NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

The present invention relates to a nitrogen-containing heterocyclic derivative EGFR inhibitor, a preparation method therefor and a use thereof. In particular, the present invention relates to a compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof as an EGFR inhibitor in treating cancer.

Claims

1. A compound as represented by general formula (II-G), or a stereoisomer or pharmaceutically acceptable salt thereof: ##STR00343## wherein: M.sub.1 is C, N or CH; ring B is selected from ##STR00344## R.sub.1 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR.sub.a, P(O).sub.p(R.sub.a).sub.n5, S(O).sub.mR.sub.a or C(O)R.sub.a, and the amino, alkyl, alkenyl, alkynyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl can be optionally further substituted; or, two R.sub.1 are connected to the atoms therebetween to form cycloalkyl, heterocyclyl, aryl and heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl can be optionally further substituted; R.sub.2 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR.sub.a, P(O).sub.p(R.sub.a).sub.n5, S(O).sub.mR.sub.a or C(O)R.sub.a, and the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl can be optionally further substituted; R.sub.4 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR.sub.a, P(O).sub.p(R.sub.a).sub.n5, S(O).sub.mR.sub.a or C(O)R.sub.a, and the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl can be optionally further substituted; or, wherein one R.sub.2 and one R.sub.4 are connected to the atoms therebetween to form cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl can be optionally further substituted; R.sub.a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl can be optionally further substituted; x is 0, 1, 2, 3, 4, 5 or 6; y is 0, 1, 2, 3, 4, 5 or 6; w is 0, 1, 2, 3, 4, 5 or 6; and p, m and n5 are each independently 0, 1, 2 or 3.

2. The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is further as represented by general formula (VII-1): ##STR00345## wherein: M.sub.5 is N or CH; R.sub.5 and R.sub.6 are independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.1-6 deuteroalkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 deuteroalkoxy or C.sub.1-6 hydroxyalkyl; and n6 is 0, 1 or 2.

3. The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.1 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl, 5- to 14-membered heteroaryl, (CH.sub.2).sub.nOR.sub.a, (CH.sub.2).sub.nP(O).sub.p(R.sub.a).sub.n5, (CH.sub.2).sub.nS(O)R.sub.aaN(R.sub.aa), (CH.sub.2).sub.nNS(O)(R.sub.aa).sub.2, (CH.sub.2).sub.nS(O).sub.mR.sub.a or (CH.sub.2).sub.nC(O)R.sub.a, and the amino, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl and 5- to 14-membered heteroaryl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 deuteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, halo C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-12 aryl, 5- to 12-membered heteroaryl, OR.sub.aa, S(O)R.sub.aaN(R.sub.aa), NS(O)(R.sub.aa).sub.2, P(O).sub.p(R.sub.aa).sub.n5, S(O).sub.mR.sub.aa, Se(O).sub.mR.sub.aa or C(O)R.sub.aa; or, two R.sub.1 are connected to the atoms therebetween to form C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl and 5- to 14-membered heteroaryl, and the C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl and 5- to 14-membered heteroaryl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy or C.sub.1-6 hydroxyalkyl; R.sub.aa is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl can be optionally further substituted; and n is independently 0, 1, 2 or 3.

4. The compound as represented by the general formula, or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.2 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl, 5- to 14-membered heteroaryl, OR.sub.a, P(O).sub.p(R.sub.a).sub.n5, S(O).sub.mR.sub.a or C(O)R.sub.a, and the amino, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl and 5- to 14-membered heteroaryl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 deuteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, halo C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-12 aryl, 5- to 12-membered heteroaryl, OR.sub.aa, P(O).sub.p(R.sub.aa).sub.n5, S(O).sub.mR.sub.aa or C(O)R.sub.aa; R.sub.aa is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl can be optionally further substituted.

5. The compound as represented by the general formula, or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.4 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl, 5- to 14-membered heteroaryl, OR.sub.a, P(O).sub.p(R.sub.a).sub.n5, S(O).sub.mR.sub.a or C(O)R.sub.a, and the amino, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl and 5- to 14-membered heteroaryl can be optionally further substituted with one or more R.sub.4-1; R.sub.4-1 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 deuteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, halo C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-12 aryl, 5- to 12-membered heteroaryl, OR.sub.aa, P(O).sub.p(R.sub.aa).sub.n5, S(O).sub.mR.sub.aa or C(O)R.sub.aa; optionally, R.sub.4-1 is substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 deuteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, halo C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-12 aryl, or 5- to 12-membered heteroaryl, and the amino, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 deuteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, halo C.sub.1-6 alkoxy, and C.sub.1-6 hydroxyalkyl are optionally substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 deuteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, halo C.sub.1-6 alkoxy, or C.sub.1-6 hydroxyalkyl; or, one R.sub.2 and one R.sub.4 are connected to the atoms therebetween to form C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl or 5- to 14-membered heteroaryl, and the C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl and 5- to 14-membered heteroaryl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 deuteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, halo C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-12 aryl, or 5- to 12-membered heteroaryl; R.sub.aa is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl can be optionally further substituted.

6. The compound as represented by the general formula, or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl, or 5- to 14-membered heteroaryl, and the amino, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl, 5- to 14-membered heteroaryl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 deuteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, halo C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-12 aryl, or 5- to 12-membered heteroaryl; and each R.sub.aa is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl, or 5- to 14-membered heteroaryl, and the amino, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl, 5- to 14-membered heteroaryl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 deuteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, halo C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-12 aryl, or 5- to 12-membered heteroaryl;

7. The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is further as represented by general formula (VII-2), (VII-3) or (VII-4): ##STR00346## R.sub.1 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-8 cycloalkyl, 3- to 10-membered heterocyclyl, (CH.sub.2).sub.nOR.sub.a, (CH.sub.2).sub.nP(O).sub.p(R.sub.a).sub.n5, (CH.sub.2).sub.nS(O)R.sub.aaN(R.sub.aa), (CH.sub.2).sub.nNS(O)(R.sub.aa).sub.2, (CH.sub.2).sub.nS(O).sub.mR.sub.a or (CH.sub.2).sub.nC(O)R.sub.a, and the amino, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-8 cycloalkyl and 3- to 10-membered heterocyclyl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3alkoxy, C.sub.1-3 hydroxyalkyl, OR.sub.aa, S(O)R.sub.aaN(R.sub.aa), NS(O)(R.sub.aa).sub.2, P(O).sub.p(R.sub.aa).sub.n5, S(O).sub.mR.sub.aa or C(O)R.sub.aa; R.sub.2 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, halo C.sub.1-3alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy or C.sub.1-3 hydroxyalkyl; R.sub.4 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, S(O).sub.mR.sub.a or C(O)R.sub.a, and the amino, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl and 3- to 10-membered heterocyclyl can be optionally further substituted with one or more R.sub.4-1; R.sub.4-1 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl or 5- to 12-membered heteroaryl; optionally, R.sub.4-1 is substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-12 aryl and 5- to 12-membered heteroaryl, and the amino, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, and C.sub.1-3 hydroxyalkyl are optionally substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy and C.sub.1-3 hydroxyalkyl; preferably, R.sub.4-1 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy or C.sub.1-3 hydroxyalkyl; optionally, R.sub.4-1 is substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl or 3- to 10-membered heterocyclyl, and the amino, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, and C.sub.1-3 hydroxyalkyl are optionally substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, or C.sub.1-3 hydroxyalkyl; R.sub.5 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, halo C.sub.1-3alkyl, deuterated C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy or C.sub.1-3 hydroxyalkyl, and the amino, C.sub.1-3 alkyl, halo C.sub.1-3alkyl and deuterated C.sub.1-3 alkyl can be optionally further substituted with one or more of deuterium, halogen, cyano, hydroxyl, nitro, C.sub.1-3 alkyl, halo C.sub.1-3 alkyl or deuterated C.sub.1-3alkyl; preferably, R.sub.5 is selected from hydrogen, hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkoxy or C.sub.1-6 hydroxyalkyl; R.sub.6 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocyclyl, S(O).sub.mR.sub.a or C(O)R.sub.a, and the amino, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl and 3- to 6-membered heterocyclyl can be optionally further substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, nitro and C.sub.1-3 alkyl; preferably, R.sub.6 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkoxy or C.sub.1-6 hydroxyalkyl; R.sub.a is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.1-3 deuteroalkyl C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl or 3- to 10-membered heterocyclyl; preferably, R.sub.a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl or 3- to 10-membered heterocyclyl; each R.sub.aa is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C.sub.1-3 haloalkyl or C.sub.1-3 deuteroalkyl; preferably, each R.sub.aa is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy or C.sub.1-3 hydroxyalkyl; x is 0, 1, 2 or 3; y is 0, 1, 2 or 3; p is 0, 1, 2 or 3; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; n5 is 0, 1, 2 or 3; and n6 is 0, 1 or 2.

8. The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 7, wherein the compound is further as represented by general formula (VII-2-1), (VII-3-1) or (VII-4-1): ##STR00347## wherein M.sub.11 is independently CH or N; R.sub.1-1 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or halomethyl; R.sub.1-2 is independently selected from amino, hydroxyl, cyano, C.sub.1-3 alkoxy, C.sub.1-3 alkyl, C.sub.3-6 cycloalkyl, or 3- to 8-membered heterocyclyl, and the amino, C.sub.1-3 alkoxy, C.sub.1-3 alkyl, C.sub.3-6 cycloalkyl, and 3- to 8-membered heterocyclyl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C(O)R.sub.ee, OR.sub.ee, P(O).sub.p(R.sub.ee).sub.n5 and S(O).sub.mR.sub.ee; preferably, R.sub.1-2 is selected from NHS(O).sub.2CH.sub.3, NCH.sub.3S(O).sub.2CH.sub.3, CH.sub.2S(O).sub.2CH.sub.3, CH.sub.2SOCH.sub.3, CH.sub.2NO.sub.2, methyl, hydrogen, ##STR00348## methoxy, cyano, CH.sub.2OCH.sub.3, CH.sub.2CN, CH(CN).sub.2, hydroxyl, CH.sub.2COCH.sub.3, ##STR00349## R.sub.2-1 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl or haloethyl; R.sub.2-2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl or haloethyl; R.sub.2-3 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl or haloethyl; R.sub.2-4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl or haloethyl; R.sub.5 is independently selected from amino, C.sub.1-3 alkyl, halo C.sub.1-3 alkyl or deuterated C.sub.1-3 alkyl, and the amino, C.sub.1-3 alkyl, halo C.sub.1-3 alkyl and deuterated C.sub.1-3 alkyl can be optionally further substituted with one or more of deuterium, halogen, cyano, hydroxyl, nitro, C.sub.1-3 alkyl, halo C.sub.1-3 alkyl or deuterated C.sub.1-3 alkyl; R.sub.4 is independently selected from halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, 3- to 8-membered heterocyclyl, S(O).sub.mR.sub.d or C(O)R.sub.d, and the amino, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl and 3- to 8-membered heterocyclyl can be optionally further substituted with one or more R.sub.4-1; R.sub.4-1 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-12 aryl or 5- to 12-membered heteroaryl; optionally, R.sub.4-1 is substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-12 aryl and 5- to 12-membered heteroaryl, and the amino, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy and C.sub.1-3 hydroxyalkyl are optionally substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy and C.sub.1-3 hydroxyalkyl; preferably, R.sub.4 is selected from fluorine, chlorine, cyano, trifluoromethyl, methyl, ethyl, nitro, hydroxyl, methoxy, OCD.sub.3, hydrogen, ##STR00350## cyclopropyl, ##STR00351## difluoromethyl, ##STR00352## ##STR00353## more preferably, R.sub.4 is selected from fluorine, chlorine, cyano, trifluromethyl, methyl, ethyl, nitro, hydroxyl, methoxy, OCD.sub.3, hydrogen, ##STR00354## cyclopropyl, ##STR00355## difluoromethyl, ##STR00356## ##STR00357## R.sub.6-1 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 alkoxy or C.sub.1-3 hydroxyalkyl; R.sub.6-2 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocyclyl, S(O).sub.mR.sub.e or C(O)R.sub.e, and the amino, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl and 3- to 6-membered heterocyclyl can be optionally further substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, nitro and C.sub.1-3 alkyl; R.sub.d is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C.sub.1-3 haloalkyl or C.sub.1-3 deuteroalkyl; R.sub.e is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C.sub.1-3 haloalkyl or C.sub.1-3 deuteroalkyl; R.sub.ee is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C.sub.1-3 haloalkyl or C.sub.1-3 deuteroalkyl; m is independently 0, 1 or 2; p is independently 0, 1 or 2; and n5 is independently 0, 1 or 2.

9. The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 8, wherein the compound is further as represented by general formula (VII-2-1-1), (VII-3-1-1) or (VII-4-1-1): ##STR00358## wherein M.sub.12 is independently selected from a bond, NR.sub.9 or CR.sub.10R.sub.11; R.sub.9 is independently selected from hydrogen, deuterium, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl; R.sub.10 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl; R.sub.11 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl; R.sub.1-1 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl; R.sub.2-1 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl or haloethyl; R.sub.2-2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl or haloethyl; R.sub.2-3 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl or haloethyl; R.sub.2-4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl or haloethyl; R.sub.5 is independently selected from amino, C.sub.1-3 alkyl, halo C.sub.1-3 alkyl or deuterated C.sub.1-3 alkyl, and the amino, C.sub.1-3 alkyl, halo C.sub.1-3 alkyl or deuterated C.sub.1-3 alkyl can be optionally further substituted with one or more of deuterium, halogen, cyano, hydroxyl, nitro, C.sub.1-3 alkyl, halo C.sub.1-3 alkyl and deuterated C.sub.1-3 alkyl; preferably, R.sub.5 is independently selected from isopropyl, CH(Me)OMe or N(Me).sub.2; R.sub.4 is independently selected from halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, 3- to 8-membered heterocyclyl, S(O).sub.mR.sub.d or C(O)R.sub.d, and the amino, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl and 3- to 8-membered heterocyclyl can be optionally further substituted with one or more R.sub.4-1; R.sub.4-1 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-12 aryl or 5- to 12-membered heteroaryl; optionally, R.sub.4-1 is substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-12 aryl and 5- to 12-membered heteroaryl, and the amino, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy and C.sub.1-3 hydroxyalkyl are optionally substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy and C.sub.1-3 hydroxyalkyl; preferably, R.sub.4 is selected from fluorine, chlorine, cyano, trifluoromethyl, methyl, ethyl, nitro, hydroxyl, methoxy, OCD.sub.3, hydrogen, ##STR00359## cyclopropyl, ##STR00360## difluoromethyl ##STR00361## ##STR00362## ##STR00363## more preferably, R.sub.4 is selected from fluorine, chlorine, cyano, trifluoromethyl, methyl, ethyl, nitro, hydroxyl, methoxy, OCD.sub.3, hydrogen, ##STR00364## cyclopropyl ##STR00365## difluoromethyl, ##STR00366## ##STR00367## R.sub.6-1 is independently selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy or C.sub.1-3 hydroxyalkyl; R.sub.6-2 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocyclyl, S(O).sub.mR.sub.e or C(O)R.sub.e, and the amino, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl and 3- to 8-membered heterocyclyl can be optionally further substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, nitro and C.sub.1-3 alkyl; R.sub.d is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C.sub.1-3 haloalkyl or C.sub.1-3 deuteroalkyl; R.sub.e is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C.sub.1-3 haloalkyl or C.sub.1-3 deuteroalkyl; and m is independently 0, 1 or 2.

10. The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is further as represented by general formula (VII-2-1-2), (VII-3-1-2) or (VII-4-1-2): ##STR00368## wherein M.sub.12 is independently selected from a bond, NR.sub.9 or CR.sub.10R.sub.11; R.sub.9 is independently selected from hydrogen, deuterium, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl; R.sub.10 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl; R.sub.11 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl; R.sub.1-1 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl; R.sub.2-1 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl or haloethyl; R.sub.2-2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl or haloethyl; R.sub.2-3 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl or haloethyl; R.sub.2-4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl or haloethyl; R.sub.5 is independently selected from amino, C.sub.1-3 alkyl, halo C.sub.1-3 alkyl or deuterated C.sub.1-3 alkyl, and the amino, C.sub.1-3 alkyl, halo C.sub.1-3 alkyl or deuterated C.sub.1-3 alkyl can be optionally further substituted with one or more of deuterium, halogen, cyano, hydroxyl, nitro, C.sub.1-3 alkyl, halo C.sub.1-3 alkyl and deuterated C.sub.1-3 alkyl; preferably, R.sub.5 is independently selected from isopropyl, CH(Me)OMe or N(Me).sub.2; L.sub.4 is independently selected from a bond, C.sub.1-3 alkylene, C.sub.2-4 alkenylene, C.sub.2-4 alkynylene, (CH.sub.2).sub.n7NH(CH.sub.2).sub.n8 or (CH.sub.2).sub.n90(CH.sub.2).sub.n10, and the C.sub.1-3 alkylene, C.sub.2-4 alkenylene, C.sub.2-4 alkynylene, (CH.sub.2).sub.n7NH(CH.sub.2).sub.n8 and (CH.sub.2).sub.n90(CH.sub.2).sub.n10 are optionally substituted with one or more of halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy and C.sub.1-3 hydroxyalkyl; ring F is independently selected from C.sub.3-6 cycloalkyl or 3- to 8-membered heterocyclyl; preferably, ring F is independently selected from ##STR00369## more preferably, ring F is independently selected from ##STR00370## R.sub.12 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy or C.sub.1-3 hydroxyalkyl; the C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy and C.sub.1-3hydroxyalkyl are optionally substituted with one or more of halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy and C.sub.1-3 hydroxyalkyl; R.sub.6-1 is independently selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy or C.sub.1-3 hydroxyalkyl; R.sub.6-2 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocyclyl, S(O).sub.mR.sub.e or C(O)R.sub.e, and the amino, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl and 3- to 8-membered heterocyclyl can be optionally further substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, nitro and C.sub.1-3 alkyl; R.sub.d is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C.sub.1-3 haloalkyl or C.sub.1-3 deuteroalkyl; R.sub.e is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C.sub.1-3 haloalkyl or C.sub.1-3 deuteroalkyl; m is independently 0, 1 or 2; n7 is independently 0, 1 or 2; n8 is independently 0, 1 or 2; n9 is independently 0, 1 or 2; n10 is independently 0, 1 or 2; and u is independently 0, 1 or 2.

11. The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or the stereoisomer or pharmaceutically acceptable salt thereof is selected from the following: ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404## ##STR00405## ##STR00406## ##STR00407##

12. A method for preparing the compound represented by general formula (II-G), or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the method comprises the following steps: reacting the compound represented by formula (XV) with the compound represented by formula (XVI) to obtain a compound represented by formula (II-G), ##STR00408## wherein X is halogen.

13. A pharmaceutical composition comprising a therapeutically effective dose of the compound of the general formula, or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

14. (canceled)

15. (canceled)

16. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective dose of the compound, the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1.

17. The method according to claim 16, wherein the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cell lymphoma, multiple myeloma or mesothelioma.

18. The method according to claim 16, wherein the cancer is non-small cell lung cancer.

19. The method according to claim 16, wherein the cancer is a non-small cell lung cancer with EGFR Del19, L858R, T790M, C797S, L858R/T790M, Del19/T790M, Del19/C797S, L858R/C797S, Del19/T790M/C797S or L858R/T790M/C797S mutation.

20. The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 3, wherein R.sub.1 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl, 5- to 14-membered heteroaryl, OR.sub.a, P(O).sub.p(R.sub.a).sub.n5, S(O).sub.mR.sub.a or C(O)R.sub.a, and the amino, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl and 5- to 14-membered heteroaryl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 deuteroalkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, halo C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-12 aryl, 5- to 12-membered heteroaryl, OR.sub.aa, P(O).sub.p(R.sub.aa).sub.n5, S(O).sub.mR.sub.aa, Se(O).sub.mR.sub.aa or C(O)R.sub.aa; or, two R.sub.1 are connected to the atoms therebetween to form C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl and 5- to 14-membered heteroaryl, and the C.sub.3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C.sub.6-14 aryl and 5- to 14-membered heteroaryl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy or C.sub.1-6 hydroxyalkyl; R.sub.2 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-12 aryl, 5- to 12-membered heteroaryl, OR.sub.a, P(O).sub.p(R.sub.a).sub.n5, S(O).sub.mR.sub.a or C(O)R.sub.a, and the amino, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-12 aryl and 5- to 12-membered heteroaryl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-2 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-10 aryl, 5- to 10-membered heteroaryl, OR.sub.aa, P(O).sub.p(R.sub.aa).sub.n5, S(O).sub.mR.sub.aa or C(O)R.sub.aa. R.sub.4 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-12 aryl, 5- to 12-membered heteroaryl, OR.sub.a, P(O).sub.p(R.sub.a).sub.n5, S(O).sub.mR.sub.a or C(O)R.sub.a, and the amino, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-12 aryl and 5- to 10-membered heteroaryl can be optionally further substituted with one or more R.sub.4-1; R.sub.4-1 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-12 aryl, 5- to 12-membered heteroaryl, OR.sub.aa, P(O).sub.p(R.sub.aa).sub.n5, S(O).sub.mR.sub.aa or C(O)R.sub.aa; optionally, R.sub.4-1 is substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-12 aryl, or 5- to 12-membered heteroaryl, and the amino, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, and C.sub.1-3 hydroxyalkyl are optionally substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, or C.sub.1-3 hydroxyalky. R.sub.a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-12 aryl, or 5- to 12-membered heteroaryl, and the amino, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-12 aryl, 5- to 12-membered heteroaryl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-10 aryl, or 5- to 10-membered heteroaryl; and each R.sub.aa is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-12 aryl, or 5- to 12-membered heteroaryl, and the amino, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-12 aryl, 5- to 12-membered heteroaryl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-10 aryl, or 5- to 10-membered heteroaryl.

