (s, 1H), 7.71 (s, 1H), 1.32 (s, 12H).

[1535] Step 3: Piperidinol (200 mg, 1.98 mmol) was dissolved in tetrahydrofuran (1 mL). Triethylamine (600 mg, 5.93 mmol) and tert-butylchlorodiphenylsilane (815 mg, 2.97 mmol) were then added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was filtered and concentrated to give 4-((tert-butyldiphenylsilyl)oxy)piperidine (300 mg) as a white solid. ES-API: [M+H].sup.+=340.3.

[1536] Step 4: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 60 mg, 170 mol) was dissolved in anhydrous dichloromethane. N,N-Diisopropylethyl amine (22 mg, 170 mol) was added, and triphosgene (106 mg, 357 mol) was added at 0 C. The reaction mixture was stirred at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to give tert-butyl (R)-3-(6-chloro-2-(chlorocarbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (71 mg) as a crude product which was directly used in the next step without purification.

[1537] Step 5: tert-Butyl (R)-3-(6-chloro-2-(chlorocarbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 169 mol) and 4-((tert-butyldiphenylsilyl)oxy)piperidine (69 mg, 202 mol) were dissolved in anhydrous dichloromethane. N,N-Diisopropylethyl amine (65 mg, 506 mol) was then added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with dichloromethane (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(2-(4-((tert-butyldiphenylsilyl)oxy)piperidine-1-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg) as a brown oil. ES-API: [M+H].sup.+=718.3.

[1538] Step 6: 3-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (28 mg, 100 mol) and tert-butyl (R)-3-(2-(4-((tert-butyldiphenylsilyl)oxy)piperidine-1-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 84 mol) were dissolved in dioxane (1 mL) and water (0.2 mL) in the presence of protective nitrogen. Potassium carbonate (35 mg, 251 mol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (6 mg, 8.35 mol) were then added and stirred at 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(2-(4-((tert-butyldiphenylsilyl)oxy)piperidine-1-carbonyl)-6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg) as a brown oil. ES-API: [M+H].sup.+=834.4.

[1539] Step 7: tert-Butyl (R)-3-(2-(4-((tert-butyldiphenylsilyl)oxy)piperidine-1-carbonyl)-6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 84 mol) was dissolved in tetrahydrofuran (1 mL). Triethylamine trihydrofluoride (541 mg, 3.36 mmol) was then added and stirred at 70 C. for 12 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-hydroxypiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg) as a brown oil. ES-API: [M+H].sup.+=596.3.

[1540] Step 8: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-hydroxypiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 83.88 mol, 1 eq) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4 mol/L, 1 mL) was then added and stirred at room temperature for 4 h. Upon completion of the reaction, the reaction mixture was filtered and purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-hydroxypiperidin-1-yl)methanone (Z555, 15.12 mg) as a white solid. ES-API: [M+H].sup.+=496.0. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.56 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.49-7.40 (m, 2H), 4.72-4.65 (m, 1H), 4.59-4.48 (m, 1H), 4.12 (dd, J=2.8, 10.0 Hz, 1H), 3.92-3.77 (m, 3H), 3.76-3.62 (m, 3H), 3.59-3.45 (m, 3H), 3.17-2.99 (m, 6H), 1.97-1.84 (m, 2H), 1.62-1.48 (m, 2H).

Example 314. Synthesis of Compound Z556

##STR00600##

[1541] Step 1: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (26 mg, 100 mol) and tert-butyl (R)-3-(2-(4-((tert-butyldiphenylsilyl)oxy)piperidine-1-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 84 mol) were dissolved in dioxane (1 mL) and water (0.2 mL) in the presence of protective nitrogen. Potassium carbonate (35 mg, 251 mol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (6 mg, 8.35 mol) were then added and stirred at 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(2-(4-((tert-butyldiphenylsilyl)oxy)piperidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg) as a brown oil. ES-API: [M+H].sup.+=814.4.

[1542] Step 2: tert-Butyl (R)-3-(2-(4-((tert-butyldiphenylsilyl)oxy)piperidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 86 mol) was dissolved in tetrahydrofuran (1 mL). Triethylamine trihydrofluoride (554 mg, 3.44 mmol) was then added and stirred at 70 C. for 12 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-hydroxypiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (55 mg) as a brown oil. ES-API: [M+H].sup.+=576.4.

[1543] Step 3: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-hydroxypiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (55 mg, 96 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4 mol/L, 1 mL) was then added and stirred at room temperature for 4 h. Upon completion of the reaction, the reaction mixture was filtered and purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(4-hydroxypiperidin-1-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z556, 15.91 mg) as a white solid. ES-API: [M+H].sup.+=476.1. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.43 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.1 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.42 (d, J=1.4 Hz, 1H), 7.18 (d, J=0.9 Hz, 1H), 4.71-4.62 (m, 1H), 4.55-4.48 (m, 1H), 4.11 (dd, J=2.8, 10.1 Hz, 1H), 3.93-3.76 (m, 3H), 3.74-3.60 (m, 3H), 3.57-3.44 (m, 3H), 3.18-2.97 (m, 6H), 2.37 (d, J=0.9 Hz, 3H), 1.96-1.85 (m, 2H), 1.61-1.46 (m, 2H).

Example 315. Synthesis of Compound Z558

##STR00601##

[1544] Step 1: Pyrrolidin-3-ol (100 mg, 1.15 mmol) was dissolved in tetrahydrofuran (1 mL). Triethylamine (348 mg, 3.44 mmol) and tert-butylchlorodiphenylsilane (473 mg, 1.72 mmol) were then added and stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was filtered and concentrated to give 3-((tert-butyldiphenylsilyl)oxy)pyrrolidine (120 mg) as a white solid. ES-API: [M+H].sup.+=326.1.

[1545] Step 2: tert-Butyl (R)-3-(6-chloro-2-(chlorocarbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 169 mol) and 3-((tert-butyldiphenylsilyl)oxy)pyrrolidine (69 mg, 202 mol) were dissolved in anhydrous dichloromethane. N,N-Diisopropylethyl amine (65 mg, 506 mol) was then added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with dichloromethane (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-(2-(3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg) as a brown oil. ES-API: [M+H].sup.+=704.4.

[1546] Step 3: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (26 mg, 102 mol) and tert-butyl (3R)-3-(2-(3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 85 mol) were dissolved in dioxane (1 mL) and water (0.2 mL). Potassium carbonate (35 mg, 256 mol) was then added, and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (6 mg, 8.52 mol) was added in the presence of protective nitrogen. The reaction mixture was stirred at 120 C. for 2 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-(2-(3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg) as a brown oil. ES-API: [M+H].sup.+=800.4.

[1547] Step 4: tert-Butyl (3R)-3-(2-(3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 87 mol) was dissolved in tetrahydrofuran (1 mL). Triethylamine trihydrofluoride (282 mg, 1.75 mmol) was then added and stirred at 70 C. for 12 h. Upon completion of the reaction, the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (1 mL3). The organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-(2-(3-hydroxypyrrolidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg) as a brown oil. ES-API: [M+H].sup.+=562.4.

[1548] Step 5: tert-Butyl (3R)-3-(2-(3-hydroxypyrrolidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 89 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4 mol/L, 1 mL) was then added and stirred at room temperature for 4 h. Upon completion of the reaction, the reaction mixture was filtered and purified by prep-HPLC (ammonium bicarbonate method) to give (3-hydroxypyrrolidin-1-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z558, 24.61 mg) as a white solid. ES-API: [M+H].sup.+=462.1. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.44 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.75 (s, 1H), 7.44 (s, 1H), 7.18 (s, 1H), 4.78-4.70 (m, 1H), 4.64-4.49 (m, 2H), 4.46-4.41 (m, 1H), 4.21-4.12 (m, 1H), 3.95-3.83 (m, 2H), 3.77-3.64 (m, 4H), 3.56-3.41 (m, 3H), 3.22-2.91 (m, 4H), 2.37 (s, 3H), 2.07-1.87 (m, 2H).

Example 316. Synthesis of Compound Z549

##STR00602##

[1549] Step 1: 8-Oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.05 g, 442 mol) was dissolved in anhydrous dichloromethane (0.5 mL). N,N-Diisopropylethyl amine (171 mg, 1.33 mmol, 231 L) was added, and triphosgene (144 mg, 486 mol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to give 8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl chloride (59 mg) as a crude product which was directly used in the next step without purification.

[1550] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50.0 mg, 142 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (54.9 mg, 425 mol, 74.0 L) and 8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl chloride (24.9 mg, 142 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-[2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (69.0 mg) as a yellow oil. ES-API: [M+H].sup.+=492.4.

[1551] Step 3: tert-Butyl (3R)-3-[2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (69 mg, 140 mol) was dissolved in anhydrous dioxane (1 mL). Bis(pinacolato)diboron (107 mg, 421 mol) was added, followed by potassium acetate (41.3 mg, 421 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (10.1 mg, 14.0 mol) was finally added under nitrogen atmosphere, and the system was heated to 110 C. and stirred for 2 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was concentrated to give tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (81 mg), which was directly used in the next step without treatment. ES-API: [M+H].sup.+=584.4.

[1552] Step 4: Water (0.2 mL) was added to the reaction mixture of tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (81 mg) obtained in the above step, followed by potassium carbonate (59.0 mg, 427 mol) and 2-bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine (66.1 mg, 284 mol). 1,1-Bis(diphenylphosphino)ferrocene dichloropalladium (20.8 mg, 28.4 mol) was added under nitrogen atmosphere, and the system was heated to 100 C. and stirred for 1 h. Upon completion of the reaction, the system was cooled, and the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (0.5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (84.7 mg) as a brown oil. ES-API: [M+H].sup.+=609.3.

[1553] Step 5: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (84.7 mg, 139 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness and purified by prep-HPLC (ammonium bicarbonate method) to give (8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z549, 4.39 mg) as a white solid. ES-API: [M+H].sup.+=509.0. .sup.1H NMR (400 MHz, CD.sub.3OD) =8.82 (s, 1H), 8.13 (d, J=1.4 Hz, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 4.72-4.66 (m, 1H), 4.63-4.56 (m, 1H), 4.56-4.49 (m, 1H), 4.34 (br s, 2H), 4.14 (dd, J=2.7, 9.6 Hz, 1H), 3.93-3.86 (m, 2H), 3.76-3.68 (m, 1H), 3.62-3.47 (m, 6H), 3.15-3.10 (m, 1H), 3.08-3.00 (m, 3H), 1.98-1.90 (m, 4H).

Example 317. Synthesis of Compound Z550

##STR00603##

[1554] Step 1: 2-Oxa-5-azabicyclo[2.2.2]octane hemioxalate (50.0 mg, 442 mol) was dissolved in anhydrous dichloromethane (0.5 mL). N,N-Diisopropylethyl amine (171 mg, 1.33 mmol, 231 L) was added, and triphosgene (0.370 g, 1.25 mmol) was added at 0 C. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to give 2-oxa-5-azabicyclo[2.2.2]octane-3-carbonyl chloride (55 mg), which was directly used in the next step without purification.

[1555] Step 2: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 0.05 g, 142 mol) was dissolved in anhydrous dichloromethane (2 mL). N,N-Diisopropylethyl amine (54.9 mg, 425 mol, 74.0 L) and 2-oxa-5-azabicyclo[2.2.2]octane-3-carbonyl chloride (27.4 mg, 156 mol) were added, and the system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was added to water (0.5 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated brine (0.4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-(2-(2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (69.0 mg) as a yellow oil. ES-API: [M+H].sup.+=492.3.

[1556] Step 3: tert-Butyl (3R)-3-(2-(2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (69.0 mg, 140 mol) was dissolved in anhydrous dioxane (1 mL). Bis(pinacolato)diboron (107 mg, 422 mol) was added, followed by potassium acetate (41.3 mg, 421 mol). Chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)[2-(2-amino-1,1-biphenylyl)]palladium (II) (10.1 mg, 14.1 mol) was finally added under nitrogen atmosphere, and the system was heated to 110 C. and stirred for 2 h in the presence of protective nitrogen. Upon completion of the reaction, tert-butyl (3R)-3-(2-(2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (82 mg) obtained by concentration was directly used in the next step without treatment. ES-API: [M+H].sup.+=584.3.

[1557] Step 4: Water (0.2 mL) was added to the reaction mixture of tert-butyl (3R)-3-(2-(2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (82 mg, 140 mol) obtained in the above step, followed by potassium carbonate (59.0 mg, 427 mol) and 2-bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine (66.1 mg, 284 mol). 1,1-Bis(diphenylphosphino)ferrocene dichloropalladium (20.8 mg, 28.4 mol) was added under nitrogen atmosphere, and the system was heated to 100 C. and stirred for 1 h. Upon completion of the reaction, the system was cooled, and the reaction mixture was added to water (1 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (0.5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (3R)-3-(2-(2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (86.0 mg) as a brown oil. ES-API: [M+H].sup.+=609.1.

[1558] Step 5: tert-Butyl (3R)-3-(2-(2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (86.0 mg, 141 mol) was dissolved in ethyl acetate (1 mL). Hydrochloric acid-ethyl acetate (4.0 mol/L, 1.0 mL) was added and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (1 mL), spun to dryness and purified by prep-HPLC (ammonium bicarbonate method) to give (2-oxa-5-azabicyclo[2.2.2]octan-5-yl)(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z550, 5.30 mg) as a white solid. ES-API: [M+H].sup.+=509.0. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.83 (s, 1H), 8.13 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 4.79-4.70 (m, 1H), 4.60-4.52 (m, 1H), 4.24-4.14 (m, 2H), 4.02-3.87 (m, 5H), 3.87-3.81 (m, 1H), 3.77-3.47 (m, 5H), 3.21-3.02 (m, 4H), 2.29-2.07 (m, 2H), 1.98-1.74 (m, 2H).

Example 318. Synthesis of Compound Z576

##STR00604##

[1559] Step 1: 5-Bromo-N,N,N-triethyl-2-hydroxy-1-tosyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-3-amine bromide (2000 mg, 3.641 mmol) was dissolved in methanol (20 mL). Sodium methoxide in methanol (5 M, 2.185 mL, 10.923 mmol) was added to the above solution. After the addition was completed, the reaction mixture was stirred at 60 C. for 17 h. Upon completion of the reaction, the reaction mixture was concentrated, and water (30 mL) was added to the residue. The obtained mixture was extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated brine (30 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (ethyl acetate/petroleum ether: 0-30%) to give 5-bromo-3-methoxy-1-tosyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-ol (1100 mg, 2.755 mmol, yield: 75.67%) as a green solid. ES-API: [M+H].sup.+=399.1, 401.1.

[1560] Step 2: A solution of 5-bromo-3-methoxy-1-tosyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-ol (800 mg, 2.004 mmol) and hydrogen chloride in methanol (4 M, 10 mL) was added to a sealed tube reactor. After sealing, the reaction mixture was stirred at 80 C. for 17 h. The reaction mixture was concentrated and neutralized with ammonia in methanol (7 M). The obtained solution was concentrated to give a crude product. The crude product was purified by a flash silica gel column (ethyl acetate/petroleum ether: 0-10%) to give 5-bromo-3-methoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.525 mmol, yield: 26.18%) as a white solid. ES-API: [M+H].sup.+=381.1, 383.1.

[1561] Step 3: 5-Bromo-3-methoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.525 mmol), sodium hydroxide (104.92 mg, 2.623 mmol), ethanol (2 mL) and water (2 mL) were added to a sealed tube reactor. After the reaction was sealed, the reaction mixture was stirred at 70 C. for 17 h, adjusted to weak acidity with dilute hydrochloric acid (1 M), and extracted with ethyl acetate (10 mL3). The organic phases were combined, washed with saturated brine (10 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (tetrahydrofuran/petroleum ether: 0-35%) to give 5-bromo-3-methoxy-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.440 mmol, yield: 83.95%) as a white solid. ES-API: [M+H].sup.+=227.1, 229.1.

[1562] Step 4: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (120 mg, 0.226 mmol) was dissolved in dioxane (5 mL) and water (1 mL). 5-Bromo-3-methoxy-1H-pyrrolo[2,3-b]pyridine (51.36 mg, 0.226 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (16.28 mg, 0.023 mmol) and potassium carbonate (93.79 mg, 0.679 mmol) were added to the above solution at room temperature. After the addition was completed, the reaction mixture was stirred at 110 C. for 5 h under nitrogen atmosphere. Upon completion of the reaction, water (10 mL) was added to the above solution, and the obtained mixture was extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0%-2%) to give tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.091 mmol, yield: 40.14%) as a yellow solid. ES-API: [M+H].sup.+=551.0.

