COMPOUND, PHARMACEUTICAL COMPOSITION COMPRISING SAME, AND USE THEREOF

Abstract

Provided are a compound of formula 0, a stereoisomer thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a polymorph thereof, a solvate thereof, a hydrate thereof, an N-oxide thereof, an isotopically labeled compound thereof, a metabolite thereof, an ester thereof, a prodrug thereof, and a pharmaceutically acceptable salt thereof. In formula 0, ring B is a 5- to 10-membered spiro ring or a 5- to 10-membered spiro heterocyclic ring. The 5- to 10-membered spiro ring and the 5- to 10-membered spiro heterocyclic ring are optionally substituted with 1-5 R.sup.1F. The compound can significantly weaken the integrated stress response (ISR) of cells and activate the activity of eIF2B, so that proteins in the cells tend to be synthesized normally.

##STR00001##

Claims

1. A compound of formula 0, or a stereoisomer thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a polymorph thereof, a solvate thereof, a hydrate thereof, an N-oxide thereof, an isotopically labeled compound thereof, a metabolite thereof, an ester thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof: ##STR00365## wherein, ring A and ring C are each independently C1-C6 alkyl, C3-C9 cycloalkyl, 3- to 9-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 6- to 10-membered aryl-D-C1-C6 alkyl, 5- to 10-membered heteroaryl-D-C1-C6 alkyl, C3-C9 cycloalkyl-D-C1-C6 alkyl or 3- to 9-membered heterocyclyl-D-C1-C6 alkyl, wherein the alkyl is optionally substituted with deuterium, halogen and C1-C6 alkyl; the cycloalkyl, heterocyclyl, aryl and heteroaryl can each be optionally substituted with 1-5 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, phenyl, cyano, C1-C10 alkyl, hydroxyl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy-C1-C6 alkenyl, amino-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 alkoxy-3- to 6-membered heterocyclyl, oxo, OR.sup.1A, NR.sup.1BR.sup.1C, NR.sup.1BC(O)R.sup.1DC(O)NR.sup.1BR.sup.1C, C(O)R.sup.1D, COOR.sup.1D, SR.sup.1E, S(O)R.sup.1D, S(O).sub.2R.sup.1D-G.sup.1, O-G.sup.1 and NR.sup.1B-G.sup.1; or 2 R.sup.1 groups on adjacent atoms taken together with the atoms to which they are attached can form C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 10-membered aryl or 5- to 6-membered heteroaryl; the C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 10-membered aryl or 5- to 6-membered heteroaryl is each optionally substituted with 1-5 R.sup.1F; with regard to options for the R.sup.1, the phenyl, C1-C10 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in the C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in the C1-C3 alkoxy-C3-C6 cycloalkyl and C1-C3 alkoxy in the C1-C3 alkoxy-3- to 6-membered heterocyclyl are each optionally substituted with halogen; each of the R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D and R.sup.1E is independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C3-C9 cycloalkyl, 3- to 9-membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C9 cycloalkyl, halogen-substituted 3- to 9-membered heterocyclyl and halogen-substituted C1-C6 alkoxy; R.sup.1B and R.sup.1C taken together with the atom to which they are attached can form 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted with 1-3 R.sup.1F; each of the G.sup.1 is independently selected from C3-C9 cycloalkyl, 3- to 9-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; each of the G.sup.1 is optionally substituted with 1-3 R.sup.1F; L.sup.1 is null, NH, ##STR00366## wherein the end is connected to ring A, and the * end is connected to ring B; preferably, the L.sup.1 is null, NH, ##STR00367## preferably, the L.sup.1 is null, ##STR00368## preferably, the L.sup.1 is null ##STR00369## preferably, the L.sup.1 is null ##STR00370## preferably, the L.sup.1 is null, ##STR00371## ring B is a 5- to 10-membered spiro ring or a 5- to 10-membered spiro heterocyclic ring, wherein the 5- to 10-membered spiro ring and the 5- to 10-membered spiro heterocyclic ring are optionally substituted with 1-5 R.sup.1F; each of the R.sup.1F is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, carboxyl, C1-C6 alkyl, C3-C9 cycloalkyl, hydroxyl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C6 alkenyl, halogen-substituted C1-C6 alkoxy-C1-C6 alkenyl, amino-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, oxo, OR.sup.1A, NR.sup.1BR.sup.1C, NR.sup.1BC(O)R.sup.1DC(O)NR.sup.1BR.sup.1C, C(O)R.sup.1D, COOR.sup.1D, P(O)R.sup.1BR.sup.1C, SR.sup.1E, S(O)R.sup.1D and S(O).sub.2R.sup.1D; L.sup.2 is null, NH, ##STR00372## wherein the end is connected to ring B, and the * end is connected to ring C; preferably, the L.sup.2 is null, NH, ##STR00373## preferably, the L.sup.2 is null, ##STR00374## preferably, the L.sup.2 is null, ##STR00375## preferably, the L.sup.2 is null ##STR00376## preferably, the L.sup.2 is null ##STR00377## each of the D is independently a linking group containing a heteroatom; preferably, each of the D is independently O or NR.sup.d or S, wherein each R.sup.d is independently selected from hydrogen, deuterium, C1-C6 alkyl and halogen-substituted C1-C6 alkyl; more preferably, each of the D is independently O or NH.

2. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein: (i) the ring A is C1-C6 alkyl, C3-C9 cycloalkyl, 3- to 9-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 6- to 10-membered aryl-D-C1-C6 alkyl, 5- to 10-membered heteroaryl-D-C1-C6 alkyl or 3- to 9-membered heterocyclyl-D-C1-C6 alkyl, wherein the alkyl is optionally substituted with halogen or C1-C6 alkyl; the cycloalkyl, heterocyclyl, aryl and heteroaryl can each be optionally substituted with 1-5 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of hydrogen, halogen, cyano, C1-C10 alkyl, hydroxyl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy-C1-C6 alkenyl, amino-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, oxo, OR.sup.1A, NR.sup.1BR.sup.1C, NR.sup.1BC(O)R.sup.1DC(O)NR.sup.1BR.sup.1C, C(O)R.sup.1D, COOR.sup.1D, SR.sup.1E, S(O)R.sup.1D, S(O).sub.2R.sup.1D-G.sup.1, O-G.sup.1 and NR.sup.1B-G.sup.1; or 2 R.sup.1 groups on adjacent atoms taken together with the atoms to which they are attached can form C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 10-membered aryl or 5- to 6-membered heteroaryl; the C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 10-membered aryl or 5- to 6-membered heteroaryl is each optionally substituted with 1-5 R.sup.1F; each of the R.sup.1A, R.sup.1B, R.sup.1C, R.sup.1D and R.sup.1E is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl, 3- to 9-membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C9 cycloalkyl, halogen-substituted 3- to 9-membered heterocyclyl and halogen-substituted C1-C6 alkoxy; R.sup.1B and R.sup.1C taken together with the atom to which they are attached can form 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted with 1-3 R.sup.1F; each of the G.sup.1 is independently selected from C3-C9 cycloalkyl, 3- to 9-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; each of the G.sup.1 is optionally substituted with 1-3 R.sup.1F; each of the R.sup.1F is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, C1-C6 alkyl, C3-C9 cycloalkyl, hydroxyl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C6 alkenyl, halogen-substituted C1-C6 alkoxy-C1-C6 alkenyl, amino-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, oxo, OR.sup.1A, NR.sup.1BR.sup.1C, NR.sup.1BC(O)R.sup.1DC(O)NR.sup.1BR.sup.1C, C(O)R.sup.1D, COOR.sup.1D, P(O)R.sup.1BR.sup.1C, SR.sup.1E, S(O)R.sup.1D and S(O).sub.2R.sup.1D; the ring C is 6- to 10-membered aryl-E-C1-C6 alkyl, C3-C9 cycloalkyl-E-C1-C6 alkyl, 3- to 9-membered heterocyclyl-E-C1-C6 alkyl, 3- to 9-membered heterocyclyl, 5- to 10-membered heteroaryl or 6- to 10-membered aryl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl can each be optionally substituted with 1-3 R.sup.2; each of the R.sup.2 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl and C1-C3 alkoxy-3- to 6-membered heterocyclyl, wherein with regard to options for the R.sup.2, the phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in the C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in the C1-C3 alkoxy-C3-C6 cycloalkyl and C1-C3 alkoxy in the C1-C3 alkoxy-3- to 6-membered heterocyclyl are each optionally substituted with halogen; or 2 R.sup.2 groups on adjacent atoms taken together with the atoms to which they are attached can form C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, 5- to 6-membered aryl (such as phenyl) or 5- to 6-membered heteroaryl; the C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, 5- to 6-membered aryl (such as phenyl) or 5- to 6-membered heteroaryl is each optionally substituted with 1-5 R.sup.1F; each of the D or E is independently a linking group containing a heteroatom; preferably, each of the D or E is independently O or NR.sup.d or S, wherein each R.sup.d is independently selected from hydrogen, deuterium and C1-C3 alkyl; more preferably, each of the D or E is independently O or NH; or (ii) the ring A is 3- to 9-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 6- to 10-membered aryl-D-C1-C6 alkyl or 3- to 9-membered heterocyclyl-D-C1-C6 alkyl, wherein the heterocyclyl, aryl and heteroaryl can each be optionally substituted with 1-5 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of hydrogen, halogen, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, OR.sup.1A, NR.sup.1BR.sup.1C, NR.sup.1BC(O)R.sup.1DC(O)NR.sup.1BR.sup.1C, C(O)R.sup.1D, -G.sup.1, O-G.sup.1 and NR.sup.1B-G.sup.1, or 2 R.sup.1 groups on adjacent atoms taken together with the atoms to which they are attached can form 6- to 10-membered aryl or 5- to 6-membered heteroaryl; the 6- to 10-membered aryl or 5- to 6-membered heteroaryl is each optionally substituted with 1-5 R.sup.1F: each of the R.sup.1A, R.sup.1B, R.sup.1C and R.sup.1D is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl, 3- to 9-membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C9 cycloalkyl, halogen-substituted 3- to 9-membered heterocyclyl and halogen-substituted C1-C6 alkoxy; R.sup.1B and R.sup.1C taken together with the atom to which they are attached can form 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted with 1-3 R.sup.1F: each of the G.sup.1 is independently selected from C3-C9 cycloalkyl, 3- to 9-membered heterocyclyl and 6- to 10-membered aryl; each of the G.sup.1 is optionally substituted with 1-3 R.sup.1F; when G.sup.1 is phenyl, the phenyl and 3- to 9-membered heterocyclyl or 5- to 10-membered heteroaryl optionally share two carbon atoms to form a fused ring; each of the R.sup.1F is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C9 cycloalkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C6 alkenyl, oxo, OR.sup.1A, NR.sup.1BR.sup.1C, NR.sup.1BC(O)R.sup.1D, C(O)NR.sup.1BR.sup.1C, C(O)R.sup.1D, P(O)R.sup.1BR.sup.1C and S(O).sub.2R.sup.1D; or (iii) the ring A is 4- to 9-membered heterocyclyl, 5- to 7-membered heteroaryl, phenyl-D-C1-C6 alkyl or 4- to 9-membered heterocyclyl-D-C1-C6 alkyl, wherein the heterocyclyl, heteroaryl and phenyl can each be optionally substituted with 1-5 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of hydrogen, halogen, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, OR.sup.1A, NR.sup.1BR.sup.1C, NR.sup.1BC(O)R.sup.1D, C(O)NR.sup.1BR.sup.1C, -G.sup.1, O-G.sup.1 and NR.sup.1B-G.sup.1; each of the R.sup.1A, R.sup.1B, R.sup.1C and R.sup.1D is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, 4- to 9-membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C4-C9 cycloalkyl, halogen-substituted 4- to 9-membered heterocyclyl and halogen-substituted C1-C6 alkoxy; R.sup.1B and R.sup.1C taken together with the atom to which they are attached can form 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted with 1-3 R.sup.1F; each of the G.sup.1 is independently selected from C3-C9 cycloalkyl, 3- to 9-membered heterocyclyl and phenyl; each of the G.sup.1 is optionally substituted with 1-3 R.sup.1F; when G.sup.1 is phenyl, the phenyl and 3- to 9-membered heterocyclyl or 5- to 7-membered heteroaryl optionally share two carbon atoms to form a fused ring; each of the R.sup.1F is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C9 cycloalkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C6 alkenyl, oxo, OR.sup.1A, NR.sup.1BR.sup.1C, P(O)R.sup.1BR.sup.1C and S(O).sub.2R.sup.1D, or (iv) the ring A is 4- to 8-membered heterocyclyl, 5- to 6-membered heteroaryl, phenyl-D-C1-C3 alkyl or 4- to 8-membered heterocyclyl-D-C1-C3 alkyl, wherein the heterocyclyl, heteroaryl and phenyl can each be optionally substituted with 1-2 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of hydrogen, halogen, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, OR.sup.1A, NR.sup.1BR.sup.1C, NR BC(O)R.sup.1D, C(O)NR.sup.1BR.sup.1C, -G.sup.1, O-G.sup.1 and NR.sup.1B-G.sup.1; each of the R.sup.1A, R.sup.1B, R.sup.1C and R.sup.1D is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, halogen-substituted C1-C3 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4- to 6-membered heterocyclyl and halogen-substituted C1-C3 alkoxy; each of the G.sup.1 is independently selected from C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl and phenyl, wherein preferably, the C3-C6 cycloalkyl is cyclobutyl or cyclopentyl, and the 3- to 6-membered heterocyclyl is oxetanyl, azetidinyl, oxocyclopentyl or azacyclopentyl; each of the G.sup.1 is optionally substituted with 1-3 R.sup.1F; when G.sup.1 is phenyl, the phenyl and 5- to 6-membered heterocyclyl or 5- to 7-membered heteroaryl optionally share two carbon atoms to form a fused ring each of the R.sup.1F is independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C1-C3 alkenyl, oxo, OR.sup.11A, NR.sup.1BR.sup.1C, P(O)R.sup.1BR.sup.1C and S(O).sub.2R.sup.1D.