21. The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 20, wherein R.sub.1 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-8 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-10 aryl, 5- to 12-membered heteroaryl, OR.sub.a, P(O).sub.p(R.sub.a).sub.n5, S(O).sub.mR.sub.a or C(O)R.sub.a, and the amino, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkyl, C.sub.3-8 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-10 aryl and 5- to 12-membered heteroaryl can be optionally further substituted with one or more of hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 deuteroalkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, halo C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, C.sub.3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C.sub.6-10 aryl, 5- to 10-membered heteroaryl, OR.sub.aa, P(O).sub.p(R.sub.aa).sub.n5, S(O).sub.mR.sub.aa or C(O)R.sub.aa;

22. The method of claim 12, wherein X is chlorine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0204] Unless stated to the contrary, the terms used in the description and claims have the following meanings.

[0205] The term alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched group containing 1 to 20 carbon atoms, preferably alkyl containing 1 to 8 carbon atoms, more preferably alkyl containing 1 to 6 carbon atoms, and most preferably alkyl containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, etc. More preferably, the alkyl is a lower alkyl group containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available connection point, and the substituent is preferably one or more of groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or a carboxylate group. In the present invention, alkyl is preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxyl-substituted alkyl.

[0206] The term alkylene refers to one hydrogen atom of alkyl being further substituted, for example: methylene refers to CH.sub.2, ethylene refers to (CH.sub.2).sub.2, propylene refers to (CH.sub.2).sub.3, and butylene refers to (CH.sub.2).sub.4, etc. The term alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl can be substituted or unsubstituted. When the alkenyl is substituted, the substituent is preferably one or more of groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0207] The term cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and a cycloalkyl ring comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

[0208] The term spirocycloalkyl refers to a polycyclic group with 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom). It may contain one or more double bonds, but no ring has a completely conjugated n electron system. Preferably, the spirocycloalkyl is 6- to 14-membered, and more preferably 7- to 10-membered. According to the number of shared spiro atoms between the rings, the spirocycloalkyl is divided into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl, preferably monospirocycloalkyl and bispirocycloalkyl. More preferably, it is a 3-membered/6-membered, 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

##STR00079##

etc.;

[0209] Also included are spirocycloalkyl groups in which monospirocycloalkyl and heterocycloalkyl share a spiro atom. Non-limiting examples include:

##STR00080##

etc.

[0210] The term fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, one or more ring of which may contain one or more double bonds, but no ring has a fully conjugated n electron system. Preferably, the fused cycloalkyl is 6- to 14-membered, and more preferably 7- to 10-membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic cycloalkyl. Non-limiting examples of fused cycloalkyl include:

##STR00081##

etc.

[0211] The term bridged cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a fully conjugated n electron system. Preferably, the bridged cycloalkyl is 6- to 14-membered, and more preferably 7- to 10-membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

##STR00082##

[0212] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is cycloalkyl, and the non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. Cycloalkyl can be optionally substituted or unsubstituted. When the cycloalkyl is substituted, the substituent is preferably one or more of groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or a carboxylate group.

[0213] The term heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which comprises 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, P(O).sub.pp or S(O).sub.mm (wherein pp and mm are integers of 0 to 2), but excluding ring moieties of OO, OSor SS, and the remaining ring atoms are carbon. Preferably, the heterocyclyl comprises 3 to 12 ring atoms, of which 1-4 are heteroatoms; more preferably, the heterocyclyl comprises 3 to 8 ring atoms or comprises 4 to 10 ring atoms; most preferably, the heterocyclyl comprises 3 to 8 ring atoms; further preferably, the heterocyclyl is a 3- to 8-membered heterocyclyl group comprising 1-3 nitrogen atoms, which is optionally substituted with 1-2 oxygen atoms, sulfur atoms or an oxo group, including nitrogen-containing monocyclic heterocyclyl, nitrogen-containing spiro heterocyclyl or nitrogen-containing fused heterocyclyl.

[0214] Non-limiting examples of monocyclic heterocyclyl include azetidinyl, pyrrolidyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepinyl, 1,4-diazacycloheptyl, pyranyl, etc., preferably pyrrolidyl, morpholinyl, piperidyl, azepinyl, 1,4-diazacycloheptyl

##STR00083##

and piperazinyl. Polycyclic heterocyclyl includes spiro, fused and bridged heterocyclyl, wherein the spiro, fused and bridged heterocyclyl groups are optionally connected to other groups through a single bond, or further fused to other cycloalkyl, heterocyclyl, aryl and heteroaryl through any two or more atoms on the ring.

[0215] The term spiroheterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group with monocyclic rings sharing one atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, P(O).sub.pp or S(O).sub.mm (wherein pp and mm are integers of 0 to 2), and the remaining ring atoms are carbon. Spiroheterocyclyl may contain one or more double bonds, but no ring has a fully conjugated n electron system. Preferably, the spiro heterocyclyl is 6- to 14-membered, and more preferably 7- to 10-membered. According to the number of shared spiro atoms between the rings, the spiro heterocyclyl is divided into monospiroheterocyclyl, bispiroheterocyclyl or polyspiroheterocyclyl, preferably monospiroheterocyclyl and bispiroheterocyclyl. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclyl. Non-limiting examples of spiro heterocyclyl include:

##STR00084##

[0216] The term fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group with each ring in the system sharing an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but no ring has a fully conjugated n electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, P(O).sub.pp or S(O).sub.mm (wherein pp and mm are integers of 0 to 2), and the remaining ring atoms are carbon. Preferably, the fused heterocyclyl is 6- to 14-membered, and more preferably 7- to 10-membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl include:

##STR00085##

[0217] The term bridged heterocyclyl refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but no ring has a fully conjugated n electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, P(O).sub.pp or S(O).sub.mm (wherein pp and mm are integers of 0 to 2), and the remaining ring atoms are carbon. Preferably, the bridged heterocyclyl is 6- to 14-membered, and more preferably 7- to 10-membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl include:

##STR00086##

[0218] The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is heterocyclyl, and the non-limiting examples thereof include:

##STR00087##

[0219] Heterocyclyl can be optionally substituted or unsubstituted. When the heterocyclyl is substituted, the substituent is preferably one or more of groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or a carboxylate group.

[0220] The term aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing an adjacent pair of carbon atoms) group having a conjugated n electron system, preferably 6- to 12-membered aryl, such as phenyl and naphthyl, and more preferably phenyl. The aryl ring can be fused to heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclyl is heterocyclyl containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms; or further including a three-membered nitrogen-containing fused ring containing a benzene ring, [0221] wherein the ring connected to the parent structure is aryl ring, and the non-limiting examples thereof include:

##STR00088##

[0222] Aryl can be substituted or unsubstituted. When the aryl is substituted, the substituent is preferably one or more of groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or a carboxylate group.

[0223] The term heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5- to 12-membered, more preferably 8- to 11-membered, 5-membered or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably, pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is heteroaryl ring, and the non-limiting examples thereof include:

##STR00089##

[0224] Heteroaryl can be optionally substituted or unsubstituted. When the heteroaryl is substituted, the substituent is preferably one or more of groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or a carboxylate group.

[0225] The term alkoxy refers to O (alkyl) and O (unsubstituted cycloalkyl), where alkyl is as defined above, preferably alkyl containing 1 to 8 carbon atoms, more preferably alkyl containing 1 to 6 carbon atoms, and most preferably alkyl containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy can be optionally substituted or unsubstituted. When the alkoxy is substituted, the substituent is preferably one or more of groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or a carboxylate group.

[0226] Haloalkyl refers to alkyl substituted with one or more halogen, wherein alkyl is defined as above.

[0227] Haloalkoxy refers to alkoxy substituted with one or more halogen, wherein alkoxy is defined as above.

[0228] Hydroxyalkyl refers to alkyl substituted with hydroxyl, wherein alkyl is defined as above.

[0229] Alkenyl refers to a chain alkenyl group, also known as an alkene group, preferably alkyl containing 2 to 8 carbon atoms, more preferably alkyl containing 2 to 6 carbon atoms, and most preferably alkyl containing 2 to 3 carbon atoms, wherein the alkenyl can be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or a carboxylate group.

[0230] Alkynyl refers to CHC, preferably alkyl containing 2 to 8 carbon atoms, more preferably alkyl containing 2 to 6 carbon atoms, and most preferably alkyl containing 2 to 3 carbon atoms. wherein the alkynyl can be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or a carboxylate group.

[0231] The term alkenylcarbonyl refers to C(O)-(alkenyl), wherein alkenyl is defined as above. Non-limiting examples of alkenylcarbonyl include: ethenylcarbonyl, propenylcarbonyl, and butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted. When the alkenylcarbonyl is substituted, the substituent is preferably one or more of groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or a carboxylate group.

[0232] Hydroxyl refers to an OH group.

[0233] Halogen refers to fluorine, chlorine, bromine or iodine.

[0234] Amino refers to NH.sub.2.

[0235] Cyano refers to CN.

[0236] Nitro refers to NO.sub.2.

[0237] Carbonyl refers to C(O).

[0238] Carboxyl refers to C(O)OH.

[0239] THF refers to tetrahydrofuran.

[0240] EtOAc refers to ethyl acetate.

[0241] MeOH refers to methanol.

[0242] DMF refers to N,N-dimethylformamide.

[0243] DIPEA refers to diisopropylethylamine.

[0244] TFA refers to trifluoroacetic acid.

[0245] MeCN refers to acetonitrile.

[0246] DMA refers to N,N-dimethylacetamide.

[0247] Et.sub.2O refers to diethyl ether.

[0248] DCE refers to 1,2-dichloroethane.

[0249] DIPEA refers to N,N-diisopropylethylamine.

[0250] NBS refers to N-bromosuccinimide.

[0251] NIS refers to N-iodosuccinimide.

[0252] Cbz-Cl refers to benzyl chloroformate.

[0253] Pd.sub.2(dba).sub.3 refers to tris(dibenzylideneacetone)dipalladium.

[0254] Dppf refers to 1,1-bisdiphenylphosphine ferrocene.

[0255] HATU refers to 2-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate.

[0256] KHMDS refers to potassium hexamethyldisilamide.

[0257] LiHMDS lithium bistrimethylsilylamide.

[0258] MeLi refers to lithium methyl.

[0259] n-BuLi refers to n-butyl lithium.

[0260] NaBH(OAc).sub.3 refers to sodium triacetoxyborohydride.

[0261] Different terms such as X is selected from A, B, or C, X is selected from A, B and C, X is A, B or C, X is A, B and C all express the same meaning, i.e., X can be any one or more of A, B, and C.

[0262] The hydrogen atoms described in the present invention can be replaced with its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced with a deuterium atom.

[0263] Optional or optionally means that the event or circumstance subsequently described may but need not to occur, and the description includes the occasions where the events or circumstances occur or do not occur. For example, heterocyclic group optionally substituted with alkyl means the alkyl may but need not be present, and the description includes the case where the heterocyclic group is substituted with alkyl and the case where the heterocyclic group is not substituted with alkyl.

[0264] Substituted refers to one or more hydrogen atoms in the group, preferably at most 5, more preferably 1-3 hydrogen atoms each independently substituted with a corresponding number of substituents. It goes without saying, the substituents may be only in their possible chemical positions, a person skilled in the art can determine the possible or impossible substitutions (by experiment or theory) without paying too much effort. For example, the amino group having a free hydrogen or a hydroxyl group may be unstable when combined the carbon atoms having an unsaturated (e.g., olefinic) bond.

[0265] The more in substituted with one or more of . . . can mean 2, 3, 4, 5, 6 or more than 6.

[0266] In various parts of the present invention, linking substituents are described. When it is clear that a linking group is required for the structure, the markush variables listed for that group should be understood as referring to the linking group. For example, if a linking group is required for the structure and the markush group definition for that variable lists alkyl or aryl, it should be understood that the alkyl or aryl respectively represents the attached alkylene group or arylene group.

[0267] Pharmaceutical composition denotes a mixture containing one or more of the compounds as described herein or physiologically/pharmaceutically acceptable salts or prodrug thereof and other chemical components, as well as other components, such as a physiologically/pharmaceutically acceptable carrier and an excipient. The purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.

[0268] Pharmaceutically acceptable salts refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and have appropriate biological activity.

DETAILED DESCRIPTION OF EMBODIMENTS

[0269] The present invention will be further described below in conjunction with examples, but these examples are not meant to limit the scope of the present invention.

EXAMPLE

[0270] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shift () is given in the unit of 10.sup.6 (ppm). NMR is determined with Bruker AVANCE-400 nuclear magnetic resonance instrument; the solvents for determination are deuterated dimethyl sulfoxide (DMSO-d.sub.6), deuterated methanol (CD.sub.3OD) and deuterated chloroform (CDCl.sub.3); and the internal standard is tetramethylsilane (TMS).

[0271] Agilent 1200 Infinity Series mass spectrometer is used for LC-MS. HPLC uses Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 1504.6 mm column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C.sub.18 1504.6 mm column).

[0272] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate is used as a thin layer chromatography silica plate, and TLC is of the specification of 0.15 mm-0.20 mm, and the specification when separating and purifying a product by thin layer chromatography is 0.4 mm-0.5 mm. For the column chromatography, Yantai Huanghai silica gel of 200-300 mesh silica gel is generally used as a carrier.

[0273] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized using or according to methods known in the art.

[0274] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius.

Intermediate 1

3-((methanesulfonyl)methyl)azetidine

##STR00090##

Step 1 Synthesis of tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate

##STR00091##

[0275] Tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (2 g, 6.73 mmol) and sodium methyl mercaptide (970 mg, 13.50 mmol) were dissolved in ACN (15 mL) and H.sub.2O (5 mL), and the mixture was warmed to 60 C. and reacted for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then separated by column chromatography to obtain the target compound tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate (1.30 g, 88.9%).

[0276] MS m/z (ESI): 162.0 [M+H-56].sup.+.

Step 2 Synthesis of tert-butyl 3-((methanesulfonyl)methyl)azetidine-1-carboxylate

##STR00092##

[0277] Tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate (1.30 g, 5.99 mmol) was dissolved in dichloromethane (15 mL), m-chloroperoxybenzoic acid (2 g, 12 mmol) was added and the mixture was stirred overnight. The reaction solution was washed with saturated sodium thiosulfate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the target compound tert-butyl 3-((methanesulfonyl)methyl)azetidine-1-carboxylate (1.30 g, 87.1%).

[0278] MS m/z (ESI): 194.0 [M+H-56].sup.+.

Step 3 Synthesis of 3-((methanesulfonyl)methyl)azetidine trifluoroacetate

##STR00093##

[0279] Tert-butyl 3-((methanesulfonyl)methyl)azetidine-1-carboxylate (1.30 g, 5.22 mmol) was dissolved in dichloromethane (15 mL), TFA (3 mL) was added, and the mixture was stirred for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the crude target compound 3-((methanesulfonyl)methyl)azetidine trifluoroacetate (740 mg).

[0280] MS m/z (ESI): 150.0 [M+H].sup.+.

Intermediate 2

1,6-dichloro-4-isopropyl-2,7-diazanaphthalene

##STR00094##

Step 1 Synthesis of 6-chloro-4-iodo-2,7-diazanaphthalen-1(2H)-one

##STR00095##

[0281] 6-Chloro-2,7-diazanaphthalen-1(2H)-one (10 g, 55.37 mmol) was dissolved in DMF (60 mL), the reaction solution was cooled to 0 C., NIS (14.80 g, 66 mmol) was added in batches, and the mixture was warmed to room temperature and stirred 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude target compound 6-chloro-4-iodo-2,7-diazanaphthalen-1(2H)-one (12 g).

[0282] MS m/z (ESI): 307.1 [M+H].sup.+.

Step 2 Synthesis of 1,6-dichloro-4-iodo-2,7-diazanaphthalene

##STR00096##

[0283] 6-Chloro-4-iodo-2,7-diazanaphthalen-1(2H)-one (12 g, 39.15 mmol) was dissolved in phosphorus oxychloride (80 mL), and the mixture was warmed to 100 C. and reacted for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the target compound 1,6-dichloro-4-iodo-2,7-diazanaphthalene (10.60 g, 83.3%).

[0284] MS m/z (ESI): 325.1 [M+H].sup.+.

Step 3 Synthesis of 1,6-dichloro-4-(prop-1-en-2-yl)-2,7-diazanaphthalene

##STR00097##

[0285] 1,6-Dichloro-4-iodo-2,7-diazanaphthalene (10.60 g, 32.62 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.50 g, 32.70 mmol) were mixed in dioxane (60 mL) and water (10 mL), potassium carbonate (13.60 g, 98.10 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (2.34 g, 3.30 mmol) were added, and the mixture was warmed to 50 C. and reacted for 1 hour. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the target compound 1,6-dichloro-4-(prop-1-en-2-yl)-2,7-diazanaphthalene (5 g, 64.1%).

[0286] MS m/z (ESI): 239.0 [M+H].sup.+.

Step 4 Synthesis of 1,6-dichloro-4-isopropyl-2,7-diazanaphthalene

##STR00098##

[0287] 1,6-Dichloro-4-(prop-1-en-2-yl)-2,7-diazanaphthalene (5 g, 20.91 mmol) was dissolved in ethyl acetate (80 mL), platinum dioxide (5.72 mg, 25.20 mmol) was added, the reaction system was evacuated, and filled with hydrogen, the operations were repeated 3 times, and the mixture was reacted under hydrogen atmosphere for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography to obtain the target compound 1,6-dichloro-4-isopropyl-2,7-diazanaphthalene (4 g, 79.3%).

[0288] MS m/z (ESI): 241.0 [M+H].sup.+.

Intermediate 3

(2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidine

##STR00099##

Step 1 Synthesis of (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate

##STR00100##

[0289] (2R,3S)-1-Diphenylmethyl-2-methylazetidin-3-ol (10 g, 39.50 mmol) was dissolved in dichloromethane (100 mL), triethylamine (4.80 g, 47.30 mmol) was added, the reaction solution was cooled to 0 C., methanesulfonyl chloride (5 g, 43.40 mmol) was slowly added dropwise, and the mixture was allowed to react at room temperature overnight. The reaction was quenched by adding water, and the mixture was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude target compound (2R, 3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate (12.80 g).

[0290] MS m/z (ESI): 332.2 [M+H].sup.+.

Step 2 Synthesis of methyl (S)-2-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(methanesulfonyl)acetate

##STR00101##

[0291] (2R,3S)-1-Diphenylmethyl-2-methylazetidin-3-yl methanesulfonate (12.80 g, 38.62 mmol) and methyl 2-(methylsulfonyl)acetate (7.70 g, 50.60 mmol) were dissolved in DMF (100 mL), sodium hydride (2.20 g, 60% in mineral oil, 55.50 mmol) was added in batches, and the mixture was reacted at room temperature for 15 minutes, and then warmed to 80 C. and reacted overnight. The reaction solution was cooled to room temperature and quenched with a saturated ammonium chloride solution, and the mixture was subjected to liquid separation with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain the target compound methyl (S)-2-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(methanesulfonyl)acetate (11.60 g, 77.5%).

[0292] MS m/z (ESI): 388.2 [M+H].sup.+.

Step 3 Synthesis of (2R,3S)-1-diphenylmethyl-2-methyl-3-((methanesulfonyl) methyl)azetidine

##STR00102##

[0293] Methyl (S)-2-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-2-(methanesulfonyl)acetate (11.60 g, 29.94 mmol) was dissolved in DMA (120 mL), lithium chloride (10.50 g, 247.50 mmol) was added, and the mixture was warmed to 150 C. and reacted for 2 hours. The reaction solution was cooled to room temperature, and subjected to liquid separation with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the target compound (2R,3S)-1-diphenylmethyl-2-methyl-3-((methanesulfonyl)methyl)azetidine (9.20 g, 93.3%).

[0294] MS m/z (ESI): 330.0 [M+H].sup.+.

Step 4 Synthesis of (2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidine

##STR00103##

[0295] (2R,3S)-1-Diphenylmethyl-2-methyl-3-((methanesulfonyl)methyl)azetidine (9.20 g, 27.92 mmol) was dissolved in methanol (120 mL), TFA (5 mL) and palladium hydroxide (2.80 g) were added, and the reaction system was evacuated and filled with hydrogen. The operations were repeated three times, and the reaction solution was reacted overnight under hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude target compound (2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidine (4 g).

[0296] MS m/z (ESI): 164.0 [M+H].sup.+.

Intermediate 4

8-bromo-3-chloro-6-fluoro-5-isopropylisoquinoline

##STR00104##

Step 1 Synthesis of 3-chloro-6-fluoroisoquinoline

##STR00105##

[0297] 1,3-Dichloro-6-fluoroisoquinoline (7.50 g, 34.72 mmol) was dissolved in glacial acetic acid (40 mL) and hydriodic acid (20 mL, 45% aqueous), red phosphorus (2.69 g, 86.8 mmol) was added, and the temperature was warmed to 100 C. and the mixture was reacted for 4 hours. The reaction solution was cooled to room temperature, concentrated, diluted with dichloromethane (100 mL), and washed with an aqueous saturated sodium carbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound 3-chloro-6-fluoroisoquinoline (4.90 g, 77.8%).

[0298] MS m/z (ESI): 182.0 [M+H].sup.+.

Step 2 Synthesis of 5-bromo-3-chloro-6-fluoroisoquinoline

##STR00106##

[0299] 3-Chloro-6-fluoroisoquinoline (3.20 g, 17.62 mmol) was dissolved in concentrated sulfuric acid (20 mL), NBS (3.45 g, 19.38 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was slowly added to ice water, and the mixture was subjected to liquid separation with ethyl acetate and water. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound 5-bromo-3-chloro-6-fluoroisoquinoline (4.0 g, 87.1%).