[1563] Step 5: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.091 mmol) was dissolved in anhydrous dichloromethane (1 mL). Trifluoroacetic acid (0.5 mL) was added to the above solution, and the reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and adjusted to neutrality with ammonia/methanol solution (7 M). The obtained mixture was concentrated again, and then purified by a flash silica gel column (methanol/dichloromethane: 0%-7%) to give (R)-2-hydroxy-1-(6-(3-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-methylpropan-1-one (Z576, 30 mg, 0.067 mmol, yield: 73.33%) as a pale yellow solid. ES-API: [M+H].sup.+=451.1.

Example 319. Synthesis of Compound Z527

##STR00605##

[1564] Step 1: tert-Butyl (R)-3-(2-(morpholine-4-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (137 mg, 0.246 mmol) was dissolved in dioxane (8 mL) and water (1 mL). 7-Chloro-5H-pyrrolo[2,3-b]pyrazine (171.38 mg, 0.737 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (17.68 mg, 0.025 mmol) and potassium carbonate (101.88 mg, 0.737 mmol) were added to the above solution at room temperature. After the addition was completed, the reaction mixture was stirred at 110 C. for 5 h under nitrogen atmosphere. Upon completion of the reaction, water (20 mL) was added to the above solution, and the obtained mixture was extracted with ethyl acetate (20 mL3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0%-2%) to give tert-butyl (R)-3-(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 0.120 mmol, yield: 48.85%) as a yellow solid. ES-API: [M+H].sup.+=583.0.

[1565] Step 2: tert-Butyl (R)-3-(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 0.120 mmol) was dissolved in anhydrous dichloromethane (1 mL). Trifluoroacetic acid (0.5 mL) was added to the above solution, and the reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and adjusted to neutrality with ammonia/methanol solution (7 M). The obtained mixture was concentrated again, and then purified by a flash silica gel column (methanol/dichloromethane: 0%-7%) to give (R)-(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(morpholino)methanone (Z527, 30 mg, 0.062 mmol, yield: 51.74%) as a pale yellow solid. ES-API: [M+H].sup.+=483.1. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.97 (s, 1H), 8.64 (s, 1H), 8.05 (s, 1H), 7.73 (s, 1H), 7.52 (s, 1H), 4.70-4.62 (m, 1H), 4.45-4.37 (m, 1H), 4.14-4.06 (m, 1H), 3.89-3.77 (m, 2H), 3.70-3.62 (m, 5H), 3.52-3.42 (m, 3H), 3.32-3.25 (m, 4H), 3.18-3.08 (m, 1H), 3.04-2.91 (m, 3H).

Example 320. Synthesis of Compound Z532

##STR00606##

[1566] Step 1: 2-Methylpyrimidine-5-carboxylic acid (117 mg, 0.85 mmol), N,N-diisopropylethyl amine (274 mg, 2.1 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (485 mg, 1.27 mmol) and dimethylformamide (10 mL) were added to a 50 mL round-bottom flask. tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (500 mg, 0.14 mmol) was slowly added at room temperature and stirred at room temperature for 1 h. Ethyl acetate (20 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (R)-3-(6-chloro-2-(2-methylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (200 mg, yield: 99.5%). ES-API: [M+H].sup.+=473.2.

[1567] Step 2: tert-Butyl (R)-3-(6-chloro-2-(6-chloro-2-(2-methylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (200 mg, 0.42 mmol), bis(pinacolato)diboron (129 mg, 0.5 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (29.8 mg, 0.04 mmol), potassium acetate (124 mg, 1.27 mmol) and dioxane (10 mL) were added to a 5 mL microwave reactor. The reaction mixture was stirred at 100 C. for 2 h, cooled to room temperature, and directly used in the next step. ES-API: [M+H].sup.+=565.3.

[1568] Step 3: The reaction mixture of tert-butyl (R)-3-(2-(2-methylpyrimidine-5-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate obtained in the above step, 5-bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (123 mg, 0.53 mmol), potassium carbonate (74 mg, 0.53 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (26 mg, 0.035 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 3 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, yield of the two steps: 66%). ES-API: [M+H].sup.+=589.2.

[1569] Step 4: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-methylpyrimidine-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg 0.13 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(6-(3-50 chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-methylpyrimidin-5-yl)methanone (Z532, 25 mg, yield: 50%). ES-API: [M+H].sup.+=489.2.

Example 321. Synthesis of Compound Z531

##STR00607##

[1570] Step 1: 2,6-Dimethylpyrimidine-4-carboxylic acid (215 mg, 1.4 mmol), N,N-diisopropylethyl amine (915 mg, 7.0 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (1616 mg, 4.2 mmol) and dimethylformamide (10 mL) were added to a 50 mL round-bottom flask. tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (500 mg, 0.14 mmol) was slowly added at room temperature and stirred at room temperature for 1 h. Ethyl acetate (20 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (R)-3-(6-chloro-2-(2,6-dimethylpyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (550 mg, yield: 79.7%). ES-API: [M+H].sup.+=487.1.

[1571] Step 2: tert-Butyl (R)-3-(6-chloro-2-(2,6-dimethylpyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 0.2 mmol), bis(pinacolato)diboron (62 mg, 0.25 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14.8 mg, 0.02 mmol), potassium acetate (60 mg, 0.61 mmol) and dioxane (2 mL) were added to a 5 mL microwave reactor. The reaction mixture was stirred at 100 C. for 3 h, cooled to room temperature, and directly used in the next step. ES-API: [M+H].sup.+=579.3.

[1572] Step 3: The reaction mixture of tert-butyl (R)-3-(2-(2,6-dimethylpyrimidine-4-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate obtained in the above step, 5-bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (141 mg, 0.61 mmol), potassium carbonate (84 mg, 0.61 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (29 mg, 0.04 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 3 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,6-dimethylpyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, yield of the two steps: 66%). ES-API: [M+H].sup.+=603.2.

[1573] Step 4: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,6-dimethylpyrimidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg 0.13 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give (R)-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(2,6-dimethylpyrimidin-4-yl)methanone (Z531, 25 mg, yield: 37%). ES-API: [M+H].sup.+=503.2.

Example 322. Synthesis of Compound Z538

##STR00608##

[1574] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 100 mg, 0.28 mmol) was dissolved in ethanol (1 mL). 1,6-Dioxaspiro[2.5]octane (68 mg, 0.56 mmol) and triethylamine (86.03 mg, 0.85 mmol) were added, and the system was heated to 75 C. and reacted for 16 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a chromatographic column (petroleum ether/ethyl acetate=1/1) to give a product tert-butyl (R)-3-(6-chloro-2-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (104 mg, yield: 78.58%). ES-API: [M+H].sup.+=467.1.

[1575] Step 2: tert-Butyl (R)-3-(6-chloro-2-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.09 mmol) was dissolved in dioxane/water (2 mL/0.4 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (26.53 mg, 0.10 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.16 mg, 0.009 mmol) and potassium carbonate (35.46 mg, 0.26 mmol) were added. The system was heated to 100 C. and reacted for 2 h. Upon completion of the reaction, the reaction mixture was spun to dryness to give a crude product. The crude product was purified by a chromatographic column (dichloromethane/methanol=20/1) to give a product tert-butyl (R)-3-(2-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, yield: 82.99%). ES-API: [M+1].sup.+=563.3.

[1576] Step 3: tert-Butyl (R)-3-(2-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1.0 mL) was added. The system was reacted at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was spun to dryness, extracted with dichloromethane and saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, filtered, and spun to dryness to give a crude product. The crude product was purified by a chromatographic column (dichloromethane/methanol=8/1) to give a product (R)-4-((6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)tetrahydro-2H-pyran-4-ol (Z538, 4.2 mg, yield: 12.77%). ES-API: [M+1].sup.+=463.2.

Example 323. Synthesis of Compound Z543

##STR00609##

[1577] Step 1: Tetrahydropyran-4-carbonyl chloride (31.58 mg, 0.21 mmol) and triethylamine (43.02 mg, 0.43 mmol) were added to a solution of tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 50 mg, 0.14 mmol) in dichloromethane (2 mL). The mixture was stirred at 0 C. for half an hour. The reaction was monitored by LCMS for completion, and the reaction was quenched by the addition of water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-60% ethyl acetate/petroleum ether, petroleum ether/ethyl acetate=1/1, Rf=0.4) to give a product tert-butyl (R)-3-(6-chloro-2-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, yield: 75.89%). ES-API: [M+H].sup.+=465.1.

[1578] Step 2: 3-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (35.94 mg, 0.13 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (7.74 mg, 0.01 mmol) and potassium carbonate (44.52 mg, 0.32 mmol) were added to a solution of compound tert-butyl (R)-3-(6-chloro-2-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.11 mmol) in dioxane/water (2 mL/0.4 mL). In the presence of protective nitrogen, the mixture was heated to 100 C. and stirred for 2 h. The reaction was monitored by LCMS for completion. The reaction mixture was treated with ethyl acetate/water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane, dichloromethane/methanol=10/1, Rf=0.6) to give a product tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, yield: 48.01%). ES-API: [M+H].sup.+=581.2.

[1579] Step 3: Trifluoroacetic acid (1 mL) was added to a solution of compound tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.05 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction was monitored by LCMS for completion. The reaction mixture was neutralized and adjusted to pH 7 with saturated sodium bicarbonate, treated with dichloromethane/water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (ammonia water method-A) to give (R)-[6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl](tetrahydro-2H-pyran-4-yl)methanone (Z543, 4.2 mg, 16.91%) as a white powder. ES-API: [M+H].sup.+=481.1.

Example 324. Synthesis of Compound Z523

##STR00610##

[1580] Step 1: 2-Amino-3-iodo-5-bromopyridine (300 mg, 1.004 mmol), cyclopropyl(trimethylsilyl)acetylene (249.81 mg, 1.807 mmol), bis(triphenylphosphine)palladium dichloride (72.26 mg, 0.100 mmol), sodium carbonate (265.94 mg, 2.509 mmol) and lithium chloride (42.54 mg, 1.004 mmol) were dissolved in N,N-dimethylformamide (5 mL). The system was reacted at 85 C. for 16 h in the presence of protective nitrogen. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give 5-bromo-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.323 mmol, yield: 32.22%). ES-API: [M+H].sup.+=309.0.

[1581] Step 2: 5-Bromo-3-cyclopropyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.323 mmol) was dissolved in tetrahydrofuran (2 mL). Tetrabutylammonium fluoride (0.647 mL, 0.647 mmol) was added, and the system was reacted at 70 C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give 5-bromo-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (60 mg, 0.253 mmol, yield: 78.27%). ES-API: [M+H].sup.+=237.1.

[1582] Step 3: tert-Butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (44 mg, 0.1 mmol), bis(pinacolato)diboron (0.055 g, 0.22 mmol), potassium acetate (21 mg, 0.22 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8 mg, 0.012 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 110 C. for 2 h. 5-Bromo-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (60 mg, 0.253 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8 mg, 0.012 mmol) and potassium carbonate (41 mg, 0.3 mmol) were added and stirred at 110 C. for 2 h. The obtained mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=97/3) to give tert-butyl (R)-3-(6-(3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, 0.045 mmol, yield: 45%). ES-API: [M+H].sup.+=561.2.

[1583] Step 4: tert-Butyl (R)-3-(6-(3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (25 mg, 0.045 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (R)-1-(6-(3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropan-1-one (Z523, 12 mg, 0.026 mmol, yield: 58.42%). ES-API: [M+H].sup.+=461.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.36 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.78 (s, 1H), 7.43 (s, 1H), 7.19 (d, J=2.0 Hz, 1H), 5.52-5.32 (m, 2H), 4.84-4.67 (m, 1H), 4.15 (s, 1H), 4.02-3.93 (m, 1H), 3.78 (d, J=10.4 Hz, 2H), 3.56-3.50 (m, 1H), 3.25-3.22 (m, 2H), 2.92-2.81 (m, 5H), 2.05-1.97 (m, 1H), 1.37 (s, 6H), 0.94-0.78 (m, 2H), 0.67-0.64 (m, 2H).

Example 325. Synthesis of Compound Z577

##STR00611##

[1584] Step 1: 4-Nitrophenyl 4-hydroxy-2,2-dimethylpyrrolidine-1-carboxylate (111 mg, 0.397 mmol), tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 70 mg, 0.198 mmol), potassium carbonate (82 mg, 0.595 mmol), and dimethylacetamide (1 mL) were added to a 5 mL microwave reactor. The reaction mixture was stirred at 130 C. overnight. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (10 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (3R)-3-(6-chloro-2-(4-hydroxy-2,2-dimethylpyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, yield: 81%). ES-API: [M+H].sup.+=494.2.

[1585] Step 2: tert-Butyl (3R)-3-(6-chloro-2-(4-hydroxy-2,2-dimethylpyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.16 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (84 mg, 0.32 mmol), potassium carbonate (67 mg, 0.48 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (11.6 mg, 0.01 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 120 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (3R)-3-(2-(4-hydroxy-2,2-dimethylpyrrolidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, yield: 63%). ES-API: [M+H].sup.+=590.3.

[1586] Step 3: tert-Butyl (3R)-3-(2-(4-hydroxy-2,2-dimethylpyrrolidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.05 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask and stirred at room temperature for 30 min.

[1587] The reaction mixture was spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method) to give (4-hydroxy-2,2-dimethylpyrrolidin-1-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z577, 7 mg, yield: 14%). ES-API: [M+H].sup.+=490.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.45 (d, J=1.9 Hz, 1H), 8.09 (s, 1H), 7.75 (s, 1H), 7.42 (s, 1H), 7.26 (s, 1H), 5.08-4.95 (m, 1H), 4.47-4.38 (m, 1H), 4.24 (d, J=12.1 Hz, 2H), 3.95 (d, J=10.1 Hz, 1H), 3.80-3.43 (m, 5H), 3.35 (s, 1H), 3.25 (s, 2H), 2.92 (s, 4H), 2.31 (s, 4H), 1.91 (s, 1H), 1.74 (s, 1H), 1.45 (d, J=9.5 Hz, 3H), 1.37 (d, J=2.3 Hz, 3H).

Example 326. Synthesis of Compound Z578

##STR00612##

[1588] Step 1: 5-Bromo-3-iodo-7-azaindole (0.8 g, 2.477 mmol) and 2-ethynyl-3-methylpyridine (0.38 g, 3.220 mmol) were dissolved in triethylamine (10 mL). Cuprous iodide (0.05 g, 0.248 mmol) and bis(triphenylphosphine)palladium dichloride (0.19 g, 0.248 mmol) were added, and the system was reacted at room temperature for 18 h. Upon completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (30 mL3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/50) to give 5-bromo-3-[(3-methylpyridin-2-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridine (430 mg, 1.377 mmol, yield: 55.60%). ES-API: [M+H].sup.+=312.0.

[1589] Step 2: tert-Butyl (R)-3-(6-chloro-2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (44 mg, 0.1 mmol), bis(pinacolato)diboron (0.055 g, 0.22 mmol), potassium acetate (21 mg, 0.22 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8 mg, 0.012 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 110 C. for 2 h. 5-Bromo-3-[(3-methylpyridin-2-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridine (68 mg, 0.22 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (10 mg, 0.014 mmol) and potassium carbonate (41 mg, 0.3 mmol) were added and stirred at 110 C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to give tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-((3-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.031 mmol, yield: 31.71%). ES-API: [M+H].sup.+=636.2.

[1590] Step 3: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropanoyl)-6-(3-((3-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (15 mg, 0.024 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). Trifluoroacetic acid (0.2 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give (R)-2-hydroxy-2-methyl-1-(6-(3-50 ((3-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (Z578, 7.5 mg, 0.014 mmol, yield: 59.34%). ES-API: [M+H].sup.+=536.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.36 (s, 1H), 8.62 (d, J=1.6 Hz, 1H), 8.42 (d, J=4.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.49 (s, 1H), 7.27-7.17 (m, 1H), 5.53-5.32 (m, 2H), 4.83-4.66 (m, 1H), 4.01-3.81 (m, 2H), 3.79 (d, J=10.0 Hz, 2H), 3.62-3.50 (m, 2H), 3.25-3.22 (m, 2H), 3.04-2.88 (m, 4H), 2.54 (s, 3H), 1.37 (s, 6H).