3-5. (canceled)

6. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the ring A is 5- to 6-membered heterocyclyl, preferably ##STR00378## or preferably ##STR00379## preferably, the number n of R.sup.1 is 1, 2 or 3; preferably, each of the R.sup.1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, C1-C3 alkyl and phenyl; and when R.sup.1 is phenyl, the phenyl and the 3- to 6-membered heterocyclyl share two carbon atoms to form a fused ring, preferably the phenyl and ##STR00380## share two carbon atoms to form a fused ring, and the phenyl is optionally substituted with halogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 haloalkoxy; further preferably, the fusion mode of the phenyl and ##STR00381## is ##STR00382## and the phenyl is optionally substituted with halogen; or the ring A is 5- to 6-membered heteroaryl, preferably any one of the following groups: (1) ##STR00383## wherein H.sup.1, H.sup.2, H.sup.3 and H.sup.4 are each independently C or a heteroatom, with at least one being a heteroatom, and preferably, the heteroatom is selected from any one of N, O and S; preferably, the R.sup.1 is selected from the group consisting of hydrogen, OR.sup.1A, NR.sup.1BR.sup.1C, -G.sup.1, O-G.sup.1 and NR.sup.1B-G.sup.1, wherein each of the R.sup.1A, R.sup.1B and R.sup.1C is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, halogen-substituted C1-C3 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4- to 6-membered heterocyclyl and halogen-substituted C1-C3 alkoxy; each of the G.sup.1 is independently selected from 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl and phenyl; each of the G.sup.1 is optionally substituted with 1-3 R.sup.1F; each of the R.sup.1F is independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkenyl, oxo, OR.sup.1A, NR.sup.1BR.sup.1C, P(O)R.sup.1BR.sup.1C and S(O).sub.2R.sup.1D, wherein the R.sup.1D is selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl and halogen-substituted C1-C3 alkoxy; or ##STR00384## wherein the ring A is 5-membered heteroaryl H.sup.1, H.sup.2, H.sup.3 and H.sup.4 are each independently selected from CH, N, O and S, and is a single bond or a double bond; each of the R.sup.1 is independently selected from the group consisting of OR.sup.1A, NR.sup.1BR.sup.1C, -G.sup.1, O-G.sup.1 and NR.sup.1B-G.sup.1; each of the R.sup.1A, R.sup.1B and R.sup.1C is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy-C1-C6 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4- to 6-membered heterocyclyl and halogen-substituted C1-C3 alkoxy; each of the G.sup.1 is independently selected from C4-C6 cycloalkyl and 4- to 9-membered heterocyclyl; each of the G.sup.1 is optionally substituted with 1-3 R.sup.1F; each of the R.sup.1F is independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkenyl, oxo, OR.sup.1A, NR.sup.1BR.sup.1C, P(O)R.sup.1BR.sup.1C and S(O).sub.2R.sup.1D, wherein the R.sup.1D is selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl and halogen-substituted C1-C3 alkoxy; preferably, the ring A is ##STR00385## further preferably, the L.sup.1 is null; preferably, the R.sup.1 is selected from OR.sup.1A, -G.sup.1, O-G.sup.1 and NR.sup.1B-G.sup.1; R.sup.1A is selected from halogen-substituted C1-C3 alkoxy-C1-C3 alkyl; R.sup.1B is selected from H and C1-C3 alkyl; each of the R.sup.1F is independently selected from the group consisting of halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkenyl, oxo, P(O)R.sup.1BR.sup.1C and S(O).sub.2R.sup.1D; R.sup.1B, R.sup.1C and R.sup.1D are each independently selected from the group consisting of hydrogen and C1-C3 alkyl; (2) ##STR00386## preferably, each R.sup.1 is independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy and phenyl, and when R.sup.1 is phenyl, the phenyl and ##STR00387## share two carbon atoms to form a fused ring, and the phenyl is optionally substituted with halogen, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 haloalkoxy; further preferably, the phenyl is optionally substituted with halogen; the number m of R.sup.1 is 1 or 2; (3) ##STR00388## preferably, the R.sup.1 is hydrogen, halogen or phenyl, wherein the phenyl is optionally substituted with 1 or more halogens, and the number m of R.sup.1 is 1 or 2; when R.sup.1 is phenyl, the phenyl and ##STR00389## optionally share two carbon atoms to form a fused ring; further preferably, the R.sup.1 is phenyl, m is 1, the fusion mode of the phenyl and ##STR00390## is ##STR00391## and the phenyl is optionally substituted with 1 or more halogens; or the ring A is phenyl-OC1-C3 alkyl, wherein the phenyl is optionally substituted with 1 or 2 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl and halogen-substituted C1-C3 alkoxy; preferably, the ring A is phenyl-O-methyl, and R.sup.1 is H or halogen; or the ring A is 4- to 8-membered heterocyclyl-OC1-C3 alkyl, wherein the heterocyclyl is optionally substituted with 1-3 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl and halogen-substituted C1-C3 alkoxy; preferably, the ring A is 4- to 7-membered heterocyclyl-O-methyl, and R.sup.1 is halogen-substituted C1-C3 alkyl or halogen-substituted C1-C3 alkoxy; or the ring A is C3-C7 cycloalkyl-OC1-C3 alkyl, wherein the C3-C7 cycloalkyl is optionally substituted with 1-3 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl and halogen-substituted C1-C3 alkoxy; preferably, the ring A is C4-C6 cycloalkyl-O-methyl, and R.sup.1 is halogen-substituted C1-C3 alkyl or halogen-substituted C1-C3 alkoxy; or the ring A is phenyl, wherein the phenyl is substituted with a group selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy; preferably, the phenyl is substituted with a group selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy; further preferably, the phenyl is substituted with C1-C3 haloalkyl; preferably, the ring A is selected from any one of the following groups: (1) ##STR00392## preferably, the R.sup.1 is selected from the group consisting of -G.sup.1, O-G.sup.1 and NR.sup.1B-G.sup.1, preferably each of the G.sup.1 is optionally substituted with 1 or 2 R.sup.1F; the R.sup.1B is selected from the group consisting of hydrogen and C1-C3 alkyl; each of the G.sup.1 is independently selected from C3-C6 cycloalkyl and 4- to 9-membered heterocyclyl; further preferably, the C3-C6 cycloalkyl is cyclobutyl or cyclopentyl; the 4- to 9-membered heterocyclyl is preferably oxocycloalkyl or azacycloalkyl, and further preferably oxetanyl, azetidinyl, oxocyclopentyl, azacyclopentyl, ##STR00393## further preferably oxetanyl, azetidinyl, oxocyclopentyl or azacyclopentyl, or further preferably ##STR00394## each of the R.sup.1F is independently selected from the group consisting of oxo, C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl and halogen-substituted C1-C3 alkoxy; moreover, the L.sup.1 is preferably null; (2) 4- to 8-membered heterocyclyl-OC1-C3 alkyl, wherein the heterocyclyl is optionally substituted with 1 or 2 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of halogen-substituted C1-C3 alkyl and halogen-substituted C1-C3 alkoxy; (3) C4-C6 cycloalkyl-OC1-C3 alkyl, wherein the C4-C6 cycloalkyl is optionally substituted with 1 or 2 R.sup.1; each of the R.sup.1 is independently selected from halogen-substituted C1-C3 alkyl and halogen-substituted C1-C3 alkoxy.

7. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the ring A is selected from any one of the following groups: ##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399## preferably, ring A is selected from any one of the following groups: ##STR00400## preferably, ring A is selected from any one of the following groups: ##STR00401## preferably, ring A is selected from any one of the following groups: ##STR00402##

8. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the spiro ring is selected from any one of the following groups: a spiro[2,5]octyl ring, a spiro[3,4]octyl ring, a spiro[3,3]heptyl ring, a spiro[3,5]nonyl ring, a spiro[4,5]decyl ring, a spiro[2,2]pentyl ring, a spiro[2,3]hexyl ring, a spiro[2,4]heptyl ring, a spiro[2,6]nonyl ring, a spiro[2,7]nonyl ring, a spiro[3,6]nonyl ring and a spiro[4,4]nonyl ring; and the spiro heterocyclic ring is a group formed by substituting any one or more carbon atoms in the spiro ring with a heteroatom(s), wherein the number of heteroatoms in the spiro heterocyclic ring is 1, 2 or 3; preferably, the heteroatom in the spiro heterocyclic ring is nitrogen, or a combination of nitrogen and oxygen; preferably, the substituent R.sup.1F of the spiro ring or the spiro heterocyclic ring is hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C3-C9 cycloalkyl, hydroxyl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl or halogen-substituted C1-C6 alkoxy; more preferably, the substituent R.sup.1F of the spiro ring or the spiro heterocyclic ring is halogen, hydroxyl or amino; most preferably, the substituent R.sup.1F of the spiro ring or the spiro heterocyclic ring is hydroxyl.

9. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 8, wherein the ring B is a 7- to 9-membered spiro ring or a 7- to 9-membered spiro heterocyclic ring; preferably, the spiro ring is selected from any one of the following groups: a spiro[2,5]octyl ring, a spiro[3,4]octyl ring, a spiro[3,3]heptyl ring and a spiro[3,5]nonyl ring; the 7- to 9-membered spiro heterocyclic ring is a group formed by substituting any one or more carbon atoms in the 7- to 9-membered spiro ring with a heteroatom(s), wherein the number of heteroatoms in the spiro heterocyclic ring is 1, 2 or 3; preferably, the heteroatom in the spiro heterocyclic ring is nitrogen, or a combination of nitrogen and oxygen; preferably, the ring B is selected from any one of the following groups: ##STR00403## wherein the end is connected to L.sup.1, and the * end is connected to L.sup.2; preferably, the ring B is selected from any one of the following groups: ##STR00404## further preferably, the ring B is selected from any one of the following groups: ##STR00405## further preferably, the ring B is selected from any one of the following groups: ##STR00406##

10. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the ring C is 6- to 10-membered aryl-E-C1-C3 alkyl, C4-C9 cycloalkyl-E-C1-C3 alkyl, 4- to 9-membered heterocyclyl-E-C1-C3 alkyl, 4- to 9-membered heterocyclyl, 5- to 10-membered heteroaryl or 6- to 10-membered aryl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl can each be optionally substituted with 1-3 R.sup.2; each of the R.sup.2 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, phenyl, C1-C3 alkyl and C1-C3 alkoxy, wherein with regard to options for the R.sup.2, the phenyl, C1-C3 alkyl and C1-C3 alkoxy are each optionally substituted with halogen; or 2 R.sup.2 groups on adjacent atoms taken together with the atoms to which they are attached can form C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl; the C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl is each optionally substituted with 1-5 R.sup.1F; when R.sup.2 is phenyl, the phenyl and 4- to 9-membered heterocyclyl or 5- to 10-membered heteroaryl optionally share two carbon atoms to form a fused ring; each of the E is independently a linking group containing a heteroatom; preferably, each of the E is independently O or NR.sup.d or S, wherein each R.sup.d is independently selected from hydrogen, deuterium and C1-C3 alkyl; more preferably, each of the E is independently O or NH.

11. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the ring C is phenyl-E-C1-C3 alkyl, wherein the phenyl is substituted with 1, 2 or 3 R.sup.2, and the E is a linking group containing a heteroatom(s); preferably, the E is O or NR.sup.d or S, and R.sup.d is selected from hydrogen, deuterium and C1-C3 alkyl; preferably, the E is O or NH; preferably, each of the R.sup.2 is independently halogen; preferably, the ring C is phenyl-OC1-C3 alkyl; or the ring C is C4-C9 cycloalkyl-E-C1-C3 alkyl or 4- to 9-membered heterocyclyl-E-C1-C3 alkyl, wherein the cycloalkyl or heterocyclyl is substituted with R.sup.2; the E is O or NR.sup.d or S, and R.sup.d is selected from hydrogen, deuterium and C1-C3 alkyl; the R.sup.2 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy; preferably, the cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl; preferably, the heterocyclyl is oxiranyl, oxetanyl, oxocyclopentyl, aziridinyl, azetidinyl or azacyclopentyl; preferably, the E is O or NH; or the ring C is 4- to 9-membered heterocyclyl, preferably 5- to 6-membered heterocyclyl; preferably, the ring C is ##STR00407## wherein the number n of the R.sup.2 is 1 or 2 or 3; preferably, each of the R.sup.2 is independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, phenyl, halophenyl and hydroxyl; when the R.sup.2 is phenyl or halophenyl, the phenyl or halophenyl and ##STR00408## optionally share two carbon atoms to form a fused ring, wherein the fusion mode is preferably ##STR00409## preferably, the ring C is ##STR00410## wherein the number n of the R.sup.2 is 1 or 2 or 3; preferably, each of the R.sup.2 is independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, phenyl and halophenyl; when the R.sup.2 is a substituent on an N atom, the R.sup.2 is selected from the group consisting of hydrogen, halogen and C1-C3 alkyl; when the R.sup.2 is phenyl or halophenyl, the phenyl or the halophenyl and morpholinyl optionally share two carbon atoms to form a fused ring, wherein the fusion mode is preferably ##STR00411## preferably, the ring C is ##STR00412## wherein the number n of the R.sup.2 is 1 or 2 or 3; preferably, each of the R.sup.2 is independently selected from the group consisting of halogen, phenyl, halophenyl and hydroxyl; when the R.sup.2 is phenyl or halophenyl, the phenyl or the halophenyl and ##STR00413## optionally share two carbon atoms to form a fused ring, wherein the fusion mode is preferably ##STR00414## or the ring C is 5- to 10-membered heteroaryl, and preferably, the ring C is any one of the following 5- to 10-membered heteroaryl groups: (1) ##STR00415## preferably, each R.sup.2 is independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl and halophenyl, wherein the number p of the R.sup.2 is 1 or 2; and when the R.sup.2 is phenyl or halophenyl, the phenyl or halophenyl and ##STR00416## share two carbon atoms to form a fused ring, wherein the fusion mode is preferably ##STR00417## respectively; (2) ##STR00418## preferably, the R.sup.2 is selected from the group consisting of hydrogen, halogen, phenyl, C1-C3 alkyl and C1-C3 alkoxy-C3-C6 cycloalkyl; the phenyl, the alkyl and the alkoxy are unsubstituted or substituted with halogen; when the R.sup.2 is phenyl, the phenyl and ##STR00419## optionally share two carbon atoms to form a fused ring, wherein the fusion mode is preferably ##STR00420## of the ring C is phenyl; the phenyl is substituted with R.sup.2; preferably, the R.sup.2 is selected from the group consisting of C1-C3 haloalkyl and C1-C3 haloalkoxy.

12. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1 wherein the ring C is selected from any one of the following groups: ##STR00421## ##STR00422## ##STR00423## preferably, the ring C is selected from any one of the following groups: ##STR00424## ##STR00425## preferably, the ring C is selected from any one of the following groups: ##STR00426## preferably, the ring C is selected from any one of the following groups: ##STR00427## preferably, the ring C is selected from any one of the following groups: ##STR00428##

13. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure as shown in formula I: ##STR00429## preferably ring A is 3- to 9-membered heterocyclyl, 5- to 10-membered heteroaryl, 6- to 10-membered aryl-D-C1-C6 alkyl or 5- to 10-membered heteroaryl-D-C1-C6 alkyl, wherein the heterocyclyl, aryl and heteroaryl can each be optionally substituted with 1-5 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of halogen, C1-C10 alkyl, hydroxyl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, -G.sup.1 and O-G.sup.1; or 2 R.sup.1 groups on adjacent atoms taken together with the atoms to which they are attached can form C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 10-membered aryl or 5- to 6-membered heteroaryl; the C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 10-membered aryl or 5- to 6-membered heteroaryl is each optionally substituted with 1-5 R.sup.1F1; each of the G.sup.1 is independently selected from C3-C9 cycloalkyl, 3- to 9-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; each of the G.sup.1 is optionally substituted with 1-3 R.sup.1F1; each of the R.sup.1F1 and R.sup.1F2 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, C1-C6 alkyl, C3-C9 cycloalkyl, hydroxyl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl and halogen-substituted C1-C6 alkoxy; preferably, each of the R.sup.1F2 is independently selected from hydrogen, halogen, hydroxyl and amino; L.sup.2 is null, NH, ##STR00430## wherein the end is connected to ring B, the * end is connected to ring C, and preferably, the end is connected to the N atom in ##STR00431## in formula I; preferably, the L.sup.2 is null, NH, ##STR00432## preferably, the L.sup.2 is null, ##STR00433## preferably, the L.sup.2 is null, ##STR00434## preferably the L.sup.2 is ##STR00435## preferably, the L.sup.2 is null, ##STR00436## ring C is 6- to 10-membered aryl-E-C1-C6 alkyl, 3- to 9-membered heterocyclyl, 5- to 10-membered heteroaryl or 6- to 10-membered aryl; the aryl, heteroaryl and heterocyclyl can each be optionally substituted with 1-3 R.sup.2; each of the R.sup.2 is independently selected from the group consisting of halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C3 alkoxy-C1-C6 alkyl, wherein with regard to options for the R.sup.2, the phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in the C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl and C1-C3 alkoxy in the C1-C3 alkoxy-C3-C6 cycloalkyl are each optionally substituted with halogen; when R.sup.2 is phenyl, the phenyl and 3- to 9-membered heterocyclyl or 6- to 10-membered heteroaryl optionally share two carbon atoms to form a fused ring; each of the D or E is independently a linking group containing a heteroatom; preferably, each of the D or E is independently O or NR.sup.d or S, wherein each R.sup.d is independently selected from hydrogen, deuterium, C1-C6 alkyl and halogen-substituted C1-C6 alkyl; more preferably, each of the D or E is independently O or NH.

14. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure as shown in formula II or formula III: ##STR00437## preferably, each of the ring A is independently 5- to 7-membered heteroaryl, phenyl-D-C1-C6 alkyl or 3- to 9-membered heterocyclyl, wherein the heteroaryl and phenyl can each be optionally substituted with 1 or 2 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of halogen, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, OR.sup.1A, NR.sup.1BR.sup.1C, -G.sup.1, O-G.sup.1 and NR.sup.1B-G.sup.1; each of the R.sup.1A, R.sup.1B, R.sup.1C and R.sup.1D is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, 4- to 9-membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C4-C9 cycloalkyl, halogen-substituted 4- to 9-membered heterocyclyl and halogen-substituted C1-C6 alkoxy; each of the G.sup.1 is independently selected from C3-C9 cycloalkyl, 3- to 9-membered heterocyclyl and phenyl; each of the G.sup.1 is optionally substituted with 1-3 R.sup.1F1; when G.sup.1 is phenyl, the phenyl and 3- to 9-membered heterocyclyl or 5- to 7-membered heteroaryl optionally share two carbon atoms to form a fused ring; each of the R.sup.1F1 is independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C9 cycloalkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C6 alkenyl, oxo, OR.sup.1A, NR.sup.1BR.sup.1C, P(O)R.sup.1BR.sup.1C and S(O).sub.2R.sup.1D; L.sup.1 is null, NH, ##STR00438## wherein the end is connected to ring A, and the * end is connected to ring B; preferably, the * end is connected to the &C atom in ##STR00439## in formula II or the &C atom in ##STR00440## in formula III; preferably, the L.sup.1 is null, NH, ##STR00441## preferably, the L.sup.1 is null ##STR00442## preferably, the L.sup.1 is null ##STR00443## further preferably, the L.sup.1 is null ##STR00444## L.sup.2 is null, NH, ##STR00445## wherein the end is connected to ring B, and the * end is connected to ring C; preferably, the end is connected to the N atom in ##STR00446## in formula II or the @C atom in ##STR00447## in formula III; preferably, the L.sup.2 is null, NH, ##STR00448## preferably, the L.sup.2 is null, ##STR00449## preferably, in the formula II, the L.sup.2 is ##STR00450## more preferably ##STR00451## preferably, in the formula III, the L.sup.2 is null, ##STR00452## more preferably is null or ##STR00453## each of the R.sup.1F2 is independently selected from hydrogen, halogen, hydroxyl and amino; preferably, each of the R.sup.1F2 is independently selected from hydrogen and hydroxyl; the ring C is selected from 6- to 10-membered aryl-E-C1-C3 alkyl, C4-C9 cycloalkyl-E-C1-C3 alkyl, 4- to 9-membered heterocyclyl-E-C1-C3 alkyl, 4- to 9-membered heterocyclyl, 5- to 10-membered heteroaryl or 6- to 10-membered aryl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl can each be optionally substituted with 1-3 R.sup.2; each of the R.sup.2 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, phenyl, C1-C3 alkyl and C1-C3 alkoxy, wherein with regard to options for the R.sup.2, the phenyl, C1-C3 alkyl and C1-C3 alkoxy are each optionally substituted with halogen; or 2 R.sup.2 groups on adjacent atoms taken together with the atoms to which they are attached can form C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl; the C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl is each optionally substituted with 1-5 R.sup.1F; when R.sup.2 is phenyl, the phenyl and 4- to 9-membered heterocyclyl or 5- to 10-membered heteroaryl optionally share two carbon atoms to form a fused ring; each of the E is independently a linking group containing a heteroatom; preferably, each of the E is independently O or NR.sup.d or S, wherein each R.sup.d is independently selected from hydrogen, deuterium and C1-C3 alkyl; more preferably, each of the E is independently O or NH.

15. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure as shown in formula IV: ##STR00454## preferably, the ring A is 4- to 8-membered heterocyclyl, 5- to 7-membered heteroaryl, phenyl-OC1-C6 alkyl or C4-C8 cycloalkyl-OC1-C6 alkyl, wherein the heterocyclyl, heteroaryl, phenyl and cycloalkyl can each be optionally substituted with 1-2 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of halogen, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, OR.sup.1A, NR.sup.1BR.sup.1C, -G.sup.1, O-G.sup.1 and NR.sup.1B-G.sup.1; each of the R.sup.1A, R.sup.1B, R.sup.1C and R.sup.1D is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4- to 6-membered heterocyclyl and halogen-substituted C1-C3 alkoxy; each of the G.sup.1 is independently selected from C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl and phenyl; each of the G.sup.1 is optionally substituted with 1-3 R.sup.1F1; when G.sup.1 is phenyl, the phenyl and 5- to 6-membered heterocyclyl or 5- to 7-membered heteroaryl optionally share two carbon atoms to form a fused ring; each of the R.sup.1F1 is independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C1-C3 alkenyl, oxo, OR.sup.1A, NR.sup.1BR.sup.1C, P(O)R.sup.1BR.sup.1C and S(O).sub.2R.sup.1D; each of the R.sup.1F2 is independently selected from hydrogen, halogen, hydroxyl and amino; preferably, each of the R.sup.1F2 is independently selected from hydrogen and hydroxyl; L.sup.1 is null, NH, ##STR00455## wherein the end is connected to ring A, and the * end is connected to ring B; preferably, the * end is connected to the N atom in ##STR00456## in formula IV; preferably, the L.sup.1 is null, NH, ##STR00457## preferably, the L.sup.1 is null, ##STR00458## preferably, the L.sup.1 is null, ##STR00459## L.sup.2 is null, NH, ##STR00460## wherein the end is connected to ring B, and the * end is connected to ring C; preferably, the end is connected to the @C atom in ##STR00461## in formula IV; preferably, the L.sup.2 is null, NH, ##STR00462## preferably, the L.sup.2 is null, ##STR00463## further preferably, the L.sup.2 is ##STR00464## the ring C is 6- to 10-membered aryl-OC1-C3 alkyl, C4-C9 cycloalkyl-OC1-C3 alkyl, 4- to 9-membered heterocyclyl-OC1-C3 alkyl, 4- to 9-membered heterocyclyl, 5- to 10-membered heteroaryl or 6- to 10-membered aryl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl can each be optionally substituted with 1-3 R.sup.2; each of the R.sup.2 is independently selected from the group consisting of halogen, hydroxyl, phenyl, C1-C3 alkyl and C1-C3 alkoxy, wherein with regard to options for the R.sup.2, the phenyl, C1-C3 alkyl and C1-C3 alkoxy are each optionally substituted with halogen; or 2 R.sup.2 groups on adjacent atoms taken together with the atoms to which they are attached can form C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl; the C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl is each optionally substituted with 1-5 R.sup.1F1; when R.sup.2 is phenyl, the phenyl and 4- to 9-membered heterocyclyl or 5- to 10-membered heteroaryl optionally share two carbon atoms to form a fused ring.

16. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure as shown in formula V: ##STR00465## preferably, the ring A is 4- to 8-membered heterocyclyl, 5- to 7-membered heteroaryl or phenyl-OC1-C6 alkyl, wherein the heterocyclyl, heteroaryl and phenyl can each be optionally substituted with 1-2 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of halogen, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, OR.sup.1A, NR.sup.1BR.sup.1C, -G.sup.1, O-G.sup.1 and NR.sup.1B-G.sup.1; each of the R.sup.1A, R.sup.1B, R.sup.1C and R.sup.1D is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4- to 6-membered heterocyclyl and halogen-substituted C1-C3 alkoxy; each of the G.sup.1 is independently selected from C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl and phenyl; each of the G.sup.1 is optionally substituted with 1-3 R.sup.1F1; when G.sup.1 is phenyl, the phenyl and 5- to 6-membered heterocyclyl or 5- to 7-membered heteroaryl optionally share two carbon atoms to form a fused ring; each of the R.sup.1F1 is independently selected from the group consisting of halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C1-C3 alkenyl, oxo, OR.sup.1A, NR.sup.1BR.sup.1C, P(O) R.sup.1BR.sup.1C and S(O).sub.2R.sup.1D; L.sup.1 is null, NH, ##STR00466## wherein the end is connected to ring A, and the * end is connected to ring B; preferably, the * end is connected to the N atom in ##STR00467## in formula V; preferably, the L.sup.1 is null, NH, ##STR00468## preferably, the L.sup.1 is null, ##STR00469## preferably, the L.sup.1 is ##STR00470## each R.sup.1F2 is independently selected from hydrogen, halogen, hydroxyl and amino; preferably, each of the R.sup.1F2 is independently selected from hydrogen and hydroxyl; L.sup.2 is null, NH, ##STR00471## wherein the end is connected to ring B, and the * end is connected to ring C; preferably, the end is connected to the @C atom in ##STR00472## in formula V; preferably, the L.sup.2 is null, NH, ##STR00473## preferably, the L.sup.2 is null, ##STR00474## preferably, the L.sup.2 is ##STR00475## the ring C is 6- to 10-membered aryl-OC1-C3 alkyl, 4- to 9-membered heterocyclyl-OC1-C3 alkyl, 4- to 9-membered heterocyclyl, 5- to 10-membered heteroaryl or 6- to 10-membered aryl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl can each be optionally substituted with 1-3 R.sup.2; each of the R.sup.2 is independently selected from the group consisting of halogen, hydroxyl, phenyl, C1-C3 alkyl and C1-C3 alkoxy, wherein with regard to options for the R.sup.2, the phenyl, C1-C3 alkyl and C1-C3 alkoxy are each optionally substituted with halogen; or 2 R.sup.2 groups on adjacent atoms taken together with the atoms to which they are attached can form C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl; the C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl is each optionally substituted with 1-5 R.sup.1F1; when R.sup.2 is phenyl, the phenyl and 4- to 9-membered heterocyclyl or 5- to 10-membered heteroaryl optionally share two carbon atoms to form a fused ring.

17. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure as shown in formula VI, formula VII, formula VIII or formula IX: ##STR00476## preferably, the ring A is 3- to 9-membered heterocyclyl, 5- to 10-membered heteroaryl, 6- to 10-membered aryl-D-C1-C6 alkyl, 5- to 10-membered heteroaryl-D-C1-C6 alkyl or 3- to 9-membered heterocyclyl-D-C1-C6 alkyl, wherein the heterocyclyl, heteroaryl and aryl can be optionally substituted with 1-5 R.sup.1; each of the R.sup.1 is independently selected from the group consisting of halogen, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, OR.sup.1A, NR.sup.1BR.sup.1C, -G.sup.1, O-G.sup.1 and NR.sup.1B-G.sup.1; each of the R.sup.1A, R.sup.1B, R.sup.1C and R.sup.1D is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4- to 6-membered heterocyclyl and halogen-substituted C1-C3 alkoxy; each of the G.sup.1 is independently selected from C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl and phenyl; each of the G.sup.1 is optionally substituted with 1-3 R.sup.1F1; when G.sup.1 is phenyl, the phenyl and 5- to 6-membered heterocyclyl or 5- to 7-membered heteroaryl optionally share two carbon atoms to form a fused ring; each of the R.sup.1F1 is independently selected from the group consisting of halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C1-C3 alkenyl, oxo, OR.sup.1A, NR.sup.1BR.sup.1C, P(O) R.sup.1BR.sup.1C and S(O).sub.2R.sup.1D; further preferably, the ring A is 5- to 7-membered heteroaryl, wherein the heteroaryl can be substituted with 1-2 R.sup.1; L.sup.1 is null, NH, ##STR00477## wherein the end is connected to ring A, and the * end is connected to ring B; preferably, the * end is connected to the &C atom in ##STR00478## in formula VI, the &C atom in ##STR00479## in formula VII, the &C atom in ##STR00480## in formula VIII or the &C atom in ##STR00481## in formula IX; preferably, the L.sup.1 is null, NH, ##STR00482## preferably, the L.sup.1 is null, ##STR00483## L.sup.2 is null, NH, ##STR00484## wherein the end is connected to ring B, and the * end is connected to ring C; preferably, the end is connected to the @C atom in ##STR00485## in formula VI, the @C atom in ##STR00486## in formula VII, the @C atom in ##STR00487## in formula VIII or the @C atom in ##STR00488## in formula IX; preferably, the L.sup.2 is null, NH, ##STR00489## preferably, the L.sup.2 is null, ##STR00490## each of the R.sup.1F2 is independently selected from hydrogen, halogen, hydroxyl, amino and carboxyl; preferably, each of the R.sup.1F2 is independently selected from hydrogen and hydroxyl; the ring C is 6- to 10-membered aryl-E-C1-C6 alkyl, C3-C9 cycloalkyl-E-C1-C6 alkyl, 3- to 9-membered heterocyclyl-E-C1-C6 alkyl, 3- to 9-membered heterocyclyl, 5- to 10-membered heteroaryl or 6- to 10-membered aryl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl can each be optionally substituted with 1-3 R.sup.2; each of the R.sup.2 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl and C1-C3 alkoxy-3- to 6-membered heterocyclyl, wherein with regard to options for the R.sup.2, the phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in the C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in the C1-C3 alkoxy-C3-C6 cycloalkyl and C1-C3 alkoxy in the C1-C3 alkoxy-3- to 6-membered heterocyclyl are each optionally substituted with halogen; or 2 R.sup.2 groups on adjacent atoms taken together with the atoms to which they are attached can form C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl; the C3-C7 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl is each optionally substituted with 1-5 R.sup.1F; each of the D or E is independently a linking group containing a heteroatom; preferably, each of the D or E is independently O or NR.sup.d or S, wherein each R.sup.d is independently selected from hydrogen, deuterium and C1-C3 alkyl; more preferably, each of the D or E is independently O or NH.

18. The compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is specifically: ##STR00491## ##STR00492## ##STR00493## ##STR00494## ##STR00495## ##STR00496## ##STR00497## ##STR00498## ##STR00499## ##STR00500## ##STR00501## ##STR00502## ##STR00503## ##STR00504## ##STR00505## ##STR00506## ##STR00507## ##STR00508## ##STR00509## ##STR00510## ##STR00511## ##STR00512## ##STR00513## ##STR00514## ##STR00515## ##STR00516## ##STR00517## ##STR00518## ##STR00519## ##STR00520## ##STR00521## ##STR00522## ##STR00523## ##STR00524## ##STR00525## ##STR00526## ##STR00527## ##STR00528## ##STR00529## ##STR00530## ##STR00531##

19. A pharmaceutical composition comprising a preparation prepared from the compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1, optionally further comprising a pharmaceutically acceptable carrier, excipient and vehicle.

20-22. (canceled)

23. A method for treating a disease or condition mediated by an integrated stress response (ISR) pathway in an individual in need thereof, wherein the method comprises administering a therapeutically effective amount of the compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1 to the individual.

24. A method for treating a disease related to regulation of eIF2B activity or level, eIF2 pathway activity or level or ISR pathway activity or level, wherein the method comprises administering a therapeutically effective amount of the compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1 to a subject.

25. A method for preventing and/or treating a disease or condition mediated by an integrated stress response (ISR) pathway, wherein the method comprises administering an effective amount of the compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1 to a subject in need thereof.

26. A method for preventing and/or treating cancer, wherein the method comprises administering an effective amount of the compound, or the stereoisomer thereof, the tautomer thereof, the geometric isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the polymorph thereof, the solvate thereof, the hydrate thereof, the N-oxide thereof, the isotopically labeled compound thereof, the metabolite thereof, the ester thereof, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 1 to a subject in need thereof.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

[0425] The known starting materials of the present disclosure can be synthesized by or in accordance with methods known in the art, or can be purchased from Bidepharm, Energy Chemical, Tansoole, PharmaBlock Sciences (Nanjing), Inc., Jiangsu Aikon Biopharmaceutical R&D Co., Ltd., Innochem (Beijing) Technology Co., Ltd., etc. Among them, tetrapropylammonium perruthenate is purchased from Tansoole, and 1-propylphosphonic anhydride is purchased from Innochem (Beijing) Technology Co., Ltd.

[0426] Unless otherwise specified in the examples, the reactions are carried out under nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. The optimal reaction temperature is room temperature, which ranges from 20 C.-30 C. Unless otherwise specified in the examples, M represents mole per liter.

[0427] The structures of the compounds are determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR shift (5) is given in the unit of 10.sup.6 (ppm). NMR is determined by using a nuclear magnetic resonance spectrometer Bruker Avance III 400. The solvents for determination are deuterated dimethyl sulfoxide (DMSO-d.sub.6), deuterated chloroform (CDCl.sub.3), and deuterated methanol (Methanol-d.sub.4), and the internal standard is tetramethylsilane (TMS). LC-MS is determined by using Shimadzu LC-MS 2020 (ESI). HPLC is determined by using a high-pressure liquid chromatograph Shimadzu LC-20A. MPLC (medium-pressure liquid chromatography) is performed using a reverse-phase preparative chromatograph Gilson GX-281. Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate is used as a thin layer chromatography silica plate, and the specification when a product is separated and purified by thin layer chromatography is 0.4 mm-0.5 mm. 200-300 mesh Yantai Huanghai silica gel is generally used as a carrier for the column chromatography.

[0428] N,N-diisopropylethylamine (also known as diisopropylethylamine) is abbreviated as DIEA or DIPEA; 2-(7-azabenzotriazol)-N,N,N,N-tetramethyluronium hexafluorophosphate is abbreviated as HATU; tetrapropylammonium perruthenate is abbreviated as TPAP; 1-propylphosphonic anhydride is abbreviated as T3P; N-methylmorpholine-N-oxide is abbreviated as NMO; trifluoroacetic acid is abbreviated as TFA; dimethylformamide is abbreviated as DMF; dichloromethane is abbreviated as DCM; petroleum ether is abbreviated as PE.

Example 1: Synthesis of Compound I-1

##STR00292##

Step 1: Synthesis of Intermediate 1b

[0429] To a mixed solution of tetrahydrofuran (40 mL), methanol (20 mL) and water (10 mL) were added starting material 1a (10 g, 42.98 mmol) and lithium hydroxide (5.97 mL, 214.92 mmol), and the reaction was stirred at 25 C. for 18 hours. Then, the resulting reaction mixture was adjusted to pH=7 with dilute hydrochloric acid (1 M) and extracted with ethyl acetate (100 mL3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate 1b.

[0430] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 13.21 (s, 1H), 7.47 (t, J=8.9 Hz, 1H), 7.07 (dd, J=11.5, 2.9 Hz, 1H), 6.87-6.76 (m, 1H), 4.73 (s, 2H).

Step 2: Synthesis of Intermediate 1d

[0431] To N,N-dimethylformamide (5 mL) were added intermediate 1b (100 mg, 0.49 mmol), intermediate 1c (0.11 mL, 0.54 mmol, Bidepharm, BD215605), HATU (278.80 mg, 0.73 mmol) and DIPEA (0.24 mL, 1.47 mmol), and the reaction was stirred at 25 C. for 1 hour. The resulting reaction mixture was quenched with a saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (dichloromethane:methanol=20:1) to obtain intermediate 1d. MS m/z: 357.2[M+H56].sup.+.

[0432] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.25 (t, J=8.6 Hz, 1H), 6.67 (dd, J=10.3, 2.9 Hz, 1H), 6.61-6.56 (m, 1H), 6.35 (s, 1H), 4.40 (s, 2H), 3.40-3.26 (m, 4H), 2.65-2.59 (m, 1H), 1.39 (s, 9H), 1.31 (dd, J=7.0, 4.3 Hz, 4H), 0.83 (dd, J=7.9, 5.8 Hz, 1H), 0.41 (d, J=5.8, 4.3 Hz, 1H).

Step 3: Synthesis of Intermediate 1e

[0433] To dichloromethane (5 mL) were added intermediate 1d (150 mg, 0.36 mmol) and trifluoroacetic acid (1 mL), and the reaction was stirred at 25 C. for 1 hour. The mixture was concentrated to dryness under reduced pressure to obtain intermediate 1e.

[0434] MS m/z: 313.2 [M+H].sup.+.

[0435] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.40 (s, 1H), 7.28 (d, J=8.7 Hz, 1H), 6.76 (s, 1H), 6.69 (dd, J=10.1, 2.8 Hz, 1H), 6.62-0.658 (m, 1H), 4.48 (s, 2H), 2.67-2.61 (m, 1H), 1.93 (d, J=11.7 Hz, 2H), 1.48 (s, 2H), 1.32-1.16 (m, 4H), 0.99 (dd, J=8.0, 6.3 Hz, 1H), 0.64 (t, J=5.5 Hz, 1H).

Step 4: Synthesis of Compound I-1

[0436] To N,N-dimethylformamide (2 mL) were added intermediate 1e (30 mg, 0.10 mmol), starting material if (0.01 mL, 0.11 mmol), HATU (54.71 mg, 0.14 mmol) and DIPEA (0.05 mL, 0.29 mmol), and the reaction was stirred at 25 C. for 1 hour. The resulting reaction mixture was quenched with a saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (eluent: petroleum ether:ethyl acetate=1:5) to obtain compound I-1.

[0437] MS m/z: 469.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.96 (d, J=3.9 Hz, 2H), 8.23 (dd, J=21.7, 4.1 Hz, 1H), 7.55-7.40 (m, 1H), 7.34-6.97 (m, 2H), 6.88-6.77 (m, 1H), 4.58 (d, J=19.6 Hz, 2H), 3.99-3.79 (m, 1H), 3.54-3.39 (m, 1H), 3.30-3.03 (m, 2H), 2.64-2.54 (m, 1H), 1.63-1.41 (m, 2H), 1.27 (d, J=43.9, 15.8 Hz, 2H), 0.83-0.74 (m, 1H), 0.68-0.59 (m, 1H).

Example 2: Synthesis of Compound 1-2

##STR00293##

Step 1: Synthesis of Compound 1-2

[0438] To N,N-dimethylformamide (2 mL) were added intermediate 1e (30 mg, 0.10 mmol), starting material 2a (0.01 mL, 0.11 mmol), HATU (54.71 mg, 0.14 mmol) and DIPEA (0.05 mL, 0.29 mmol), and the reaction was stirred at 25 C. for 2 hours. The resulting reaction mixture was quenched with a saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL3) to obtain the organic phase. The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (eluent: dichloromethane:methanol=20:1) to obtain compound I-2.

[0439] MS m/z: 491.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.24 (d, J=4.0 Hz, 1H), 7.81 (d, J=2.2 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.8, 2.3 Hz, 2H), 7.31 (s, 1H), 7.04 (dd, J=11.6, 2.9 Hz, 1H), 6.84 (dd, J=9.5, 2.6 Hz, 1H), 4.59 (s, 2H), 3.95-3.43 (m, 3H), 3.31 (s, 1H), 2.64-2.57 (m, 1H), 1.53 (d, J=10.3 Hz, 2H), 1.30 (d, J=12.0 Hz, 2H), 0.79 (dd, J=8.1, 5.4 Hz, 1H), 0.65 (t, J=5.0 Hz, 1H).

Example 3: Synthesis of Compound 1-3

##STR00294##

Step 1: Synthesis of Intermediate 3b

[0440] To dichloromethane (5 mL) were added starting material 3a (80 mg, 0.27 mmol), tetrapropylammonium perruthenate (18.76 mg, 0.05 mmol) and NMO (187.60 mg, 1.60 mmol), and the reaction was stirred at 25 C. for 2 hours. The resulting reaction mixture was concentrated to dryness under reduced pressure to obtain intermediate 3b.

[0441] MS m/z: 312.1 [MH].sup..

Step 2: Synthesis of Intermediate 3c

[0442] To N,N-dimethylformamide (2 mL) were added intermediate 3b (50 mg, 0.16 mmol), intermediate 1e (49.85 mg, 0.16 mmol), HATU (90.90 mg, 0.24 mmol) and DIPEA (0.08 mL, 0.48 mmol), and the reaction was stirred at 25 C. for 2 hours. The resulting reaction mixture was quenched with a saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL3) to obtain the organic phase. The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (eluent: petroleum ether:ethyl acetate=1:5) to obtain intermediate 3c.

[0443] MS m/z: 508.2 [M+H100].sup.+.

Step 3: Synthesis of Compound 1-3

[0444] To dichloromethane (5 mL) were added intermediate 3c (50 mg, 0.08 mmol) and trifluoroacetic acid (1 mL), and the reaction was stirred at 25 C. for 1 hour. The resulting reaction mixture was concentrated to dryness under reduced pressure to obtain a crude. Sodium bicarbonate (100 mg) was added to the crude, and the reaction was stirred at 25 C. for 1 hour. The resulting mixture was filtered. The filter cake was washed with dichloromethane (20 mL3), and the filtrate was concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (eluent: dichloromethane:methanol=20:1) to obtain compound I-3.