[0300] MS m/z (ESI): 260.0 [M+H].sup.+.

Step 3 Synthesis of 3-chloro-6-fluoro-5-(prop-1-en-2-yl)isoquinoline

##STR00107##

[0301] 5-Bromo-3-chloro-6-fluoroisoquinoline (4.0 g, 15.36 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.71 g, 16.72 mmol) were dissolved in 1,4-dioxane (20 mL) and water (3 mL), and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (562 mg, 0.77 mmol) and cesium carbonate (10.01 g, 30.71 mmol) were added, and the mixture was warmed to 80 C. and reacted for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then separated by column chromatography to obtain the target compound 3-chloro-6-fluoro-5-(prop-1-en-2-yl)isoquinoline (3.0 g, 88.1%).

[0302] MS m/z (ESI): 222.0 [M+H].sup.+.

Step 4 Synthesis of 3-chloro-6-fluoro-5-isopropylisoquinoline

##STR00108##

[0303] 3-Chloro-6-fluoro-5-(prop-1-en-2-yl)isoquinoline (3.0 g, 13.53 mmol) was dissolved in ethyl acetate (30 mL), platinum dioxide (615 mg, 2.71 mmol) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography to obtain the target compound 3-chloro-6-fluoro-5-isopropylisoquinoline (2.10 g, 69.4%).

[0304] MS m/z (ESI): 224.1 [M+H].sup.+.

Step 5 Synthesis of 8-bromo-3-chloro-6-fluoro-5-isopropylisoquinoline

##STR00109##

[0305] In an ice bath, to a solution of 3-chloro-6-fluoro-5-isopropylisoquinoline (800 mg, 3.58 mmol) in concentrated sulfuric acid (5 mL) was slowly added dibromohydantoin (1.12 g, 3.93 mmol) in batches, and the mixture was stirred in the ice bath for additional 0.5 hours. The reaction solution was carefully added to ice water and the mixture was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound 8-bromo-3-chloro-6-fluoro-5-isopropylisoquinoline (320 mg, 29.6%).

[0306] MS m/z (ESI): 302.0 [M+H].sup.+.

Intermediate 5

N-methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate

##STR00110##

Step 1 Synthesis of (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate

##STR00111##

[0307] (2R,3S)-1-Diphenylmethyl-2-methylazetidin-3-ol (100 g, 397 mmol), triethylamine (110 mL, 793 mmol) and anhydrous dichloromethane (1000 mL) were added to a 2 L reaction bottle. The mixture was cooled to 5 C. under nitrogen atmosphere, and methanesulfonic anhydride (138 g, 795 mmol) was added in batches, and the mixture was warmed to room temperature and stirred for 2 h. The reaction solution was subjected to liquid separation with water and dichloromethane, and the organic phase was separated and washed sequentially with 5% sodium carbonate solution and a saturated sodium chloride solution. The organic phase was separated and dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude target product (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate (138 g).

[0308] MS m/z (ESI): 332.1[M+H].sup.+.

Step 2 Synthesis of N-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00112##

[0309] At room temperature, (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate (138 g, 0.42 mol) was dissolved in MeCN (950 mL), Cs.sub.2CO.sub.3 (273 g, 0.84 mol) and N-methyl methanesulfonamide (82 g, 0.75 mol) were added, and the mixture was stirred overnight at 80 C. under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (0.5 L) was added to the reaction solution, and the mixture was extracted with ethyl acetate (1 L2). The organic phases were combined and washed with an aqueous saturated sodium chloride solution, and separated to obtain the organic phases, which were dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and separated by column chromatography to obtain the target product N-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-N-methyl methanesulfonamide (110 g, 76.7%).

[0310] MS m/z (ESI): 345.1 [M+H].sup.+.

Step 3 Synthesis of N-methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate

##STR00113##

[0311] N-((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)-N-methyl methanesulfonamide (85 g, 0.247 mol) was dissolved in a mixed solution of MeOH (850 mL) and TFA (52 mL), 10% Pd(OH).sub.2/C (28 g) was added, and the mixture was stirred overnight at room temperature under H2 atmosphere. The reaction solution was filtered over celite, and the filtrate was concentrated under reduced pressure to obtain the crude target product N-methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate (66 g).

[0312] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.88 (s, 1H), 4.62-4.56 (m, 1H), 4.31-4.25 (m, 1H), 4.10-4.06 (m, 1H), 3.95-3.91 (m, 1H), 2.95 (s, 3H), 2.83 (s, 3H), 1.40 (d, J=6.0 Hz, 3H);

[0313] MS m/z (ESI): 179.1 [M+H].sup.+.

Intermediate 6

3-chloro-5-isopropyl-8-(3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline

##STR00114##

Step 1 Synthesis of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonic acid

##STR00115##

[0314] 8-Bromo-3-chloroisoquinolin-5-ol (5 g, 19.50 mmol) was dissolved in dichloromethane (50 mL), TEA (7.90 g, 78 mmol) was added, and the reaction solution was cooled to 60 C., (TfO).sub.2O (16.50 g, 58.50 mmol) was slowly added dropwise, and the mixture was warmed to room temperature and reacted for 4 hours. The reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonic acid (6.50 g, 85.3%).

[0315] MS m/z (ESI): 390.0 [M+H].sup.+.

Step 2 Synthesis of 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline

##STR00116##

[0316] 8-Bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonic acid (6.50 g, 16.64 mmol) was dissolved in dioxane (60 mL) and H.sub.2O (6 mL), isopropenylboronic acid pinacol ester (4.20 g, 25 mmol), potassium carbonate (4.60 g, 33.40 mmol), and PdCl.sub.2(dppf) (610 mg, 0.84 mmol) were added, and the mixture was warmed to 100 C. and reacted for 4 hours. The reaction solution was cooled to room temperature, and concentrated. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the target compound 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline (2.90 g, 61.7%).

[0317] MS m/z (ESI): 282.0 [M+H].sup.+.

Step 3 Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline

##STR00117##

[0318] 8-Bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline (2.90 g, 10.26 mmol) was dissolved in ethyl acetate (100 mL), PtO.sub.2 (700 mg, 3.10 mmol) was added, the reaction system was evacuated, and filled with hydrogen, the operations were repeated 3 times, and the mixture was stirred under hydrogen atmosphere for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography to obtain the target compound 8-bromo-3-chloro-5-isopropylisoquinoline (2.70 g, 92.5%).

[0319] MS m/z (ESI): 284.0 [M+H].sup.+.

Step 4 Synthesis of 3-chloro-5-isopropyl-8-(3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline

##STR00118##

[0320] 8-Bromo-3-chloro-5-isopropylisoquinoline (500 mg, 1.76 mmol) and 3-((methanesulfonyl)methyl)azetidine trifluoroacetate (435 mg, 1.77 mmol) were dissolved in dioxane (10 mL), cesium carbonate (1.15 g, 3.54 mmol) and Xantphos Pd G4 (164 mg, 0.17 mmol) were added, and the mixture was warmed to 100 C. and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the target compound 3-chloro-5-isopropyl-8-(3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline (286 mg, 46.0%).

[0321] MS m/z (ESI): 353.0 [M+H].sup.+.

Reference Example 1

N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00119##

Step 1 Synthesis of 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline

##STR00120##

[0322] 8-Bromo-3-chloro-5-isopropylisoquinoline (500 mg, 1.76 mmol) and (2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidine (462 mg, 2.83 mmol) were dissolved in dioxane (10 mL), cesium carbonate (1.15 g, 3.54 mmol) and Xantphos Pd G4 (164 mg, 0.17 mmol) were added, and the mixture was warmed to 100 C. and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline (318 mg, 49.2%).

[0323] MS m/z (ESI): 367.1 [M+H].sup.+.

Step 2 Synthesis of 2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine

##STR00121##

[0324] 2-Chloropyrimidin-4-amine (1.29 g, 10 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.58 g, 11 mmol) and potassium carbonate (3.46 g, 25 mmol) were mixed in dioxane (20 mL) and water (2 mL), bis(triphenylphosphine)palladium dichloride (702 mg, 1 mmol) was added, and the mixture was warmed to 100 C. and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound 2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (1.05 g, 52.2%).

[0325] MS m/z (ESI): 202.1 [M+H].sup.+.

Step 3 Synthesis of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00122##

[0326] 3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline (100 mg, 0.27 mmol) and 2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine (54 mg, 0.27 mmol) were dissolved in dioxane (5 mL), cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G3 (24 mg, 27 mol) were added, and the mixture was warmed to 100 C. and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (31 mg, 21.6%).

[0327] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.22 (s, 1H), 9.09 (s, 1H), 8.82 (s, 1H), 8.36-8.32 (m, 2H), 8.05 (s, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.15-7.05 (m, 1H), 6.59 (d, J=8.1 Hz, 1H), 4.68 (t, J=7.5 Hz, 1H), 4.25-4.16 (m, 1H), 3.87-3.80 (m, 1H), 3.68-3.51 (m, 4H), 3.00 (s, 3H), 2.95-2.85 (m, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.38 (dd, J=6.8, 3.9 Hz, 6H), 1.17-1.11 (m, 2H), 1.06-1.00 (m, 2H);

[0328] MS m/z (ESI): 532.2 [M+H].sup.+.

Reference Example 2

Preparation of 2-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethanol

##STR00123##

Step 1 Synthesis of 4-bromo-3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

##STR00124##

[0329] 4-Bromo-3-chloro-1H-pyrazole (1.09 g, 6 mmol) and potassium carbonate (2.49 g, 18 mmol) were mixed in acetonitrile (20 mL), 2-(trimethylsilyl)ethoxymethyl chloride (1.50 g, 9 mmol) was added dropwise, and the mixture was reacted at room temperature for 3 hours. The reaction solution was diluted with dichloromethane and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, and the residue was separated by silica gel column chromatography to obtain the title compound 4-bromo-3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.59 g, 85.0%).

[0330] MS m/z (ESI): 311.0 [M+H].sup.+.

Step 2 Synthesis of 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

##STR00125##

[0331] 4-Bromo-3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.59 g, 5.1 mmol) and 4,4,4,4,5,5,5,5-octamethyl-2,2-di(1,3,2-dioxaborolane) (2.59 g, 10.2 mmol) were dissolved in dioxane (30 mL), potassium phosphate (3.18 g, 15 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (412.4 mg, 0.5 mmol) were added, and the mixture was warmed to 95 C. and stirred for 12 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure to remove the solvent. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.22 g, 66.7%).

[0332] MS m/z (ESI): 359.2 [M+H].sup.+.

Step 3 Synthesis of 2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine

##STR00126##

[0333] 2-Chloropyrimidin-4-amine (388.6 mg, 3 mmol), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.22 g, 3.4 mmol) and potassium carbonate (1.38 g, 10 mmol) were added to a mixed solvent of dioxane (10 mL) and water (2 mL), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (247.4 mg, 0.3 mmol) was added and the reaction solution was warmed to 100 C. and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove the solvent, and the residue was separated by silica gel column chromatography to obtain the title compound 2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (490 mg, 50.1%).

[0334] MS m/z (ESI): 326.1 [M+H].sup.+.

Step 4 Synthesis of N-(2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00127##

[0335] 3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline (100 mg, 0.27 mmol) and 2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (88 mg, 0.27 mmol) were dissolved in dioxane (3 mL), cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G3 (24 mg, 27 mol) were added, and the mixture was warmed to 105 C. and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound N-(2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-amine (81 mg, 45.7%).

[0336] MS m/z (ESI): 656.3 [M+H].sup.+.

Step 5 Synthesis of N-(2-(3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00128##

[0337] N-(2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-amine (81 mg, 0.12 mmol) was dissolved in THF (2 mL), 1 M TBAF solution (2 mL, 2 mmol) was added, and the mixture was warmed to reflux and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound N-(2-(3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (31 mg, 49.1%).

[0338] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 13.50 (s, 1H), 10.22 (s, 1H), 9.09 (s, 1H), 8.68 (s, 1H), 8.41 (d, J=6.0 Hz, 1H), 8.35 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.25-7.18 (m, 1H), 6.58 (d, J=8.2 Hz, 1H), 4.68 (t, J=7.6 Hz, 1H), 4.25-4.15 (m, 1H), 3.65 (t, J=7.1 Hz, 1H), 3.61-3.49 (m, 3H), 3.00 (s, 3H), 2.95-2.84 (m, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.36-1.26 (m, 6H);

[0339] MS m/z (ESI): 526.2 [M+H].sup.+.

Step 6 Synthesis of 2-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethanol

##STR00129##

[0340] N-(2-(3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (57.9 mg, 0.11 mmol) was dissolved in DMF (2 mL), cesium carbonate (107.5 mg, 0.33 mmol) was added, and the mixture was warmed to 40 C. and reacted for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound 2-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethanol (21.1 mg, 33.6%).

[0341] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.19 (s, 1H), 9.10 (s, 1H), 8.53 (s, 1H), 8.41 (d, J=6.0 Hz, 1H), 8.32 (s, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.32-7.25 (m, 1H), 6.58 (d, J=8.0 Hz, 1H), 5.03 (t, J=5.2 Hz, 1H), 4.72-4.64 (m, 1H), 4.24-4.15 (m, 3H), 3.82-3.75 (m, 2H), 3.68-3.63 (m, 1H), 3.60-3.51 (m, 3H), 3.00 (s, 3H), 2.96-2.86 (m, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.35-1.27 (m, 6H);

[0342] MS m/z (ESI): 570.2 [M+H].sup.+.

[0343] 2-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethanol was also prepared with reference to reference example 1.

Example 1

Preparation of N-(2-(1,3-dimethyl-1H-pyrazolyl-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine

##STR00130##

[0344] N-(2-(1,3-dimethyl-1H-pyrazolyl-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0345] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.08 (s, 1H), 9.09 (s, 1H), 8.56 (s, 1H), 8.36 (d, J=5.8 Hz, 1H), 8.18 (s, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.21-7.14 (m, 1H), 6.56 (d, J=8.0 Hz, 1H), 4.67-4.65 (m, 1H), 4.29-4.10 (m, 1H), 3.84 (s, 3H), 3.67-3.62 (m, 1H), 3.60-3.51 (m, 3H), 2.99 (s, 3H), 2.91-2.83 (m, 1H), 2.49 (s, 3H), 1.42 (d, J=5.6 Hz, 3H), 1.35-1.30 (m, 6H);

[0346] MS m/z (ESI): 520.2 [M+H].sup.+.

Example 2

Preparation of 5-isopropyl-N-(2-(3-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00131##

[0347] 5-Isopropyl-N-(2-(3-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0348] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.09 (s, 1H), 9.10 (s, 1H), 8.57 (s, 1H), 8.37 (d, J=5.8 Hz, 1H), 8.19 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.19 (d, J=5.4 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 4.72-4.65 (m, 1H), 4.25-4.17 (m, 1H), 3.68-3.51 (m, 4H), 3.00 (s, 3H), 2.94-2.86 (m, 1H), 2.50 (s, 3H), 1.44 (d, J=6.1 Hz, 3H), 1.37-1.31 (m, 6H);

[0349] MS m/z (ESI): 523.2 [M+H].sup.+.

Example 3

Preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-N-(2-(1-methyl-3-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine

##STR00132##

[0350] 5-Isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-N-(2-(1-methyl-3-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0351] MS m/z (ESI): 523.2 [M+H].sup.+.

Example 4

Preparation of N-(2-(1,3-bis(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine

##STR00133##

[0352] N-(2-(1,3-bis(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0353] MS m/z (ESI): 526.2 [M+H].sup.+.

Example 5

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine

##STR00134##

[0354] N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1

[0355] or synthesized according to the following steps:

Step 1 Synthesis of 4-bromo-3-chloro-1-methyl-1H-pyrazole

##STR00135##

[0356] 3-Chloro-1-methyl-1H-pyrazole (500 mg, 4.29 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0 C., NBS (764 mg, 4.29 mmol) was added in batches, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound 4-bromo-3-chloro-1-methyl-1H-pyrazole (790 mg, 94.2%).

Step 2 Synthesis of 3-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

##STR00136##

[0357] 4-Bromo-3-chloro-1-methyl-1H-pyrazole (790 mg, 4.04 mmol) and 4,4,4,4,5,5,5,5-octamethyl-2,2-di(1,3,2-dioxaborolane) (1.23 g, 4.85 mmol) were dissolved in dioxane (15 mL), potassium phosphate (793 mg, 8.08 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (300 mg, 0.41 mmol) were added, and the mixture was warmed to 95 C. and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound 3-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (590 mg, 60.2%).

[0358] MS m/z (ESI): 243.1 [M+H].sup.+.

Step 3 Synthesis of 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

##STR00137##

[0359] 2-Chloropyrimidin-4-amine (259 mg, 2 mmol), 3-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (534 mg, 2.20 mmol) and potassium carbonate (829 mg, 6 mmol) were mixed with dioxane (5 mL) and water (1 mL), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (146 mg, 0.20 mmol) was added, and the mixture was warmed to 95 C. and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water, the organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (143 mg, 34.2%).

[0360] MS m/z (ESI): 210.0 [M+H].sup.+.

Step 4 Synthesis of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine

##STR00138##

[0361] 3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl) azetidin-1-yl)isoquinoline (100 mg, 0.27 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (57 mg, 0.27 mmol) were dissolved in dioxane (5 mL), cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G3 (24 mg, 27 mol) were added, and the mixture was warmed to 100 C. and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine (44 mg, 30.5%).

[0362] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.18 (s, 1H), 9.10 (s, 1H), 8.59 (s, 1H), 8.40 (d, J=5.9 Hz, 1H), 8.33 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.25 (d, J=5.8 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 4.68 (t, J=7.5 Hz, 1H), 4.21 (t, J=6.2 Hz, 1H), 3.90 (s, 3H), 3.68-3.51 (m, 4H), 3.00 (s, 3H), 2.94-2.85 (m, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.34-1.26 (m, 6H);

[0363] MS m/z (ESI): 540.2 [M+H].sup.+.

Example 6

Preparation of N-(2-(3-chloro-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00139##

[0364] N-(2-(3-chloro-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0365] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.19 (s, 1H), 9.10 (s, 1H), 8.59 (s, 1H), 8.40 (d, J=5.9 Hz, 1H), 8.33 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.25 (d, J=5.6 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 4.71-4.64 (m, 1H), 4.24-4.16 (m, 1H), 3.67-3.48 (m, 4H), 3.00 (s, 3H), 2.93-2.85 (m, 1H), 1.43 (d, J=6.1 Hz, 3H), 1.33-1.27 (m, 6H);

[0366] MS m/z (ESI): 543.2 [M+H].sup.+.

Example 7

Preparation of N-(2-(1-cyclopropyl-3-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00140##

[0367] N-(2-(1-cyclopropyl-3-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0368] MS m/z (ESI): 546.2 [M+H].sup.+.

Example 8

Preparation of N-(2-(1-cyclopropyl-3-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine

##STR00141##

[0369] N-(2-(1-cyclopropyl-3-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0370] MS m/z (ESI): 549.2 [M+H].sup.+.

Example 9

Preparation of N-(2-(1-cyclopropyl-3-fluoro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00142##

[0371] N-(2-(1-cyclopropyl-3-fluoro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0372] MS m/z (ESI): 550.2 [M+H].sup.+.

Example 10

Preparation of 2-(1-cyclopropyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine

##STR00143##

[0373] 2-(1-Cyclopropyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine was prepared with reference to reference example 1.

[0374] MS m/z (ESI): 538.2 [M+H].sup.+.

Example 11

Preparation of N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazol-5-amine

##STR00144##

[0375] N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazol-5-amine was prepared with reference to reference example 1.

[0376] MS m/z (ESI): 512.2 [M+H].sup.+.

Example 12

Preparation of 2-(1,3-dimethyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine

##STR00145##

[0377] 2-(1,3-Dimethyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine was prepared with reference to reference example 1.

[0378] MS m/z (ESI): 526.2 [M+H].sup.+.

Example 13

Preparation of 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine

##STR00146##

[0379] 2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine was prepared with reference to reference example 1.

[0380] MS m/z (ESI): 546.2 [M+H].sup.+.

Example 14

Preparation of 2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine

##STR00147##

[0381] 2-(3-Fluoro-1-methyl-1H-pyrazol-4-yl)-N-(8-isopropyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)quinazolin-2-yl)thiazol-5-amine was prepared with reference to reference example 1.

[0382] MS m/z (ESI): 530.2 [M+H].sup.+.

Example 15

Preparation of N-(2-(1-cyclopropyl-1H-pyrazolyl-4-yl)-3-fluoropyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine

##STR00148##

[0383] N-(2-(1-cyclopropyl-1H-pyrazolyl-4-yl)-3-fluoropyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0384] MS m/z (ESI): 549.2 [M+H].sup.+.

Example 16

Preparation of N-(3-fluoro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00149##

[0385] N-(3-fluoro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0386] MS m/z (ESI): 523.2 [M+H].sup.+.

Example 17

Preparation of N-(2-(1,3-dimethyl-1H-pyrazolyl-4-yl)-3-fluoropyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine

##STR00150##

[0387] N-(2-(1,3-dimethyl-1H-pyrazolyl-4-yl)-3-fluoropyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0388] MS m/z (ESI): 537.2 [M+H].sup.+.

Example 18

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-fluoropyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine

##STR00151##

[0389] N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-fluoropyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1 or example 5.

[0390] MS m/z (ESI): 557.2 [M+H].sup.+.