Example 327. Synthesis of Compound Z579

##STR00613##

[1591] Step 1: 2-Oxa-6-azaspiro[3.3]heptane (200 mg, 2.018 mmol) was dissolved in dichloromethane (8 mL). Triethylamine (0.841 mL, 6.053 mmol) and p-nitrophenyl chloroformate (447.32 mg, 2.219 mmol) were added to the above solution under an ice bath condition, and the system was reacted at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 1-8%) to give 4-nitrophenyl 2-oxa-6-azaspiro[3.3]heptane-6-carboxylate (400 mg, 1.514 mmol, yield: 75.03%) as a white solid. ES-API: [M+H].sup.+=265.0.

[1592] Step 2: 4-Nitrophenyl 2-oxa-6-azaspiro[3.3]heptane-6-carboxylate (44.92 mg, 0.170 mmol) was dissolved in N,N-dimethylacetamide (3 mL). tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 60 mg, 0.170 mmol) and potassium carbonate (70.50 mg, 0.510 mmol) were then added to the above solution. The system was reacted at 130 C. for 17 h. Upon completion of the reaction, water (30 mL) was added to the above solution, and the obtained mixture was extracted with ethyl acetate (30 mL3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (tetrahydrofuran/petroleum ether: 0%-40%) to give tert-butyl (R)-3-(6-chloro-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (48.76 mg, 0.102 mmol, yield: 60%) as a pale yellow solid. ES-API: [M+H].sup.+=478.1.

[1593] Step 3: tert-Butyl (R)-3-(6-chloro-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.126 mmol) was dissolved in dioxane (5 mL) and water (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (81.00 mg, 0.314 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.03 mg, 0.013 mmol) and potassium carbonate (52.04 mg, 0.377 mmol) were added to the above solution at room temperature. After the addition was completed, the reaction mixture was stirred at 110 C. for 2 h under nitrogen atmosphere. Upon completion of the reaction, water (10 mL) was added to the above solution, and the obtained mixture was extracted with ethyl acetate (10 mL3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0%-2%) to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (35 mg, 0.061 mmol, yield: 48.4%) as a white solid. ES-API: [M+H].sup.+=574.3.

[1594] Step 4: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (35 mg, 0.061 mmol) was dissolved in anhydrous dichloromethane (1 mL). Trifluoroacetic acid (0.5 mL) was added to the above solution, and the reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and adjusted to neutrality with ammonia/methanol solution (7 M). The obtained mixture was concentrated again, and then purified by a flash silica gel column (methanol/dichloromethane: 0%-4%) to give (R)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-oxa-6-oxaspiro[3.3]heptan-6-yl)methanone (Z579, 15 mg, 0.032 mmol, yield: 51.92%) as a pale yellow solid. ES-API: [M+H].sup.+=474.2. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.40 (s, 1H), 8.42 (d, J=1.6 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.73 (s, 1H), 7.25 (s, 1H), 7.04 (s, 1H), 4.79-4.69 (m, 6H), 4.45-4.36 (m, 1H), 4.18-4.11 (m, 4H), 3.90-3.76 (m, 2H), 3.73-3.64 (m, 1H), 3.52-3.41 (m, 3H), 3.22-3.11 (m, 1H), 3.06-2.97 (m, 1H), 2.90-2.82 (m, 2H), 2.29 (s, 3H).

Example 328. Synthesis of Compound Z580

##STR00614##

[1595] Step 1: 1-(Oxetan-3-yl)piperazine (200 mg, 1.406 mmol) was dissolved in dichloromethane (8 mL). Triethylamine (0.586 mL, 4.219 mmol) and p-nitrophenyl chloroformate (340.19 mg, 1.688 mmol) were added to the above solution under an ice bath condition, and the system was reacted at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 1-8%) to give 4-nitrophenyl 4-(oxetan-3-yl)piperazine-1-carboxylate (400 mg, 1.302 mmol, yield: 92.55%) as a white solid. ES-API: [M+H].sup.+=308.0.

[1596] Step 2: 4-Nitrophenyl 4-(oxetan-3-yl)piperazine-1-carboxylate (149.77 mg, 0.567 mmol) was dissolved in N,N-dimethylacetamide (3 mL). tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 100 mg, 0.283 mmol) and potassium carbonate (117.50 mg, 0.850 mmol) were then added to the above solution. The system was reacted at 130 C. for 17 h. Upon completion of the reaction, water (30 mL) was added to the above solution, and the obtained mixture was extracted with ethyl acetate (30 mL3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0%-3%) to give tert-butyl (R)-3-(6-chloro-2-(4-(oxetan-3-yl)piperazine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 0.192 mmol, yield: 67.84%) as a pale yellow solid. ES-API: [M+H].sup.+=521.1.

[1597] Step 3: tert-Butyl (R)-3-(6-chloro-2-(4-(oxetan-3-yl)piperazine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 0.192 mmol) was dissolved in dioxane (5 mL) and water (1 mL). 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (123.85 mg, 0.480 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (13.81 mg, 0.019 mmol) and potassium carbonate (79.57 mg, 0.576 mmol) were added to the above solution at room temperature. After the addition was completed, the reaction mixture was stirred at 110 C. for 2 h under nitrogen atmosphere. Upon completion of the reaction, water (20 mL) was added to the above solution, and the obtained mixture was extracted with ethyl acetate (20 mL3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0%-4%) to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-(oxetan-3-yl)piperazine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.065 mmol, yield: 33.79%) as a white solid. ES-API: [M+H].sup.+=617.3.

[1598] Step 4: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-(oxetan-3-yl)piperazine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.065 mmol) was dissolved in anhydrous dichloromethane (1 mL). Trifluoroacetic acid (0.5 mL) was added to the above solution, and the reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and adjusted to neutrality with ammonia/methanol solution (7 M). The obtained mixture was concentrated again, and then purified by a flash silica gel column (methanol/dichloromethane: 0%-6%) to give (R)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-(oxetan-3-yl)piperazin-1-yl)methanone (Z580, 20 mg, 0.038 mmol, yield: 58.49%) as a pale yellow solid. ES-API: [M+H].sup.+=517.3.

Example 329. Synthesis of Compound Z581

##STR00615##

[1599] Step 1: (S)-3-Methylmorpholine (220 mg, 2.18 mmol) was dissolved in tetrahydrofuran (5 mL). Triethylamine (660 mg, 6.53 mmol) and 4-nitrobenzoyl chloride (525 mg, 2.61 mmol) were added successively, and the reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction checked by LC-MS, water (10 mL) was added, and the obtained mixture was extracted with ethyl acetate (20 mL2). The organic layer was washed with saturated sodium chloride solution (20 mL2), concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=10%-30%) to give 4-nitrophenyl (S)-3-methylmorpholine-4-carboxylate (550 mg, 2.07 mmol, yield: 94.85%). ES-API: [M+H].sup.+=267.1.

[1600] Step 2: 4-Nitrophenyl (S)-3-methylmorpholine-4-carboxylate (455 mg, 1.71 mmol) was dissolved in N,N-dimethylacetamide (2 mL) in a sealed tube. tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 550 mg, 1.56 mmol) and potassium carbonate (1075 mg, 7.79 mmol) were added, and the reaction mixture was stirred at 130 C. overnight. Upon completion of the reaction checked by LC-MS, water (5 mL) was added, and the obtained mixture was extracted with ethyl acetate (20 mL2). The organic layer was washed with saturated sodium chloride solution (10 mL2), concentrated, and purified by silica gel column chromatography (methanol/dichloromethane=2%-5%) to give tert-butyl (R)-3-(6-chloro-2-((S)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (101 mg, 0.21 mmol, yield: 12.33%). ES-API: [M+H].sup.+=480.2.

[1601] Step 3: tert-Butyl (R)-3-(6-chloro-2-((S)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (101 mg, 0.21 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (65 mg, 0.25 mmol), potassium carbonate (58 mg, 0.42 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (15 mg, 0.02 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at 100 C. for 2 h. Upon completion of the reaction checked by LC-MS, water (5 mL) was added, and the obtained mixture was extracted with ethyl acetate (10 mL2). The organic layer was washed with saturated sodium chloride solution (5 mL2), concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=30%-70%) to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (93 mg, 0.16 mmol, yield: 77.02%). ES-API: [M+H].sup.+=576.3.

[1602] Step 4: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (93 mg, 0.16 mmol) was dissolved in anhydrous dichloromethane (5 mL). Trifluoroacetic acid (3 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia/methanol solution (1 mL), the obtained mixture was concentrated again, and the residue was purified by prep-HPLC (ammonium bicarbonate method-A) to give (6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-3-methylmorpholino)methanone (Z581, 13 mg, 0.03 mmol, yield: 18.75%). ES-API: [M+H].sup.+=476.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.46 (d, J=1.6 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.76 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 4.67-4.35 (m, 4H), 3.99-3.97 (m, 1H), 3.87 (d, J=7.2 Hz, 1H), 3.83-3.66 (m, 3H), 3.61-3.45 (m, 4H), 3.30-3.22 (m, 3H), 3.01-2.87 (m, 4H), 2.32 (s, 3H), 1.74 (s, 2H).

Example 330. Synthesis of Compound Z606

##STR00616##

[1603] Step 1: In the presence of protective nitrogen, a mixture of tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (90 mg, 0.18 mmol), bis(pinacolato)diboron (60 mg, 0.24 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (13 mg, 0.02 mmol) and potassium acetate (54 mg, 0.55 mmol) in 1,4-dioxane (2 mL) was stirred at 110 C. for 2 h. Upon completion of the reaction, the reaction mixture was filtered and concentrated to give tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (106 mg, crude product). ES-API: [M+H].sup.+=584.2.

[1604] Step 2: In the presence of protective nitrogen, a mixture of tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (106 mg, 0.18 mmol), 2-bromo-7-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (216 mg, 0.55 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (13 mg, 0.02 mmol) and potassium carbonate (75 mg, 0.55 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was dissolved in ethyl acetate (20 mL), and washed with saturated brine (10 mL) and water (10 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-100% tetrahydrofuran/petroleum ether) to give tert-butyl (R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(7-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, yield: 42.7%) as a colorless oil. ES-API: [M+H].sup.+=773.2.

[1605] Step 3: Under an ice bath condition, trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl (R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(7-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.08 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated, neutralized with 7 M amine-methanol (5 mL), concentrated, and then purified by prep-HPLC (ammonium bicarbonate) to give (8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(8-((R)-morpholin-3-yl)6-(7-(trifluoromethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z606, 11.63 mg, purity: 100%, yield: 27.61%) as a white solid. ES-API: [M+H].sup.+=543.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.95 (s, 1H), 8.52 (s, 1H), 8.15 (s, 1H), 7.81 (s, 1H), 4.63-4.53 (m, 1H), 4.48-4.40 (m, 1H), 4.28 (s, 2H), 4.07-3.96 (m, 1H), 3.85-3.75 (m, 2H), 3.56 (t, J=9.2 Hz, 1H), 3.49-3.35 (m, 4H), 3.20-3.04 (m, 3H), 3.02-2.90 (m, 4H), 1.85-1.75 (m, 4H).

Example 331. Synthesis of Compound Z608

##STR00617##

[1606] Step 1: In the presence of protective nitrogen, a mixture of tert-butyl (R)-3-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (130 mg, 0.27 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (152 mg, 0.54 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (20 mg, 0.03 mmol) and potassium carbonate (113 mg, 0.82 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 100 C. for 1 h. Upon completion of the reaction, the reaction mixture was dissolved in ethyl acetate (20 mL), and washed with saturated brine (10 mL) and water (10 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-100% tetrahydrofuran/petroleum ether) to give tert-butyl (R)-3-(2-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (120 mg, yield: 74%) as a colorless oil. ES-API: [M+H].sup.+=594.1.

[1607] Step 2: Under an ice bath condition, trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl (R)-3-(2-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (120 mg, 0.20 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated, neutralized with 7 M amine-methanol (5 mL), concentrated, and then purified by prep-HPLC (ammonium bicarbonate) to give ((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z608, 33.4 mg, purity: 100%, yield: 33.5%) as a white solid. ES-API: [M+H].sup.+=494.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.07 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.48 (s, 1H), 4.68-4.60 (m, 1H), 4.56 (s, 1H), 4.48-4.40 (m, 1H), 4.36 (s, 1H), 4.02-3.94 (m, 1H), 3.90-3.84 (m, 1H), 3.82-3.72 (m, 2H), 3.72-3.67 (m, 1H), 3.60-3.45 (m, 3H), 3.44-3.36 (m, 1H), 3.30-3.20 (m, 2H), 3.01-2.87 (m, 4H), 1.74 (s, 2H).

Example 332. Synthesis of Compound Z624

##STR00618##

[1608] Step 1: A mixture of 4,4-difluoropiperidine hydrochloride (89 mg, 0.57 mmol) in dichloromethane (5 mL) was cooled to 0 C. Triethylamine (0.12 mL, 0.85 mmol) and triphosgene (168 mg, 0.57 mmol) were added successively and stirred for 0.5 h. The reaction mixture was concentrated and subsequently dissolved in dichloromethane (5 mL). Triethylamine (0.12 mL, 0.85 mmol) and tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 100 mg, 0.28 mol) were added and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution (10 mL), and the reaction mixture was extracted with dichloromethane (10 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-40% tetrahydrofuran/petroleum ether) to give tert-butyl (R)-3-(6-chloro-2-(4,4-difluoropiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (130 mg, yield: 92%). ES-API: [M+H].sup.+=500.1.

[1609] Step 2: In the presence of protective nitrogen, a mixture of tert-butyl (R)-3-(6-chloro-2-(4,4-difluoropiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (90 mg, 0.18 mmol), bis(pinacolato)diboron (59 mg, 0.23 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (13 mg, 0.02 mmol) and potassium acetate (53 mg, 0.54 mmol) in 1,4-dioxane (2 mL) was stirred at 110 C. for 2 h. Upon completion of the reaction, the reaction mixture was filtered and concentrated to give tert-butyl (R)-3-(2-(4,4-difluoropiperidine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (106 mg, crude product). ES-API: [M+H].sup.+=592.3.

[1610] Step 3: In the presence of protective nitrogen, a mixture of tert-butyl (R)-3-(2-(4,4-difluoropiperidine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (106 mg, 0.18 mmol), tert-butyl 2-bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (112 mg, 0.36 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (13 mg, 0.02 mmol) and potassium carbonate (74 mg, 0.54 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was dissolved in ethyl acetate (20 mL), and washed with saturated brine (10 mL) and water (10 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-100% tetrahydrofuran/petroleum ether) to give tert-butyl (R)-3-(6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(4,4-difluoropiperidine)-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (110 mg, yield: 88%) as a colorless oil. ES-API: [M+H].sup.+=697.3.

[1611] Step 4: Under an ice bath condition, trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl (R)-3-(6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(4,4-difluoropiperidine)-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (110 mg, 0.16 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated, neutralized with 7 M amine-methanol (5 mL), concentrated, and then purified by prep-HPLC (ammonium bicarbonate) to give (R)-(4,4-difluoropiperidin-1-yl)(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z624, 49.3 mg, purity: 100%, yield: 62.9%) as a white solid. ES-API: [M+H].sup.+=497.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.72 (s, 1H), 8.74 (s, 1H), 8.15 (s, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 4.69-4.58 (m, 1H), 4.56-4.45 (m, 1H), 4.02-3.93 (m, 1H), 3.84-3.72 (m, 2H), 3.59-3.41 (m, 3H), 3.37-3.33 (m, 2H), 3.32-3.25 (m, 3H), 3.03-2.92 (m, 4H), 2.35 (s, 3H), 2.09-1.97 (m, 4H).

Example 333. Synthesis of Compound Z607

##STR00619##

[1612] Step 1: A mixture of (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (192 mg, 1.42 mmol) in dichloromethane (5 mL) was cooled to 0 C. Triethylamine (0.29 mL, 2.12 mmol) and triphosgene (420 mg, 1.42 mmol) were added successively and stirred for 0.5 h. The reaction mixture was concentrated and subsequently dissolved in dichloromethane (5 mL). Triethylamine (0.29 mL, 2.12 mmol) and tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 250 mg, 0.71 mol) were added and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution (10 mL), and the reaction mixture was extracted with dichloromethane (10 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-40% tetrahydrofuran/petroleum ether) to give tert-butyl (R)-3-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (270 mg, yield: 80%). ES-API: [M+H].sup.+=478.1.