[0445] MS m/z: 508.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.21 (s, 1H), 7.49 (t, J=8.9 Hz, 1H), 7.03 (d, J=10.4 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.67 (d, J=9.5 Hz, 1H), 6.58 (d, J=2.5 Hz, 1H), 6.45 (dd, J=8.5, 2.5 Hz, 1H), 6.18 (s, 1H), 4.87 (d, J=11.3 Hz, 1H), 4.58 (d, J=3.9 Hz, 2H), 3.87-3.52 (m, 2H), 3.45-3.35 (m, 2H), 2.63-2.55 (m, 1H), 1.31 (m, 6H), 0.76 (d, J=6.9 Hz, 1H), 0.61 (t, J=5.2 Hz, 1H).

Example 4: Synthesis of Compound 1-4

##STR00295##

Step 1: Synthesis of Compound 1-4

[0446] To acetonitrile (3 mL) were added compound I-3 (30 mg, 0.06 mmol), dimethyl sulfate (0.01 mL, 0.12 mmol) and potassium carbonate (24.47 mg, 0.18 mmol), and the mixture was degassed and subjected to nitrogen replacement 3 time. The reaction was stirred at 70 C. for 18 hours. The resulting reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL3) to obtain the organic phase. The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (eluent: dichloromethane:methanol=40:1) to obtain compound I-4.

[0447] MS m/z: 522.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.21 (s, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.03 (d, J=9.8 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.74-6.64 (m, 2H), 6.59-6.53 (m, 1H), 5.08 (d, J=12.3 Hz, 1H), 4.58 (d, J=3.6 Hz, 2H), 3.62 (m, 2H), 3.32-3.24 (m, 2H), 2.86 (q, J=1.8 Hz, 3H), 2.58 (s, 1H), 1.47-1.11 (m, 6H), 0.76 (s, 1H), 0.62 (s, 1H).

Example 5: Synthesis of Compound 1-5

##STR00296##

Step 1: Synthesis of Intermediate 5a

[0448] To a mixed solution of water (3 mL) and glacial acetic acid (6 mL) were added intermediate 1e (100 mg, 0.32 mmol) and sodium nitrite (0.07 mL, 1.28 mmol), and the reaction was stirred at 25 C. for 18 hours. The resulting reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL3) to obtain the organic phase. The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain intermediate 5a. MS m/z: 341.8 [M+H].sup.+.

Step 2: Synthesis of Intermediate 5b

[0449] To a mixed solution of tetrahydrofuran (2 mL) and water (2 mL) were added intermediate 5a (100 mg, 0.29 mmol), glacial acetic acid (0.5 mL) and zinc (97 mg, 1.48 mmol), and the reaction was stirred at 25 C. for 18 hours. The reaction mixture was quenched with a saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL3) to obtain the organic phase. The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain intermediate 5b. MS m/z: 312.8 [M+H16].sup.+.

Step 3: Synthesis of Compound 1-5

[0450] To N,N-dimethylformamide (3 mL) were added intermediate 5b (30 mg, 0.09 mmol), intermediate 1b (20.60 mg, 0.10 mmol), HATU (52.20 mg, 0.14 mmol) and DIPEA (0.05 mL, 0.27 mmol), and the reaction was stirred at 25 C. for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL3) to obtain the organic phase. The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (eluent: dichloromethane:methanol=20:1) to obtain compound I-5.

[0451] MS m/z: 514.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.01 (m, 1H), 8.08 (d, J=4.5 Hz, 1H), 7.53-7.41 (m, 2H), 7.08-6.96 (m, 2H), 6.86-6.73 (m, 2H), 4.89 (s, 1H), 4.55 (d, J=7.1 Hz, 2H), 4.47 (d, J=4.6 Hz, 1H), 3.06-2.72 (m, 2H), 2.71-2.56 (m, 2H), 1.90 (s, 1H), 1.37 (d, J=17.5 Hz, 2H), 1.27-0.89 (m, 2H), 0.67 (t, J=6.4 Hz, 1H), 0.56-0.46 (m, 1H).

Example 6: Synthesis of Compound 1-6

##STR00297##

Step 1: Synthesis of Compound 1-6

[0452] To N,N-dimethylformamide (2 mL) were added intermediate 5b (30 mg, 0.09 mmol), starting material 2a (0.01 mL, 0.10 mmol), HATU (52.20 mg, 0.14 mmol) and DIPEA (0.05 mL, 0.27 mmol), and the reaction was stirred at 25 C. for 18 hours. The resulting reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL3) to obtain the organic phase. The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (eluent: dichloromethane:methanol=20:1) to obtain compound I-6.

[0453] MS m/z: 506.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.81 (s, 1H), 8.09 (d, J=4.6 Hz, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.55-7.45 (m, 3H), 7.04 (dd, J=11.4, 2.9 Hz, 1H), 6.88-6.80 (m, 1H), 4.57 (s, 2H), 2.96-2.71 (m, 4H), 1.45 (s, 4H), 0.85 (t, J=6.5 Hz, 1 Hz), 0.70 (d, J=8.0, 5.1 Hz, 1 Hz), 0.56 (t, J=4.8 Hz, 1 Hz).

Example 7: Synthesis of Compound I-7

##STR00298##

Step 1: Synthesis of Intermediate 7a

[0454] To N,N-dimethylformamide (5 mL) were added intermediate 5b (60 mg, 0.18 mmol), intermediate 3b (63.17 mg, 0.20 mmol), HATU (104.40 mg, 0.27 mmol) and DIPEA (0.09 mL, 0.55 mmol), and the reaction was stirred at 25 C. for 18 hours. The resulting reaction mixture was quenched with a saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL3) to obtain the organic phase. The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (eluent: ethyl acetate:petroleum ether=4:1) to obtain intermediate 7a. MS m/z: 568.8 [M+H56].sup.+.

Step 2: Synthesis of Compound I-7

[0455] To a solution of dichloromethane (5 mL) were added intermediate 7a (50 mg, 0.08 mmol) and trifluoroacetic acid (1 mL), and the reaction was stirred at 25 C. for 1 hour. The resulting reaction mixture was concentrated to dryness under reduced pressure to obtain a crude. The crude was dissolved in dichloromethane (5 mL), and the mixture was adjusted to pH=7 with sodium carbonate and filtered. The filter cake was washed with dichloromethane (20 mL3). The filtrate was concentrated to dryness under reduced pressure to obtain compound I-7.

[0456] MS m/z: 524.4 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.03 (s, 1H), 8.09 (d, J=4.4 Hz, 1H), 7.49 (td, J=8.9, 3.9 Hz, 1H), 7.03 (dd, J=11.3, 2.9, 1.3 Hz, 1H), 6.85-6.80 (m, 1H), 6.75 (d, J=8.5 Hz, 1H), 6.61-6.55 (m, 1H), 6.52-6.46 (m, 1H), 6.15 (d, J=33.4 Hz, 1H), 4.59-4.51 (m, 2H), 4.38 (dd, J=7.3, 2.8 Hz, 1H), 3.44-3.36 (m, 1H), 3.22-3.15 (m, 1H), 2.74 (s, 2H), 2.69 (s, 2H), 2.58 (dt, J=8.3, 4.3 Hz, 1H), 1.39 (s, 2H), 1.23 (s, 2H), 0.70-0.65 (m, 1H), 0.53 (d, J=4.8 Hz, 1H).

Example 8: Synthesis of Compound I-8

##STR00299##

Step 1: Synthesis of Intermediate 8a

[0457] To a solution of dichloromethane (5 mL) were added intermediate 3a (200 mg, 0.67 mmol) and trifluoroacetic acid (1 ml), and the resulting mixture was stirred at 25 C. for 2 hours. The reaction solution was concentrated to obtain intermediate 8a. MS m/z: 200.6 [M+H].sup.+.

Step 2: Synthesis of Intermediate 8b

[0458] To a solution of acetonitrile (10 mL) was added intermediate 8c (133 mg, 0.67 mmol). At 25 C., potassium carbonate (276.22 mg, 2.00 mmol) and dimethyl sulfate (338.03 mg, 2.68 mmol) were added. Under nitrogen atmosphere, the resulting mixture was stirred at 70 C. for 18 hours. The reaction solution was filtered. The filter cake was washed with ethyl acetate (20 mL3), and the filtrate was concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (eluent: petroleum ether:ethyl acetate=1:1) to obtain intermediate 8b. MS m/z: 214.6 [M+H].sup.+.

Step 3: Synthesis of Intermediate 8c

[0459] To a solution of dichloromethane (5 mL) was added a solution of intermediate 8b (100 mg, 0.33 mmol), tetrapropylammonium perruthenate (23.45 mg, 0.07 mmol) and NMO (234.50 mg, 2.00 mmol), and the reaction was stirred at 25 C. for 2 hours. The resulting mixture was concentrated to dryness under reduced pressure to obtain intermediate 8c. MS m/z: 228.6 [M+H].sup.+.

Step 4: Synthesis of Compound I-8

[0460] To a solution of N,N-dimethylformamide (3 mL) were added intermediate 5b (50 mg, 0.15 mmol), intermediate 8c (34.72 mg, 0.15 mmol), HATU (87.00 mg, 0.23 mmol) and DIPEA (0.08 mL, 0.46 mmol), and the reaction was stirred at 25 C. for 2 hours. The resulting reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL3) to obtain the organic phase. The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by HPLC (Phenomenex Gemini 150 mm*25 mm*10 um column (eluent: 30% to 60% (v/v) CH.sub.3CN and H.sub.2O and 0.025% HCOOH)) to obtain compound I-8. MS m/z: 537.4 [M+H].sup.+.

Example 9: Synthesis of Compound I-9

##STR00300##

Step 1: Synthesis of Intermediate 9a

[0461] Starting material 2a (100 mg, 0.51 mmol), starting material 1c (115.12 mg, 0.51 mmol), DIPEA (197.24 mg, 1.53 mmol) and HATU (232.10 mg, 0.61 mmol) were added to DMF (5 mL), and the mixture was reacted at 25 C. for 3 hours. The resulting mixture was washed with water (30 mL) and then extracted with ethyl acetate (10 mL3). Liquid separation was performed to obtain the organic phase. The organic phase was washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: v/v (PE/EtOAc)=20/1 to 1/1) to obtain intermediate 9a. MS m/z: 405.0[M+H].sup.+.

Step 2: Synthesis of Intermediate 9b

[0462] Intermediate 9a (160 mg, 0.40 mmol) and TFA (2 mL) were added to DCM (10 mL), and the mixture was reacted at 25 C. for 2 hours. The resulting reaction mixture was concentrated under reduced pressure to obtain intermediate 9b. MS m/z: 305.0 [M+H].sup.+.

Step 3: Synthesis of Compound I-9

[0463] Intermediate 9b (50 mg, 0.16 mmol), starting material 2a (26.88 mg, 0.14 mmol), DIPEA (53.01 mg, 0.42 mmol) and HATU (62.4 mg, 0.16 mmol) were added to DMF (1 mL), and the mixture was reacted at 25 C. for 2 hours. The resulting reaction mixture was washed with water (10 mL) and then extracted with EtOAc (5 mL3). Liquid separation was performed to obtain the organic phase. The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative HPLC (eluent: v/v (acetonitrile/water)=43% to 100% with 0.225% formic acid) to obtain compound I-9.

[0464] MS m/z: 483.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO) 8.91 (d, J=3.5 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.80 (s, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.56 (s, 1H), 7.52-7.43 (m, 2H), 7.34 (s, 1H), 3.82 (d, J=39.9 Hz, 2H), 2.79 (d, J=3.8 Hz, 1H), 1.68-1.10 (m, 6H), 0.88 (dd, J=11.9, 4.7 Hz, 2H).

Example 10: Synthesis of Compound I-10

##STR00301##

Step 1: Synthesis of Intermediate 10a

[0465] Intermediate 9b (70 mg, 0.23 mmol) and sodium nitrite (135.84 mg, 1.97 mmol) were added to AcOH (4 mL) and water (12 mL), and the mixture was reacted at 60 C. for 18 hours. The resulting reaction mixture was washed with water (20 mL) and then extracted with DCM (5 mL3). Liquid separation was performed to obtain the organic phase. The organic phase was washed with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain a crude product. The crude product was separated by TLC (PE/EtOAc (v/v)=1/1) to obtain intermediate 10a.

[0466] MS m/z: 334.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO) 8.95 (d, J=3.9 Hz, 1H), 7.89 (dd, J=4.2, 2.1 Hz, 1H), 7.70 (dd, J=8.8, 5.0 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.52-7.47 (m, 1H), 4.17 (ddd, J=107.1, 44.7, 36.3 Hz, 3H), 2.82 (ddd, J=12.4, 7.9, 4.3 Hz, 1H), 1.62 (m, 5H), 0.98-0.89 (m, 2H).

Step 2: Synthesis of Intermediate 10b

[0467] Intermediate 10a (60 mg, 0.18 mmol) and zinc powder (117.53 mg, 1.80 mmol) were added to a mixed solution of THF (2.5 mL), H.sub.2O (2.5 mL) and AcOH (0.5 mL), and the mixture was reacted at 25 C. for 3 hours. The resulting reaction mixture was adjusted to pH 9 with aqueous ammonia (20%, 3 M) and then extracted with EtOAc (8 mL3). Liquid separation was performed to obtain the organic phase. The organic phase was washed and extracted with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain intermediate 10b. MS m/z: 320.0 [M+H].sup.+.

Step 3: Synthesis of Compound I-10

[0468] Intermediate 2a (33.5 mg, 0.17 mmol), intermediate 10b (59.94 mg, 0.19 mmol), DIPEA (66.07 mg, 0.51 mmol) and HATU (77.75 mg, 0.20 mmol) were added to DMF (5 mL), and the mixture was reacted at 25 C. for 2 hours. The resulting reaction mixture was washed with water (10 mL) and then extracted with EtOAc (5 mL3). Liquid separation was performed to obtain the organic phase. The organic phase was washed and extracted with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative HPLC (eluent: 43% to 100% (v/v) CH.sub.3CN and H.sub.2O with 0.225% HCOOH) to obtain compound I-10.

[0469] MS m/z: 498.0 [M+H].sup.+.