Example 19

Preparation of N-(3-fluoro-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine

##STR00152##

[0391] N-(3-fluoro-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0392] MS m/z (ESI): 541.2 [M+H].sup.+.

Example 20

Preparation of 1-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

##STR00153##

[0393] 1-Isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine was prepared with reference to reference example 1.

[0394] MS m/z (ESI): 496.2 [M+H].sup.+.

Example 21

Preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

##STR00154##

[0395] N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine was prepared with reference to reference example 1.

[0396] MS m/z (ESI): 522.2 [M+H].sup.+.

Example 22

Preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

##STR00155##

[0397] N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine was prepared with reference to reference example 1.

[0398] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.00 (s, 1H), 8.58 (s, 1H), 8.33 (d, J=6.0 Hz, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.04-6.99 (m, 1H), 4.68-4.60 (m, 1H), 4.37 (d, J=7.4 Hz, 1H), 4.18 (d, J=6.6 Hz, 1H), 3.82 (s, 3H), 3.80-3.75 (m, 1H), 3.55-3.50 (m, 2H), 2.98 (s, 3H), 2.93-2.86 (m, 1H), 2.54 (s, 3H), 1.52 (d, J=6.1 Hz, 3H), 1.43 (d, J=5.6 Hz, 6H);

[0399] MS m/z (ESI): 510.2 [M+H].sup.+.

Example 23

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

##STR00156##

[0400] N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine was prepared with reference to reference example 1 or example 5.

[0401] MS m/z (ESI): 530.2 [M+H].sup.+.

Example 24

Preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazolyl-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

##STR00157##

[0402] N-(2-(3-fluoro-1-methyl-1H-pyrazolyl-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine was prepared with reference to reference example 1.

[0403] MS m/z (ESI): 514.2 [M+H].sup.+.

Example 25

Preparation of 1-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine

##STR00158##

[0404] 1-Isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-3-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine was prepared with reference to reference example 1.

[0405] MS m/z (ESI): 495.2 [M+H].sup.+.

Example 26

Preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine

##STR00159##

[0406] N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine was prepared with reference to reference example 1.

[0407] MS m/z (ESI): 521.2 [M+H].sup.+.

Example 27

Preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine

##STR00160##

[0408] N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine was prepared with reference to reference example 1.

[0409] MS m/z (ESI): 509.2 [M+H].sup.+.

Example 28

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine

##STR00161##

[0410] N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine was prepared with reference to reference example 1 or example 5.

[0411] MS m/z (ESI): 529.2 [M+H].sup.+.

Example 29

Preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine

##STR00162##

[0412] N-(2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1-isopropyl-3-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine was prepared with reference to reference example 1.

[0413] MS m/z (ESI): 513.2 [M+H].sup.+.

Example 30

Preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetin-1-yl)isoquinolin-3-amine

##STR00163##

[0414] N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0415] MS m/z (ESI): 499.2 [M+H].sup.+.

Example 31

Preparation of 5-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine

##STR00164##

[0416] 5-Isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0417] MS m/z (ESI): 473.2 [M+H].sup.+.

Example 32

Preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine

##STR00165##

[0418] N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0419] MS m/z (ESI): 487.2 [M+H].sup.+.

Example 33

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine

##STR00166##

[0420] N-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0421] MS m/z (ESI): 507.2 [M+H].sup.+.

Example 34

Preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine

##STR00167##

[0422] N-(2-(3-Fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3R)-2-methyl-3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0423] MS m/z (ESI): 491.2 [M+H].sup.+.

Example 35

Preparation of N-(2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine

##STR00168##

[0424] N-(2-(1-Cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0425] MS m/z (ESI): 485.2 [M+H].sup.+.

Example 36

Preparation of 5-isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-(3-(nitromethyl)azacyclodextrin-1-yl)isoquinolin-3-amine

##STR00169##

[0426] 5-Isopropyl-N-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-(3-(nitromethyl)azacyclodextrin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0427] MS m/z (ESI): 459.2 [M+H].sup.+.

Example 37

Preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine

##STR00170##

[0428] N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0429] MS m/z (ESI): 473.2 [M+H].sup.+.

Example 38

Preparation of N-(2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine

##STR00171##

[0430] N-(2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(nitromethyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0431] MS m/z (ESI): 477.2 [M+H].sup.+.

Example 39

Preparation of ((2R,3S)-1-(3-((2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride

##STR00172##

[0432] ((2R,3S)-1-(3-((2-(1-Cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride was prepared with reference to reference example 1.

[0433] MS m/z (ESI): 536.2 [M+H].sup.+.

Example 40

Preparation of ((2R,3S)-1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methyl nitride-3-yl)methanesulfonyl fluoride

##STR00173##

[0434] ((2R,3S)-1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methyl nitride-3-yl)methanesulfonyl fluoride was prepared with reference to reference example 1.

[0435] MS m/z (ESI): 510.2 [M+H].sup.+.

Example 41

Preparation of ((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride

##STR00174##

[0436] ((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride was prepared with reference to reference example 1.

[0437] MS m/z (ESI): 524.2 [M+H].sup.+.

Example 42

Preparation of ((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methyl azetidin-3-yl)methanesulfonyl fluoride

##STR00175##

[0438] ((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride was prepared with reference to reference example 1.

[0439] MS m/z (ESI): 544.2 [M+H].sup.+.

Example 43

Preparation of ((2R,3S)-1-(3-((2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride

##STR00176##

[0440] ((2R,3S)-1-(3-((2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonyl fluoride was prepared with reference to reference example 1.

[0441] MS m/z (ESI): 528.2 [M+H].sup.+.

Example 44

Preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide

##STR00177##

Step 1 Synthesis of N-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide

##STR00178##

[0442] 8-Bromo-3-chloro-5-isopropylisoquinoline (300 mg, 1.05 mmol) and N-(azetidin-3-yl)methanesulfonamide (158 mg, 1.05 mmol) were dissolved in dioxane (10 mL), cesium carbonate (1.15 g, 3.54 mmol) and Xantphos Pd G4 (164 mg, 0.17 mmol) were added, and the mixture was warmed to 125 C. by microwave and reacted for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound N-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide (170 mg, 45.6%).

[0443] MS m/z (ESI): 354.1 [M+H].sup.+.

Step 2 Synthesis of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide

##STR00179##

[0444] N-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide (50 mg, 0.14 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (30 mg, 0.14 mmol) were dissolved in dioxane (5 mL), cesium carbonate (81 mg, 0.25 mmol) and Xantphos Pd G4 (26 mg, 27 mol) were added, and the mixture was reacted under microwave at 120 C. for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide (11 mg, 14.9%).

[0445] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.16 (s, 1H), 9.08 (s, 1H), 8.57 (s, 1H), 8.42-8.39 (m, 1H), 8.33 (s, 1H), 7.85-7.82 (m, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.29-7.25 (m, 1H), 6.45 (d, J=8.2 Hz, 1H), 4.57-4.51 (m, 2H), 4.40-4.33 (m, 1H), 3.95-3.91 (m, 2H), 3.90 (s, 3H), 3.59-3.51 (m, 1H), 2.98 (s, 3H), 1.31-1.28 (m, 6H);

[0446] MS m/z (ESI): 527.1 [M+H].sup.+.

Example 45

Preparation of N-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methyl azetidin-3-yl)methanesulfonimide

##STR00180##

[0447] N-((2R,3S)-1-(3-((2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropyl quinolin-8-yl)-2-methyl azetidin-3-yl)methanesulfonimide was prepared with reference to reference example 1 or example 44.

[0448] MS m/z (ESI): 521.2 [M+H].sup.+.

Example 46

Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide

##STR00181##

[0449] N-((2R,3S)-1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide was prepared with reference to reference example 1 or example 44.

[0450] MS m/z (ESI): 541.2 [M+H].sup.+.

Example 47

Preparation of N-((2R,3S)-1-(3-((2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide

##STR00182##

[0451] N-((2R,3S)-1-(3-((2-(3-Fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide was prepared with reference to reference example 1 or example 44.

[0452] MS m/z (ESI): 525.2 [M+H].sup.+.

Example 48

Preparation of 5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-N-(2-(1-methyl-5-nitro-1H-pyrrol-3-yl)pyrimidin-4-yl)isoquinolin-3-amine

##STR00183##

[0453] 5-Isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-N-(2-(1-methyl-5-nitro-1H-pyrrol-3-yl)pyrimidin-4-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0454] MS m/z (ESI): 550.2 [M+H].sup.+.

Example 49

Preparation of N-(2-(1,2-dimethyl-5-nitro-1H-pyrrol-3-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00184##

[0455] N-(2-(1,2-Dimethyl-5-nitro-1H-pyrrol-3-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0456] MS m/z (ESI): 564.2 [M+H].sup.+.

Example 50

Preparation of N-(2-(2-chloro-1-methyl-5-nitro-1H-pyrrol-3-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00185##

[0457] N-(2-(2-Chloro-1-methyl-5-nitro-1H-pyrrol-3-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0458] MS m/z (ESI): 584.2 [M+H].sup.+.

Example 51

Preparation of 4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1-methyl-1,5-dihydro-2H-pyrrol-2-one

##STR00186##

[0459] 4-(4-((5-Isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1-methyl-1,5-dihydro-2H-pyrrol-2-one was prepared with reference to reference example 1.

[0460] MS m/z (ESI): 521.2 [M+H].sup.+.

Example 52

Preparation of 3-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1-methyl-1,5-dihydro-2H-pyrrol-2-one

##STR00187##

[0461] 3-(4-((5-Isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1-methyl-1,5-dihydro-2H-pyrrol-2-one was prepared with reference to reference example 1.

[0462] MS m/z (ESI): 521.2 [M+H].sup.+.

Example 53

Preparation of 5-isopropyl-N-(2-(1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00188##

[0463] 5-Isopropyl-N-(2-(1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0464] MS m/z (ESI): 507.2 [M+H].sup.+.

Example 54

Preparation of 5-isopropyl-N-(2-(2-methyl-2H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00189##

[0465] 5-Isopropyl-N-(2-(2-methyl-2H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0466] MS m/z (ESI): 507.2 [M+H].sup.+.

Example 55

Preparation of N-(6-(3-chloro-1-methyl-1H-pyrazol-4-yl)-5-fluoropyridin-2-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine

##STR00190##

[0467] N-(6-(3-chloro-1-methyl-1H-pyrazol-4-yl)-5-fluoropyridin-2-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1 or example 5.

[0468] MS m/z (ESI): 557.2 [M+H].sup.+.

Example 56

Preparation of N-(6-(3-chloro-1-methyl-1H-pyrazol-4-yl)-5-methoxypyridin-2-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine

##STR00191##

[0469] N-(6-(3-chloro-1-methyl-1H-pyrazol-4-yl)-5-methoxy pyridin-2-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1 or example 5.

[0470] MS m/z (ESI): 569.2 [M+H].sup.+.

Example 57

Preparation of 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-6-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-yl)amino)nicotinonitrile

##STR00192##

[0471] 2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-6-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-yl)amino)nicotinonitrile was prepared with reference to reference example 1 or example 5.

[0472] MS m/z (ESI): 564.2 [M+H].sup.+.

Example 58

Preparation of N-(5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)-8-methyl-6,8-dihydropyrazole [4,3: 4,5]pyrano[3,2-b]pyridin-2-amine

##STR00193##

[0473] N-(5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)-8-methyl-6,8-dihydropyrazole [4,3: 4,5]pyrano[3,2-b]pyridin-2-amine was prepared with reference to reference example 1.

[0474] MS m/z (ESI): 533.2 [M+H].sup.+.

Example 59

Preparation of N-((2R,3S)-1-(7-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-diazanaphthalen-4-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00194##

Step 1 Synthesis of 5-bromo-N-(tert-butyl)-2-chloroisonicotinamide

##STR00195##

[0475] 5-Bromo-2-chloroisonicotinic acid (20 g, 84.60 mmol) and 2-methylpropan-2-amine (7.31 g, 100 mmol) were dissolved in DMF (150 mL), HATU (38 g, 100 mmol) was added in batches, and the mixture was reacted at room temperature for 3 hours. The reaction solution was subjected to liquid separation with ethyl acetate and water, and the organic phase was washed with an aqueous saturated NaCl solution. The organic phase was separated and dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography to obtain the target compound 5-bromo-N-(tert-butyl)-2-chloroisonicotinamide (15.50 g, 62.8%).

[0476] MS m/z (ESI): 291.0 [M+H].sup.+.

Step 2 Synthesis of (E)-N-(tert-butyl)-2-chloro-5-(2-ethoxyethenyl) isonicotinamide

##STR00196##

[0477] 5-Bromo-N-(tert-butyl)-2-chloroisonicotinamide (15.50 g, 53.16 mmol) was dissolved in dioxane (150 mL) and water (30 mL), (E)-2-(2-ethoxyethenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.59 g, 58.50 mmol), cesium carbonate (32.58 g, 100 mmol) and PdCl.sub.2(dppf) (3.89 g, 5.32 mmol) were added, and the mixture was warmed to 80 C. and reacted for 2 hours. The reaction solution was cooled to room temperature, and concentrated. The residue was subjected to liquid separation with dichloromethane and water, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound (E)-N-(tert-butyl)-2-chloro-5-(2-ethoxyethenyl)isonicotinamide (9.50 g, 63.2%).

[0478] MS m/z (ESI): 283.1 [M+H].sup.+.

Step 3 Synthesis of 7-chloro-2,6-diazanaphthalen-1-ol

##STR00197##

[0479] (E)-N-(tert-butyl)-2-chloro-5-(2-ethoxyethenyl)isonicotinamide (9.50 g, 33.59 mmol) was dissolved in TFA (50 mL), and the mixture was warmed to 100 C. and reacted for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude target compound 7-chloro-2,6-diazanaphthalen-1-ol (5.66 g, 93.3%).

[0480] MS m/z (ESI): 181.0 [M+H].sup.+.

Step 4 Synthesis of 4-bromo-7-chloro-2,6-diazanaphthalen-1-ol

##STR00198##

[0481] 7-Chloro-2,6-diazanaphthalen-1-ol (5.66 g, 31.34 mmol) was dissolved in dichloromethane (75 mL), NBS (6.69 g, 37.61 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was filtered under reduced pressure, and the filter cake was collected and then dried to obtain the crude target compound 4-bromo-7-chloro-2,6-diazanaphthalen-1-ol (5.80 g, 71.3%).

[0482] MS m/z (ESI): 259.0 [M+H].sup.+.

Step 5 Synthesis of 4-bromo-7-chloro-2,6-diazanaphthalen-1-yl trifluoromethanesulfonic acid

##STR00199##

[0483] 4-Bromo-7-chloro-2,6-diazanaphthalen-1-ol (5.80 g, 22.35 mmol) was dissolved in dichloromethane (80 mL) and TEA (4.52 g, 44.70 mmol), the reaction solution was cooled to 75 C., (TfO).sub.2O (25.39 g, 90 mmol) was slowly added dropwise, and the mixture was reacted at 75 C. for 0.5 hours and slowly warmed to room temperature and reacted for 0.5 hours. The reaction was quenched by adding water and extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography to obtain the target compound 4-bromo-7-chloro-2,6-diazanaphthalen-1-yl trifluoromethanesulfonic acid (5.71 g, 65.3%).

[0484] MS m/z (ESI): 391.0 [M+H].sup.+.

Step 6 Synthesis of 4-bromo-7-chloro-1-iodo-2,6-diazanaphthalene

##STR00200##

[0485] 4-Bromo-7-chloro-2,6-diazanaphthalen-1-yl trifluoromethanesulfonic acid (5.71 g, 14.58 mmol) and NaI (10.94 g, 73 mmol) were mixed in ACN (100 mL), the reaction solution was cooled to 0 C., a solution of trifluoromethanesulfonic acid (4.50 g, 30 mmol) in ACN (10 mL) was slowly added dropwise, and the mixture was reacted at room temperature for 2 hours. The reaction solution was subjected to liquid separation with EA and water, and the organic phase was washed with an aqueous saturated NaCl solution. The organic phase was separated and dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude target compound 4-bromo-7-chloro-1-iodo-2,6-diazanaphthalene (5.28 g, 98.0%).

[0486] MS m/z (ESI): 369.0 [M+H].sup.+.

Step 7 Synthesis of 4-bromo-7-chloro-1-(prop-1-en-2-yl)-2,6-diazanaphthalene

##STR00201##

[0487] 4-Bromo-7-chloro-1-iodo-2,6-diazanaphthalene (5.28 g, 14.29 mmol) was dissolved in dioxane (50 mL) and H.sub.2O (5 mL), isopropenylboronic acid pinacol ester (2.35 g, 14 mmol), potassium carbonate (4.60 g, 33.40 mmol), and PdCl.sub.2(dppf) (610 mg, 0.84 mmol) were added, and the mixture was warmed to 100 C. and reacted for 4 hours. The reaction solution was cooled to room temperature, and concentrated. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the target compound 4-bromo-7-chloro-1-(prop-1-en-2-yl)-2,6-diazanaphthalene (2.05 g, 50.6%).

[0488] MS m/z (ESI): 283.0 [M+H].sup.+.

Step 8 Synthesis of 4-bromo-7-chloro-1-isopropyl-2,6-diazanaphthalene

##STR00202##

[0489] 4-Bromo-7-chloro-1-(prop-1-en-2-yl)-2,6-diazanaphthalene (2.05 g, 7.23 mmol) was dissolved in ethyl acetate (80 mL), PtO2 (2.04 g, 9 mmol) was added, and the mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography to obtain the target compound 4-bromo-7-chloro-1-isopropyl-2,6-diazanaphthalene (1.20 g, 58.1%).

[0490] MS m/z (ESI): 285.0 [M+H].sup.+.

Step 9 Synthesis of N-((2R,3S)-1-(7-chloro-1-isopropyl-2,6-diazanaphthalen-4-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00203##

[0491] 4-Bromo-7-chloro-1-isopropyl-2,6-diazanaphthalene (471 mg, 1.65 mmol) and N-methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate (470 mg, 1.70 mmol) were mixed in dioxane (10 mL), cesium carbonate (1.15 g, 3.54 mmol) and Xantphos Pd G4 (164 mg, 0.17 mmol) were added, and the mixture was warmed to 100 C. and stirred for 5 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound N-((2R,3S)-1-(7-chloro-1-isopropyl-2,6-diazanaphthalen-4-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide (230 mg, 36.4%).

[0492] MS m/z (ESI): 383.1 [M+H].sup.+.

Step 10 Synthesis of N-((2R,3S)-1-(7-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-diazanaphthalen-4-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00204##

[0493] N-((2R,3S)-1-(7-chloro-1-isopropyl-2,6-diazanaphthalen-4-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide (100 mg, 0.26 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (55 mg, 0.26 mmol) were dissolved in dioxane (5 mL), cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G4 (24 mg, 26 mol) were added, and the mixture was warmed to 100 C. and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and separated by column chromatography to obtain the target compound N-((2R,3S)-1-(7-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-diazanaphthalen-4-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide (56 mg, 38.7%).

[0494] MS m/z (ESI): 556.2 [M+H].sup.+.

Example 60

Preparation of N-(1-(7-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-diazanaphthalen-4-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00205##

[0495] N-(1-(7-((2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-diazanaphthalen-4-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 59.

[0496] MS m/z (ESI): 522.2 [M+H].sup.+.

Example 61

Preparation of N-((2R,3S)-1-(7-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-diazanaphthalen-4-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00206##

[0497] N-((2R,3S)-1-(7-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-diazanaphthalen-4-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 59.

[0498] MS m/z (ESI): 536.2 [M+H].sup.+.

Example 62

Preparation of 2-(3-fluoro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azabut-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethanol

##STR00207##

[0499] 2-(3-Fluoro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azabut-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethanol was prepared with reference to reference example 1 or 2.

[0500] MS m/z (ESI): 554.2 [M+H].sup.+.

Example 63

Preparation of (S)N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-9-methyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-8,9-dihydro-7H-cyclopentane [f]isoquinolin-2-amine

##STR00208##

[0501] (S)N-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-9-methyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-8,9-dihydro-7H-cyclopentane[f]isoquinolin-2-amine was prepared with reference to reference example 1 or example 5.

[0502] MS m/z (ESI): 552.2 [M+H].sup.+.

Example 64

Preparation of (R)N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-9-methyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-8,9-dihydro-7H-cyclopentane [f]isoquinolin-2-amine

##STR00209##

[0503] (R)N-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-9-methyl-5-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-8,9-dihydro-7H-cyclopentane[f]isoquinolin-2-amine was prepared with reference to reference example 1 or example 5.

[0504] MS m/z (ESI): 552.2 [M+H].sup.+.

Example 65

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5,5-dimethyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-4,5-dihydrocyclopentane [de]isoquinolin-3-amine

##STR00210##

[0505] N-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5,5-dimethyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-4,5-dihydrocyclopentane [de]isoquinolin-3-amine was prepared with reference to reference example 1 or example 5.

[0506] MS m/z (ESI): 552.2 [M+H].sup.+.

Example 66

Preparation of N-((2R,3S)-1-(5-isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide

##STR00211##

[0507] N-((2R,3S)-1-(5-Isopropyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonimide was prepared with reference to reference example 1 or example 44.

[0508] MS m/z (ESI): 507.2 [M+H].sup.+.

Example 67

Preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00212##

Step 1 Synthesis of N-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00213##

[0509] N-(1-(3-Chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide (300 mg, 0.85 mmol) was dissolved in DMF (6 mL), cesium carbonate (552 mg, 1.70 mmol) and iodomethane (144 mg, 1.02 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water, and the organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound N-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide (150 mg, 48.1%).