[1613] Step 2: In the presence of protective nitrogen, a mixture of tert-butyl (R)-3-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (90 mg, 0.19 mmol), bis(pinacolato)diboron (62 mg, 0.25 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.02 mmol) and potassium acetate (55 mg, 0.57 mmol) in 1,4-dioxane (2 mL) was stirred at 110 C. for 2 h. Upon completion of the reaction, the reaction mixture was filtered and concentrated to give tert-butyl (R)-3-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (106 mg, crude product). ES-API: [M+H].sup.+=570.2.

[1614] Step 3: In the presence of protective nitrogen, a mixture of tert-butyl (R)-3-(2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (106 mg, 0.19 mmol), tert-butyl 2-bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (116 mg, 0.37 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (14 mg, 0.02 mmol) and potassium carbonate (77 mg, 0.56 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was dissolved in ethyl acetate (20 mL), and washed with saturated brine (10 mL) and water (10 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-100% tetrahydrofuran/petroleum ether) to give tert-butyl (R)-3-(2-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, yield: 80%) as a colorless oil. ES-API: [M+H].sup.+=675.3.

[1615] Step 4: Under an ice bath condition, trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl (R)-3-(2-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 0.10 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated, neutralized with 7 M amine-methanol (5 mL), concentrated, and then purified by prep-HPLC (ammonium bicarbonate) to give ((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z607, 45.22 mg, purity: 100%, yield: 64.3%) as a white solid. ES-API: [M+H].sup.+=475.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.72 (s, 1H), 8.74 (s, 1H), 8.14 (s, 1H), 7.82 (s, 1H), 7.67 (s, 1H), 4.70-4.61 (m, 1H), 4.56 (s, 1H), 4.54-4.43 (m, 1H), 4.36 (s, 1H), 4.02-3.94 (m, 1H), 3.87 (d, J=7.2 Hz, 1H), 3.82-3.74 (m, 2H), 3.72-3.66 (m, 1H), 3.64-3.44 (m, 3H), 3.40 (s, 1H), 3.30-3.20 (m, 2H), 3.03-2.87 (m, 4H), 2.35 (s, 3H), 1.74 (s, 2H).

Example 334. Synthesis of Compound Z611

##STR00620##

[1616] Step 1: In the presence of protective nitrogen, a mixture of tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2)-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (90 mg, 0.19 mmol), 5-bromo-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (99 mg, 0.37 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (14 mg, 0.02 mmol) and potassium carbonate (77 mg, 0.56 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was dissolved in ethyl acetate (20 mL), and washed with saturated brine (10 mL) and water (10 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-100% tetrahydrofuran/petroleum ether) to give tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(3-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine)-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, yield: 17%) as a colorless oil. ES-API: [M+H].sup.+=642.1.

[1617] Step 2: Under an ice bath condition, a solution of tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(3-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine)-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.03 mmol) in dichloromethane (1 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated, neutralized with 7 M amine-methanol (5 mL), concentrated, and then purified by prep-HPLC (ammonium bicarbonate) to give (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(6-(3-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine)-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z611, 0.51 mg, purity: 100%, yield: 3%) as a white solid. ES-API: [M+H].sup.+=542.2.

Example 335. Synthesis of Compound Z595

##STR00621##

[1618] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 120 mg, 0.34 mmol), N,N-diisopropyl ethylenediamine (131 mg, 1.0 mmol) and dichloromethane (10 mL) were added to a 50 mL round-bottom flask. 1,4-Oxazinane-4-carbonyl chloride (153 mg, 1.0 mmol) was slowly added to the reaction mixture, and the obtained mixture was stirred at room temperature for 1 h. Ethyl acetate (20 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-chloro-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-2-carboxylate (150 mg, yield: 95%). ES-API: [M+H].sup.+=466.2.

[1619] Step 2: tert-Butyl (R)-3-(6-chloro-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-2-carboxylate (170 mg, 0.37 mmol), bis(pinacolato)diboron (139 mg, 0.55 mmol), potassium acetate (107 mg, 1.1 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (52 mg, 0.07 mmol) and dioxane (10 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 105 C. for 3 h, and the reaction mixture was cooled to room temperature and directly used in the next step.

[1620] Step 3: The reaction mixture of tert-butyl (R)-3-(2-(morpholine-4-carbonyl)-6-(4,4,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-2-carboxylate obtained in the above step, tert-butyl 2-bromo-7-methylpyrrolo[2,3-b]pyrazine-5-carboxylate (83 mg, 0.15 mmol), potassium carbonate (62 mg, 0.45 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (21 mg, 0.03 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted under microwave at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-2-carboxylate (60 mg, yield of the two steps: 24%). ES-API: [M+H].sup.+=663.3.

[1621] Step 4: tert-Butyl (R)-3-(6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(morpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-2-carboxylate (60 mg 0.09 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give (R)-(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(morpholinyl)methanone (Z595, 20 mg, yield: 48%). ES-API: [M+H].sup.+=463.3. .sup.1H NMR (400 MHz, DMSO-d6) 11.72 (s, 1H), 8.74 (s, 1H), 8.15 (s, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 4.61 (d, J=16.6 Hz, 1H), 4.48 (d, J=16.7 Hz, 1H), 3.96 (d, J=8.4 Hz, 1H), 3.78 (t, J=9.1 Hz, 2H), 3.68-3.40 (m, 8H), 3.27-3.17 (m, 5H), 2.96 (d, J=8.8 Hz, 4H), 2.35 (s, 3H).

Example 336. Synthesis of Compound Z603

##STR00622##

[1622] Step 1: tert-Butyl (R)-3-(2-((S)-3-fluoropyrrolidine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (112 mg, 0.2 mmol), tert-butyl 2-bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (156 mg, 0.5 mmol), potassium carbonate (83 mg, 0.6 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (30 mg, 0.04 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(S)-3-fluoropyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, yield of the two steps: 75%). ES-API: [M+H].sup.+=665.3.

[1623] Step 2: tert-Butyl (R)-3-(6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-(S)-3-fluoropyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg 0.15 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give ((S)-3-fluoropyrrolidin-1-yl)(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z603, 30 mg, yield: 43%). ES-API: [M+H].sup.+=465.2. .sup.1H NMR (400 MHz, DMSO-d6) 11.72 (s, 1H), 8.74 (s, 1H), 8.16 (s, 1H), 7.82 (s, 1H), 7.67 (s, 1H), 5.32 (d, J=53.4 Hz, 1H), 4.62 (d, J=16.5 Hz, 1H), 4.44 (d, J=16.5 Hz, 1H), 3.98 (d, J=7.9 Hz, 1H), 3.85-3.39 (m, 8H), 3.31-2.85 (m, 7H), 2.35 (s, 3H), 2.20-1.86 (m, 2H),

Example 337. Synthesis of Compound Z604

##STR00623##

[1624] Step 1: (3S)-3-Fluorotetrahydropyrrole (151 mg, 1.7 mmol), triethylamine (343 mg, 3.4 mmol) and dichloromethane (10 mL) were added to a 25 mL round-bottom flask. Triphosgene (336 mg, 1.13 mmol) was slowly added at 0 C. and stirred at room temperature for 1 h. tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 200 mg, 0.57 mmol) was then added and stirred at room temperature for 1 h. Dichloromethane (20 mL) was added to the reaction mixture, and the obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-chloro-2-((S)-3-fluoropyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (200 mg, yield: 75%). ES-API: [M+H].sup.+=468.2.

[1625] Step 2: tert-Butyl (R)-3-(6-chloro-2-((S)-3-fluoropyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (200 mg, 0.43 mmol), bis(pinacolato)diboron (162 mg, 0.64 mmol), potassium acetate (125 mg, 1.3 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (61 mg, 0.09 mmol) and dioxane (10 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 3 h, and the reaction mixture was cooled to room temperature and directly used in the next step. ES-API: [M+H].sup.+=560.3.

[1626] Step 3: The reaction mixture of tert-butyl (R)-3-(2-((S)-3-fluoropyrrolidine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate, 5-bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (139 mg, 0.6 mmol), potassium carbonate (83 mg, 0.6 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (30 mg, 0.04 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3-fluoropyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (110 mg, yield of the two steps: 43%). ES-API: [M+H].sup.+=584.3.

[1627] Step 4: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3-fluoropyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (110 mg 0.19 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give (6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-3-fluoropyrrolidin-1-yl)methanone (Z604, 30 mg, yield: 33%). ES-API: [M+H].sup.+=484.2. .sup.1H NMR (400 MHz, DMSO-d6) 12.07 (s, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 7.81-7.70 (m, 2H), 7.48 (s, 1H), 5.32 (d, J=53.5 Hz, 1H), 4.6-4.31 (m, 2H), 3.98 (d, J=8.4 Hz, 1H), 3.81-3.41 (m, 8H), 3.30-3.22 (m, 15H), 3.05-2.85 (m, 4H), 2.16-1.91 (m, 2H).

Example 338. Synthesis of Compound Z630

##STR00624##

[1628] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 200 mg, 0.57 mmol), (3S)-tetrahydrofuran-3-carboxylic acid (497 mg, 1.7 mmol), N,N-diisopropyl ethylenediamine (438 mg, 3.4 mmol) and dimethylformamide (10 mL) were added to a 50 mL round-bottom flask. 2-(7-Azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (646 mg, 1.7 mmol) was slowly added to the reaction mixture, and the obtained mixture was stirred at room temperature for 1 h. Ethyl acetate (20 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-chloro-2-((S)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (240 mg, yield: 94%). ES-API: [M+H].sup.+=451.2.

[1629] Step 2: tert-Butyl (R)-3-(6-chloro-2-((S)-3-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (220 mg, 0.49 mmol), bis(pinacolato)diboron (185 mg, 0.73 mmol), potassium acetate (143 mg, 1.45 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (70 mg, 0.1 mmol) and dioxane (10 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 3 h, and the reaction mixture was cooled to room temperature and directly used in the next step.

[1630] Step 3: The reaction mixture of tert-butyl (R)-3-(2-((S)-tetrahydrofuran-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate obtained in the above step, tert-butyl 2-bromo-7-methylpyrrolo[2,3-b]pyrazine-5-carboxylate (195 mg, 0.62 mmol), potassium carbonate (103 mg, 0.75 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (36 mg, 0.05 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted under microwave at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (R)-3-(6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-((S)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, yield of the two steps: 31%). ES-API: [M+H].sup.+=648.3.

[1631] Step 4: tert-Butyl (R)-3-(6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-((S)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg 0.17 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give (6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-tetrahydrofuran-3-yl)methanone (Z630, 50 mg, yield: 72%). ES-API: [M+H].sup.+=448.3. H NMR (400 MHz, DMSO-d6) 11.73 (s, 1H), 8.75 (d, J=5.5 Hz, 1H), 8.17 (d, J=17.6 Hz, 1H), 7.84 (s, 1H), 7.67 (s, 1H), 4.79 (dd, J=117.5, 16.3 Hz, 2H), 4.10-3.36 (m, 12H), 3.24 (t, J=10.4 Hz, 1H), 3.02-2.86 (m, 4H), 2.35 (s, 3H), 2.15-1.95 (m, 2H).

Example 339. Synthesis of Compound Z631

##STR00625##

[1632] Step 1: tert-Butyl (R)-3-(2-((S)-tetrahydrofuran-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (135 mg, 0.25 mmol), 5-bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (173 mg, 0.75 mmol), potassium carbonate (103 mg, 0.75 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (36 mg, 0.05 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted under microwave at 110 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, yield: 70%). ES-API: [M+H].sup.+=567.3.

[1633] Step 2: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg 0.17 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give (6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-tetrahydrofuran-3-yl)methanone (Z631, 20 mg, yield: 24%). ES-API: [M+H].sup.+=467.2. .sup.1H NMR (400 MHz, DMSO-d6) 12.07 (s, 1H), 8.60 (s, 1H), 8.09 (s, 1H), 7.86-7.70 (m, 2H), 7.51 (s, 1H), 4.77 (dd, J=117.8, 16.9 Hz, 2H), 4.10-3.91 (m, 2H), 3.85-3.40 (m, 10H), 3.27-3.18 (m, 1H), 3.04-2.86 (m, 4H), 2.13-1.96 (m, 2H).

Example 340. Synthesis of Compound Z613

##STR00626##

[1634] Step 1: (S)-3-Methylmorpholine (195 mg, 1.92 mmol), triethylamine (292 mg, 2.89 mmol) and dichloromethane (10 mL) were added to a 25 mL round-bottom flask. Triphosgene (286 mg, 0.96 mmol) was slowly added at 0 C. and stirred at room temperature for 1 h. tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 170 mg, 0.48 mmol) was then added and stirred at room temperature for 1 h. Dichloromethane (20 mL) was added to the reaction mixture, and the obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-chloro-2-((S)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-3-carboxylate (190 mg, yield: 82%). ES-API: [M+H].sup.+=480.2.

[1635] Step 2: tert-Butyl (R)-3-(6-chloro-2-((S)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-3-carboxylate (190 mg, 0.40 mmol), bis(pinacolato)diboron (201 mg, 0.79 mmol), potassium acetate (116 mg, 1.19 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (57 mg, 0.08 mmol) and dioxane (10 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted under microwave at 100 C. for 3 h. The reaction mixture was cooled to room temperature, and ethyl acetate (20 mL) was added. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(2-((S)-3-methylmorpholine-4-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl) morpholine-2-carboxylate (114 mg, yield: 50%). ES-API: [M+H].sup.+=572.3.

[1636] Step 3: tert-Butyl (R)-3-(2-((S)-3-methylmorpholine-4-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-2-carboxylate (114 mg, 0.2 mmol), 5-bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (139 mg, 0.6 mmol), potassium carbonate (83 mg, 0.6 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (29 mg, 0.04 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-5-carboxylate (70 mg, yield of the two steps: 58%). ES-API: [M+H].sup.+=596.3.

[1637] Step 4: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((S)-3-methylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-5-carboxylate (70 mg 0.11 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give (6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,6R)-2,6-dimethylmorpholinyl)methanone (Z613, 10 mg, yield: 17%). ES-API: [M+H].sup.+=496.2. .sup.1H NMR (400 MHz, DMSO-d6) 12.07 (s, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.47 (s, 1H), 4.59 (d, J=16.8 Hz, 1H), 4.43 (d, J=16.5 Hz, 1H), 3.95 (d, J=8.9 Hz, 1H), 3.83-3.68 (m, 4H), 3.65-3.33 (m, 7H), 3.29-3.13 (m, 3H), 3.03-2.91 (m, 7H), 1.20 (d, J=6.6 Hz, 3H).

Example 341. Synthesis of Compound Z600

##STR00627##

[1638] Step 1: tert-Butyl (R)-3-(2-((2R,6R)-2,6-dimethylmorpholine-4-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (176 mg, 0.3 mmol), tert-butyl 2-bromo-7-methylpyrrolo[2,3-b]pyrazine-5-carboxylate (187 mg, 0.6 mmol), potassium carbonate (124 mg, 0.9 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (43 mg, 0.06 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 3 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-((2R,6R)-2,6-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (110 mg, yield: 62%). ES-API: [M+H].sup.+=691.4.

[1639] Step 2: tert-Butyl (R)-3-(6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-((2R,6R)-2,6-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (110 mg 0.11 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give ((2R,6R)-2,6-dimethylmorpholinyl)(6-(7-methyl-5H-pyrrolo[2,3-b]pyridin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z600, 10 mg, yield: 11%). ES-API: [M+H].sup.+=491.4. .sup.1H NMR (400 MHz, DMSO-d6) 11.72 (s, 1H), 8.74 (s, 1H), 8.15 (s, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 4.63 (t, J=16.2 Hz, 1H), 4.55-4.41 (m, 1H), 3.99-3.85 (m, 3H), 3.81-3.71 (m, 2H), 3.59-3.34 (m, 3H), 3.31-3.20 (m, 4H), 2.98-2.88 (m, 6H), 2.35 (s, 3H), 1.23-1.10 (m, J=6.9 Hz, 6H).

Example 342. Synthesis of Compound Z599

##STR00628##

[1640] Step 1: tert-Butyl (R)-3-(6-chloro-2-((2R,6R)-2,6-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (310 mg, 0.62 mmol), bis(pinacolato)diboron (318 mg, 1.25 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (90 mg, 0.12 mmol), potassium acetate (184 mg, 1.88 mmol) and dioxane (10 mL,) were added to a 25 mL microwave reactor. The reaction mixture was stirred at 100 C. for 3 h, cooled to room temperature, and directly used in the next step. ES-API: [M+H].sup.+=586.3.