[0470] .sup.1H NMR (400 MHz, DMSO) 9.87 (s, 1H), 8.78 (d, J=4.5 Hz, 1H), 7.88 (dd, J=9.3, 2.2 Hz, 2H), 7.70 (dd, J=8.8, 3.5 Hz, 2H), 7.54 (d, J=6.3 Hz, 2H), 7.50-7.47 (m, 2H), 2.98-2.81 (m, 5H), 1.56 (d, J=15.0 Hz, 4H), 0.83-0.78 (m, 2H).

Example 11: Synthesis of Compound II-10

##STR00302##

Step 1: Synthesis of Intermediate 11b

[0471] To intermediate 1b (448.07 mg, 2.19 mmol) in DMF (10 mL) was added a solution of intermediate 11a (500 mg, 2.19 mmol), DIPEA (1.09 mL, 6.57 mmol) and HATU (999.36 mg, 2.63 mmol), and the mixture was stirred at 20 C. for 1 hour. The reaction was poured into water (50 mL) and extracted with EtOAc (50 mL2) to obtain the organic phase. The organic phase was washed with a saturated NaCl solution (100 mL), and the organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (mobile phase: PE:EtOAc=1:1) and concentrated in vacuo to obtain intermediate 11b. MS m/z: 359.0 [M+H56].sup.+.

Step 2: Synthesis of Intermediate 11c

[0472] To intermediate 11b (100 mg, 0.24 mmol) in DCM (5 mL) was added TFA (1 mL, 13.42 mmol), and the reaction was stirred at 20 C. for 3 hours and concentrated under reduced pressure to obtain intermediate 11c. MS m/z: 315.0 [M+H].sup.+.

Step 3: Synthesis of Compound II-10

[0473] To a solution of intermediate 11c (76 mg, 0.24 mmol) in DMF (5 mL) were added intermediate if (0.03 mL, 0.24 mmol), DIEA (0.12 mL, 0.72 mmol) and HATU (110.18 mg, 0.29 mmol), and the reaction was stirred at 20 C. for 1 hour. The resulting reaction mixture was poured into water (20 ml) and extracted with EtOAc (20 ml3) to obtain the organic phase. The organic phase was combined and washed with a saturated NaCl solution (40 ml). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by preparative TLC (eluted with PE:EtOAc=1:1) and concentrated in vacuo to obtain compound II-10.

[0474] MS m/z: 471.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.22 (d, J=1.9 Hz, 1H), 8.98 (d, J=2.8 Hz, 1H), 8.34 (t, J=5.9 Hz, 1H), 7.50 (td, J=8.9, 6.7 Hz, 1H), 7.27 (dd, J=54.0, 2.7 Hz, 1H), 7.07 (dt, J=7.7, 2.9 Hz, 1H), 6.88-6.81 (m, 1H), 4.66 (dd, J=21.7, 11.0, 1.6 Hz, 1H), 4.57-4.51 (m, 3H), 4.39-4.20 (m, 2H), 4.15-4.06 (m, 1H), 3.95 (td, J=8.7, 6.2 Hz, 1H), 3.65 (td, J=8.2, 4.5 Hz, 1H), 2.85 (s, 1H), 2.69 (s, 1H).

Example 12: Synthesis of Compound II-11

##STR00303##

Step 1: Synthesis of Compound II-11

[0475] To a solution of intermediate 11c (80 mg, 0.25 mmol), intermediate 1b (52 mg, 0.25 mmol) and DIEPA (0.17 mL, 1.02 mmol) in DMF (3 mL) was added HATU (116 mg, 0.31 mmol), and the mixture was stirred at 25 C. for 2 hours. The resulting reaction mixture was poured into H.sub.2O (50 mL) and extracted with EtOAc (25 mL3) to obtain the organic phase. The combined organic phase was washed with saturated brine (30 mL2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (PE:EtOAc=1:1) to obtain compound II-11.

[0476] MS m/z: 501.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO) 8.33 (d, J=6.4 Hz, 1H), 7.49 (td, J=8.9, 6.3 Hz, 2H), 7.07 (dt, J=11.4, 3.3 Hz, 2H), 6.89-6.76 (m, 2H), 4.76-4.61 (m, 2H), 4.54 (s, 2H), 4.31 (dd, J=16.9, 10.0 Hz, 2H), 4.21 (t, J=9.0 Hz, 1H), 4.03 (dd, J=32.2, 10.6 Hz, 1H), 3.95-3.81 (m, 2H), 3.63 (dd, J=8.9, 4.4 Hz, 1H), 2.43-2.34 (m, 1H), 2.19-2.10 (m, 1H).

Example 13: Synthesis of Compound II-12

##STR00304##

Step 1: Synthesis of Compound II-12

[0477] To a solution of intermediate 11c (113 mg, 0.36 mmol), intermediate 2a (70 mg, 0.36 mmol) and DIEPA (0.24 mL, 1.44 mmol) in DMF (3 mL) was added HATU (164 mg, 0.43 mmol), and the mixture was stirred at 25 C. for 2 hours. The resulting reaction mixture was poured into H.sub.2O (50 mL) and extracted with EtOAc (25 mL3) to obtain the organic phase. The combined organic phase was washed with brine (30 mL2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (PE:EtOAc=7:3) to obtain compound II-12.

[0478] MS m/z: 493.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO) 8.37 (d, J=6.4 Hz, 1H), 7.85 (s, 1H), 7.75-7.63 (m, 1H), 7.59-7.43 (m, 3H), 7.08 (dd, J=11.4, 2.8 Hz, 1H), 6.85 (dd, J=8.9, 1.9 Hz, 1H), 4.70 (dd, J=26.2, 10.0 Hz, 1H), 4.61-4.50 (m, 3H), 4.36 (d, J=7.1 Hz, 1H), 4.22 (dd, J=32.4, 10.6 Hz, 1H), 4.10-4.03 (m, 1H), 3.97 (dd, J=14.9, 5.9 Hz, 1H), 3.67 (d, J=4.7 Hz, 1H), 2.44 (d, J=12.1 Hz, 1H), 2.25-2.16 (m, 1H).

Example 14: Synthesis of Compound II-13

##STR00305##

Step 1: Synthesis of Intermediate 14a

[0479] To a solution of intermediate 11c (151.7 mg, 0.48 mmol), intermediate 3b (151 mg, 0.48 mmol) and HATU (219.92 mg, 0.58 mmol) in DMF (3 mL) was added DIPEA (0.32 mL, 1.93 mmol). The mixture was stirred at 25 C. for 3 hours. The resulting reaction mixture was poured into water (20 mL) and then extracted with EtOAc (30 mL3) to obtain the organic phase. The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (eluent: EtOAc) to obtain intermediate 14a. MS m/z: 554.0 [M+H56].sup.+.

Step 2: Synthesis of Compound II-13

[0480] To a solution of intermediate 14a (140 mg, 0.23 mmol) in DCM (4 mL) was added CF.sub.3COOH (1 mL, 13.42 mmol) to form a mixture, and the mixture was stirred at 25 C. for 20 h. The reaction was concentrated under reduced pressure to obtain a crude product, and then DCM (5 mL) and Na.sub.2CO.sub.3 (30 mg) were added to the crude product. The mixture was stirred at 25 C. for 30 min and filtered, and the filtrate was concentrated to obtain compound II-13.

[0481] MS m/z: 510.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO) 8.42-8.24 (m, 1H), 7.49 (tdd, J=9.1, 6.2, 2.9 Hz, 1H), 7.07 (dd, J=11.4, 2.7 Hz, 1H), 6.84 (dd, J=9.0, 1.8 Hz, 1H), 6.78-6.68 (m, 1H), 6.59 (t, J=2.2 Hz, 1H), 6.52-6.42 (m, 1H), 6.19 (s, 1H), 4.79-4.66 (m, 1H), 4.54 (s, 2H), 4.52-3.72 (m, 7H), 3.62 (dd, J=8.9, 4.4 Hz, 1H), 3.30 (d, J=12.4 Hz, 1H), 2.43-2.28 (m, 1H), 2.20-2.06 (m, 1H).

Example 15: Synthesis of Compound II-14

##STR00306##

Step 1: Synthesis of Compound II-14

[0482] To a solution of compound II-13 in ACN (5 mL) were added dimethyl sulfate (0.02 mL, 0.20 mmol) and K.sub.2CO.sub.3 (40.62 mg, 0.29 mmol). The mixture was stirred at 70 C. for 20 hours. Then, the resulting reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (eluent: PE:EtOAc=2:1) to obtain compound II-14.

[0483] MS m/z: 524.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO) 8.32 (t, J=5.4 Hz, 1H), 7.49 (dd, J=11.3, 6.3 Hz, 1H), 7.07 (dd, J=11.3, 2.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.74 (ddd, J=16.4, 12.9, 5.1 Hz, 2H), 6.63-6.54 (m, 1H), 4.89 (s, 1H), 4.52 (d, J=11.8 Hz, 2H), 4.51-3.70 (m, 7H), 3.62 (s, 1H), 3.30 (d, J=9.1 Hz, 1H), 2.85 (d, J=15.8 Hz, 3H), 2.43-2.33 (m, 1H), 2.18-2.08 (m, 1H).

Example 16: Synthesis of Compound III-10

##STR00307##

Step 1: Synthesis of Intermediate 16b

[0484] Intermediate 1b (100 mg, 0.49 mmol), intermediate 16a (121.69 mg, 0.54 mmol), DIPEA (189.53 mg, 1.47 mmol) and HATU (223.04 mg, 0.59 mmol) were sequentially added to DMF (1.5 mL), and the mixture was reacted at 25 C. for 18 hours. The resulting reaction mixture was washed with water (30 mL) and then extracted with EtOAc (10 mL3). Liquid separation was performed to obtain the organic phase. The organic phase was washed and extracted with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (PE/EtOAc (v/v)=1/1) to obtain intermediate 16b. MS m/z: 413.0 [M+H].sup.+.

Step 2: Synthesis of Intermediate 16c

[0485] Intermediate 16b (100 mg, 0.24 mmol) and TFA (1 mL) were added to DCM (5 mL), and the mixture was reacted at 25 C. for 2 hours. The resulting reaction mixture was concentrated under reduced pressure to obtain intermediate 16c. MS m/z: 313.0 [M+H].sup.+.

Step 3: Synthesis of Compound III-10

[0486] Intermediate 16c (44 mg, 0.21 mmol), intermediate 1b (47 mg, 0.23 mmol), DIPEA (84 mg, 0.64 mmol) and HATU (102 mg, 0.26 mmol) were added to DMF (5 mL), and the mixture was reacted at 25 C. for 18 hours. The resulting reaction mixture was washed with water (20 mL) and then extracted with EtOAc (5 mL3). Liquid separation was performed to obtain the organic phase. The organic phase was washed and extracted with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative TLC (eluent: petroleum ether:EtOAc=1:1) to obtain compound III-10.

[0487] MS m/z: 499.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO) 8.29 (d, J=7.8 Hz, 2H), 7.56-7.43 (m, 2H), 7.06 (dt, J=9.5, 4.7 Hz, 2H), 6.91-6.78 (m, 2H), 4.49 (d, J=14.7 Hz, 4H), 4.17 (dt, J=16.1, 8.2 Hz, 2H), 2.40-2.31 (m, 2H), 2.16 (dd, J=7.8, 3.1 Hz, 2H), 2.06-1.94 (m, 4H).

Example 17: Synthesis of Compound IV-11

##STR00308##

Step 1: Synthesis of Intermediate 17b

[0488] To a solution of intermediate 1b (85.12 mg, 0.42 mmol) in DMF (5 mL) were added intermediate 17a (100 mg, 0.42 mmol), DIPEA (0.21 mL, 1.25 mmol) and HATU (189.84 mg, 0.50 mmol), and the mixture was stirred and reacted at 20 C. for 1 hour. The resulting reaction mixture was poured into water (50 ml) and extracted with EtOAc (50 ml2) to obtain the organic phase. The resulting organic phase was washed with a saturated NaCl solution (100 ml), and the EtOAc layer (100 ml) was dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EtOAc (V/V)=1/1) and concentrated in vacuo to obtain intermediate 17b. MS m/z: 371.0 [M+H56].sup.+.

Step 2: Synthesis of Intermediate 17c

[0489] To a solution of intermediate 17b (140 mg, 0.33 mmol) in DCM (10 mL) was added TFA (2 mL, 26.84 mmol), and the mixture was stirred and reacted at 20 C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain intermediate 17c. MS m/z: 327.0 [M+H].sup.+.

Step 3: Synthesis of Compound IV-11

[0490] To a solution of intermediate 1b (66.36 mg, 0.32 mmol) in DMF (5 mL) were added intermediate 17c (106 mg, 0.32 mmol), DIEA (0.16 mL, 0.97 mmol) and HATU (148.00 mg, 0.39 mmol), and the mixture was stirred and reacted at 20 C. for 1 hour. The resulting reaction mixture was poured into water (50 ml) and extracted with EtOAc (50 ml2) to obtain the organic phase. The resulting organic phase was washed with a saturated NaCl solution (100 ml), and the EtOAc layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting residue was separated and purified by silica gel column chromatography (mobile phase: PE/EtOAc (V/V)=1/1) and concentrated in vacuo to obtain compound IV-11.

[0491] MS m/z: 513.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.35 (t, J=7.4 Hz, 1H), 7.48 (dt, J=20.2, 8.8 Hz, 2H), 7.12-7.02 (m, 2H), 6.89-6.77 (m, 2H), 4.87 (d, J=7.7 Hz, 2H), 4.50 (s, 2H), 4.29 (p, J=7.9 Hz, 1H), 3.35 (s, 4H), 2.16 (t, J=9.7 Hz, 2H), 1.80 (d, J=12.8 Hz, 2 Hz), 1.55 (dt, J=40.7, 15.8 Hz, 4 Hz).