[0510] MS m/z (ESI): 368.1 [M+H].sup.+.

Step 2 Synthesis of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00214##

[0511] N-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide (60 mg, 0.16 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (34 mg, 0.16 mmol) were dissolved in dioxane (5 mL), cesium carbonate (104 mg, 0.32 mmol) and Xantphos Pd G4 (26 mg, 27 mol) were added, and the mixture was reacted under microwave at 120 C. for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide (18 mg, 20.4%).

[0512] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.15 (s, 1H), 9.12 (s, 1H), 8.56 (s, 1H), 8.41-8.39 (m, 1H), 8.33 (s, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.32-7.27 (m, 1H), 6.47 (d, J=8.2 Hz, 1H), 4.70-4.65 (m, 1H), 4.43-4.38 (m, 2H), 4.25-4.21 (m, 2H), 3.90 (s, 3H), 3.61-3.54 (m, 1H), 2.96 (s, 3H), 2.93 (s, 3H), 1.31-1.28 (m, 6H);

[0513] MS m/z (ESI): 541.2 [M+H].sup.+.

Example 68

Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00215##

[0514] N-((2R,3S)-1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0515] MS m/z (ESI): 555.2 [M+H].sup.+.

Example 69

Preparation of N-(1-(3-((2-(3-chloro-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00216##

[0516] N-(1-(3-((2-(3-Chloro-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0517] MS m/z (ESI): 544.2 [M+H].sup.+.

Example 70

Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00217##

[0518] N-((2R,3S)-1-(3-((2-(3-Chloro-1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0519] MS m/z (ESI): 558.2 [M+H].sup.+.

Example 71

Preparation of N-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00218##

[0520] N-(1-(3-((2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0521] MS m/z (ESI): 521.2 [M+H].sup.+.

Example 72

Preparation of N-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00219##

[0522] N-((2R,3S)-1-(3-((2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0523] MS m/z (ESI): 535.2 [M+H].sup.+.

Example 73

Preparation of N-(2-(3-chloro-1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00220##

[0524] N-(2-(3-Chloro-1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1 or 2.

[0525] MS m/z (ESI): 583.2 [M+H].sup.+.

Example 74

Preparation of N-(2-(3-chloro-1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00221##

[0526] N-(2-(3-Chloro-1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1 or 2.

[0527] MS m/z (ESI): 597.2 [M+H].sup.+.

Example 75

Preparation of N-(1-(3-((2-(1-(2-aminoethyl)-3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00222##

[0528] N-(1-(3-((2-(1-(2-Aminoethyl)-3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0529] MS m/z (ESI): 570.2 [M+H].sup.+.

Example 76

Preparation of N-(1-(3-((2-(3-chloro-1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00223##

[0530] N-(1-(3-((2-(3-Chloro-1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0531] MS m/z (ESI): 584.2 [M+H].sup.+.

Example 77

Preparation of N-(1-(3-((2-(3-chloro-1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00224##

[0532] N-(1-(3-((2-(3-Chloro-1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0533] MS m/z (ESI): 598.2 [M+H].sup.+.

Example 78

Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00225##

[0534] N-((2R,3S)-1-(3-((2-(3-Chloro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0535] MS m/z (ESI): 585.2 [M+H].sup.+.

Example 79

Preparation of N-(1-(3-((2-(3-chloro-1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00226##

[0536] N-(1-(3-((2-(3-Chloro-1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0537] MS m/z (ESI): 583.2 [M+H].sup.+.

Example 80

Preparation of N-(2-(3-chloro-1-(((S)-oxetan-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00227##

[0538] N-(2-(3-Chloro-1-(((S)-oxetan-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1 or 2.

[0539] MS m/z (ESI): 596.2 [M+H].sup.+.

Example 81

Preparation of N-(2-(3-chloro-1-(((R)-oxetan-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00228##

[0540] N-(2-(3-chloro-1-(((R)-oxetan-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1 or 2.

[0541] MS m/z (ESI): 596.2 [M+H].sup.+.

Example 82

Preparation of (S)N-(1-(3-((2-(3-chloro-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00229##

[0542] (S)N-(1-(3-((2-(3-Chloro-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0543] MS m/z (ESI): 597.2 [M+H].sup.+.

Example 83

Preparation of (R)N-(1-(3-((2-(3-chloro-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00230##

[0544] (R)N-(1-(3-((2-(3-Chloro-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0545] MS m/z (ESI): 597.2 [M+H].sup.+.

Example 84

Preparation of N-(1-(3-((2-(3-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00231##

[0546] N-(1-(3-((2-(3-Chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0547] MS m/z (ESI): 577.2 [M+H].sup.+.

Example 85

Preparation of N-(2-(3-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00232##

[0548] N-(2-(3-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1 or 2.

[0549] MS m/z (ESI): 576.2 [M+H].sup.+.

Example 86

Preparation of N-(1-(3-((2-(3-chloro-1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00233##

[0550] N-(1-(3-((2-(3-Chloro-1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0551] MS m/z (ESI): 585.2 [M+H].sup.+.

Example 87

Preparation of N-(1-(3-((2-(3-chloro-1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00234##

[0552] N-(1-(3-((2-(3-Chloro-1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0553] MS m/z (ESI): 580.2 [M+H].sup.+.

Example 88

Preparation of N-(1-(3-((2-(3-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00235##

[0554] N-(1-(3-((2-(3-Chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0555] MS m/z (ESI): 611.2 [M+H].sup.+.

Example 89

Preparation of N-(1-(3-((2-(5-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00236##

[0556] N-(1-(3-((2-(5-Fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0557] MS m/z (ESI): 525.2 [M+H].sup.+.

Example 90

Preparation of N-(2-(5-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00237##

[0558] N-(2-(5-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0559] MS m/z (ESI): 524.2 [M+H].sup.+.

Example 91

Preparation of N-(1-(3-((2-(5-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00238##

[0560] N-(1-(3-((2-(5-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0561] MS m/z (ESI): 541.2 [M+H].sup.+.

Example 92

Preparation of N-(2-(5-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00239##

[0562] N-(2-(5-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0563] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.24 (s, 1H), 9.10 (s, 1H), 8.67 (s, 1H), 8.42 (d, J=5.8 Hz, 1H), 8.18 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.24 (d, J=5.6 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 4.72-4.64 (m, 1H), 4.24-4.18 (m, 1H), 3.90 (s, 3H), 3.69-3.63 (m, 1H), 3.60-3.50 (m, 3H), 3.00 (s, 3H), 2.92-2.86 (m, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.35-1.30 (m, 6H);

[0564] MS m/z (ESI): 540.2 [M+H].sup.+.

Example 93

Preparation of N-(1-(3-((2-(5-fluoro-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00240##

[0565] N-(1-(3-((2-(5-Fluoro-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0566] MS m/z (ESI): 539.2 [M+H].sup.+.

Example 94

Preparation of N-(1-(3-((2-(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00241##

[0567] N-(1-(3-((2-(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0568] MS m/z (ESI): 555.2 [M+H].sup.+.

Example 95

Preparation of N-(2-(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00242##

[0569] N-(2-(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 1.

[0570] MS m/z (ESI): 554.2 [M+H].sup.+.

Example 96

Preparation of (R)-2-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide

##STR00243##

[0571] (R)-2-(1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide was prepared with reference to reference example 1 or example 5.

[0572] MS m/z (ESI): 552.2 [M+H].sup.+.

Example 97

Preparation of (S)-2-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide

##STR00244##

[0573] (S)-2-(1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide was prepared with reference to reference example 1 or example 5.

[0574] MS m/z (ESI): 552.2 [M+H].sup.+.

Example 98

Preparation of (R)-2-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide

##STR00245##

[0575] (R)-2-(1-(3-((2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide was prepared with reference to reference example 1.

[0576] MS m/z (ESI): 532.2 [M+H].sup.+.

Example 99

Preparation of (S)-2-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide

##STR00246##

[0577] (S)-2-(1-(3-((2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide was prepared with reference to reference example 1.

[0578] MS m/z (ESI): 532.2 [M+H].sup.+.

Example 100

Preparation of N-(((1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(methyl)(carbonyl)-16-sulfanylidene)cyanamide

##STR00247##

[0579] N-(((1-(3-((2-(3-Chloro-1-methyl-1-pyrazol-4-ylpyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(methyl)(carbonyl)-16-sulfanylidene)cyanamide was prepared with reference to example 67 or example 5.

[0580] MS m/z (ESI): 550.2 [M+H].sup.+.

Example 101

Preparation of N-(((1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(methyl)(carbonyl)-16-sulfanylidene)cyanamide

##STR00248##

[0581] N-(((1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(methyl)(carbonyl)-16-sulfanylidene)cyanamide was prepared with reference to example 67 or example 5.

[0582] MS m/z (ESI): 550.2 [M+H].sup.+.

Example 102

Preparation of ((1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)imino)dimethyl-16-sulfanone

##STR00249##

[0583] ((1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)imino)dimethyl-16-sulfanone was prepared with reference to example 67 or example 5.

[0584] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.14 (s, 1H), 9.09 (s, 1H), 8.55 (s, 1H), 8.40 (d, J=5.8 Hz, 1H), 8.33 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.27 (d, J=6.0 Hz, 1H), 6.41 (d, J=8.0 Hz, 1H), 4.48-4.39 (m, 3H), 3.90 (s, 3H), 3.82-3.78 (m, 2H), 3.58-3.55 (m, 1H), 3.05 (s, 6H), 1.30 (d, J=6.8 Hz, 6H);

[0585] MS m/z (ESI): 525.2 [M+H].sup.+.

Example 103

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((1s,3s)-3-((methanesulfonyl)methyl)cyclobutyl)isoquinolin-3-amine

##STR00250##

[0586] N-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((1s,3s)-3-((methanesulfonyl)methyl)cyclobutyl)isoquinolin-3-amine was prepared with reference to example 67 or example 5.

[0587] MS m/z (ESI): 525.2 [M+H].sup.+.

Example 104

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((1r,3r)-3-((methanesulfonyl)methyl)cyclobutyl)isoquinolin-3-amine

##STR00251##

[0588] N-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((1r,3r)-3-((methanesulfonyl)methyl)cyclobutyl)isoquinolin-3-amine was prepared with reference to example 67 or example 5.

[0589] MS m/z (ESI): 525.2 [M+H].sup.+.

Example 105

Preparation of N-((1s,3s)-3-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)cyclobutyl)-N-methyl methanesulfonamide

##STR00252##

[0590] N-((1s,3s)-3-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)cyclobutyl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0591] MS m/z (ESI): 540.2 [M+H].sup.+.

Example 106

Preparation of N-((1r,3r)-3-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)cyclobutyl)-N-methyl methanesulfonamide

##STR00253##

[0592] N-((1r,3r)-3-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)cyclobutyl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0593] MS m/z (ESI): 540.2 [M+H].sup.+.

Example 107

Preparation of 3-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-1,2,3-oxathiazolidine 2,2-dioxide

##STR00254##

[0594] 3-(1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-1,2,3-oxathiazolidine 2,2-dioxide was prepared with reference to reference example 1 or example 5.

[0595] MS m/z (ESI): 555.2 [M+H].sup.+.

Example 108

Preparation of 3-(1-(3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)oxazolidin-2-one

##STR00255##

[0596] 3-(1-(3-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)oxazolidin-2-one was prepared with reference to reference example 1 or example 5.

[0597] MS m/z (ESI): 519.2 [M+H].sup.+.

Example 109

Preparation of 3-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)oxazolidin-2-one

##STR00256##

[0598] 3-((2R,3S)-1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)oxazolidin-2-one was prepared with reference to example 5.

[0599] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.26 (s, 1H), 9.08 (s, 1H), 8.52 (s, 1H), 8.35 (d, J=6.0 Hz, 1H), 8.28 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.20 (d, J=5.2 Hz, 1H), 6.60 (d, J=8.1 Hz, 1H), 4.58 (t, J=7.5 Hz, 1H), 4.40-4.36 (m, 1H), 4.30-4.18 (m, 2H), 3.84 (s, 3H), 3.79 (t, J=7.2 Hz, 1H), 3.68-3.58 (m, 2H), 3.55-3.48 (m, 2H), 1.34 (d, J=6.0 Hz, 3H), 1.24 (t, J=6.0 Hz, 6H);

[0600] MS m/z (ESI): 533.2 [M+H].sup.+.

Example 110

Preparation of 1-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

##STR00257##

[0601] 1-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol was prepared with reference to reference example 2.

[0602] MS m/z (ESI): 598.2 [M+H].sup.+.

Example 111

Preparation of 3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropanenitrile

##STR00258##

[0603] 3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropanenitrile was prepared with reference to reference example 2.

[0604] MS m/z (ESI): 607.2 [M+H].sup.+.

Example 112

Preparation of 2-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile

##STR00259##

[0605] 2-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile was prepared with reference to reference example 2.

[0606] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.20 (s, 1H), 9.11 (s, 1H), 8.51-8.40 (m, 3H), 7.43 (d, J=7.8 Hz, 1H), 7.36 (s, 1H), 6.58 (d, J=8.0 Hz, 1H), 4.68 (t, J=7.6 Hz, 1H), 4.46-4.40 (m, 2H), 4.21 (t, J=6.4 Hz, 1H), 3.65 (t, J=7.0 Hz, 1H), 3.59-3.50 (m, 4H), 3.00 (s, 3H), 2.96-2.85 (m, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.33-1.26 (m, 9H);

[0607] MS m/z (ESI): 593.2 [M+H].sup.+.

Example 113

Preparation of 3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-1,1,1-trifluoropropan-2-ol

##STR00260##

[0608] 3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-1,1,1-trifluoropropan-2-ol was prepared with reference to reference example 2.

[0609] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.20 (s, 1H), 9.10 (s, 1H), 8.51-8.41 (m, 3H), 7.45 (d, J=8.0 Hz, 1H), 6.86-6.81 (m, 1H), 6.58 (d, J=8.0 Hz, 1H), 5.34-5.30 (m, 1H), 4.70-4.66 (m, 1H), 4.30-4.19 (m, 2H), 3.66-3.48 (m, 5H), 3.00 (s, 3H), 2.92-2.87 (m, 1H), 2.03-1.95 (m, 1H), 1.33-1.27 (m, 9H);

[0610] MS m/z (ESI): 638.2 [M+H].sup.+.

Example 114

Preparation of 1-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)propan-2-one

##STR00261##

[0611] 1-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)propan-2-one was prepared with reference to reference example 2.

[0612] MS m/z (ESI): 582.2 [M+H].sup.+.

Example 115

Preparation of 2-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)propanenitrile

##STR00262##

[0613] 2-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)propanenitrile was prepared with reference to reference example 2.

[0614] .sup.1H NMR (400 MHz, DMSO) 10.24 (s, 1H), 9.10 (s, 1H), 8.55 (s, 1H), 8.48 (s, 1H), 8.44 (d, J=5.9 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.36 (d, J=4.3 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 5.93 (q, J=7.1 Hz, 1H), 4.68 (t, J=7.5 Hz, 1H), 4.23-4.17 (m, 1H), 3.65 (t, J=7.1 Hz, 1H), 3.60-3.50 (m, 3H), 3.00 (s, 3H), 2.95-2.82 (m, 1H), 1.86 (d, J=7.1 Hz, 3H), 1.43 (d, J=6.0 Hz, 3H), 1.30-1.26 (m, 6H);

[0615] MS m/z (ESI): 579.2 [M+H].sup.+.

Example 116A

Preparation of N-(2-(3-chloro-1-(2-methoxypropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00263##

[0616] N-(2-(3-chloro-1-(2-methoxypropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0617] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.19 (s, 1H), 9.10 (s, 1H), 8.53 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.30 (d, J=5.1 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 4.68 (t, J=7.5 Hz, 1H), 4.35-4.06 (m, 3H), 3.88-3.68 (m, 1H), 3.68-3.43 (m, 4H), 3.20 (s, 3H), 3.00 (s, 3H), 2.90 (dt, J=14.6, 7.2 Hz, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.30 (dd, J=12.1, 6.3 Hz, 6H), 1.11 (d, J=6.2 Hz, 3H);

[0618] MS m/z (ESI): 598.2 [M+H].sup.+.

Example 116

Preparation of N-(2-(3-chloro-1-((S)-2-methoxypropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00264##

[0619] N-(2-(3-chloro-1-((S)-2-methoxypropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2. MS m/z (ESI): 598.2 [M+H].sup.+.

Example 117

Preparation of N-(2-(3-chloro-1-((R)-2-methoxypropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00265##

[0620] N-(2-(3-chloro-1-((R)-2-methoxypropyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2. MS m/z (ESI): 598.2 [M+H].sup.+.

Example 118

Preparation of (S)-3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile

##STR00266##

[0621] (S)-3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile was prepared with reference to reference example 2.

[0622] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.20 (s, 1H), 9.10 (s, 1H), 8.47-8.41 (m, 3H), 7.43 (d, J=8.0 Hz, 1H), 7.35 (d, J=4.6 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 4.68 (t, J=7.5 Hz, 1H), 4.47-4.38 (m, 2H), 4.22-4.19 (m, 1H), 3.65 (t, J=7.1 Hz, 1H), 3.60-3.50 (m, 4H), 3.00 (s, 3H), 2.94-2.87 (m, 1H), 1.43 (d, J=6.1 Hz, 3H), 1.30-1.27 (m, 9H);

[0623] MS m/z (ESI): 593.2 [M+H].sup.+.

Example 119

Preparation of (R)-3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile

##STR00267##

[0624] (R)-3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-2-methylpropanenitrile was prepared with reference to reference example 2.

[0625] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.20 (s, 1H), 9.10 (s, 1H), 8.47-8.41 (m, 3H), 7.43 (d, J=8.0 Hz, 1H), 7.35 (d, J=4.6 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 4.68 (t, J=7.5 Hz, 1H), 4.47-4.38 (m, 2H), 4.22-4.19 (m, 1H), 3.65 (t, J=7.1 Hz, 1H), 3.60-3.50 (m, 4H), 3.00 (s, 3H), 2.94-2.87 (m, 1H), 1.43 (d, J=6.1 Hz, 3H), 1.30-1.27 (m, 9H);

[0626] MS m/z (ESI): 593.2 [M+H].sup.+.

Example 120

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00268##

[0627] N-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to example 5 or prepared as follows: Step 1 Synthesis of 3-chloro-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline

##STR00269##

[0628] 8-Bromo-3-chloro-6-fluoro-5-isopropylisoquinoline (500 mg, 1.65 mmol) and (2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidine (297 mg, 1.82 mmol) were dissolved in dioxane (10 mL), cesium carbonate (1.15 g, 3.54 mmol) and Xantphos Pd G4 (164 mg, 0.17 mmol) were added, and the mixture was warmed to 100 C. and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound 3-chloro-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline (418 mg, 65.8%).

[0629] MS m/z (ESI): 385.1 [M+H].sup.+.

Step 2 Synthesis of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00270##

[0630] 3-Chloro-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinoline (100 mg, 0.26 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (54 mg, 0.26 mmol) were dissolved in dioxane (5 mL), cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G4 (24 mg, 26 mol) were added, and the mixture was warmed to 100 C. and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The resulting mixture was separated by column chromatography to obtain the target compound N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (61 mg, 42%).

[0631] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.14 (s, 1H), 8.96 (s, 1H), 8.53 (s, 1H), 8.35 (d, J=5.8 Hz, 1H), 8.24 (s, 1H), 7.19 (d, J=5.8 Hz, 1H), 6.27 (d, J=14.4 Hz, 1H), 4.70-4.62 (m, 1H), 4.21-4.14 (m, 1H), 3.83 (s, 3H), 3.72-3.64 (m, 1H), 3.57-3.41 (m, 3H), 2.93 (s, 3H), 2.87-2.77 (m, 1H), 1.39-1.26 (m, 9H);

[0632] MS m/z (ESI): 558.2 [M+H].sup.+.

Example 121

Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00271##

[0633] N-((2R,3S)-1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67. [0634] or prepared as follows:

Step 1 Synthesis of N-((2R,3S)-1-(3-chloro-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00272##

[0635] 8-Bromo-3-chloro-6-fluoro-5-isopropylisoquinoline (500 mg, 1.65 mmol) and N-methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate (470 mg, 1.70 mmol) were mixed in dioxane (10 mL), cesium carbonate (1.15 g, 3.54 mmol) and Xantphos Pd G4 (164 mg, 0.17 mmol) were added, and the mixture was warmed to 100 C. and stirred for 5 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography to obtain the target compound N-((2R,3S)-1-(3-chloro-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide (330 mg, 50.0%).

[0636] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.08 (s, 1H), 8.07 (s, 1H), 6.68-6.65 (m, 1H), 4.76-4.69 (m, 1H), 4.59-4.55 (m, 1H), 4.26-4.22 (m, 1H), 3.98-3.96 (m, 1H), 3.67-3.59 (m, 1H), 2.95 (s, 3H), 2.83 (s, 3H), 1.40 (d, J=6.0 Hz, 3H), 1.37-1.31 (m, 6H);

[0637] MS m/z (ESI): 400.1 [M+H].sup.+.

Step 2 Synthesis of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00273##

[0638] N-((2R,3S)-1-(3-Chloro-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide (100 mg, 0.25 mmol) and 2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (55 mg, 0.25 mmol) were dissolved in dioxane (5 mL), cesium carbonate (274 mg, 0.84 mmol) and BrettPhos Pd G4 (24 mg, 26 mol) were added, and the mixture was warmed to 100 C. and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to liquid separation with dichloromethane and water, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography to obtain the target compound N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide (73 mg, 50.9%).