[1641] Step 2: The reaction mixture of tert-butyl (R)-3-(2-((2R,6R)-2,6-dimethylmorpholine-4-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate obtained in the above step, 5-bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (208 mg, 0.9 mmol), potassium carbonate (124 mg, 0.9 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (44 mg, 0.06 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 3 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((2R,6R)-2,6-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-5-carboxylate (110 mg, yield of the two steps: 29%). ES-API: [M+H].sup.+=610.2.

[1642] Step 3: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-((2R,6R)-2,6-dimethylmorpholine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-5-carboxylate (70 mg 0.11 mmol), trifluoroacetic acid (3 mL,) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness to give a crude product. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give (6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,6R)-2,6-dimethylmorpholinyl)methanone (Z599, 25 mg, yield: 27%). ES-API: [M+H].sup.+=510.2. .sup.1H NMR (400 MHz, DMSO-d6) 11.72 (s, 1H), 8.74 (s, 1H), 8.15 (s, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 4.63 (t, J=16.2 Hz, 1H), 4.53-4.44 (m, 1H), 3.96 (d, J=8.0 Hz, 3H), 3.81-3.35 (m, 5H), 3.27-3.21 (m, 2H), 2.98-2.86 (m, 6H), 2.35 (s, 3H), 1.17 (t, J=6.9 Hz, 6H).

Example 343. Synthesis of Compounds Z643 and Z644

##STR00629##

[1643] Step 1: tert-Butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.08 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (42 mg, 0.16 mmol), potassium carbonate (34 mg, 0.24 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6 mg, 0.008 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 120 C. for 3 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, yield: 80%). ES-API: [M+H].sup.+=588.3.

[1644] Step 2: tert-Butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (40 mg, 0.06 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) and resolved by a chiral column (chromatographic column: IB column, 250 mm4.6 mm5 m, mobile phase: ACN:IPA:DEA=90:10:2, flow rate: 1 mL/min, column temperature=30 C.) to give two isomeric compounds. One of the compounds was arbitrarily assigned as ((1S,4S)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridine-5-methyl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z644, 7 mg, retention time: 9.171 min, yield: 21%). ES-API: [M+H].sup.+=488.2. .sup.1H NMR (400 MHz, DMSO-d6) 11.36 (s, 1H), 8.49 (s, 1H), 8.14 (d, J=4.8 Hz, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.27 (s, 1H), 4.58 (d, J=16.4 Hz, 1H), 4.41 (d, J=16.4 Hz, 1H), 4.23-3.41 (m, 14H), 3.17-2.83 (m, 4H), 2.32 (s, 3H), 2.11-1.65 (m, 4H).

[1645] The other compound was arbitrarily assigned as ((1R,4R)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridine-5-methyl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z643, 7 mg, retention time: 10.639 min, yield: 21%). ES-API: [M+H].sup.+=488.2. .sup.1H NMR (400 MHz, DMSO-d6) 11.37 (s, 1H), 8.51 (s, 1H), 8.14 (d, J=4.6 Hz, 1H), 7.81 (s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 4.59 (d, J=16.4 Hz, 1H), 4.40 (d, J=16.3 Hz, 1H), 4.28-3.44 (m, 14H), 2.96 (s, 4H), 2.32 (s, 3H), 2.05-1.66 (m, 4H).

Example 344. Synthesis of Compound Z582

##STR00630##

[1646] Step 1: In the presence of protective nitrogen, a mixture of tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2)-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.16 mmol), 5-bromo-3-methoxy-1H-pyrrolo[2,3-b]pyridine (37 mg, 0.16 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (12 mg, 0.02 mmol) and potassium carbonate (69 mg, 0.50 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was dissolved in ethyl acetate (20 mL), and washed with saturated brine (10 mL) and water (10 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-100% tetrahydrofuran/petroleum ether) to give tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(3-methoxy-1H-pyrrolo[2,3-b]pyridine)-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, yield: 70%) as a colorless oil. ES-API: [M+H].sup.+=604.3.

[1647] Step 2: Under an ice bath condition, a solution of tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(3-methoxy-1H-pyrrolo[2,3-b]pyridine)-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 0.10 mmol) in dichloromethane (1 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated, neutralized with 7 M amine-methanol (5 mL), concentrated, and then purified by prep-HPLC (formic acid) to give (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(6-(3-methoxy-1H-pyrrolo[2,3-b]pyridine)-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z582, 12 mg, purity: 100%, yield: 19%, formate) as a white solid. ES-API: [M+H].sup.+=504.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.10 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.23 (s, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.74 (s, 1H), 7.43 (s, 1H), 7.07 (d, J=2.4 Hz, 1H), 4.75-4.67 (m, 1H), 4.60-4.52 (m, 1H), 3.98-3.93 (m, 1H), 3.92-3.88 (m, 2H), 3.84 (s, 3H), 3.81-3.74 (m, 2H), 3.67 (t, J=10.4 Hz, 2H), 3.61-3.52 (m, 5H), 3.34-3.23 (m, 1H), 2.99-2.89 (m, 4H), 1.87-1.72 (m, 4H).

Example 345. Synthesis of Compounds Z584 and Z583

##STR00631##

[1648] Step 1: A mixture of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (170 mg, 1.14 mmol) in dichloromethane (5 mL) was cooled to 0 C. Triethylamine (0.4 mL, 2.88 mmol) and triphosgene (340 mg, 1.15 mmol) were added successively and stirred for 0.5 h. The reaction mixture was concentrated and subsequently dissolved in dichloromethane (5 mL). Triethylamine (0.4 mL, 2.88 mmol) and tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 300 mg, 0.85 mol) were added and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution (10 mL), and the reaction mixture was extracted with dichloromethane (10 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-40% tetrahydrofuran/petroleum ether) to give tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (380 mg, yield: 91%). ES-API: [M+H].sup.+=492.2.

[1649] Step 2: In the presence of protective nitrogen, a mixture of tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (220 mg, 0.45 mmol), bis(pinacolato)diboron (148 mg, 0.58 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (32 mg, 0.04 mmol) and potassium acetate (132 mg, 1.34 mmol) in 1,4-dioxane (2 mL) was stirred at 110 C. for 2 h. Upon completion of the reaction, the reaction mixture was filtered and concentrated to give tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (260 mg, crude product). ES-API: [M+H].sup.+=584.2.

[1650] Step 3: In the presence of protective nitrogen, a mixture of tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.16 mmol), 2-chloro-7-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (100 mg, 0.28 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (12 mg, 0.02 mmol) and potassium carbonate (69 mg, 0.50 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 100 C. for 2 h. Upon completion of the reaction, the reaction mixture was dissolved in ethyl acetate (20 mL), and washed with saturated brine (10 mL) and water (10 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-100% tetrahydrofuran/petroleum ether) to give tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(7-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, yield: 62%) as a colorless oil. ES-API: [M+H].sup.+=773.2.

[1651] Step 4: Under an ice bath condition, trifluoroacetic acid (0.5 mL) was added dropwise to a solution of tert-butyl (3R)-3-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-6-(7-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (80 mg, 0.10 mmol) in dichloromethane (1 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated, and 7 M amine-methanol (5 mL) was added. The obtained mixture was stirred at 60 C. for 1 h, concentrated, and then purified by prep-HPLC (ammonium bicarbonate) to give two compounds. One of the compounds was (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(8-((R)-morpholin-3-yl)-6-(7-(trifluoromethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z584, 3.2 mg, purity: 100%, yield: 5.7%, retention time: 7.35 min) as a white solid. ES-API: [M+H].sup.+=543.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.96 (s, 1H), 8.53 (s, 1H), 8.15 (s, 1H), 7.82 (s, 1H), 4.82-4.70 (m, 1H), 4.68-4.56 (m, 1H), 4.03-3.95 (m, 1H), 3.95-3.88 (m, 2H), 3.83-3.75 (m, 2H), 3.73-3.63 (m, 2H), 3.60-3.50 (m, 5H), 3.30-3.27 (m, 1H), 3.03-2.91 (m, 4H), 1.89-1.72 (m, 4H).

[1652] The other compound was 2-(2-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((R)-morpholin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonitrile (Z583, 12 mg, purity: 100%, yield: 23%, retention time: 7.00 min) as a white solid. ES-API: [M+H].sup.+=500.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.01 (s, 1H), 8.79 (s, 1H), 8.23 (s, 1H), 7.88 (s, 1H), 4.82-4.70 (m, 1H), 4.64-4.55 (m, 1H), 4.03-3.96 (m, 1H), 3.95-3.89 (m, 2H), 3.85-3.76 (m, 2H), 3.68 (t, J=10.4 Hz, 2H), 3.61-3.52 (m, 5H), 3.28-3.22 (m, 1H), 3.03-2.92 (m, 4H), 1.91-1.72 (m, 4H).

Example 346. Synthesis of Compound Z585

##STR00632##

[1653] Step 1: In the presence of protective nitrogen, a mixture of tert-butyl (R)-3-(6-chloro-2-(4-fluoropiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (140 mg, 0.29 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.58 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (21 mg, 0.03 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 110 C. for 2 h. Upon completion of the reaction, the reaction mixture was dissolved in ethyl acetate (20 mL), and washed with saturated brine (10 mL) and water (10 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a flash silica gel column (0-100% tetrahydrofuran/petroleum ether) to give tert-butyl (R)-3-(2-(4-fluoropiperidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (150 mg, yield: 89%) as a colorless oil. ES-API: [M+H].sup.+=578.2.

[1654] Step 2: Under an ice bath condition, trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl (R)-3-(2-(4-fluoropiperidine-1-carbonyl)-6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (150 mg, 0.26 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated, neutralized with 7 M amine-methanol (5 mL), concentrated, and then purified by prep-HPLC (ammonium bicarbonate) to give (R)-(4-fluoropiperidin-1-yl)(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z585, 45 mg, purity: 100%, yield: 36%) as a white solid. ES-API: [M+H].sup.+=478.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.34 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.75 (d, J=1.2 Hz, 1H), 7.42 (s, 1H), 7.26 (s, 1H), 4.97-4.75 (m, 1H), 4.57 (d, J=16.4 Hz, 1H), 4.44 (d, J=16.4 Hz, 1H), 4.00-3.92 (m, 1H), 3.84- 3.71 (m, 2H), 3.59-3.49 (m, 1H), 3.48-3.40 (m, 2H), 3.41-3.34 (m, 2H), 3.30-3.24 (m, 1H), 3.21-3.07 (m, 2H), 3.02-2.85 (m, 4H), 2.31 (s, 3H), 2.01-1.82 (m, 2H), 1.81-1.64 (m, 2H).

Example 347. Synthesis of Compound Z586

##STR00633##

[1655] Step 1: tert-Butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (99 mg, 0.17 mmol), tert-butyl 2-bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (212 mg, 0.68 mmol), potassium carbonate (70 mg, 0.51 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (49 mg, 0.07 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 115 C. for 3 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, yield: 51%). ES-API: [M+H].sup.+=689.3.

[1656] Step 2: tert-Butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.08 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give (2-oxo-5-azabicyclo[2.2.2]octan-5-yl)(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z586, 30 mg, yield: 70%). ES-API: [M+H].sup.+=489.2. .sup.1H NMR (400 MHz, DMSO-d6) 11.74 (s, 1H), 8.77 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.68 (s, 1H), 4.60 (d, J=16.5 Hz, 1H), 4.44 (d, J=16.5 Hz, 1H), 4.20-3.38 (m, 14H), 3.13-2.81 (m, 4H), 2.35 (s, 3H), 2.10-1.62 (m, 4H).

Example 348. Synthesis of Compound Z589

##STR00634##

[1657] Step 1: 4-Methoxypiperidine (200 mg, 1.74 mmol), triethylamine (1403 mg, 13.9 mmol) and dichloromethane (10 mL) were added to a 25 mL round-bottom flask. Triphosgene (515 mg, 1.74 mmol) was slowly added at 0 C. and stirred at room temperature for 1 h. tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 200 mg, 0.57 mmol) was then added and stirred at room temperature for 1 h. Dichloromethane (20 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-chloro-2-(4-methoxypiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (230 mg, yield: 81%). ES-API: [M+H].sup.+=494.2.

[1658] Step 2: tert-Butyl (R)-3-(6-chloro-2-(4-methoxypiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (230 mg, 0.46 mmol), bis(pinacolato)diboron (236 mg, 0.93 mmol), potassium acetate (137 mg, 1.4 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (67 mg, 0.09 mmol) and dioxane (10 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted under microwave at 105 C. for 3 h, and the reaction mixture was cooled to room temperature and directly used in the next step. ES-API: [M+H].sup.+=586.3.

[1659] Step 3: The reaction mixture of tert-butyl (R)-3-(2-(4-methoxypiperidine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate, 5-bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (108 mg, 0.42 mmol), potassium carbonate (312 mg, 1.35 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (66 mg, 0.09 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 2 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-methoxypiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (190 mg, yield of the two steps: 68%). ES-API: [M+H].sup.+=610.3.

[1660] Step 4: tert-Butyl (R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-methoxypiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (190 mg 0.31 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give (R)-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-methoxypiperidin-1-yl)methanone (Z589, 70 mg, yield: 44%). ES-API: [M+H].sup.+=510.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.07 (s, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.08 (d, J=1.9 Hz, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.46 (s, 1H), 4.56 (d, J=16.5 Hz, 1H), 4.42 (d, J=16.4 Hz, 1H), 3.94 (d, J=9.7 Hz, 1H), 3.77 (t, J=9.5 Hz, 2H), 3.61-3.34 (m, 6H), 3.30-3.23 (m, 4H), 3.0-2.81 (m, 7H), 2.0-1.81 (m, 2H), 1.70-1.14 (m, 2H).

Example 349. Synthesis of Compounds Z590 and Z591

##STR00635##

[1661] Step 1: tert-Butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (120 mg, 0.24 mmol), bis(pinacolato)diboron (124 mg, 0.49 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (17.5 mg, 0.02 mmol), potassium acetate (71 mg, 0.73 mmol) and dioxane (10 mL) were added to a 5 mL microwave reactor. The reaction mixture was stirred at 100 C. for 2 h, cooled to room temperature, and directly used in the next step. ES-API: [M+H].sup.+=584.3.

[1662] Step 2: The reaction mixture of tert-butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate obtained in the above step, 2-bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine (80 mg, 0.13 mmol), potassium carbonate (56 mg, 0.41 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (40 mg, 0.05 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 3 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, yield of the two steps: 41%). ES-API: [M+H].sup.+=609.2.

[1663] Step 3: tert-Butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (70 mg, 0.11 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) and resolved by a chiral column (chromatographic column: Daicel CHIRALPAK, 250 mm4.6 mm5 m, mobile phase: n-hexane:MeOH:DEA=60:40:2, flow rate: 1 mL/min, column temperature=30 C.) to give two isomeric compounds. One of the isomeric compounds was arbitrarily assigned as ((1S,4S)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z590, 10 mg, retention time: 21.084 min, yield: 17%). ES-API: [M+H].sup.+=509.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.47 (s, 1H), 8.92 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 4.61 (d, J=16.6 Hz, 1H), 4.44 (d, J=16.5 Hz, 1H), 4.14-3.42 (m, 13H), 3.15-2.81 (m, 5H), 2.05 (dd, J=41.0, 10.6 Hz, 2H), 1.86-1.60 (m, 2H).

[1664] The other isomeric compound was arbitrarily assigned as ((1R,4R)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)(6-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z591, 10 mg, retention time: 24.207 min, yield: 17%). ES-API: [M+H].sup.+=509.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.48 (s, 1H), 8.96 (s, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 7.91 (s, 1H), 4.62 (d, J=16.6 Hz, 1H), 4.44 (d, J=16.6 Hz, 1H), 4.12-3.46 (m, 13H), 3.15-2.89 (m, 5H), 2.10-1.65 (m, 4H).

Example 350. Synthesis of Compound Z592

##STR00636##

[1665] Step 1: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (75 mg, 0.152 mmol), bis(pinacolato)diboron (77.42 mg, 0.305 mmol), potassium acetate (44.8 mg, 0.457 mmol) and chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.98 mg, 0.015 mmol) were dissolved in 1,4-dioxane (2.5 mL) and stirred at 110 C. for 2 h. 5-Bromo-3-methoxy-1H-pyrrolo[2,3-b]pyridine (69.3 mg, 0.305 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (6.27 mg, 0.009 mmol), potassium carbonate (63.43 mg, 0.459 mmol) and water (0.5 mL) were added and stirred at 110 C. for 2 h. The obtained mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to give tert-butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(3-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.05 mmol, yield: 32.6%). ES-API: [M+H].sup.+=604.2.