Example 18: Synthesis of Compound V-10

##STR00309##

Step 1: Synthesis of Intermediate 18b

[0492] To a solution of intermediate 1b (85.12 mg, 0.42 mmol) in DMF (5 mL) were added 18a (100 mg, 0.42 mmol), DIPEA (0.21 mL, 1.25 mmol) and HATU (189.84 mg, 0.50 mmol), and the mixture was stirred and reacted at 20 C. for 1 hour. The resulting reaction mixture was poured into water (50 ml) and extracted with EtOAc (50 ml2) to obtain the organic phase. The resulting organic phase was washed with a saturated NaCl solution (100 ml), and the EtOAc layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting residue was separated and purified by silica gel column chromatography (mobile phase: PE/EtOAc (V/V)=1/1) and concentrated under reduced pressure to obtain intermediate 18b. MS m/z: 371.0 [M+H56].sup.+.

Step 2: Synthesis of Intermediate 18c

[0493] To a solution of intermediate 18b (90 mg, 0.21 mmol) in DCM (5 mL) was added TFA (1 mL, 13.42 mmol), and the mixture was stirred and reacted at 20 C. for 1 hour. After the reaction was completed, the resulting reaction mixture was concentrated under reduced pressure to obtain intermediate 18c. MS m/z: 327.0 [M+H].sup.+.

Step 3: Synthesis of Compound V-10

[0494] To a solution of intermediate 1b (42.96 mg, 0.21 mmol) in DMF (5 mL) were added intermediate 18c (68.63 mg, 0.21 mmol), DIPEA (0.10 mL, 0.63 mmol) and HATU (95.82 mg, 0.25 mmol), and the mixture was stirred and reacted at 20 C. for 1 hour. The resulting reaction mixture was poured into water (50 ml) and extracted with EtOAc (50 ml2) to obtain the organic phase. The resulting organic phase was washed with a saturated NaCl solution (100 ml), and the EtOAc layer (100 ml) was dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting residue was separated and purified by silica gel column chromatography (mobile phase: PE/EtOAc (V/V)=1/1) and concentrated in vacuo to obtain compound V-10. MS m/z: 513.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.93 (t, J=7.1 Hz, 1H), 7.53-7.45 (m, 2H), 7.07 (dd, J=11.4, 3.9, 2.7 Hz, 2H), 6.87-6.79 (m, 2H), 4.67 (d, J=7.0 Hz, 2H), 4.50 (d, J=1.9 Hz, 2H), 3.88 (d, J=24.1 Hz, 2H), 3.61 (s, 2H), 3.54 (s, 1H), 1.85 (d, J=12.9 Hz, 2 Hz), 1.65 (s, 2H), 1.50 (t, J=13.0 Hz, 2H), 1.32-1.22 (m, 2H).

Example 19: Synthesis of Compound III-11

##STR00310##

Step 1: Synthesis of Compound III-11

[0495] Intermediate 16c (100 mg, 0.32 mmol), intermediate if (50.61 mg, 0.29 mmol), DIPEA (112.70 mg, 0.87 mmol) and HATU (132.62 mg, 0.35 mmol) were added to DMF (5 mL), and the mixture was reacted at 25 C. for 2 hours. To the resulting reaction mixture was added water (30 mL), and then the mixture was extracted with EtOAc (10 mL3). Liquid separation was performed to obtain the organic phase. The organic phase was washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE/EtOAc (v/v)=1/1) to obtain compound III-11.

[0496] MS m/z: 469.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO) 9.42-9.11 (m, 2H), 9.01 (s, 1H), 8.30 (d, J=7.8 Hz, 1H), 7.49 (d, J=8.9 Hz, 1H), 7.36-7.05 (m, 2H), 6.85 (dd, J=8.9, 2.7 Hz, 1H), 4.48 (s, 2H), 4.37 (dd, J=16.4, 8.2 Hz, 1H), 4.18 (dd, J=16.3, 8.2 Hz, 1H), 2.40 (s, 2H), 2.22 (d, J=8.4 Hz, 4H), 2.04 (s, 2H).

Example 20: Synthesis of Compound III-13

##STR00311##

Step 1: Synthesis of Intermediate 20a

[0497] To N,N-dimethylformamide (5 mL) were added intermediate 16c (90 mg, 0.29 mmol), intermediate 3b (99.30 mg, 0.32 mmol), HATU (164.12 mg, 0.43 mmol) and DIPEA (ethyldiisopropylamine) (111.58 mg, 0.86 mmol), and the reaction was stirred at 25 C. for 2 hours. The resulting reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL3) to obtain the organic phase. The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (eluent: petroleum ether:ethyl acetate=10:1) to obtain intermediate 20a. MS m/z: 608.5[M+H].sup.+.

Step 2: Synthesis of Compound III-13

[0498] To dichloromethane (5 mL) were added 20a (120 mg, 0.20 mmol) and trifluoroacetic acid (1 mL), and the reaction was stirred at 25 C. for 1 hour. The resulting reaction mixture was concentrated to dryness under reduced pressure to obtain a crude. The crude was purified by preparative TLC (eluent: petroleum ether:ethyl acetate=5:1) to obtain compound III-13.

[0499] MS m/z: 508.4 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.28 (d, J=7.8 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.07 (dd, J=11.4, 2.8 Hz, 1H), 6.89-6.83 (m, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.59 (dd, J=2.5, 1.0 Hz, 1H), 6.53-6.48 (m, 1H), 6.18 (s, 1H), 4.47 (s, 2H), 4.41 (dt, J=7.5, 2.8 Hz, 1H), 4.14 (p, J=8.2 Hz, 2H), 3.42 (d, J=12.2 Hz, 1H), 3.16 (dd, J=11.9, 7.4 Hz, 1H), 2.38-2.28 (m, 2H), 2.15 (s, 2H), 2.08-1.95 (m, 4H).

Example 21: Synthesis of Compound IV-12

##STR00312##

Step 1: Synthesis of Compound IV-12

[0500] To a solution of intermediate 17c (53 mg, 0.16 mmol) in DMF (5 mL) were added intermediate if (28.24 mg, 0.16 mmol), DIPEA (0.08 mL, 0.48 mmol) and HATU (73.01 mg, 0.19 mmol), and the mixture was stirred and reacted at 20 C. for 1 hour. The resulting reaction mixture was poured into water (20 ml) and extracted with EtOAc (20 ml2) to obtain the organic phase. The resulting organic phase was washed with a saturated NaCl solution (40 ml), and the EtOAc layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting residue was separated and purified by preparative TLC (eluent: DCM/MeOH=20/1) and concentrated under reduced pressure to obtain compound IV-12.

[0501] MS m/z: 483.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.98 (s, 1H), 8.94 (s, 1H), 8.35 (dd, J=11.8, 7.7 Hz, 1H), 7.50 (td, J=8.9, 4.8 Hz, 1H), 7.08 (dt, J=11.4, 3.0 Hz, 1H), 6.90-6.82 (m, 1H), 4.50 (d, J=4.0 Hz, 2H), 4.28 (dq, J=16.4, 8.2 Hz, 1H), 3.67-3.51 (m, 2H), 3.33-3.19 (m, 3H), 2.19 (q, J=10.0 Hz, 2H), 1.80 (q, J=10.6 Hz, 2H), 1.58 (dt, J=31.9, 26.1, 6.0 Hz, 4H).

Example 22: Synthesis of Compound IV-13

##STR00313##

Step 1: Synthesis of Intermediate 22a

[0502] To a solution of intermediate 17c (53 mg, 0.16 mmol) in DMF (5 mL) were added intermediate 3b (50.88 mg, 0.16 mmol), DIPEA (0.08 mL, 0.48 mmol) and HATU (73.01 mg, 0.19 mmol), and the mixture was stirred and reacted at 20 C. for 1 hour. The resulting reaction mixture was poured into water (50 ml) and extracted with EtOAc (50 ml2) to obtain the organic phase. The resulting organic phase was washed with a saturated NaCl solution (100 ml), and the EtOAc layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting residue was separated and purified by silica gel column chromatography (mobile phase: PE/EtOAc (V/V)=1/1) and concentrated in vacuo to obtain intermediate 22a. MS m/z: 522.2 [M+H100].sup.+.

Step 2: Synthesis of Compound IV-13

[0503] To a solution of intermediate 22a (90 mg, 0.14 mmol) in DCM (5 mL) was added TFA (0.5 mL, 6.71 mmol), and the mixture was stirred and reacted at 20 C. for 1 hour. The resulting reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by preparative TLC (mobile phase: DCM/MeOH(V/V)=20/1) and concentrated in vacuo to obtain compound IV-13.

[0504] MS m/z: 522.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.35 (d, J=7.2 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.08 (dd, J=11.4, 2.9 Hz, 1H), 6.86 (dd, J=9.0, 2.9, 1.2 Hz, 1H), 6.68 (d, J=8.5 Hz, 1H), 6.58 (d, J=2.5 Hz, 1H), 6.46 (dd, J=8.5, 2.6 Hz, 1H), 6.18 (t, J=2.6 Hz, 1H), 4.90 (d, J=8.5 Hz, 1H), 4.50 (s, 2H), 4.28 (q, J=8.2 Hz, 1H), 3.58-3.35 (m, 3H), 3.26 (dd, J=12.5, 7.0, 2.1 Hz, 1H), 2.16 (q, J=12.9, 11.3 Hz, 2H), 1.79 (t, J=9.9 Hz, 2H), 1.54 (dd, J=43.5, 24.0 Hz, 4H).

Example 23: Synthesis of Compound V-11

##STR00314##

Step 1: Synthesis of Compound V-11

[0505] To a solution of intermediate 18c (23 mg, 0.07 mmol) in DMF (2 mL) were added intermediate if (0.01 mL, 0.07 mmol), DIPEA (0.03 mL, 0.21 mmol) and HATU (32.11 mg, 0.08 mmol), and the mixture was stirred and reacted at 20 C. for 1 hour. The resulting reaction mixture was poured into water (20 ml) and extracted with EtOAc (20 ml2) to obtain the organic phase. The resulting organic phase was washed with a saturated NaCl solution (40 ml), and the EtOAc layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was separated and purified by preparative TLC (mobile phase: PE/EtOAc (V/V)=1/1) and concentrated in vacuo to obtain compound V-11. MS m/z: 483.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.20 (d, J=5.1 Hz, 1H), 8.99 (s, 1H), 7.92 (dd, J=26.8, 8.0 Hz, 1H), 7.50 (td, J=8.8, 1.6 Hz, 1H), 7.27 (dd, J=53.9, 3.3 Hz, 1H), 7.10-7.04 (m, 1H), 6.85 (d, J=9.0 Hz, 1H), 4.50 (d, J=5.2 Hz, 2H), 4.25 (d, J=28.7 Hz, 2H), 3.80 (d, J=26.3 Hz, 2H), 3.63 (s, 1H), 1.91 (d, J=12.9 Hz, 2H), 1.66 (d, J=12.7 Hz, 2H), 1.54 (t, J=12.6 Hz, 2H), 1.38-1.27 (m, 2H).

Example 24: Synthesis of Compound V-12

##STR00315##

Step 1: Synthesis of Intermediate 24a

[0506] To a solution of intermediate 18c (38 mg, 0.12 mmol) in DMF (3 mL) were added intermediate 3b (36.48 mg, 0.12 mmol), DIPEA (0.06 mL, 0.35 mmol) and HATU (53.06 mg, 0.14 mmol), and the mixture was stirred and reacted at 20 C. for 1 hour. The resulting reaction mixture was poured into water (50 ml) and extracted with EtOAc (50 ml2) to obtain the organic phase. The resulting organic phase was washed with a saturated NaCl solution (100 ml), and the EtOAc layer (100 ml) was dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting residue was separated and purified by silica gel column chromatography (mobile phase: PE/EtOAc (V/V)=1/1) and concentrated in vacuo to obtain intermediate 24a. MS m/z: 566.2 [M+H56].sup.+.

Step 2: Synthesis of Compound V-12

[0507] To a solution of intermediate 24a (48 mg, 0.08 mmol) in DCM (5 mL) was added TFA (0.5 mL, 6.71 mmol), and the mixture was stirred and reacted at 20 C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude. The crude was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH(V/V)=20/1) and concentrated in vacuo to obtain the target compound V-12. MS m/z: 522.0 [M+H].sup.+.

[0508] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.92 (dd, J=8.1, 3.6 Hz, 1H), 7.50 (t, J=8.8 Hz, 1H), 7.06 (dd, J=11.4, 2.8 Hz, 1H), 6.84 (dd, J=8.9, 2.9, 1.2 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 6.59 (dd, J=3.7, 2.5 Hz, 1H), 6.49 (dd, J=8.3, 5.5, 2.5 Hz, 1H), 6.18 (d, J=7.1 Hz, 1H), 4.70 (dt, J=6.0, 3.0 Hz, 1H), 4.49 (d, J=1.1 Hz, 2H), 3.97 (dd, J=33.6, 28.2, 8.9 Hz, 2H), 3.64-3.55 (m, 2H), 3.55-3.48 (m, 1H), 3.42-3.36 (m, 1H), 3.30 (d, J=13.0 Hz, 1H), 1.81 (d, J=18.3 Hz, 2H), 1.64 (d, J=12.0 Hz, 2H), 1.47 (d, J=13.2 Hz, 2H), 1.27 (d, J=15.5 Hz, 2H).

Example 25: Synthesis of Compound IV-15

##STR00316##

Step 1: Synthesis of Compound IV-15

[0509] To a solution of compound 22 (40 mg, 0.08 mmol) in CH.sub.3CN (5 ml) were added K.sub.2CO.sub.3 (31.75 mg, 0.23 mmol) and dimethyl sulfate (0.03 ml, 0.31 mmol), and the mixture was stirred and reacted at 70 C. for 18 hours. The resulting reaction mixture was separated and purified by preparative TLC (mobile phase: DCM/MeOH (V/V)=20/1) to obtain compound IV-15.

[0510] MS m/z: 536.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.35 (d, J=7.8 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.08 (dd, J=11.3, 2.9 Hz, 1H), 6.86 (dd, J=9.2, 2.9 Hz, 1H), 6.73-6.66 (m, 2H), 6.56 (dd, J=8.4, 2.4 Hz, 1H), 5.09 (s, 1H), 4.50 (s, 2H), 4.29 (d, J=8.8 Hz, 1H), 3.58-3.36 (m, 5H), 3.27 (dd, J=12.3, 6.8 Hz, 1H), 2.85 (s, 3H), 2.15 (d, J=21.8 Hz, 2H), 1.86-1.74 (m, 2H), 1.55 (dd, J=47.1, 22.9 Hz, 3H), 1.35 (d, J=1.9 Hz, 1H).