[0639] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.21 (s, 1H), 9.05 (s, 1H), 8.60 (s, 1H), 8.42 (d, J=5.8 Hz, 1H), 8.30 (s, 1H), 7.28 (d, J=6.0 Hz, 1H), 6.47-6.43 (m, 1H), 4.71-4.69 (m, 1H), 4.53-4.49 (m, 1H), 4.23-4.18 (m, 1H), 3.94-3.91 (m, 1H), 3.89 (s, 3H), 3.63-3.58 (m, 1H), 2.95 (s, 3H), 2.84 (s, 3H), 1.40 (d, J=6.0 Hz, 6H), 1.36-1.32 (m, 3H);

[0640] MS m/z (ESI): 573.2 [M+H].sup.+.

Example 122

Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00274##

[0641] N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67 or 121.

[0642] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.21 (s, 1H), 9.12 (s, 1H), 8.61 (s, 1H), 8.41 (d, J=5.8 Hz, 1H), 8.34 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.26 (d, J=5.6 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 4.66-4.63 (m, 1H), 4.45-4.41 (m, 1H), 4.21-4.18 (m, 1H), 3.91 (s, 3H), 3.82-3.79 (m, 1H), 3.59-3.55 (m, 1H), 2.95 (s, 3H), 2.83 (s, 3H), 1.41 (d, J=6.0 Hz, 3H), 1.33-1.31 (m, 6H);

[0643] MS m/z (ESI): 555.2 [M+H].sup.+.

Example 123

Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide

##STR00275##

[0644] N-((2R,3S)-1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide was prepared with reference to example 44.

[0645] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.14 (s, 1H), 9.03 (s, 1H), 8.54 (s, 1H), 8.34 (d, J=5.8 Hz, 1H), 8.27 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.18 (d, J=5.8 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H), 4.73-4.71 (m, 1H), 4.08-4.06 (m, 1H), 3.89-3.87 (m, 1H), 3.84 (s, 3H), 3.62-3.59 (m, 2H), 2.89 (s, 3H), 1.36 (d, J=6.0 Hz, 3H), 1.24-1.22 (m, 6H);

[0646] MS m/z (ESI): 541.2 [M+H].sup.+.

Example 124

Preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00276##

[0647] N-(1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67 or 120.

[0648] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.18 (s, 1H), 9.06 (s, 1H), 8.56 (s, 1H), 8.42 (d, J=5.8 Hz, 1H), 8.30 (s, 1H), 7.31 (d, J=5.8 Hz, 1H), 6.28-6.25 (m, 1H), 4.70-4.68 (m, 1H), 4.46-4.43 (m, 2H), 4.32-4.29 (m, 2H), 3.89 (s, 3H), 3.59-3.56 (m, 1H), 2.95-2.93 (m, 6H), 1.38-1.36 (m, 6H);

[0649] MS m/z (ESI): 559.2 [M+H].sup.+.

Example 125

Preparation of N-(2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00277##

[0650] N-(2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to example 5 or 120.

[0651] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (s, 1H), 8.96 (s, 1H), 8.47 (s, 1H), 8.31 (d, J=5.8 Hz, 1H), 8.07 (s, 1H), 7.17-7.09 (m, 1H), 6.31-6.23 (m, 1H), 4.66 (t, J=7.6 Hz, 1H), 4.18 (t, J=6.2 Hz, 1H), 3.77 (s, 3H), 3.68 (t, J=7.2 Hz, 1H), 3.56-3.44 (m, 3H), 2.93 (s, 3H), 2.86-2.77 (m, 1H), 2.44 (s, 3H), 1.39-1.31 (m, 9H);

[0652] MS m/z (ESI): 538.2 [M+H].sup.+.

Example 126

Preparation of N-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00278##

[0653] N-((2R,3S)-1-(3-((2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67 or 121.

[0654] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.11 (s, 1H), 9.12 (s, 1H), 8.58 (s, 1H), 8.37 (d, J=5.8 Hz, 1H), 8.19 (s, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.20 (d, J=5.8 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 4.66-4.63 (m, 1H), 4.44-4.42 (m, 1H), 4.21-4.19 (m, 1H), 3.85 (s, 3H), 3.82-3.79 (m, 1H), 3.58-3.56 (m, 1H), 2.96 (s, 3H), 2.83 (s, 3H), 2.52 (s, 3H), 1.41 (d, J=6.0 Hz, 3H), 1.34-1.31 (m, 6H);

[0655] MS m/z (ESI): 535.2 [M+H].sup.+.

Example 127

Preparation of N-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide

##STR00279##

[0656] N-((2R,3S)-1-(3-((2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67 or 121.

[0657] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.12 (s, 1H), 9.05 (s, 1H), 8.55 (s, 1H), 8.38 (d, J=5.8 Hz, 1H), 8.14 (s, 1H), 7.22 (d, J=5.6 Hz, 1H), 6.47 (d, J=14.3 Hz, 1H), 4.75-4.67 (m, 1H), 4.57-4.48 (m, 1H), 4.27-4.19 (m, 1H), 3.97-3.91 (m, 1H), 3.84 (s, 3H), 3.64-3.52 (m, 1H), 2.95 (s, 3H), 2.84 (s, 3H), 2.51 (s, 3H), 1.46-1.37 (m, 9H);

[0658] MS m/z (ESI): 553.2 [M+H].sup.+.

Example 128

Preparation of N-((2R,3S)-1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide

##STR00280##

[0659] N-((2R,3S)-1-(3-((2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide was prepared with reference to example 44.

[0660] MS m/z (ESI): 521.2 [M+H].sup.+.

Example 129

Preparation of N-(1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00281##

[0661] N-(1-(3-((2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67 or 120.

[0662] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.00 (s, 1H), 9.00 (s, 1H), 8.43 (s, 1H), 8.32 (d, J=5.8 Hz, 1H), 8.07 (s, 1H), 7.21-7.17 (m, 1H), 6.23-6.15 (m, 1H), 4.67-4.60 (m, 1H), 4.39 (t, J=8.2 Hz, 2H), 4.29-4.22 (m, 2H), 3.77 (s, 3H), 3.55-3.47 (m, 1H), 2.91-2.84 (m, 6H), 2.44 (s, 3H), 1.34 (d, J=6.6 Hz, 6H);

[0663] MS m/z (ESI): 539.2 [M+H].sup.+.

Example 130

Preparation of N-(1-(6-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-isopropyl-2,7-diazanaphthalen-1-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00282##

[0664] N-(1-(6-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-isopropyl-2,7-diazanaphthalen-1-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0665] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.37 (s, 1H), 9.12 (s, 1H), 8.48-8.46 (m, 2H), 8.34 (s, 1H), 8.00 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 4.74-4.49 (m, 5H), 3.91 (s, 3H), 3.45-3.40 (m, 1H), 2.95 (s, 6H), 1.31 (d, J=7.6 Hz, 6H);

[0666] MS m/z (ESI): 542.2 [M+H].sup.+.

Example 131

Preparation of N-(1-(7-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-diazanaphthalen-4-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00283##

[0667] N-(1-(7-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1-isopropyl-2,6-diazanaphthalen-4-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67.

[0668] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.38 (s, 1H), 9.21 (s, 1H), 8.73 (s, 1H), 8.44 (d, J=5.8 Hz, 1H), 8.37 (s, 1H), 7.65 (s, 1H), 7.23 (d, J=5.8 Hz, 1H), 4.73 (t, J=7.0 Hz, 1H), 4.55-4.48 (m, 2H), 4.39-4.33 (m, 2H), 3.91 (s, 3H), 3.84-3.77 (m, 1H), 2.96 (s, 6H), 1.31 (d, J=6.8 Hz, 6H);

[0669] MS m/z (ESI): 542.2 [M+H].sup.+.

Example 132

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-2,7-diazanaphthalen-3-amine

##STR00284##

[0670] N-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-2,7-diazanaphthalen-3-amine was prepared with reference to example 5.

[0671] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.39 (s, 1H), 9.09 (s, 1H), 8.48-8.45 (m, 2H), 8.34 (s, 1H), 8.01 (s, 1H), 7.32 (d, J=8.0 Hz, 1H), 4.88-4.86 (m, 1H), 4.58-4.55 (m, 1H), 4.02-3.98 (m, 1H), 3.91 (s, 3H), 3.57-3.54 (m, 2H), 3.44-3.36 (m, 1H), 3.00 (s, 3H), 2.91-2.88 (m, 1H), 1.50 (d, J=7.6 Hz, 3H), 1.31 (d, J=7.6 Hz, 6H);

[0672] MS m/z (ESI): 541.2 [M+H].sup.+.

Example 133

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-2,6-diazanaphthalen-3-amine

##STR00285##

[0673] N-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)-2,6-diazanaphthalen-3-amine was prepared with reference to example 5.

[0674] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.42 (s, 1H), 9.17 (s, 1H), 8.75 (s, 1H), 8.44 (d, J=5.8 Hz, 1H), 8.37 (s, 1H), 7.75 (s, 1H), 7.224-7.15 (m, 1H), 4.80-4.73 (m, 1H), 4.36-4.30 (m, 1H), 3.91 (s, 3H), 3.85-3.76 (m, 2H), 3.60-3.55 (m, 2H), 3.01 (s, 3H), 2.95-2.91 (m, 1H), 1.49 (d, J=6.2 Hz, 3H), 1.31 (d, J=6.6 Hz, 6H);

[0675] MS m/z (ESI): 541.2 [M+H].sup.+.

Example 134

Preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(dimethylamino)-6-fluoroisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00286##

[0676] N-(1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(dimethylamino)-6-fluoroisoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67 or 120.

[0677] MS m/z (ESI): 560.2 [M+H].sup.+.

Example 135

Preparation of (R)N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-(1-methoxyethyl)isoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00287##

[0678] (R)N-(1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-(1-methoxyethyl)isoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67 or 120.

[0679] MS m/z (ESI): 575.2 [M+H].sup.+.

Example 136

Preparation of (S)N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-(1-methoxyethyl)isoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide

##STR00288##

[0680] (S)N-(1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-(1-methoxyethyl)isoquinolin-8-yl)azetidin-3-yl)-N-methyl methanesulfonamide was prepared with reference to example 67 or 120.

[0681] MS m/z (ESI): 575.2 [M+H].sup.+.

Example 137

Preparation of N3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-N5,N5-dimethyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3,5-diamine

##STR00289##

[0682] N3-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-N5,N5-dimethyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline-3,5-diamine was prepared with reference to example 5 or 120.

[0683] MS m/z (ESI): 559.2 [M+H].sup.+.

Example 138

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-((R)-1-methoxyethyl)-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00290##

[0684] N-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-((R)-1-methoxyethyl)-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to example 5 or 120.

[0685] MS m/z (ESI): 574.2 [M+H].sup.+.

Example 139

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-((S)-1-methoxyethyl)-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00291##

[0686] N-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-6-fluoro-5-((S)-1-methoxyethyl)-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to example 5 or 120.

[0687] MS m/z (ESI): 574.2 [M+H].sup.+.

Example 140

Preparation of N-(2-(3-chloro-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00292##

[0688] N-(2-(3-Chloro-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0689] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.11 (s, 1H), 9.03 (s, 1H), 8.46-8.32 (m, 3H), 7.35 (d, J=8.0 Hz, 1H), 7.24 (s, 1H), 6.50 (d, J=8.1 Hz, 1H), 4.62-4.59 (m, 1H), 4.17-4.11 (m, 1H), 3.80-3.41 (m, 7H), 2.93 (s, 3H), 2.85-2.78 (m, 1H), 2.27-1.90 (m, 4H), 1.76-1.68 (m, 1H), 1.36 (d, J=6.1 Hz, 3H), 1.23-1.18 (m, 6H), 1.09 (d, J=6.4 Hz, 3H);

[0690] MS m/z (ESI): 624.2 [M+H].sup.+.

Example 141

Preparation of N-(2-(3-chloro-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00293##

[0691] N-(2-(3-Chloro-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0692] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.18 (s, 1H), 9.09 (s, 1H), 8.63-8.39 (m, 3H), 7.43 (d, J=8.0 Hz, 1H), 7.31-7.23 (m, 1H), 6.71-6.65 (m, 1H), 4.88-4.51 (m, 5H), 4.25-4.20 (m, 1H), 3.61-3.50 (m, 2H), 3.00 (s, 3H), 2.90-2.60 (m, 4H), 2.14-2.00 (m, 4H), 1.44-1.21 (m, 9H);

[0693] MS m/z (ESI): 622.2 [M+H].sup.+.

Example 142

Preparation of N-(2-(3-chloro-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00294##

[0694] N-(2-(3-Chloro-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0695] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.13 (s, 1H), 9.10 (s, 1H), 8.47-8.40 (m, 3H), 7.43 (d, J=8.0 Hz, 1H), 7.33-7.26 (m, 1H), 6.58 (d, J=8.0 Hz, 1H), 5.35-5.30 (m, 1H), 5.10-5.06 (m, 1H), 4.65-4.60 (m, 1H), 4.22-4.19 (m, 1H), 4.01-3.95 (m, 3H), 3.86-3.82 (m, 1H), 3.65-3.45 (m, 2H), 2.99 (s, 3H), 2.03-1.97 (m, 4H), 1.31-1.27 (m, 9H);

[0696] MS m/z (ESI): 596.2 [M+H].sup.+.

Example 143

Preparation of N-(2-(3-chloro-1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00295##

[0697] N-(2-(3-Chloro-1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0698] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.19 (s, 1H), 9.10 (s, 1H), 8.47-8.40 (m, 3H), 7.43 (d, J=7.2 Hz, 1H), 7.30 (br s, 1H), 6.56 (d, J=7.6 Hz, 1H), 5.09-5.06 (m, 1H), 4.70-4.65 (m, 1H), 4.23-4.18 (m, 1H), 4.03-3.83 (m, 4H), 3.86-3.80 (m, 1H), 3.65-3.52 (m, 2H), 2.99 (s, 3H), 2.91-2.88 (m, 1H), 2.35-2.30 (m, 1H), 2.03-1.95 (m, 2H), 1.37-1.16 (m, 9H);

[0699] MS m/z (ESI): 596.2 [M+H].sup.+.

Example 144

Preparation of N-(2-(3-chloro-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00296##

[0700] N-(2-(3-Chloro-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0701] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.12 (s, 1H), 9.03 (s, 1H), 8.44 (s, 1H), 8.34 (d, J=5.8 Hz, 1H), 8.25 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.24 (s, 1H), 6.51 (d, J=8.2 Hz, 1H), 4.61 (t, J=7.5 Hz, 1H), 4.23-4.03 (m, 4H), 3.73-3.63 (m, 1H), 3.63-3.39 (m, 5H), 2.93 (s, 3H), 2.82 (q, J=7.3 Hz, 1H), 1.98-1.86 (m, 1H), 1.83-1.64 (m, 2H), 1.62-1.49 (m, 1H), 1.36 (d, J=6.0 Hz, 3H), 1.23 (dd, J=9.2, 6.8 Hz, 6H);

[0702] MS m/z (ESI): 610.2 [M+H].sup.+.

Example 145

Preparation of N-(2-(3-chloro-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00297##

[0703] N-(2-(3-Chloro-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0704] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.19 (s, 1H), 9.10 (s, 1H), 8.51 (s, 1H), 8.41 (d, J=5.8 Hz, 1H), 8.32 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.33-7.28 (m, 1H), 6.58 (d, J=8.1 Hz, 1H), 4.68 (t, J=7.5 Hz, 1H), 4.31-4.10 (m, 4H), 3.82-3.70 (m, 1H), 3.68-3.61 (m, 2H), 3.61-3.50 (m, 3H), 3.00 (s, 3H), 2.90 (q, J=7.3 Hz, 1H), 2.05-1.93 (m, 1H), 1.88-1.74 (m, 2H), 1.69-1.56 (m, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.35-1.21 (m, 6H);

[0705] MS m/z (ESI): 610.2 [M+H].sup.+.

Example 146

Preparation of N-(2-(3-chloro-1-(((R)-1-methylazetidin-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00298##

[0706] N-(2-(3-Chloro-1-(((R)-1-methylazetidin-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0707] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.20 (s, 1H), 9.10 (s, 1H), 8.54 (s, 1H), 8.41 (d, J=6.0 Hz, 1H), 8.33 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.32-7.26 (m, 1H), 6.58 (d, J=8.0 Hz, 1H), 4.72-4.66 (m, 1H), 4.23-4.15 (m, 3H), 3.67-3.61 (m, 1H), 3.59-3.50 (m, 4H), 3.00 (s, 3H), 2.93-2.87 (m, 1H), 2.73-2.66 (m, 1H), 2.03 (s, 3H), 2.01-1.97 (m, 2H), 1.86-1.80 (m, 1H), 1.43 (d, J=6.4 Hz, 3H), 1.31 (d, J=6.8 Hz, 6H);

[0708] MS m/z (ESI): 609.2 [M+H].sup.+.

Example 147

Preparation of N-(2-(3-chloro-1-(((S)-1-methylazetidin-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00299##

[0709] N-(2-(3-Chloro-1-(((S)-1-methylazetidin-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0710] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.13 (s, 1H), 9.03 (s, 1H), 8.47 (s, 1H), 8.34 (d, J=6.0 Hz, 1H), 8.27 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.22 (s, 1H), 6.51 (d, J=8.0 Hz, 1H), 4.64-4.59 (m, 1H), 4.16-4.09 (m, 3H), 3.61-3.55 (m, 1H), 3.52-3.44 (m, 4H), 2.93 (s, 3H), 2.86-2.80 (m, 1H), 2.66-2.61 (m, 1H), 1.96 (s, 3H), 1.93-1.88 (m, 2H), 1.79-1.73 (m, 1H), 1.36 (d, J=6.0 Hz, 3H), 1.24 (d, J=6.8 Hz, 6H);

[0711] MS m/z (ESI): 609.2 [M+H].sup.+.

Example 148

Preparation of N-(2-(3-chloro-1-(((R)-1-methylpyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00300##

[0712] N-(2-(3-Chloro-1-(((R)-1-methylpyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0713] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.19 (s, 1H), 9.10 (s, 1H), 8.57-8.20 (m, 3H), 7.43 (d, J=7.2 Hz, 1H), 7.31 (br s, 1H), 6.56 (d, J=7.2 Hz, 1H), 4.70-4.65 (m, 1H), 4.23-4.02 (m, 3H), 3.73-3.53 (m, 5H), 2.99-2.80 (m, 5H), 2.35-2.20 (m, 4H), 2.03-1.95 (m, 2H), 1.75-1.17 (m, 11H);

[0714] MS m/z (ESI): 623.3 [M+H].sup.+.

Example 149

Preparation of N-(2-(3-chloro-1-(((S)-1-methylpyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00301##

[0715] N-(2-(3-Chloro-1-(((S)-1-methylpyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0716] MS m/z (ESI): 623.3 [M+H].sup.+.

Example 150

Preparation of N-(2-(3-chloro-1-(2-methyloctahydrocyclopentadieno[c]pyrrol-5-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00302##

[0717] N-(2-(3-Chloro-1-(2-methyloctahydrocyclopentadieno[c]pyrrol-5-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0718] MS m/z (ESI): 649.3 [M+H].sup.+.

Example 151A

Preparation of 3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

##STR00303##

[0719] 3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile was prepared with reference to reference example 2.

[0720] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.13 (s, 1H), 9.03 (s, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 8.35 (d, J=5.8 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.22 (s, 1H), 6.51 (d, J=8.0 Hz, 1H), 4.90-4.84 (m, 1H), 4.63-4.59 (m, 1H), 4.16-4.12 (m, 1H), 3.60-3.55 (m, 1H), 3.49-3.43 (m, 4H), 2.93 (s, 3H), 2.84-2.76 (m, 5H), 1.36 (d, J=6.0 Hz, 3H), 1.25-1.20 (m, 6H);

[0721] MS m/z (ESI): 605.2 [M+H].sup.+.

Example 151

Preparation of (1r,3r)-3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

##STR00304##

[0722] (1r,3r)-3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile was prepared with reference to reference example 2.

[0723] MS m/z (ESI): 605.2 [M+H].sup.+.

Example 152

Preparation of (1s,3s)-3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

##STR00305##

[0724] (1s,3s)-3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile was prepared with reference to reference example 2.

[0725] MS m/z (ESI): 605.2 [M+H].sup.+.

Example 153

Preparation of N-(2-(3-chloro-1-(3-methoxy cyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00306##

[0726] N-(2-(3-Chloro-1-(3-methoxy cyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0727] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.20 (s, 1H), 9.09 (s, 1H), 8.57 (s, 1H), 8.44-8.39 (m, 2H), 7.43 (d, J=7.8 Hz, 1H), 7.27 (s, 1H), 6.58 (d, J=8.0 Hz, 1H), 5.01 (t, J=7.0 Hz, 1H), 4.68 (t, J=7.2 Hz, 1H), 4.24-4.15 (m, 1H), 3.64 (t, J=7.2 Hz, 1H), 3.59-3.51 (m, 2H), 3.21 (s, 3H), 3.00 (s, 3H), 2.94-2.86 (m, 1H), 2.76-2.65 (m, 2H), 2.05-1.95 (m, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.37-1.20 (m, 9H);

[0728] MS m/z (ESI): 610.2 [M+H].sup.+.

Example 154A

Preparation of 3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutan-1-ol

##STR00307##

[0729] 3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutan-1-ol was prepared with reference to reference example 2.