[1666] Step 2: tert-Butyl (3R)-3-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-6-(3-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.05 mmol) was dissolved in anhydrous dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added, and the system was reacted at room temperature for 2 h. The reaction was monitored by LC-MS for completion, and the reaction mixture was concentrated to dryness under reduced pressure. After neutralization with ammonia water/methanol solution (1 mL), the obtained mixture was concentrated again and purified by HPLC acid process (trifluoroacetic acid method) to give (8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(3-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z592, 8.9 mg, 0.018 mmol, yield: 35.5%, trifluoroacetate). ES-API: [M+H].sup.+=504.2.

Example 351. Synthesis of Compounds Z587 and Z588

##STR00637##

[1667] Step 1: tert-Butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (99 mg, 0.17 mmol), tert-butyl 2-bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (212 mg, 0.68 mmol), potassium carbonate (70 mg, 0.5 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (49 mg, 0.068 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 115 C. for 3 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give a desired product tert-butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, yield: 51%). ES-API: [M+H].sup.+=689.3.

[1668] Step 2: tert-Butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(5-(tert-butoxycarbonyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (60 mg, 0.09 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) and resolved by a chiral column (chromatographic column: IB column, 250 mm4.6 mm5 m, mobile phase: ACN:IPA:DEA=70:30:2, flow rate: 1 L/min, column temperature=30 C.) to give two isomeric compounds. One of the isomeric compounds was arbitrarily assigned as ((1S,4S)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z587, 12 mg, retention time: 15.654 min, yield: 28%). ES-API: [M+H].sup.+=489.2.

[1669] The other isomeric compound was arbitrarily assigned as ((1R,4R)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)(6-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z588, 12 mg, retention time: 17.233 min, yield: 28%). ES-API: [M+H].sup.+=489.2. .sup.1H NMR (400 MHz, DMSO-d6) 11.75 (s, 1H), 8.79 (s, 1H), 8.16 (d, J=19.0 Hz, 1H), 7.88 (s, 1H), 7.68 (s, 1H), 4.61 (d, J=16.4 Hz, 1H), 4.43 (d, J=16.4 Hz, 1H), 4.25-3.98 (m, 2H), 3.93-3.38 (m, 12H), 3.21-2.95 (m, 4H), 2.35 (s, 3H), 2.07-1.68 (m, 4H).

Example 352. Synthesis of Compounds Z594 and Z593

##STR00638##

[1670] Step 1: 5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.55 mmol), trimethylsilylacetylene (182 mg, 1.8 mmol), bis(triphenylphosphine)dichloropalladium (II) (60 mg, 0.08 mmol), cuprous iodide (14.7 mg, 0.08 mmol) and triethylamine (10 mL) were added to a 25 mL round-bottom flask. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at room temperature overnight. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give 5-bromo-3-((trimethylsilyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (350 mg, yield: 77%). ES-API: [M+H].sup.+=293.0.

[1671] Step 2: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (100 mg, 0.19 mmol), 5-bromo-3-((trimethylsilyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (110 mg, 0.38 mmol), potassium carbonate (78 mg, 0.57 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (27 mg, 0.04 mmol), dioxane (3 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 1 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(2-(2-hydroxy-2-methylpropyl)-6-(3-(trimethylsilyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, yield: 26%). ES-API: [M+H].sup.+=617.3.

[1672] Step 3: tert-Butyl (R)-3-(2-(2-hydroxy-2-methylpropyl)-6-(3-(trimethylsilyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.05 mmol), potassium fluoride (10 mg, 0.017 mmol) and dimethylformamide (10 mL) were added to a 25 mL round-bottom flask. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at room temperature for 1 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-3-(6-(3-ethynyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, yield: 76%). ES-API: [M+H].sup.+=545.3.

[1673] Step 4: tert-Butyl (R)-3-(6-(3-ethynyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxy-2-methylpropyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, 0.03 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min, spun to dryness, and then dissolved in dichloromethane (2 mL). Ammonia/methanol (7 M, 2 mL) was added, and the obtained mixture was stirred for 1 h and then spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give two compounds. One of the compounds was (R)-1-(6-(3-ethynyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropan-1-one (Z594, 1 mg, yield: 6%, retention time: 7.147 min). ES-API: [M+H].sup.+=445.2.

[1674] The other compound was (R)-1-(6-(3-acetyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropan-1-one (Z593, 3.5 mg, yield: 20%, retention time: 7.006 min). ES-API: [M+H].sup.+=463.2.

Example 353. Synthesis of Compounds Z619 and Z620

##STR00639##

[1675] Step 1: tert-Butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (99 mg, 0.2 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (168 mg, 0.6 mmol), potassium carbonate (83 mg, 0.6 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (14 mg, 0.02 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 120 C. for 3 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, yield: 24%). ES-API: [M+H].sup.+=608.3.

[1676] Step 2: tert-Butyl (3R)-3-(2-(2-oxo-5-azabicyclo[2.2.2]octane-5-carbonyl)-6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (30 mg, 0.03 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask and stirred at room temperature for 30 min. The reaction mixture was spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) and resolved by a chiral column (chromatographic column: Daicel CHIRALPAK, 250 mm4.6 mm5 m, mobile phase: n-hexane:MeOH:DEA=50:50:2, flow rate: 1 mL/min, column temperature=30 C.) to give two isomeric compounds. One of the isomeric compounds was arbitrarily assigned as ((1R,4R)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)(6-(3-chloro-1H-pyrrolo[2,3-b]pyridine-5-methyl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z619, 3 mg, retention time: 24.496 min, yield: 18%). ES-API: [M+H].sup.+=508.2. .sup.1H NMR (400 MHz, DMSO-d6) 12.07 (s, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.75 (d, J=15.9 Hz, 2H), 7.47 (s, 1H), 4.58 (d, J=16.3 Hz, 1H), 4.41 (d, J=16.3 Hz, 1H), 4.10-3.69 (m, 9H), 3.61-3.41 (m, 4H), 3.26 (d, J=10.6 Hz, 1H), 3.04-2.86 (m, 4H), 2.13-1.65 (m, 4H).

[1677] The other isomeric compound was arbitrarily assigned as ((1S,4S)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)(6-(3-chloro-1H-pyrrolo[2,3-b]pyridine-5-methyl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Z620, 3 mg, retention time: 23.482 min, yield: 18%). ES-API: [M+H].sup.+=508.2. .sup.1H NMR (400 MHz, DMSO-d6) 12.07 (s, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.75 (d, J=16.1 Hz, 2H), 7.47 (s, 1H), 4.58 (d, J=16.5 Hz, 1H), 4.42 (d, J=16.3 Hz, 1H), 4.10-3.40 (m, 13H), 3.26 (d, J=10.5 Hz, 1H), 2.99-2.84 (m, 4H), 2.07-1.64 (m, 4H).

Example 354. Synthesis of Compound Z615

##STR00640##

[1678] Step 1: 4-Methyltetrahydropyran-4-carboxylic acid (144 mg, 1.0 mmol), two drops of N,N-dimethylformamide, and dichloromethane (10 mL) were added to a 50 mL round-bottom flask. Oxalyl chloride (317 mg, 2.5 mmol) was slowly added at 0 C. and stirred at room temperature for 1 h. The reaction mixture was spun to dryness and dissolved in dichloromethane (10 mL). Triethylamine (120 mg, 1.2 mmol) and tert-butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (5a, 70 mg, 0.2 mmol) were added to the mixture and stirred at room temperature for 1 h. Dichloromethane (20 mL) was added to the reaction mixture, and the obtained mixture was washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-chloro-2-(4-methyltetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (90 mg, yield: 95%). ES-API: [M+H].sup.+=479.2.

[1679] Step 2: tert-Butyl (R)-3-(6-chloro-2-(4-methyltetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (150 mg, 0.31 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (161 mg, 0.63 mmol), potassium carbonate (129 mg, 0.94 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (22 mg, 0.03 mmol), dioxane (10 mL) and water (1 mL) were added to a 25 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 100 C. for 4 h. Ethyl acetate (30 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-methyltetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (110 mg, yield: 61%). ES-API: [M+H].sup.+=575.3.

[1680] Step 3: tert-Butyl (R)-3-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-methyltetrahydro-2H-pyran-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (110 mg 0.19 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 25 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give (R)-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-(morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-methyltetrahydro-2H-pyran-4-yl)methanone (Z615, 50 mg, yield: 55%). ES-API: [M+H].sup.+=475.3. .sup.1H NMR (400 MHz, DMSO-d6) 11.35 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.10 (d, J=1.9 Hz, 1H), 7.76 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 4.98 (d, J=16.9 Hz, 1H), 4.73 (d, J=16.9 Hz, 1H), 3.98-3.46 (m, 10H), 3.28 (s, 1H), 3.02-2.64 (m, 5H), 2.31 (s, 3H), 2.07 (d, J=12.5 Hz, 2H), 1.53 (dd, J=22.4, 9.6 Hz, 2H), 1.32 (s, 3H).

Example 355. Synthesis of Compound Z617

##STR00641##

[1681] Step 1: tert-Butyl (3R)-3-(2-(4-hydroxy-2,2-dimethylpyrrolidine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (50 mg, 0.09 mmol), 5-bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (40 mg, 0.17 mmol), potassium carbonate (35 mg, 0.26 mmol), chloro (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenylyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (12 mg, 0.02 mmol), dioxane (2 mL) and water (0.3 mL) were added to a 5 mL microwave reactor. The system was replaced with nitrogen three times and then protected with a nitrogen balloon. The system was reacted at 115 C. for 3 h. Ethyl acetate (10 mL) was added to the reaction mixture. The obtained mixture was washed with saturated brine (5 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (methanol:dichloromethane=10:100) to give tert-butyl (3R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-hydroxy-2,2-dimethylpyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg, yield: 38%). ES-API: [M+H].sup.+=610.3.

[1682] Step 2: tert-Butyl (3R)-3-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(4-hydroxy-2,2-dimethylpyrrolidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (20 mg 0.03 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL) were added to a 5 mL single-neck round-bottom flask. The reaction mixture was stirred at room temperature for 30 min and spun to dryness. The crude product was purified by prep-HPLC (ammonium bicarbonate method-A) to give (6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-((R)-morpholin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-hydroxy-2,2-dimethylpyrrolidin-1-yl)methanone (Z617, 1.3 mg, yield: 7%). ES-API: [M+H].sup.+=510.2.

Example 356: Derivatization of Intermediate 5a and Determination of Absolute Configuration by Single Crystal Growth

##STR00642##

[1683] Step 1: tert-Butyl (R)-3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (1000 mg, 2.83 mmol) was dissolved in acetonitrile (6 mL). K.sub.2CO.sub.3 (1174 mg, 8.50 mmol) in water (4 mL) was added with stirring. The above mixture was stirred at 0 C. Benzyl bromide (0.269 mL, 2.267 mmol) was added, and the system was reacted at 0 C. to room temperature overnight. The reaction mixture was extracted with ethyl acetate (30 mL2). The organic phases were combined, washed twice with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=1:4) to give tert-butyl (R)-3-(2-benzyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (860 mg, yield: 69%). ES-API: [M+H].sup.+=443.0.

[1684] Step 2: tert-Butyl (R)-3-(2-benzyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine-4-carboxylate (440 mg, 0.99 mmol) was dissolved in dichloromethane (5 mL). The reaction mixture was stirred at room temperature, and trifluoroacetic acid (3 mL) was added. The system was reacted overnight. The reaction mixture was concentrated under reduced pressure to give (R)-3-(2-benzyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine (390 mg, crude product, brown liquid), which was directly used in the next step without purification. ES-API: [M+H].sup.+=343.0.

[1685] Step 3: (R)-3-(2-Benzyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine (195 mg, crude product) obtained above and 2,4-dinitrobenzoic acid (212 mg, 1.00 mmol) were dissolved in N,N-dimethylformamide (2.5 mL). The reaction mixture was stirred at 0 C., and diisopropylethyl amine (0.44 mL, 2.50 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (380 mg, 1.0 mmol) were added successively and stirred at 0 C. to room temperature overnight. Water (75 mL) was added to the system with stirring, and a large amount of brown-yellow solid was precipitated. The mixture was filtered to give a brown-yellow solid. The solid obtained by filtration was dissolved in dichloromethane/isopropanol (20 mL, 4:1). The mixture was washed with saturated NaHCO.sub.3 solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by a flash silica gel column (ethyl acetate:petroleum ether=0-50%) to give (R)-(3-(2-benzyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine)(2,4-dinitrophenyl)methanone (170 mg, yield of the two steps: 63%). ES-API: [M+H].sup.+=537.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.87 (d, J=2.2 Hz, 1H), 8.61 (s, 1H), 7.75 (s, 1H), 7.45-7.02 (m, 7H), 5.50 (s, 1H), 4.35-4.05 (m, 1H), 3.99-3.50 (m, 7H), 3.39 (d, J=11.7 Hz, 1H), 3.20 (d, J=13.8 Hz, 1H), 2.85 (d, J=6.1 Hz, 2H), 2.76-2.54 (m, 2H).

[1686] The prepared ((R)-(3-(2-benzyl-6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)morpholine)(2,4-dinitrophenyl)methanone) was subjected to single crystal growth. The specific procedures were as follows: 20 mg of a compound was weighed out and dissolved in 3 mL of MeOH/dichloromethane (1:1), a single crystal was obtained by volatilization method, and X-ray single-crystal diffraction test was performed by Bruker D8 Venture instrument. The results are shown in Table 1 below and FIG. 1. FIG. 1 shows an ellipsoid plot of the molecular three-dimensional structure.

Instrument Parameters:

TABLE-US-00001 light source: Mo target X-ray: MoK (=0.71073 ) detector: a CMOS plane detector resolution: 0.80 current and voltage: 50 kV, 1.4 mA exposure time: 5 s distance between the plane detector test temperature: 170(2) K and the sample: 40 mm

Structure Analysis and Refinement Procedures:

[1687] After the diffraction data were integrated and converted by adopting the SAINT program, empirical absorption correction was performed on the data by adopting the SADABS program; the structure of the single crystal was analyzed by a direct method using SHELXT2014, and the structure was refined by adopting the least square method; hydrogen atom refinement procedures were obtained by isotropic calculation, and the hydrogen atoms on CH were obtained by calculation of hydrogenation and refined by adopting a riding model. The Flack constant was 0.04(8). C17 in FIG. 1 is R configuration.