[0730] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.11 (s, 1H), 9.03 (s, 1H), 8.46 (s, 1H), 8.34 (d, J=5.8 Hz, 1H), 8.32 (s, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.21 (s, 1H), 6.51 (d, J=8.0 Hz, 1H), 5.27 (d, J=6.8 Hz, 1H), 4.63-4.59 (m, 1H), 4.39-4.32 (m, 1H), 4.16-4.10 (m, 1H), 3.96-3.88 (m, 1H), 3.58 (t, J=7.2 Hz, 1H), 3.53-3.43 (m, 3H), 2.93 (s, 3H), 2.85-2.80 (m, 1H), 2.72-2.65 (m, 2H), 2.36-2.28 (m, 2H), 1.36 (d, J=6.0 Hz, 3H), 1.24-1.19 (m, 6H);

[0731] MS m/z (ESI): 596.2 [M+H].sup.+.

Example 154

Preparation of (1s,3s)-3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutan-1-ol

##STR00308##

[0732] (1s,3s)-3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutan-1-ol was prepared with reference to reference example 2.

[0733] MS m/z (ESI): 596.2 [M+H].sup.+.

Example 155

Preparation of (1r,3r)-3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutan-1-ol

##STR00309##

[0734] (1r,3r)-3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutan-1-ol was prepared with reference to reference example 2.

[0735] MS m/z (ESI): 596.2 [M+H].sup.+.

Example 156

Preparation of 3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutan-1-one

##STR00310##

[0736] 3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)cyclobutan-1-one was prepared with reference to reference example 2.

[0737] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.29 (s, 1H), 9.11 (s, 1H), 8.88 (s, 1H), 8.46 (d, J=5.9 Hz, 1H), 8.19 (d, J=14.2 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 6.75 (d, J=14.1 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 4.68 (t, J=7.5 Hz, 1H), 4.26-4.15 (m, 1H), 3.65 (t, J=7.2 Hz, 1H), 3.60-3.49 (m, 3H), 3.00 (s, 3H), 2.94-2.85 (m, 1H), 2.33 (s, 3H), 2.05-1.93 (m, 2H), 1.43 (d, J=6.1 Hz, 3H), 1.33-1.13 (m, 6H);

[0738] MS m/z (ESI): 594.2 [M+H].sup.+.

Example 157

Preparation of N-(2-(3-chloro-1-(5-methyl-5-azaspiro [3.4]octan-2-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00311##

[0739] N-(2-(3-Chloro-1-(5-methyl-5-azaspiro [3.4]octan-2-yl)-1H-pyrazol-4-yl) pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl) azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0740] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.19 (s, 1H), 9.09 (s, 1H), 8.45-8.38 (m, 3H), 7.43 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 6.59 (d, J=8.0 Hz, 1H), 5.36-5.30 (m, 1H), 4.73-4.67 (m, 1H), 4.223-4.17 (m, 1H), 3.67-3.61 (m, 1H), 3.58-3.52 (m, 4H), 3.00 (s, 3H), 2.94-2.88 (m, 1H), 2.57-2.52 (m, 2H), 2.45-2.40 (m, 2H), 2.21 (s, 3H), 2.04-1.94 (m, 2H), 1.43 (d, J=6.0 Hz, 6H), 1.34-1.26 (m, 6H);

[0741] MS m/z (ESI): 649.3 [M+H].sup.+.

Example 158

Preparation of N-(2-(3-chloro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00312##

[0742] N-(2-(3-Chloro-1-(1-methyl piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0743] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.19 (s, 1H), 9.10 (s, 1H), 8.55-8.40 (m, 3H), 7.43 (d, J=8.0 Hz, 1H), 7.26-7.21 (m, 1H), 6.58 (d, J=8.0 Hz, 1H), 5.35-5.30 (m, 1H), 4.70-4.65 (m, 1H), 4.22-4.17 (m, 2H), 3.66-3.50 (m, 4H), 2.99 (s, 3H), 2.92-2.87 (m, 4H), 2.21 (s, 3H), 2.03-1.95 (m, 4H), 1.33-1.27 (m, 9H);

[0744] MS m/z (ESI): 623.3 [M+H].sup.+.

Example 159

Preparation of N-(2-(3-chloro-1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00313##

[0745] N-(2-(3-Chloro-1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0746] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.13 (s, 1H), 9.03 (s, 1H), 8.43 (d, J=4.0 Hz, 2H), 8.35 (d, J=5.9 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.26 (d, J=5.9 Hz, 1H), 6.51 (d, J=8.0 Hz, 1H), 4.99-4.84 (m, 1H), 4.61 (t, J=7.5 Hz, 1H), 4.16-4.09 (m, 1H), 3.58 (t, J=7.2 Hz, 1H), 3.53-3.42 (m, 3H), 3.17-3.10 (m, 4H), 2.93 (s, 3H), 2.82 (q, J=7.2 Hz, 1H), 1.36 (d, J=6.1 Hz, 3H), 1.21 (t, J=4.0 Hz, 6H);

[0747] MS m/z (ESI): 616.2 [M+H].sup.+.

Example 160

Preparation of N-(2-(3-chloro-1-(3-(dimethylamino)cyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00314##

[0748] N-(2-(3-Chloro-1-(3-(dimethylamino)cyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0749] MS m/z (ESI): 623.3 [M+H].sup.+.

Example 161

Preparation of 3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carbonitrile

##STR00315##

[0750] 3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carbonitrile was prepared with reference to reference example 2.

[0751] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.13 (s, 1H), 9.03 (s, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 8.34 (d, J=6.0 Hz, 1H), 7.38 (s, 1H), 7.24 (s, 1H), 6.51 (d, J=8.0 Hz, 1H), 5.28-5.24 (m, 1H), 5.11-5.06 (m, 1H), 4.64-4.59 (m, 1H), 4.14 (t, J=6.4 Hz, 1H), 3.60-3.52 (m, 1H), 3.53-3.46 (m, 4H), 2.93 (s, 3H), 2.86-2.78 (m, 1H), 2.66-2.58 (m, 2H), 1.52 (s, 3H), 1.36 (d, J=6.0 Hz, 3H), 1.26-1.19 (m, 6H);

[0752] MS m/z (ESI): 619.2 [M+H].sup.+.

Example 162

Preparation of N-(2-(3-chloro-1-(3-(methoxymethyl)cyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00316##

[0753] N-(2-(3-Chloro-1-(3-(methoxymethyl)cyclobutyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0754] .sup.1H NMR (400 MHz, DMSO) 10.20 (s, 1H), 9.10 (s, 1H), 8.59 (s, 1H), 8.44-8.37 (m, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.26 (d, J=5.0 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 4.99 (p, J=7.8 Hz, 1H), 4.68 (t, J=7.5 Hz, 1H), 4.21 (p, J=5.9 Hz, 1H), 3.65 (t, J=7.1 Hz, 1H), 3.55 (qt, J=9.9, 5.1 Hz, 3H), 3.47 (d, J=6.0 Hz, 2H), 3.32 (s, 3H), 3.00 (s, 3H), 2.95-2.81 (m, 1H), 2.68-2.53 (m, 3H), 2.30 (dt, J=15.4, 6.0 Hz, 2H), 1.43 (d, J=6.0 Hz, 3H), 1.29 (dd, J=6.7, 4.1 Hz, 6H);

[0755] MS m/z (ESI): 624.2 [M+H].sup.+.

Example 163

Preparation of (1s,3s)-3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-1-methyl cyclobutan-1-ol

##STR00317##

[0756] (1s,3s)-3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1-ol was prepared with reference to reference example 2.

[0757] MS m/z (ESI): 610.2 [M+H].sup.+.

Example 164

Preparation of (1r,3r)-3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1-ol

##STR00318##

[0758] (1r,3r)-3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1-ol was prepared with reference to reference example 2.

[0759] MS m/z (ESI): 610.2 [M+H].sup.+.

Example 165

Preparation of N-(2-(3-chloro-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00319##

[0760] N-(2-(3-Chloro-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0761] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.20 (s, 1H), 9.10 (s, 1H), 8.51 (s, 1H), 8.42 (d, J=5.8 Hz, 1H), 8.36 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.32 (s, 1H), 6.58 (d, J=8.0 Hz, 1H), 5.33 (t, J=4.8 Hz, 1H), 5.08-5.04 (m, 1H), 4.68 (t, J=7.6 Hz, 1H), 4.57-4.28 (m, 5H), 4.25-4.17 (m, 1H), 3.72-3.44 (m, 4H), 3.00 (s, 3H), 2.95-2.85 (m, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.36-1.28 (m, 6H);

[0762] MS m/z (ESI): 596.2 [M+H].sup.+.

Example 166

Preparation of ((1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(imino)(methyl)-16-sulfanone

##STR00320##

[0763] ((1-(3-((2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(imino)(methyl)-16-sulfanone was prepared with reference to example 5.

[0764] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.05 (s, 1H), 9.10 (s, 1H), 8.53 (s, 1H), 8.36 (d, J=5.8 Hz, 1H), 8.18 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.21 (d, J=5.9 Hz, 1H), 6.41 (d, J=8.0 Hz, 1H), 4.42-4.35 (m, 2H), 4.05-3.93 (m, 2H), 3.85 (s, 3H), 3.74 (s, 1H), 3.58-3.46 (m, 3H), 3.31-3.27 (m, 1H), 2.93 (s, 3H), 2.51 (s, 3H), 1.33 (d, J=6.8 Hz, 6H);

[0765] MS m/z (ESI): 505.2 [M+H].sup.+.

Example 167

Preparation of N-(((1-(3-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(methyl)(carbonyl)-16-sulfanylidene)cyanamide

##STR00321##

[0766] N-(((1-(3-((2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methyl)(methyl)(carbonyl)-16-sulfanylidene)cyanamide was prepared with reference to example 5.

[0767] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.07 (s, 1H), 9.09 (s, 1H), 8.54 (s, 1H), 8.37 (d, J=5.8 Hz, 1H), 8.18 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.21 (d, J=5.5 Hz, 1H), 6.44 (d, J=8.1 Hz, 1H), 4.46-4.36 (m, 2H), 4.13 (d, J=7.2 Hz, 2H), 4.06-3.97 (m, 2H), 3.85 (s, 3H), 3.58-3.51 (m, 4H), 3.42-3.39 (m, 1H), 2.51 (s, 3H), 1.33 (d, J=6.8 Hz, 6H);

[0768] MS m/z (ESI): 530.2 [M+H].sup.+.

Example 168

Preparation of (R)-3-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-5-methyloxazolidin-2-one

##STR00322##

[0769] (R)-3-(1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-5-methyl oxazolidin-2-one was prepared with reference to example 5.

[0770] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.10 (s, 1H), 9.06 (s, 1H), 8.50 (s, 1H), 8.34 (d, J=5.9 Hz, 1H), 8.26 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.21 (d, J=5.7 Hz, 1H), 6.41 (d, J=8.0 Hz, 1H), 4.74-4.57 (m, 2H), 4.32 (q, J=8.1 Hz, 2H), 4.25-4.12 (m, 2H), 3.87 (t, J=8.4 Hz, 1H), 3.84 (s, 3H), 3.51 (dt, J=13.7, 6.7 Hz, 1H), 1.90-1.96 (m, 1H), 1.29 (d, J=6.2 Hz, 3H), 1.23 (d, J=6.8 Hz, 6H);

[0771] MS m/z (ESI): 533.2 [M+H].sup.+.

Example 169

Preparation of N3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline-3,6-diamine

##STR00323##

[0772] N3-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline-3,6-diamine was prepared with reference to example 5.

[0773] MS m/z (ESI): 555.2 [M+H].sup.+.

Example 170

Preparation of N-(2-(3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00324##

[0774] N-(2-(3-Chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0775] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 13.50 (s, 1H), 10.22 (s, 1H), 9.09 (s, 1H), 8.68 (s, 1H), 8.41 (d, J=6.0 Hz, 1H), 8.35 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.22 (s, 1H), 6.58 (d, J=8.0 Hz, 1H), 4.68 (t, J=7.6 Hz, 1H), 4.24-4.17 (m, 1H), 3.69-3.62 (m, 1H), 3.60-3.51 (m, 3H), 3.00 (s, 3H), 2.93-2.85 (m, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.34-1.28 (m, 6H);

[0776] MS m/z (ESI): 526.2 [M+H].sup.+.

Example 171

Preparation of (S)-3-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-5-methyloxazolidin-2-one

##STR00325##

[0777] (S)-3-(1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)-5-methyl oxazolidin-2-one was prepared with reference to example 5.

[0778] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.17 (s, 1H), 9.12 (s, 1H), 8.57 (s, 1H), 8.40 (d, J=5.9 Hz, 1H), 8.33 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.27 (d, J=5.3 Hz, 1H), 6.47 (d, J=8.0 Hz, 1H), 4.85-4.62 (m, 2H), 4.38 (q, J=8.1 Hz, 2H), 4.31-4.17 (m, 2H), 3.97-3.82 (m, 4H), 3.57 (dt, J=13.6, 6.7 Hz, 2H), 1.35 (d, J=6.2 Hz, 3H), 1.29 (d, J=6.8 Hz, 6H);

[0779] MS m/z (ESI): 533.2 [M+H].sup.+.

Example 172

Preparation of 1-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-3-fluoropropan-2-ol

##STR00326##

[0780] 1-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)-3-fluoropropan-2-ol was prepared with reference to reference example 2.

[0781] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.20 (s, 1H), 9.10 (s, 1H), 8.53 (s, 1H), 8.42 (d, J=6.0 Hz, 1H), 8.32 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.29 (s, 1H), 6.58 (d, J=8.0 Hz, 1H), 5.65-5.58 (m, 1H), 4.71-4.66 (m, 1H), 4.49-4.13 (m, 6H), 3.70-3.62 (m, 1H), 3.60-3.53 (m, 3H), 3.00 (s, 3H), 2.92-2.86 (m, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.35-1.27 (m, 6H);

[0782] MS m/z (ESI): 602.2 [M+H].sup.+.

Example 173

Preparation of 5-isopropyl-N-(2-(3-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00327##

[0783] 5-Isopropyl-N-(2-(3-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0784] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.84 (s, 1H), 10.10 (s, 1H), 9.09 (s, 1H), 8.66 (s, 1H), 8.37 (d, J=5.8 Hz, 1H), 8.10 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.16 (s, 1H), 6.57 (d, J=8.0 Hz, 1H), 4.71-4.66 (m, 1H), 4.22-4.18 (m, 1H), 3.68-3.63 (m, 1H), 3.59-3.49 (m, 3H), 2.99 (s, 3H), 2.92-2.87 (m, 1H), 2.62 (s, 3H), 1.43 (d, J=6.0 Hz, 3H), 1.31 (d, J=6.8 Hz, 6H);

[0785] MS m/z (ESI): 506.2 [M+H].sup.+.

Example 174

Preparation of 2-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide

##STR00328##

[0786] 2-(1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-isopropylisoquinolin-8-yl)azetidin-3-yl)tetrahydrothiophene 1,1-dioxide was prepared with reference to example 5.

[0787] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.14 (s, 1H), 9.02 (s, 1H), 8.53 (s, 1H), 8.34 (d, J=5.9 Hz, 1H), 8.27 (s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.21 (d, J=5.2 Hz, 1H), 6.43 (d, J=8.1 Hz, 1H), 4.41 (d, J=8.6 Hz, 2H), 4.16 (d, J=8.7 Hz, 2H), 3.84 (s, 3H), 3.54-3.48 (m, 1H), 3.18-3.01 (m, 2H), 2.29-2.23 (m, 2H), 1.96-1.91 (m, 1H), 1.86-1.81 (m, 1H), 1.59-1.54 (m, 2H), 1.24 (d, J=6.8 Hz, 6H);

[0788] MS m/z (ESI): 552.2 [M+H].sup.+.

Example 175

Preparation of N-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00329##

[0789] N-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to example 5.

[0790] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.06 (s, 1H), 9.09 (s, 1H), 8.57 (s, 1H), 8.32 (s, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.11 (s, 1H), 6.56 (d, J=8.0 Hz, 1H), 4.68 (t, J=7.6 Hz, 1H), 4.24-4.17 (m, 1H), 3.90 (s, 3H), 3.68-3.63 (m, 1H), 3.60-3.51 (m, 3H), 3.00 (s, 3H), 2.92-2.85 (m, 1H), 2.37 (s, 3H), 1.43 (d, J=6.0 Hz, 3H), 1.32-1.27 (m, 6H);

[0791] MS m/z (ESI): 554.2 [M+H].sup.+.

Example 176

Preparation of N-(2-(3-chloro-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00330##

[0792] N-(2-(3-Chloro-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl) azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0793] MS m/z (ESI): 638.2 [M+H].sup.+.

Example 177

Preparation of N-(2-(3-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00331##

[0794] N-(2-(3-Chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0795] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.36 (s, 1H), 9.10 (s, 1H), 8.81 (s, 1H), 8.60 (br s, 1H), 8.46 (d, J=7.2 Hz, 1H), 7.89 (d, J=60 Hz, 1H), 7.42 (d, J=7.2 Hz, 1H), 7.33 (br s, 1H), 6.58 (d, J=7.2 Hz, 1H), 4.70-4.66 (m, 1H), 4.22-4.19 (m, 1H), 3.67-3.52 (m, 4H), 3.00 (s, 3H), 2.92-2.87 (m, 1H), 1.37-1.16 (m, 9H);

[0796] MS m/z (ESI): 576.2 [M+H].sup.+.

Example 178

Preparation of N-(1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide

##STR00332##

[0797] N-(1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanesulfonamide was prepared with reference to example 44.

[0798] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.24 (s, 1H), 9.08 (s, 1H), 8.63 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.36 (s, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.35 (br s, 1H), 6.36 (d, J=8.0 Hz, 1H), 4.69-4.65 (m, 2H), 4.44-4.41 (m, 1H), 4.08-4.04 (m, 2H), 3.95 (s, 3H), 3.58-3.52 (m, 1H), 3.04 (s, 3H), 1.44-1.33 (m, 6H);

[0799] MS m/z (ESI): 545.2 [M+H].sup.+.

Example 179

Preparation of N-(2-(3-chloro-1-((2S,4S)-1,2-dimethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00333##

[0800] N-(2-(3-Chloro-1-((2S,4S)-1,2-dimethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl) azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0801] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.12 (s, 1H), 9.03 (s, 1H), 8.48 (s, 1H), 8.34 (d, J=5.8 Hz, 1H), 8.30 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.16 (s, 1H), 6.51 (d, J=8.0 Hz, 1H), 5.30-5.22 (m, 1H), 4.61 (t, J=7.6 Hz, 1H), 4.23-4.09 (m, 2H), 3.62-3.39 (m, 4H), 2.93 (s, 3H), 2.89-2.77 (m, 2H), 2.13 (s, 3H), 1.97-1.83 (m, 5H), 1.36 (d, J=6.0 Hz, 3H), 1.27-1.20 (m, 6H), 1.01 (d, J=6.0 Hz, 3H);

[0802] MS m/z (ESI): 637.2 [M+H].sup.+.

Example 180

Preparation of N-(2-(3-chloro-1-((3S,6R)-1,6-dimethylpiperidin-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00334##

[0803] N-(2-(3-Chloro-1-((3S,6R)-1,6-dimethylpiperidin-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl) azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0804] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.11 (s, 1H), 9.03 (s, 1H), 8.44 (s, 1H), 8.38-8.31 (m, 1H), 8.28 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.23 (s, 1H), 6.51 (d, J=8.0 Hz, 1H), 5.26 (t, J=4.8 Hz, 1H), 4.61 (t, J=7.6 Hz, 1H), 4.18-4.09 (m, 2H), 3.96-3.87 (m, 1H), 3.58 (d, J=7.2 Hz, 1H), 3.53-3.42 (m, 3H), 2.93 (s, 3H), 2.87-2.77 (m, 1H), 2.19 (s, 3H), 1.99-1.87 (m, 5H), 1.36 (d, J=6.2 Hz, 3H), 1.26-1.19 (m, 6H), 0.83 (d, J=6.4 Hz, 3H);

[0805] MS m/z (ESI): 637.2 [M+H].sup.+.

Example 181

Preparation of N-(2-(3-chloro-1-((3R,6S)-1,6-dimethylpiperidin-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00335##

[0806] N-(2-(3-Chloro-1-((3R,6S)-1,6-dimethylpiperidin-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl) azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0807] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.20 (s, 1H), 9.12 (s, 1H), 8.54 (s, 1H), 8.46-8.40 (m, 1H), 8.37 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.24 (s, 1H), 6.60 (d, J=8.0 Hz, 1H), 5.41-5.29 (m, 1H), 4.70 (t, J=7.6 Hz, 1H), 4.28-4.19 (m, 2H), 4.06-3.96 (m, 1H), 3.71-3.45 (m, 4H), 3.02 (s, 3H), 2.96-2.87 (m, 1H), 2.28 (s, 3H), 2.07-1.97 (m, 5H), 1.45 (d, J=6.2 Hz, 3H), 1.41-1.23 (m, 6H), 0.93 (d, J=6.4 Hz, 3H);

[0808] MS m/z (ESI): 637.2 [M+H].sup.+.

Example 182

Preparation of N-(2-(3-chloro-1-(((S)-oxetan-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00336##

[0809] N-(2-(3-Chloro-1-(((S)-oxetan-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0810] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.20 (s, 1H), 9.10 (s, 1H), 8.51 (s, 1H), 8.41 (d, J=6.0 Hz, 1H), 8.36 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.31 (d, J=5.8 Hz, 1H), 6.58 (d, J=8.0 Hz, 1H), 5.11-5.00 (m, 1H), 4.68 (t, J=7.6 Hz, 1H), 4.56-4.27 (m, 4H), 4.26-4.15 (m, 1H), 3.65 (t, J=7.2 Hz, 1H), 3.60-3.49 (m, 3H), 3.00 (s, 3H), 2.96-2.83 (m, 1H), 2.77-2.64 (m, 1H), 2.49-2.38 (m, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.34-1.27 (m, 6H);

[0811] MS m/z (ESI): 596.2 [M+H].sup.+.

Example 183

Preparation of (R)-5-((3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-2-one

##STR00337##

[0812] (R)-5-((3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-2-one was prepared with reference to reference example 2.

[0813] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.25 (s, 1H), 9.10 (s, 1H), 8.66 (s, 1H), 8.51-8.33 (m, 1H), 8.24 (s, 1H), 7.81 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.26 (s, 1H), 6.61 (t, J=16.8 Hz, 1H), 4.68 (t, J=7.5 Hz, 1H), 4.35-4.16 (m, 3H), 4.16-3.92 (m, 1H), 3.66 (t, J=7.1 Hz, 1H), 3.61-3.47 (m, 3H), 3.00 (s, 3H), 2.96-2.79 (m, 1H), 2.18-2.05 (m, 3H), 1.98-1.89 (m, 1H), 1.43 (d, J=6.1 Hz, 3H), 1.32 (t, J=6.3 Hz, 6H);

[0814] MS m/z (ESI): 623.2 [M+H].sup.+.

Example 184

Preparation of (S)-5-((3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-2-one

##STR00338##

[0815] (S)-5-((3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-2-one was prepared with reference to reference example 2.

[0816] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.24 (s, 1H), 9.10 (s, 1H), 8.65 (s, 1H), 8.43 (d, J=5.9 Hz, 1H), 8.27-8.14 (m, 1H), 7.79 (d, J=12.8 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.25 (s, 1H), 6.56 (t, J=13.9 Hz, 1H), 4.68 (t, J=7.5 Hz, 1H), 4.29-4.16 (m, 3H), 4.10-3.80 (m, 1H), 3.66 (t, J=7.1 Hz, 1H), 3.61-3.47 (m, 3H), 3.00 (s, 3H), 2.96-2.79 (m, 1H), 2.18-2.05 (m, 3H), 1.94 (dt, J=10.0, 5.7 Hz, 1H), 1.43 (d, J=6.0 Hz, 3H), 1.32 (dd, J=6.7, 2.9 Hz, 6H);

[0817] MS m/z (ESI): 623.2 [M+H].sup.+.

Example 185

Preparation of 3-(3-chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)butyronitrile

##STR00339##

[0818] 3-(3-Chloro-4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl) methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)butyronitrile was prepared with reference to reference example 2.

[0819] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.19 (s, 1H), 9.10 (s, 1H), 8.50 (s, 1H), 8.49 (s, 1H), 8.42 (d, J=5.9 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.33 (s, 1H), 6.58 (d, J=8.0 Hz, 1H), 4.84-4.79 (m, 1H), 4.68 (t, J=7.5 Hz, 1H), 4.20 (t, J=6.2 Hz, 1H), 3.65 (t, J=7.1 Hz, 1H), 3.60-3.48 (m, 3H), 3.18 (d, J=6.7 Hz, 2H), 3.00 (s, 3H), 2.92-2.86 (m, 1H), 1.55 (d, J=6.7 Hz, 3H), 1.43 (d, J=6.0 Hz, 3H), 1.29 (t, J=6.8 Hz, 6H);

[0820] MS m/z (ESI): 593.2 [M+H].sup.+.

Example 186

Preparation of N-((2R,3S)-1-(3-((2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide

##STR00340##

[0821] N-((2R,3S)-1-(3-((2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-6-fluoro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide was prepared with reference to example 44.

[0822] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.16 (s, 1H), 8.96 (s, 1H), 8.54 (s, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.24 (s, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.20 (br s, 1H), 6.36 (br s, 1H), 4.82-4.77 (m, 1H), 4.16-4.10 (m, 1H), 3.88-3.83 (m, 4H), 3.62-3.54 (m, 2H), 2.90 (s, 3H), 1.37-1.16 (m, 9H);

[0823] MS m/z (ESI): 559.2 [M+H].sup.+.

Example 187

Preparation of N3-(2-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-N5,N5-dimethyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline-3,5-diamine

##STR00341##

[0824] N3-(2-(3-Chloro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-N5,N5-dimethyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinoline-3,5-diamine was prepared with reference to example 5.

[0825] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.23 (s, 1H), 9.07 (s, 1H), 8.86 (s, 1H), 8.42-8.34 (m, 2H), 7.23 (d, J=8.2 Hz, 1H), 7.13 (d, J=5.8 Hz, 1H), 6.54 (d, J=8.3 Hz, 1H), 4.66-4.59 (m, 1H), 4.21-4.12 (m, 1H), 3.93 (s, 3H), 3.62-3.46 (m, 3H), 3.00 (s, 3H), 2.92-2.84 (m, 1H), 2.75 (s, 6H), 1.41 (d, J=6.0 Hz, 3H);

[0826] MS m/z (ESI): 541.2 [M+H].sup.+.

Example 188

Preparation of N-(2-(3-chloro-1-((4-methyloxetan-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

##STR00342##

[0827] N-(2-(3-Chloro-1-((4-methyloxetan-2-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared with reference to reference example 2.

[0828] MS m/z (ESI): 610.2 [M+H].sup.+.

Biological Test and Evaluation

[0829] The present invention will be further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.

Test Example 1. Determination of the Inhibitory Effect of the Compounds of the Present Invention on the Activity of EGFR Del19/T790M/C797S and EGFR L858R/T790M/C797S Mutant Kinases

[0830] Experimental objective: The objective of this test example is to test the inhibitory activity of the compounds on the activity of EGFR del19/T790M/C797S and EGFR L858R/T790M/C797S mutant kinases.

[0831] Experimental instruments: The centrifuge (5810R) was purchased from Eppendorf, the pipette was purchased from Eppendorf or Rainin, and the microplate reader was purchased from BioTek (United States) with a model of SynergyH1 multifunctional microplate reader.

[0832] Experimental method: This experiment used Cisbio's HTRF kinase assay method (Cisbio #62TK0PEB), wherein a catalytic reaction occurred between the substrate polypeptide TK and ATP in the presence of the tyrosine kinase with EGFR del19/T790M/C797S or EGFR L858R/T790M/C797S mutation, the substance was phosphorylated, and the activity of the kinase was characterized by measuring the content of the phosphorylated substrate generated during the reaction, and the half inhibitory concentration IC.sub.50 of the compound on the activity of EGFR de119/T790M/C797S or EGFR L858R/T790M/C797S mutant kinase was obtained.

[0833] Specific experimental operations were as follows: [0834] the kinase reaction was carried out in a white 384-well plate (Perkin Elmer #6008280), and 1-5 L of compounds of different concentrations which were diluted with 1% DMSO-containing ddH.sub.2O were added; to the positive control wells were added 1-5 L of 1% DMSO-containing ddH.sub.2O, followed by 1-5 L of 0.5-5 nM 4EGFR de119/T790M/C797S or EGFR L858R/T790M/C797S mutant kinase solution which was diluted with Dilution buffer (5kinase buffer, MgCl.sub.2 6.65 Mm, MnCl.sub.2 1.33 mM, DTT 1.33 mM); to the negative control wells were added 1-5 L of Dilution buffer; to all the wells were added 1-5 L of 4 M 4 substrate TK solution which was prepared with 10 Dilution buffer, and finally added 1-5 L of 24 M 4ATP solution which was diluted with Dilution buffer to start the reaction; after reacting at room temperature for 120 minutes, 10 L of detection solution (TK antibody 16 nM, XL665 0.5 M) was added to each well, same was reacted at room temperature in the dark for 20 minutes, and then the chemiluminescence value was detected using a BioTek Synergy H1 microplate reader.

Experimental Data Processing Method:

[0835] The percent inhibition data for compound-treated wells was calculated according to the positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate {% inhibition rate=100[(test compound value-negative control value)]/(positive control valuenegative control value)100}. GraphPad prism was used to fit different concentrations and corresponding percent inhibition rate data to a 4-parameter nonlinear logistic equation to calculate IC.sub.50 values.

[0836] Experimental results and conclusions: The compounds in this example of the present invention have good inhibitory effects on EGFR L858R/T790M/C797S and EGFR del19/T790M/C797S drug-resistant mutant kinases.

Test Example 2: Cell Proliferation Inhibition Experiment

[0837] Experimental objective: The objective of this test example is to test the inhibitory activity of compounds on the proliferation of different EGFR C797S drug-resistant mutant cell lines Ba/F3 EGFR Del19/T790M/C797S, Ba/F3 EGFR L858R/T790M/C797S, and Ba/F3 EGFR Del19/C797S.

Experimental Instruments:

[0838] Centrifuge (Eppendorf 5810R); Microplate reader (BioTek Synergy H1) [0839] Pipette (Eppendorf or Rainin); Carbon dioxide incubator (Thermo 311) [0840] Cell counter (Life Countess II)

Experimental Reagents and Consumables:

[0841] Ba/F3 EGFR Del19/T790M/C797S cells were purchased from KYinno Biotechnology Co., Ltd.; [0842] Ba/F3 EGFR Del19/C797S cells were purchased from CoBioer Biosciences Co., Ltd.; [0843] Ba/F3 EGFR L858R/T790M/C797S cells were purchased from CoBioer Biosciences Co., Ltd.; [0844] Cell Titer-Glo was purchased from Promega, with a catalog number of G7573; [0845] RPMI 1640 was purchased from Gibco, with a catalog number of 22400089; [0846] FBS was purchased from Gibco, with a catalog number of 10091148; [0847] cell culture plates were purchased from Corning, with a catalog number of 3610.

Experimental Method:

[0848] The inhibitory activity of the compound on the proliferation of different EGFR C797S drug-resistant mutant cell lines was detected using the Cell Titer-Glo method. The different cell lines were cultured in RPMI 1640 complete culture medium containing 10% FBS under conditions of 37 C. and 5% CO.sub.2, the cells were collected by centrifugation when growing to a certain density, and adjusted to appropriate cell density after counting, the cells were spread on a white 96-well plate at 90 L/well, and cultured in a 37 C., 5% CO.sub.2 incubator overnight, prepared compound solutions of different concentrations were added at 10 L/well, corresponding solvent controls were set, and all wells were cultured in a 37 C., 5% CO.sub.2 incubator for 72 hours, 50 L of CellTiter-Glo solution was added to each well, shook and mixed evenly, and incubated in the dark for 10 minutes, and a BioTek Synergy H1 microplate reader was used for reading.

Experimental Data Processing Method:

[0849] The luminescence signal value was used to calculate the inhibition rate. Graphpad Prism software was used to fit the concentration and inhibition rate to a nonlinear regression curve, so as to obtain the IC.sub.50 value, as shown in the Table below for details.

TABLE-US-00001 TABLE 1 Ba/F3 EGFR Del19_T790M_C797S Example number IC.sub.50 (nM) 1 4.5 2 6.2 4 7.7 5 3.7 6 5.1 44 10.0 67 4.0 .sup.116A 7.6 120 7.1 121 4.5 122 2.9 123 3.3 125 6.8 126 2.1 127 4.5 130 8.1 132 5.6 172 5.0 182 4.4 186 5.9

TABLE-US-00002 TABLE 2 Ba/F3 EGFR L858R_T790M_C797S Example IC.sub.50 (nM) 5 11.0 6 13.0 120 14.0 121 15.0 122 8.2 123 13.0 126 7.5 132 15 182 10 186 8.8

TABLE-US-00003 TABLE 3 Example number Ba/F3 EGFR Del19/C797S IC50 (nM) 1 12.0 2 13.0 3 16.0 4 20.0 5 5.1 6 5.1 9 57.0 44 8.4 59 5.0 60 5.6 61 6.0 67 3.2 71 17.0 102 73.0 109 14.0 112 52 113 60 114 39 115 73 .sup.116A 33 120 11.0 121 6.2 122 5.1 123 6.5 124 14.0 125 18 126 3.0 127 7.8 129 22 130 5.9 131 7.4 132 6.4 133 27 141 64 142 41.0 143 30.0 144 26.0 145 45.0 146 80 150 70 .sup.151A 41 .sup.154A 22 156 42.0 158 50.0 165 22 167 74 169 52 170 60 172 33 177 43 178 19 185 80 186 2.6 188 65

Experimental Conclusion

[0850] According to the above-mentioned schemes, it can be concluded that the compounds shown in the present invention show a significant inhibitory activity against the proliferation of different EGFR C797S drug-resistant mutant cell lines in the proliferation inhibitory activity test.

Test Example 3: Rat Pharmacokinetic Evaluation Test

1. Study Objective

[0851] SD rats were used as test animals to study the pharmacokinetic behavior of the compounds of the present invention in the rat body (plasma) after oral administration at a dose of 5 mg/kg.

2. Experimental Scheme

2.1 Experimental Drugs: The Example Compound of the Present Invention, Made in House.

2.2 Experimental Animals: 3 SD Rats/Group, Male, from Shanghai Jiesijie Experimental Animal Co., Ltd., Animal Production License Number (SCXK (Shanghai) 2013-0006 No. 311620400001794).

2.3 Formulation Prescription:

[0852] Oral administration drug preparation: 20% solutol HS15 in 0.5% MC (methylcellulose)

[0853] 20 g of a Solutol HS15 solid and 0.5 g of a MC solid powder were weighed and dissolved in 80 mL of purified water, and the mixture was vortexed, mixed until uniform, and subjected to ultrasound treatment to obtain a clear solution of 20% solutol HS15 in 0.5% MC.

[0854] The example compound was weighed into a 20 mL glass bottle, the solution was added thereto and the mixture was subjected to ultrasound treatment for 10 minutes to obtain a clear solution with a concentration of 0.5 mg/mL.

2.4 Administration:

[0855] 3 male SD rats were administered p.o. respectively after the 3 male SD rats were fasted overnight; the p.o. dose was 5 mg/kg and the administration volume was 10 mL/kg.

2.5 Sample Collection:

[0856] Blood collection: Before and after administration to rats, 0.2 mL of blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h, and placed in an EDTA-K.sub.2 anticoagulation tube, which was centrifuged at 6000 rpm at 4 C. for 6 min to separate plasma which was stored at 80 C.; the rats were fed 4 h after administration.

2.6 Sample Treatment:

[0857] 1) 160 L of acetonitrile was added to 40 L of plasma sample for precipitation, mixed and centrifuged at 3500g for 5 to 20 min.

[0858] 2) the treated supernatant solution was taken and subjected to LC/MS/MS to analyze the concentrations of the test compounds. LC/MS/MS analysis instrument: AB Sciex API 4000 Qtrap.

2.7 Liquid Phase Analysis:

[0859] Liquid phase conditions: Shimadzu LC-20AD pump [0860] Chromatographic column: Agilent ZORBAX XDB-C18 (502.1 mm, 3.5 m) mobile phase: liquid A is 0.1% aqueous formic acid solution, liquid B is acetonitrile [0861] Flow rate: 0.4 mL/min [0862] Elution time: 0-4.0 min, the eluent is as follows:

TABLE-US-00004 Time/min Liquid A Liquid B 0.01 90% 10% 0.5 90% 10% 0.8 5% 95% 2.4 5% 95% 2.5 90% 10% 4.0 Stop

3. Experimental Results and Analysis

[0863] The main pharmacokinetic parameters were calculated using WinNonlin 6.1. The results of pharmacokinetic experiments in rats are as shown in Table 4 below:

TABLE-US-00005 TABLE 4 Cmax AUC.sub.0-t T.sub.1/2 Example (ng/mL) (hr*ng/mL) (h) 1 287 1406 2.7 3 458 2377 4.1 5 239 1259 4.1 67 186 2173 2.7 120 178 2102 2.3 121 142 1771 3.9 122 97 1262 3.5 126 240 3143 3.3 127 157 2005 3.9 132 180 1568 3.0

3.4 Experimental Conclusion

[0864] The data in the table show that in the rat pharmacokinetic evaluation experiment, the example compounds of the present invention show high exposure after oral administration.

Test Example 4: In Vivo Pharmacodynamic Study of the Compound in a Nude Mouse Subcutaneous Transplanted Tumor Model of Mouse Primary B Cell Line Ba/F.SUB.3 .EGFR Del19/C797S

1.1 Experimental Objective

[0865] The objective of this test example is to evaluate the in vivo efficacy of the compound in a nude mouse subcutaneous transplanted tumor model of mouse primary B cell line Ba/F.sub.3 EGFR Del19/C797S.

1.2 Experimental Instruments and Reagents

1.2.1 Instruments

[0866] 1. Refrigerator (BCD-268TN, Haier) [0867] 2. Biological safety cabinet (BSC-130011 A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory) [0868] 3. Ultra-clean workbench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.) [0869] 4. Electric pipette-aid (Easypet 3, Eppendorf) [0870] 5. Thermostat water bath (HWS-12, Shanghai Yiheng Science) [0871] 6. CO.sub.2 incubator (Thermo-311, Thermo) [0872] 7. Centrifuge (Centrifuge 5720R, Eppendorf) [0873] 8. Full-automatic cell counter (Countess 11, Life Technologies) [0874] 9. Vernier caliper (CD-6AX, Mitutoyo) [0875] 10. Cell culture flask (T25/T75/T225, Corning) [0876] 11. Electronic balance (CPA2202S, Sartorius) [0877] 12. Electronic balance (BSA2202S-CW, Sartorius) [0878] 13. Ultrasonic cleaner (115F0032, Shanghai Kudos) [0879] 14. Water purifier (Pacific TII, Thermo) [0880] 15. Magnetic stirrer (08-2G, Chijiu)

1.2.2 Reagents

[0881] 1. RPMI 1640 medium (22400-089, Gibco) [0882] 2. Fetal bovine serum (FBS) (10099-141C, Gibco) [0883] 3. Phosphate buffer solution (PBS) (10010-023, Gibco) [0884] 4. Kolliphor HS15 (42966-1KG, Sigma-Aldrich) [0885] 5. Methylcellulose M450 (69016482, Sinopharm Chemical Reagent Co., Ltd.)

1.3 Experimental Operations and Data Processing

1.3.1 Animals

[0886] BALB/c nude mice, 6-8 weeks old, , purchased from the Laboratory Animal Business Department of Shanghai Institute of Planned Parenthood Research

1.3.2 Cell Culture and Cell Suspension Preparation

[0887] a. A Ba/F.sub.3 EGFR Del19/C797S cell line was taken out from the cell bank, and the cells were recovered with RPMI-1640 medium (RPMI-1640+10% FBS). The recovered cells were cultured in a CO.sub.2 incubator (incubator temperature: 37 C., CO.sub.2 concentration: 5%).

[0888] b. The cells were passaged every three days, and after passage, the cells were placed in a CO.sub.2 incubator to continue the culture. This process was repeated until the cell number meets the needs of in vivo efficacy.

[0889] c. The cells in the exponential growth phase were collected, counted using a full-automatic cell counter, resuspended to 210.sup.7 cells/mL with PBS according to the counting results, and then placed in an ice box until use.

1.3.3 Cell Inoculation

[0890] a. Nude mouse was marked with a disposable universal ear tag for mice and rats before inoculation.

[0891] b. At the time of inoculation, the cell suspension was mixed well, 0.1-1 mL of cell suspension was taken with a 1 mL syringe, and after removing air bubbles, the syringe was placed on an ice bag until use.

[0892] c. The nude mouse was secured with the left hand. The position of the right back near the right shoulder of the nude mouse (inoculation site) was disinfected with a 75% alcohol cotton ball, and inoculation was carried out after 30 seconds.

[0893] d. The nude mice were inoculated successively (inoculation with 0.1 mL of cell suspension per mouse).

1.3.4 Tumor Volume Measurement, Grouping and Administration in Tumor-Bearing Mice

[0894] a. Tumor was measured on days 9-12 after inoculation depending on the tumor growth, and tumor size was calculated.

tumor volume (mm.sup.3)=length (mm)width (mm)width (mm)/2Tumor volume calculation:

[0895] b. According to the weight of tumor-bearing mice and the size of the tumor, the mice were grouped by random grouping.

[0896] c. According to the grouping results, the test drug was started to be administered (administration method: oral administration; administration volume: 10 mL/kg; administration frequency: once/day or twice/day; administration cycle: 14 days; vehicle: 10% Solutol HS15/0.5% MC).

[0897] d. Tumors were measured and weighed twice a week after starting administration of test drugs.

[0898] e. Animals were euthanized at the end of the experiment.

[0899] f. The data was processed with software such as Excel. Calculation of tumor growth inhibition (TGI) (%) of a compound: when the tumor did not regress, TGI (%)=[(1(average tumor volume at the end of administration in a treatment groupaverage tumor volume at the beginning of administration in the treatment group))/(average tumor volume at the end of administration in the solvent control groupaverage tumor volume at the beginning of administration in the solvent control group)]100%. When the tumor regressed, TGI (%)=[1(average tumor volume at the end of administration in a treatment groupaverage tumor volume at the beginning of administration in the treatment group)/average tumor volume at the beginning of administration in the treatment group]100%.

1.4 Experimental Results and Conclusion

[0900] The key example compounds of the present invention exhibit excellent tumor inhibition effects in the model. When administered orally at a dose of 50 mpk QD, the compounds exhibited an excellent tumor inhibition effect, with tumor growth inhibition (TGI) (%)>80%, and the tumor growth inhibition (TGI) (%) of the key preferred compounds >100%. When administered orally at a dose of 75 mpk QD, the compounds exhibited an excellent tumor inhibition effect, with tumor growth inhibition (TGI) (%)>100%, and the tumor growth inhibition (TGI) (%) of the key preferred compounds >150%. When administered orally at a dose of 120 mpk QD, the compounds exhibited an excellent tumor inhibition effect, with tumor growth inhibition (TGI) (%)>150%, and the tumor growth inhibition (TGI) (%) of the key preferred compounds >190%, and there was no significant weight loss.