Crystal Data:

TABLE-US-00002 TABLE 1 C.sub.27H.sub.25ClN.sub.4O.sub.6 F(000) = 560 M.sub.r = 536.96 D.sub.x = 1.420 Mg m.sup.3 Monoclinic, P2.sub.1 Mo K radiation, = 0.71073 a = 5.2791 (16) Cell parameters from 2023 reflections b = 9.626 (3) = 2.5-23.7 c = 24.718 (8) = 0.20 mm.sup.1 = 90 T = 100 K V = 1256.2 (7) .sup.3 Block, colourless Z = 2 0.12 0.08 0.05 mm

[1688] Referring to the reaction route described for the compound of formula (ID) above and the preparation methods of the above Examples, the compounds shown in Table (C) were prepared by modifying some of the starting materials:

TABLE-US-00003 TABLE (C) MS Structure and Number [M + H].sup.+ [00643] 517.2 Z596 [00644] 516.2 Z597 [00645] 478.2 Z598 [00646] 544.3 Z601 [00647] 518.2 Z602 [00648] 505.3 Z605 [00649] 529.2 Z609 [00650] 528.2 Z610 [00651] 505.3 Z612 [00652] 530.2 Z614 [00653] 491.3 Z616 [00654] 508.2 Z618 [00655] 504.3 Z621 [00656] 542.2 Z622 [00657] 543.2 Z623 [00658] 496.2 Z625 [00659] 516.2 Z626 [00660] 512.2 Z627 [00661] 550.2 Z628 [00662] 491.3 Z629 [00663] 517.3 Z632 [00664] 510.1 Z633 [00665] 543.2 Z634 [00666] 544.2 Z635 [00667] 495.2 Z636 [00668] 519.2 Z637 [00669] 545.2 Z638 [00670] 531.2 Z639 [00671] 517.2 Z640 [00672] 545.2 Z641 [00673] 544.3 Z642

[1689] Referring to the preparation methods of the above Examples, the compounds shown in Table (A) were prepared by modifying some of the starting materials:

TABLE-US-00004 TABLE (A) MS Structure and Number [M + H].sup.+ [00674] 357.2 Z5 [00675] 362.2 Z6 [00676] 379.3 Z7 [00677] 387.2 Z8 [00678] 365.3 Z9 [00679] 381.3 Z10 [00680] 357.2 Z11 [00681] 361.2 Z12 [00682] 466.2 Z13 [00683] 473.2 Z14 [00684] 351.2 Z15 [00685] 385.2 Z16 [00686] 383.2 Z17 [00687] 397.2 Z18 [00688] 373.2 Z19 [00689] 385.2 Z20 [00690] 424.2 Z21 [00691] 400.2 Z22 [00692] 357.2 Z23 [00693] 416.2 Z24 [00694] 417.2 Z91 [00695] 443.2 Z92 [00696] 390.2 Z200 [00697] 378.2 Z201 [00698] 391.2 Z202 [00699] 391.2 Z203 [00700] 398.2 Z204 [00701] 379.2 Z205 [00702] 391.2 Z206 [00703] 363.2 Z207 [00704] 357.2 Z208 [00705] 413.2 Z209

[1690] Referring to the preparation methods of the above Examples, the compounds shown in Table (B) were prepared by modifying some of the starting materials:

TABLE-US-00005 TABLE (B) MS Structure and Number [M + H].sup.+ [00706] 324.2 Z25 [00707] 365.1 Z26 [00708] 329.2 Z27 [00709] 335.2 Z28 [00710] 334.2 Z29 [00711] 335.2 Z30 [00712] 336.2 Z31 [00713] 335.2 Z32 [00714] 361.2 Z33 [00715] 391.2 Z34 [00716] 389.2 Z35 [00717] 382.2 Z36 [00718] 411.2 Z37 [00719] 329.2 Z38 [00720] 335.2 Z39 [00721] 329.2 Z40 [00722] 329.2 Z41 [00723] 343.2 Z42 [00724] 335.2 Z43 [00725] 337.2 Z44 [00726] 369.2 Z45 [00727] 383.2 Z46 [00728] 355.2 Z47 [00729] 345.2 Z48 [00730] 381.2 Z49 [00731] 395.2 Z50 [00732] 362.2 Z51 [00733] 404.2 Z52 [00734] 507.3 Z53 [00735] 468.2 Z54 [00736] 474.3 Z55 [00737] 461.2 Z56 [00738] 395.2 Z57 [00739] 415.2 Z58 [00740] 379.2 Z59 [00741] 424.2 Z60 [00742] 410.2 Z61 [00743] 453.2 Z62 [00744] 347.2 Z63 [00745] 408.2 Z64 [00746] 422.2 Z65 [00747] 346.2 Z66 [00748] 345.2 Z67 [00749] 412.2 Z68 [00750] 402.2 Z69 [00751] 408.2 Z70 [00752] 398.2 Z71 [00753] 335.2 Z72 [00754] 334.2 Z73 [00755] 336.2 Z74 [00756] 334.2 Z75 [00757] 338.2 Z76 [00758] 383.1 Z77 [00759] 349.1 Z78 [00760] 393.1 Z79 [00761] 339.2 Z80 [00762] 424.2 Z81 [00763] 425.2 Z82 [00764] 477.2 Z83 [00765] 453.1 Z84 [00766] 453.2 Z85 [00767] 391.2 Z86 [00768] 375.2 Z87 [00769] 411.2 Z88 [00770] 455.2 Z89 [00771] 416.2 Z90 [00772] 397.2 Z102 [00773] 336.2 Z108 [00774] 364.2 Z116 [00775] 363.2 Z117 [00776] 343.2 Z118 [00777] 350.2 Z120 [00778] 413.2 Z129 [00779] 388.2 Z133 [00780] 449.3 Z134 [00781] 335.2 Z135 [00782] 403.2 Z140 [00783] 418.2 Z141 [00784] 417.2 Z143 [00785] 432.2 Z144 [00786] 348.2 Z145 [00787] 414.2 Z146 [00788] 362.2 Z147 [00789] 348.2 Z148 [00790] 378.2 Z149 [00791] 348.2 Z150 [00792] 320.2 Z151 [00793] 324.2 Z152 [00794] 405.2 Z153 [00795] 373.2 Z154 [00796] 349.2 Z155 [00797] 377.2 Z156 [00798] 446.2 Z157 [00799] 470.2 Z158 [00800] 482.2 Z159 [00801] 375.2 Z160 [00802] 375.2 Z161 [00803] 437.2 Z162 [00804] 440.2 Z163 [00805] 481.3 Z164 [00806] 451.3 Z165 [00807] 435.2 Z166 [00808] 361.2 Z167 [00809] 429.2 Z168 [00810] 417.2 Z169 [00811] 352.2 Z170 [00812] 449.3 Z171 [00813] 435.2 Z172 [00814] 366.2 Z173 [00815] 349.2 Z174 [00816] 375.2 Z175 [00817] 323.2 Z176 [00818] 374.2 Z177 [00819] 402.2 Z178 [00820] 324.2 Z179 [00821] 329.2 Z180 [00822] 375.2 Z182 [00823] 508.2 Z183 [00824] 340.2 Z184 [00825] 349.2 Z185 [00826] 509.3 Z187 [00827] 437.2 Z188 [00828] 365.2 Z189 [00829] 375.2 Z191 [00830] 351.2 Z192 [00831] 365.2 Z193 [00832] 366.2 Z194 [00833] 379.2 Z195 [00834] 354.2 Z196 [00835] 357.3 Z197 [00836] 434.3 Z198 [00837] 360.2 Z240 [00838] 468.2 Z241 [00839] 436.2 Z248 [00840] 400.2 Z253 [00841] 413.2 Z254 [00842] 387.2 Z255 [00843] 425.2 Z263 [00844] 466.2 Z257 [00845] 387.2 Z258 [00846] 438.2 Z259 [00847] 424.2 Z260 [00848] 459.2 Z264 [00849] 424.2 Z265 [00850] 396.2 Z266 [00851] 473.2 Z267 [00852] 511.2 Z268 [00853] 443.2 Z269 [00854] 457.2 Z270 [00855] 487.2 Z271 [00856] 506.2 Z272 [00857] 452.2 Z273 [00858] 452.2 Z274 [00859] 437.2 Z275 [00860] 453.2 Z276 [00861] 473.2 Z277 [00862] 429.2 Z278 [00863] 513.3 Z326 [00864] 499.3 Z329 [00865] 413.2 Z321 [00866] 413.2 Z322 [00867] 363.2 Z338 [00868] 468.2 Z324 [00869] 391.2 Z325 [00870] 452.2 Z332 [00871] 481.2 Z352 [00872] 431.2 Z334 [00873] 495.2 Z353 [00874] 514.2 Z360 [00875] 436.2 Z363 [00876] 352.2 Z367 [00877] 491.2 Z366-1 [00878] 491.2 Z366-2 [00879] 457.2 Z369 [00880] 452.2 Z370 [00881] 413.2 Z371 [00882] 421.2 Z378 [00883] 447.2 Z379 [00884] 413.2 Z380 [00885] 455.2 Z381 [00886] 445.2 Z383 [00887] 454.2 Z384 [00888] 419.2 Z403 [00889] 445.3 Z407 [00890] 472.3 Z390 [00891] 458.3 Z391 [00892] 458.3 Z392 [00893] 458.3 Z393 [00894] 458.3 Z394 [00895] 486.3 Z395 [00896] 456.3 Z396 [00897] 488.3 Z397 [00898] 411.2 Z398 [00899] 416.2 Z399 [00900] 413.2 Z400 [00901] 445.3 Z407 [00902] 425.2 Z408 [00903] 501.2 Z409 [00904] 461.3 Z434 [00905] 521.2 Z412 [00906] 447.2 Z432 [00907] 434.3 Z431 [00908] 503.2 Z415 [00909] 489.3 Z417 [00910] 455.2 Z418 [00911] 441.2 Z427 [00912] 445.3 Z420 [00913] 432.3 Z421 [00914] 435.2 Z426 [00915] 449.3 Z423 [00916] 449.3 Z424 [00917] 515.3 Z520 [00918] 437.2 Z521 [00919] 485.2 Z524 [00920] 451.2 Z525 [00921] 431.2 Z526 [00922] 469.2 Z529 [00923] 464.3 Z530 [00924] 436.2 Z534 [00925] 482.3 Z535 [00926] 477.2 Z536 [00927] 529.2 Z537 [00928] 483.2 Z539 [00929] 484.2 Z542 [00930] 440.2 Z547 [00931] 493.2 Z548 [00932] 460.2 Z553 [00933] 461.2 Z554 [00934] 501.3 Z557 [00935] 517.3 Z559 [00936] 475.3 Z560 [00937] 495.2 Z561 [00938] 488.3 Z564

Test Example 1. SLP76 Phosphorylation Assay

[1691] RPMI-1640: purchased from Gibco; Cat. No: 11875-093; FBS: purchased from Gibco; Cat. No: 10099-141C; PS: purchased from Gibco; Cat. No: 15140-122; PBS: purchased from Hyclone; Cat. No: SH30256.01; EDTA, 0.5M, pH 8.0: purchased from absin; Cat. No: abs9133; Dynabeads anti-human CD3: purchased from Thermo Fisher; Cat. No: 11151D; 96 well F-bottom TC plate: purchased from Corning; Cat. No: 3599; 96 well V-storage plate: purchased from Corning; Cat. No: 3894; Halt Protease Inhibitor Cocktail, EDTA-Free (100): purchased from Thermo Fisher; Cat. No: 78439; PathScan Phospho-SLP-76 (Ser376) Sandwich ELISA Kit: purchased from CST; Cat. No: 78222CA;

[1692] Intracellular HPK1 inhibitory activity was tested by the detection of SLP76 phosphorylation at S376. The cells used in this experiment were Jurkat, Clone E6-1 which expressed HPK1 and SLP76.

[1693] Cell culture: Jurkat, Clone E6-1 cells (purchased from ATCC; Cat. No: TIB-512; complete medium: RPMI-1640+10% FBS+1% PS), in RPMI-1640 complete medium containing 10% fetal bovine serum and 1% double antibiotics (a mixed solution of penicillin and streptomycin), were placed in a 5% CO.sub.2 incubator at 37 C. for culture, passed 2-3 times per week, and maintained a culture density at 110.sup.5/mL110.sup.6/mL.

[1694] Preparation of 1000 drug stock plate: a 1000 compound stock plate was prepared. 10 mM or 5 mM of compound stock solution was diluted with DMSO, with an initial concentration of 10 mM (5 mM), 9 concentration gradients, and 3.162-fold dilution. The compound stock plate was sealed with a sealing film and stored in a 20 C. refrigerator for later use.

[1695] Preparation of Beads wash buffer: 0.1 mL FBS and 0.4 mL 0.5 M EDTA (with a final concentration of 2 mM) were added to 100 mL PBS and stored in a 4 C. refrigerator for later use.

[1696] Preparation of 5 protein lysis buffer: 10 Cell lysis buffer was taken and diluted to 5 with deionized water. 100 Protease Inhibitor Cocktail in 1/20 total volume was added and stored on wet ice for later use. The buffer was ready to use.

[1697] Cell inoculation and dosing: the 1000 drug stock plate was taken and melted at room temperature in the dark. Then 10 drug intermediate plate was prepared using fresh RPMI-1640 complete medium and mixed well. Jurkat cells in the logarithmic growth phase were selected and collected. After centrifugation, the pellet was resuspended using fresh complete medium, counted, and adjusted the cell density to 2.2210.sup.6/mL. The cells were inoculated into a 96-well plate (the volume was 90 L per well), and a blank control well (without cells inoculation, and in which 110 L of medium was added) was set. 10 L of a drug-containing culture medium (10) was transferred from the 10 drug intermediate plate into the 96-well cell plate (with a final concentration of 0.1% DMSO), and set a DMSO control group (in which 0.1% DMSO was added to the treated cells), a stimulated control group (in which 10 L of culture medium was added to treat cells) and an unstimulated group (in which 10 L of culture medium was added to treat cells). The wells were duplicated, gently patted, mixed, and then placed into a 5% CO.sub.2 incubator at 37 C. for 1 h.

[1698] Anti-CD3 beads stimulation: Dynabeads anti-human CD3 was taken, shaken, and mixed for 60 s. The required volume of beads was pipetted, and an equal volume or at least 1 mL of washing solution was added to wash once. Fresh complete medium was then added to resuspend and adjust the density of the beads to 410.sup.7/mL, and the beads were placed on ice for later use. At the end of drug pre-incubation, the cell culture plate was taken out. 10 L Dynabeads anti-human CD3 was added to each well to treat the cells, and 10 L the culture medium was added to the unstimulated group. The cell culture plate was shaken to mix well at 2500 rpm for 10 s, and then placed into a 5% CO.sub.2 incubator at 37 C. and continued to culture for 20 min.

[1699] Detection of p-SLP76 protein level: PathScan Phospho-SLP-76 (Ser376) Sandwich ELISA Kit was applied to detect p-SLP76 protein level. At the end of the Anti-CD3 beads stimulation, the cell culture plate was removed from the incubator. 27 L of 5 protein lysis buffer pre-chilled on ice was added to each well, and the plate was placed on ice for 30 min. After lysis, the cell culture plate was centrifuged at 4 C., 400g for 5 min. 25 L of sample and 75 L of sample diluent were added to each well, and the plate was placed in a 5% CO.sub.2 incubator at 37 C. for 2 h. The subsequent detection steps were carried out following the kit instructions, and the absorbance (OD value) of each well was read at 450 nm by a microplate reader.

[1700] Data analysis processing: the inhibition rate of p-SLP76 protein level was calculated according to the following formula: Inhibition rate %=[1(OD.sub.compoundOD.sub.Blank control)/(ODDMSO.sub.controlOD.sub.Blank control)]100%, wherein OD.sub.Compound is the reading of the well treated with compound, OD.sub.Blank control is the reading of the blank control well, and OD.sub.DMSO control is the reading of the cells DMSO control well. The Dose response one site/f(x) 205[fit=(A+((BA)/(1+((C/x){circumflex over ()}AD))))] model was used to fit the pharmacodynamics inhibition rate curves with XLfit 5.5.x software, and the IC.sub.50 values of the drugs were calculated.

[1701] It may be seen from the experimental results that the compounds of the present disclosure have a high inhibitory activity on SLP76 phosphorylation, with an IC.sub.50 value of less than 5000 nM (e.g. 1 nM to 5000 nM); IC.sub.50 values for some compounds are even less than 3000 nM (e.g. 1 nM to 3000 nM) or less than 1000 nM (e.g. 1 nM to 1000 nM). The experimental results of some compounds are shown in Table 2.

TABLE-US-00006 TABLE 2 p-SLP76 p-SLP76 p-SLP76 p-SLP76 Number IC.sub.50(nM) Number IC.sub.50(nM) Number IC.sub.50(nM) Number IC.sub.50(nM) Z2 2897.1 Z3 853.1 Z3-1 >10000 Z3-2 603.8 Z4 3574.9 Z93 438.6 Z93-2 235.0 Z94 2846.4 Z94-2 1388.0 Z95 1077.0 Z95-2 623.3 Z96 1001.1 Z97 377.0 Z97-2 164.3 Z98 237.3 Z98-2 151.5 Z100 211.6 Z100-2 327.9 Z101 162.6 Z101-2 110.9 Z103 545.4 Z104 77.0 Z105 198.5 Z106 132.8 Z107 525.3 Z223 301.0 Z225 1337.0 Z104-2 196.9 Z137 159.41 Z199 116.6 Z181 1705.0 Z228-1 84.4 Z136 7909.7 Z229 275.7 Z231 >10000 Z109 1061.0 Z112 304.9 Z110 2838.1 Z108-1 570.7 Z236 3810.4 Z237 100.2 Z138 132.1 Z244 96.58 Z238 354.42 Z139 158.7 Z251 131.41 Z250 193.07 Z243 2508.09 Z219-2 122.06 Z279 161.97 Z271-2 379.75 Z281 2029.08 Z283 285.8 Z285 322.74 Z132 352.2 Z121 185.2 Z122 179.1 Z126 252.0 Z125 301.0 Z123 343.0 Z124 260.1 Z127 204.29 Z130 1805.4 Z210 226.9 Z211 463.1 Z212 909.4 Z119 358.0 Z213 318.2 Z214 180.5 Z215 443.6 Z216 107.5 Z34-1 265.4 Z119-1 390.2 Z54-1 400.6 Z217 133.0 Z37-1 143.3 Z218 367.4 Z219 257.4 Z220 469.0 Z221 215.0 Z222 201.0 Z224 333.0 Z104-1 126.2 Z186 3760.6 Z190 494.43 Z226 10697.0 Z227 118.6 Z228-2 49.3 Z131 663.79 Z230 437.7 Z232 1658.59 Z111 814.7 Z113 10005.8 Z233 520.0 Z235 735.4 Z242 175.45 Z245 118.68 Z252 1772.47 Z249 208.06 Z444 334.63 Z75-1 475.43 Z219-1 173.74 Z240-1 769.82 Z271-1 330.83 Z280 315.7 Z282 471.4 Z284 366.02 Z239 239.29 Z286 244.37 Z287 338.14 Z246 278.73 Z288 320.8 Z289 378.33 Z290 272.12 Z291 161.98 Z292 272.3 Z293 112.87 Z294 95.33 Z285-1 239.14 Z88-1 91.27 Z295 213.75 Z296 223.27 Z297 1011.49 Z298 668.33 Z299 376.23 Z300 274.42 Z301 253.61 Z302 125.33 Z303 236.39 Z304 388.62 Z305 297.3 Z306 169.79 Z307 276.56 Z151-1 739.21 Z308 440.76 Z38-1 719.14 Z309-1 82.59 Z309-2 Z310 567.19 Z311 146 Z312 88.37 Z313 Z314 452.46 Z315 224.81 Z316 313.53 Z317 199.9 Z318 528.15 Z319 110.54 Z320 121.45 Z247 150.6 Z327 149.93 Z333 205.23 Z365 315.06 Z364 327.49 Z323 203.64 Z330 204.66 Z331 174.4 Z328 90.73 Z336 174.49 Z335 169.98 Z356 62.06 Z256 279.28 Z402 453.52 Z337 359.42 Z401 462.05 Z405 89.76 Z367-1 999.27 Z362 92.92 Z345 764.77 Z359-1 135.45 Z437 119.11 Z339 148.52 Z368 417.36 Z388 43.09 Z389 47.14 Z357-1 99.3 Z357-2 80.74 Z358-2 53.25 Z361 101.55 Z359-2 98.08 Z358-1 67.4 Z343 176.69 Z261 842.27 Z262 627.45 Z438 338.8 Z344 386.05 Z348 182.88 Z350 177.6 Z354 268.63 Z349 240.47 Z351 125.59 Z376 211.09 Z375 257.72 Z372 105.73 Z382 474.26 Z443 210.82 Z404 112.51 Z387 2402.03 Z385 Z386 632.29 Z439 209.96 Z440 141.99 Z414 2608.75 Z441 197.04 Z442 411.91 Z433 111.45 Z424-1 128.88 Z418-1 61.3 Z340 240.65 Z355 195.52 Z346 225.84 Z341 492.46 Z314-1 969.45 Z347 318.58 Z342 270.8 Z374 265.75 Z429 159 Z385 3.3 Z452 237.83 Z453 147.97 Z456 315.3 Z457 60.94 Z454 655.29 Z455 4428.47 Z460 176.81 Z445 253.18 Z458 127.05 Z459 170.82 Z448 120.42 Z422 348.97 Z446 195.63 Z447 44.8 Z419 74.21 Z450 157.77 Z377 189.83 Z449 Z497 185.95 Z451 44.17 Z545 559.74 Z531 385.19 Z461 195.33 Z463 292.92 Z464 193.14 Z465 143.55 Z466 305.94 Z467 385.04 Z468 340.07 Z469 125.43 Z470 127.32 Z471 179.94 Z472 215.75 Z473 143.46 Z496 62.7 Z475 116.86 Z476 66.97 Z477 422.44 Z435 257.58 Z416 63.12 Z373 158.74 Z478 328.98 Z479 146.74 Z480 118.02 Z481 442.8 Z482 311.43 Z483 111.95 Z484 364.27 Z485 125.7 Z486 153.27 Z487 153.49 Z488 149.98 Z489 82.14 Z490 429.81 Z491 307.95 Z492 95.73 Z493 295.07 Z494 452.93 Z495 129.49 Z411 428.07 Z569 154.44 Z570 31.89 Z571 108.22 Z572 28.05 Z573 121.94 Z574 83.91 Z562 146.64 Z540 524.03 Z533 228.92 Z528 42.4 Z541 33.67 Z563 174.25 Z565 245.19 Z500 143.3 Z499 218.96 Z498 195.47 Z501 284.62 Z504 232.15 Z503 168.45 Z502 169.35 Z519 196.81 Z512 147.59 Z505 263.4 Z544 50.12 Z575 420.26 Z551 497.69 Z555 481.28 Z556 961.58 Z543 235.67 Z523 51.77 Z558 936.41 Z549 66.29 Z550 117.11 Z506 685.05 Z576 188.1 Z527 163.75 Z507 118.94 Z532 393.54 Z518 129.51 Z577 78.11 Z578 163.46 Z579 276.14 Z585 83.17 Z581 86.69 Z462 255.4 Z568 66.24 Z552 104.76 Z567 125.37 Z522 110.22 Z510 283.43 Z566 81.76 Z515 172.61 Z508 303.8 Z594 824.88 Z593 317.26 Z514 134.34 Z516 161.26 Z592 215 Z590 61.75 Z591 275.3 Z589 246.14 Z586 44.97 Z606 62.9 Z608 67.09 Z624 76.03 Z607 76.15 Z611 98.87 Z595 109.31 Z603 67.41 Z604 108.04 Z630 247.18 Z631 240.09 Z613 135.71 Z600 103.07 Z599 183.58 Z643 294.21 Z644 61.59 Z582 160 Z583 2668.11 Z584 127.28 Z620 161.36 Z619 60.61 Z617 86.22 Z615 207.16 Z588 214.69 Z587 44.81 Z538 1051

Test Example 2. HPK1 Kinase Activity Assay

[1702] Adp-Glo Kinase Assay was purchased from Promega; Cat. No: V9102; HPK1 was purchased from Carna; Cat. No: 07-410; ATP was purchased from Promega; BSA was purchased from Sigma; Cat. No: B2064-100G; MgCl2 was purchased from Shyuanye; Cat. No: R21455; MBP was purchased from Millipore; Cat. No: 13-110; Briji-35 was purchased from Sigma; Cat. No: B4184-100ML; Tris-HCl was purchased from Sigma; DTT was purchased from Thermo Fisher; Cat. No: R0861; V-storage plate was purchased from coming; Cat. No: 3894; ProxiPlate-384-Plates was purchased from PerkinElmer; Cat. No: 6008289.

[1703] Preparation of buffer: Ix reaction buffer (40 mM Tris-HCl, 20 mM MgCl.sub.2, 0.01% Brij35, 50 M DTT, 0.1 mg/ml BSA) was prepared using sterile water, which was prepared and used on the day of the experiment.

[1704] Preparation of 1000 drug stock plate: a 1000 compound stock plate was prepared. 10 mM of compound stock solution was diluted with DMSO, with an initial concentration of 1 mM, 10 concentration gradients, and 3.162-fold dilution. The compound stock plate was sealed with a sealing film and stored in a 20 C. refrigerator for later use.

[1705] Compound preparation and dosing: the 1000 drug stock plate was taken and melted at room temperature in the dark. Then 5 drug intermediate plate was prepared using reaction buffer and mixed well. 2 L was transferred from the 5 drug intermediate plate into a 384-well plate, and negative control well and positive control well (in which 2 L reaction buffer containing 0.5% DMSO was added) were set. Each point was repeated twice.

[1706] Preparation and incubation of reaction mixture: HPK1 protein was diluted to a 2.5 working solution with reaction buffer. 4 L 2.5HPK1 protein was added to each well containing test compound and positive control well, and 4 L of reaction buffer without HPK1 protein was added to the negative control well. The obtained mixture was centrifuged at 1000 rpm for 1 min and then incubated in a 20 C. incubator for 15 min. A 2.5 mixed working solution of MBP protein and ATP was prepared with reaction buffer at concentrations of 0.5 g/L and 50 M, respectively. 4 L of the mixed working solution of MBP and ATP was added to each well, centrifuged at 1000 rpm for 1 min, and then incubated in a 20 C. incubator for 90 min.

[1707] ADP-Glo detection and reading plate: 10 l ADP-Glo was added to each well of the test plate. The resulting mixture was centrifuged at 1000 rpm for 1 min and incubated in a 20 C. incubator for 60 min. Then 10 L of the final incubation solution was transferred from the test plate to a new 384-well plate. 10 L of kinase detection reagent was added to each well, centrifuged at 400 g for 1 min, and incubated in a 20 C. incubator for 60 min Chemiluminescent signals were read by a microplate reader.

[1708] Data analysis processing: Inhibition rate %=(1(test wellnegative control well)/(positive control wellnegative control well))*100%; negative control well: 10 M ATP+0.1 g/L MBP+DMSO; positive control well: 1 nM HPK 1+10 M ATP+0.1 g/L MBP+DMSO; test well: 1 nM HPK1+10 M ATP+0.1 g/L MBP+a compound; the data were analyzed using Graphpad Prism 8.0.1; pharmacodynamics inhibition rate curves were fitted using a four-parameter method, and IC.sub.50 values for the drugs were calculated.

[1709] It may be seen from the experimental results that the compounds of the present disclosure have a high inhibitory activity on HPK1 kinase, with an IC.sub.50 value of less than 500 nM (e.g. 0.1 nM to 500 nM); IC.sub.50 values for some compounds are even less than 100 nM (e.g. 0.1 nM to 100 nM) or less than 50 nM (e.g. 0.1 nM to 50 nM), more even less than 10 nM (e.g. 0.1 nM to 10 nM). The experimental results of some of the compounds are shown in Table 3.

TABLE-US-00007 TABLE 3 HPK1 Kinase HPK1 Kinase HPK1 Kinase HPK1 Kinase activity activity activity activity Number IC.sub.50(nM) Number IC.sub.50(nM) Number IC.sub.50(nM) Number IC.sub.50(nM) Z2 2.72 Z3 4.34 Z3-1 230.6 Z3-2 3.37 Z4 48.68 Z93 1.62 Z93-1 162.9 Z93-2 0.71 Z94 4.34 Z94-1 92.7 Z94-2 1.53 Z95 3.11 Z95-1 18.38 Z95-2 1.45 Z96 4.13 Z97 1.54 Z97-1 120.08 Z97-2 0.67 Z98 0.90 Z98-1 49.41 Z98-2 0.50 Z100 4.26 Z100-1 61.88 Z100-2 1.52 Z101 0.49 Z101-1 42.70 Z101-2 0.99 Z103 2.65 Z104 0.29 Z105 0.47 Z106 0.53 Z107 5.79 Z104-1 0.62 Z186 34.24 Z190 1.89 Z226 3.25 Z227 0.52 Z228-2 0.41 Z131 7.54 Z230 1.04 Z232 20.53 Z114 138.43 Z111 5.81 Z113 62.20 Z110 26.95 Z233 4.01 Z234-1 154.34 Z235 1.32 Z138 0.81 Z242 0.52 Z245 0.45 Z252 5.1 Z249 0.38 Z444 0.65 Z75-1 1.7 Z219-1 0.42 Z240 2.28 Z271-1 1.03 Z280 0.54 Z282 0.38 Z284 0.83 Z239 Z132 3.64 Z121 0.50 Z122 0.71 Z126 0.78 Z125 1.43 Z123 1.35 Z124 0.33 Z127 0.58 Z128 167.95 Z130 3.06 Z210 0.62 Z211 1.70 Z212 3.76 Z119 1.54 Z213 0.64 Z214 1.04 Z215 0.51 Z216 0.41 Z34-1 0.55 Z119-1 1.06 Z119-2 90.03 Z54-1 0.60 Z217 0.44 Z37-1 0.82 Z218 0.81 Z219 0.66 Z220 2.26 Z221 1.27 Z222 0.80 Z223 1.60 Z224 1.11 Z225 0.72 Z104-2 0.74 Z137 0.37 Z199 0.32 Z181 14.60 Z228-1 0.48 Z136 31.23 Z229 0.46 Z231 35.26 Z109 9.78 Z115 257.03 Z112 3.55 Z116-1 843.42 Z116-2 >1000 Z108-1 4.12 Z234-2 >1000 Z236 29.59 Z237 0.71 Z244 0.35 Z238 1.48 Z139 0.39 Z251 0.49 Z250 0.42 Z243 16.49 Z219-2 0.35 Z279 0.44 Z271-2 1.06 Z281 Z283 0.3 Z285 0.91 Z286 0.46 Z287 0.4 Z246 0.48 Z288 0.69 Z289 1.35 Z290 0.77 Z291 0.6 Z292 0.97 Z293 0.47 Z294 0.52 Z285-1 0.87 Z88-1 0.38 Z295 1.22 Z296 0.86 Z297 2.37 Z298 3.3 Z299 1.06 Z300 0.64 Z301 0.61 Z302 0.93 Z303 0.83 Z304 1.18 Z305 0.84 Z306 0.64 Z307 0.53 Z151-1 2.52 Z308 2.06 Z38-1 2.97 Z309- 0.58 Z309-2 22.67 Z310 1.79 Z311 0.56 Z312 0.47 Z313 Z314 2.42 Z315 0.29 Z316 0.74 Z317 0.88 Z318 1.06 Z319 0.28 Z320 0.73 Z247 0.61 Z347 0.61 Z342 0.64 Z327 0.33 Z333 0.49 Z365 0.97 Z364 1.01 Z323 0.49 Z330 0.73 Z331 0.7 Z328 0.33 Z336 0.36 Z335 0.25 Z356 0.28 Z256 0.8 Z402 1.2 Z337 1.57 Z401 3.19 Z405 0.23 Z367-1 1.44 Z362 0.22 Z345 1.11 Z359-1 0.27 Z437 0.58 Z339 0.58 Z368 1.41 Z436 39.1 Z389 0.21 Z357-1 0.31 Z357-2 0.26 Z358-2 0.23 Z361 0.36 Z359-2 0.36 Z358-1 0.23 Z343 0.4 Z261 2.63 Z262 1.72 Z438 1.13 Z344 1.52 Z348 0.75 Z350 0.67 Z354 1.02 Z349 0.47 Z35 0.87 Z386 2.74 Z439 0.78 Z440 0.37 Z414 20.63 Z441 0.52 Z442 1.5 Z376 0.33 Z375 0.59 Z372 0.18 Z382 1.35 Z418-1 0.19 Z424-1 0.31 Z433 0.22 Z404 0.32 Z443 0.65 Z340 0.57 Z355 0.45 Z346 0.43 Z341 1.09 Z314-1 2.62 Z374 0.38 Z429 0.41 Z387 3.8 Z497 0.4 Z445 0.85 Z446 0.83 Z447 0.18 Z448 0.29 Z422 0.72 Z377 0.28 Z449 12.44 Z419 0.11 Z450 0.22 Z451 0.11 Z473 0.24 Z469 0.06 Z489 0.21 Z490 1.66 Z491 1.29 Z492 0.18 Z493 0.41 Z494 0.81 Z495 0.38 Z411 1.12 Z496 0.22 Z416 0.29 Z570 0.13 Z572 0.16 Z574 0.41 Z512 0.35 Z518 0.22 Z488 0.21 Z600 0.08 Z604 0.36 Z603 0.21 Z595 0.21 Z611 0.37 Z607 0.27 Z624 0.36 Z608 0.27 Z606 0.25 Z587 0.27 Z588 0.67 Z615 0.76 Z617 0.36 Z619 0.28 Z620 0.77 Z644 0.25 Z585 0.25 Z586 0.19 Z590 0.24 Z566 0.24 Z552 0.22 Z568 0.33 Z571 0.49 Z528 0.16 Z541 0.16 Z544 0.12 Z549 0.11 Z507 0.43 Z523 0.17 Z577 0.25 Z581 0.24 Z476 0.21 Z457 0.14
the present disclosure have been described in detail with reference to specific embodiments, but those skilled in the art will understand that various modifications and alterations can be made to the technical solution of the present disclosure based on all teachings of the disclosure without departing from the scope of the present disclosure. The appended claims and any equivalents thereof define the full scope of the present disclosure.