Example 26: Synthesis of Compound III-12

##STR00317##

Step 1: Synthesis of Compound III-12

[0511] To acetonitrile (5 mL) were added compound III-13 (60 mg, 0.12 mmol), dimethyl sulfate (0.01 mL, 0.12 mmol) and potassium carbonate (16.31 mg, 0.12 mmol), and the mixture was degassed and subjected to nitrogen replacement 3 time. The reaction was stirred at 70 C. for 18 hours. The resulting reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL3) to obtain the organic phase. The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude. The crude was separated and purified by preparative TLC (mobile phase: PE/EtOAc (V/V)=5/1) to obtain compound III-12.

[0512] MS m/z: 522.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.28 (d, J=7.8 Hz, 1H), 8.21 (d, J=7.8 Hz, 1H), 7.50 (t, J=8.8 Hz, 1H), 7.07 (dd, J=11.4, 2.9 Hz, 1H), 6.87-6.79 (m, 2H), 6.69 (d, J=2.5 Hz, 1H), 6.62 (dd, J=8.4, 2.5 Hz, 1H), 4.60 (dt, J=7.3, 2.4 Hz, 1H), 4.47 (s, 2H), 4.13 (q, J=8.0 Hz, 2H), 3.38 (dd, J=12.0, 3.0 Hz, 1H), 3.17 (dd, J=11.9, 7.2 Hz, 1H), 2.82 (s, 3H), 2.37-2.32 (m, 2H), 2.15 (s, 2H), 2.08-1.95 (m, 4H).

Example 27: Synthesis of Compound IV-14

##STR00318##

Step 1: Synthesis of Intermediate 27b

[0513] At room temperature, to a 100 mL single-necked flask were added compound 27a (1.0 g, 5.86 mmol) and 1,2-dichloroethane (50.0 mL). Under stirring, the compound N,N-carbonyldiimidazole (1.3 g, 8.21 mmol) was added. The mixture was reacted at 25 C. for 16 hours. To the resulting reaction solution was added 25 mL of water. Liquid separation was performed. The resulting organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude. The crude was separated and purified by silica gel column chromatography to obtain intermediate 27b.

Step 2: Synthesis of Compound IV-14

[0514] At room temperature, to a 50 mL single-necked flask were added intermediate 17c (100 mg, 0.31 mmol) and NN-dimethylformamide (5.0 mL). Under stirring, intermediate 27b (84 mg, 0.43 mmol), DIEA (159 mg, 1.22 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (28 mg, 0.45 mmol) were sequentially added. The mixture was reacted at 25 C. for 16 hours. To the resulting reaction solution was added 25 mL of water. Liquid separation was performed. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude. The crude was separated and purified by HPLC (ammonium bicarbonate/acetonitrile/water system) to obtain compound IV-14.

[0515] MS m/z: 505.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3-d) 7.86-7.83 (m, 2H), 7.46-7.36 (m, 2H), 7.34-7.26 (m, 1H), 6.80-6.77 (m, 1H), 6.71-6.70 (m, 1H), 6.69-6.60 (m, 1H), 4.56-4.49 (m, 1H), 4.44 (s, 2H), 3.65-3.60 (m, 4H), 2.47-2.45 (m, 2H), 1.84-1.82 (m, 4H), 1.79-1.76 (m, 2H).

Example 28: Synthesis of Compound IV-18

##STR00319##

Step 1: Synthesis of Intermediate 28a

[0516] At room temperature, to a 50 mL single-necked flask were added intermediate 3b (85 mg, 0.27 mmol) and NN-dimethylformamide (5 mL). Under stirring, intermediate 17a (65 mg, 0.27 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (154 mg, 0.41 mmol) and DIEA (130 mg, 1.08 mmol) were sequentially added. The mixture was reacted at 25 C. for 12 hours. To the resulting reaction solution was added 50 mL of water. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude. The crude was separated and purified by silica gel column chromatography to obtain intermediate 28a. MS m/z: 436.2 [M+H].sup.+.

Step 2: Synthesis of Intermediate 28b

[0517] At 25 C., to a 50 mL single-necked flask were added intermediate 28a (101 mg, 0.19 mmol) and dichloromethane (3 mL). Under stirring, trifluoroacetic acid (1 mL) was added. The mixture was reacted at 25 C. for 30 minutes. The resulting reaction solution was concentrated under reduced pressure to obtain intermediate 28b. MS m/z: 336.0 [M+H100].sup.+.

Step 3: Synthesis of Intermediate 28c

[0518] At room temperature, to a 50 mL single-necked flask were added intermediate 28b (76 mg, 0.23 mmol) and NN-dimethylformamide (5 mL). Under stirring, intermediate 3b (92 mg, 0.29 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (128 mg, 0.34 mmol) and DIEA (108 mg, 0.90 mmol) were sequentially added. The mixture was reacted at 25 C. for 12 hours. To the resulting reaction solution was added 50 mL of water. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude. The crude was separated and purified by silica gel column chromatography to obtain intermediate 28c. MS m/z: 629.2[MH100].sup.+.

Step 4: Synthesis of Compound IV-18

[0519] At 25 C., to a 50 mL single-necked flask were added intermediate 28c (106 mg, 0.17 mmol) and dichloromethane (3 mL). Under stirring, trifluoroacetic acid (1 mL) was added. The mixture was reacted at 25 C. for 30 minutes. The resulting reaction solution was concentrated under reduced pressure to obtain a crude. The crude was separated and purified by HPLC (ammonium bicarbonate/acetonitrile/water system) to obtain compound IV-18.

[0520] MS m/z: 531.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 8.20-8.18 (m, 1H), 6.74-6.72 (m, 1H), 6.62-6.60 (m, 1H), 6.53-6.50 (m, 2H), 6.43-6.41 (m, 1H), 6.40-6.38 (m, 1H), 6.13-6.11 (m, 2H), 4.83-4.80 (m, 1H), 4.35-4.32 (m, 1H), 4.20-4.18 (m, 1H), 3.52-3.35 (m, 4H), 3.20-3.18 (m, 4H), 2.20-1.99 (m, 2H), 1.85-1.65 (m, 2H), 1.65-1.28 (m, 4H).

Example 29: Synthesis of Compound IV-19

##STR00320##

Step 1: Synthesis of Compound IV-19

[0521] To a solution of intermediate 17c (170 mg, 0.39 mmol) and intermediate 2a (85 mg, 0.43 mmol) in dichloromethane (6 mL) were added DIEA (102 mg, 0.79 mmol) and 1-propylphosphonic anhydride (493 mg, 0.77 mmol) to obtain a mixture. The mixture was stirred and reacted at 25 C. for 12 h. The resulting reaction mixture was poured into H.sub.2O (15 mL) and extracted with EtOAc (10 mL3) to obtain the organic phase. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The resulting crude was separated and purified by preparative TLC (eluent: PE/EtOAc (V/V)=3/1) to obtain compound IV-19.

[0522] MS m/z: 505.1 [M+H].sup.+. .sup.1H NMR (DMSO-d6) : 8.35 (d, J=7.6 Hz, 1H), 7.81 (d, J=2.1 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.44-7.53 (m, 2H), 7.31 (s, 1H), 7.05-7.11 (m, 1H), 6.86 (dd, J=8.9, 1.8 Hz, 1H), 4.50 (s, 2H), 4.24-4.35 (m, 1H), 3.62 (s, 2H), 3.54 (s, 2H), 2.16-2.24 (m, 2H), 1.76-1.87 (m, 2H), 1.61-1.69 (m, 2H), 1.55-1.61 (m, 2H).

Example 30: Synthesis of Compound IV-20

##STR00321##

Step 1: Synthesis of Intermediate 30a

[0523] At 25 C., to a 100 mL single-necked flask were added intermediate 2a (150 mg, 0.76 mmol) and DMF (5.0 mL). Under stirring, intermediate 17a (220 mg, 0.92 mmol), 1-propylphosphonic anhydride (970 mg, 1.53 mmol) and DIEA (395 mg, 3.04 mmol) were sequentially added. The mixture was reacted at 25 C. for 16 h. The resulting reaction solution was poured into 50 mL of water and then extracted with EtOAc (50 mL3) to obtain the organic phase. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude. The crude was separated and purified by silica gel column chromatography to obtain intermediate 30a. MS m/z: 363.0 [M+H56].sup.+.

Step 2: Synthesis of Intermediate 30b

[0524] At 25 C., to a 50 mL single-necked flask were added intermediate 30a (120 mg, 0.29 mmol) and dichloromethane (3 mL). Under stirring, trifluoroacetic acid (1 mL) was added. The mixture was reacted at 25 C. for 30 minutes. The resulting reaction solution was concentrated under reduced pressure to obtain intermediate 30b. MS m/z: 319.0 [M+H].sup.+.

Step 3: Synthesis of Compound IV-20

[0525] At 25 C., to a 50 mL single-necked flask were added intermediate 30b (89 mg, 0.28 mmol) and DMF (5 mL). Under stirring, intermediate 2a (65 mg, 0.33 mmol), 1-propylphosphonic anhydride (355 mg, 0.56 mmol, 50% in dimethylformamide) and DIEA (134 mg, 1.12 mmol) were sequentially added. The mixture was reacted at 25 C. for 16 h. The resulting reaction solution was poured into 50 mL of water and then extracted with EtOAc (50 mL3) to obtain the organic phase. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude. The crude was purified by HPLC (formic acid/acetonitrile/water system) to obtain compound IV-20.

[0526] MS m/z: 497.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 9.05 (d, J=7.7 Hz, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.83 (d, J=2.2 Hz, 1H), 7.74-7.70 (m, 2H), 7.53 (s, 1H) 7.51-7.46 (m, 2H), 7.33 (s, 1H), 4.50-4.44 (m, 1H), 3.61 (d, J=31.6 Hz, 4H), 2.30-2.24 (m, 2H), 2.00-1.94 (m, 2H), 1.70-1.62 (m, 4H).

Example 31: Synthesis of Compound IV-16

##STR00322##

Step 1: Synthesis of Intermediate 31b

[0527] Under ice bath, to a 100 mL three-necked flask were added intermediate 31a (300 mg, 1.61 mmol) and ethyl acetate (20 mL). Under stirring in the dark, silver trifluoromethanesulfonate (1.41 g, 4.83 mmol), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (855 mg, 2.42 mmol), potassium fluoride (374 mg, 6.44 mmol), 2-fluoropyridine (469 mg, 4.83 mmol) and (trifluoromethyl)trimethylsilane (686 mg, 4.83 mmol) were added. The mixture was reacted at 25 C. for 16 h. The resulting reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude. The crude was separated and purified by silica gel column chromatography to obtain intermediate 31b. .sup.1H NMR (400 MHz, DMSO-d6) 4.62-4.35 (m, 1H), 3.92 (s, 2H), 3.73 (t, J=6.9 Hz, 1H), 2.87-2.68 (m, 2H), 2.12-2.10 (m, 2H), 1.42 (s, 9H).

Step 2: Synthesis of Intermediate 31c

[0528] At 25 C., to a 50 mL single-necked flask were added intermediate 31b (246 mg, 0.97 mmol) and dichloromethane (3 mL). Under stirring, trifluoroacetic acid (1 mL) was added. The mixture was reacted at 25 C. for 30 minutes. The resulting reaction solution was concentrated under reduced pressure to obtain intermediate 31c.

Step 3: Synthesis of Intermediate 31d

[0529] At 25 C., to a 50 mL single-necked flask were added intermediate 31c (230 mg, 1.07 mmol) and DMF (5 mL). Under stirring, intermediate 17a (283 mg, 1.18 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (610 mg, 1.60 mmol) and DIEA (556 mg, 4.28 mmol) were sequentially added. The mixture was reacted at 25 C. for 12 h. To the resulting reaction solution was added 50 mL of water. The resulting organic phase was separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude. The crude was separated and purified by silica gel column chromatography to obtain intermediate 31d. MS m/z: 381.0 [M+H56].sup.+.

Step 4: Synthesis of Intermediate 31e

[0530] At 25 C., to a 50 mL single-necked flask were added intermediate 31d (140 mg, 0.32 mmol) and dichloromethane (3 mL). Under stirring, trifluoroacetic acid (1 mL) was added. The mixture was reacted at 25 C. for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain intermediate 31e. MS m/z: 337.0 [M+H].sup.+.

Step 5: Synthesis of Compound IV-16

[0531] At 25 C., to a 50 mL single-necked flask were added intermediate 31e (66 mg, 0.21 mmol) and DMF (5 mL). Under stirring, intermediate 2a (50 mg, 0.25 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (120 mg, 0.32 mmol) and DIEA (109 mg, 0.84 mmol) were sequentially added. The mixture was reacted at 25 C. for 12 h. To the resulting reaction solution was added 50 mL of water. The resulting organic phase was separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude. The crude was separated and purified by HPLC (ammonium bicarbonate/acetonitrile/water system) to obtain compound IV-16.

[0532] MS m/z: 515.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 8.04 (d, J=8.0 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.73-7.71 (m, 1H), 7.48-7.44 (m, 1H), 7.32 (s, 1H), 4.54-4.46 (m, 1H), 4.32-4.26 (m, 1H), 3.76 (s, 2H), 3.75-3.68 (m, 1H), 3.64-3.62 (m, 2H), 3.60-3.54 (m, 2H), 2.78-2.74 (m, 2H), 2.20-2.14 (m, 4H), 1.86-1.80 (m, 2H), 1.66-1.58 (m, 4H).

Example 32: Synthesis of Compound IV-17

##STR00323##

Step 1: Synthesis of Compound IV-17

[0533] At 25 C., to a 50 mL single-necked flask were added intermediate 31e (106 mg, 0.31 mmol) and DMF (5 mL). Under stirring, intermediate 1b (74 mg, 0.35 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (78 mg, 0.21 mmol) and DIEA (161 mg, 1.24 mmol) were sequentially added. The mixture was reacted at 25 C. for 12 h. To the resulting reaction solution was added 50 mL of water. The resulting organic phase was separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude. The crude was separated and purified by HPLC (formic acid/acetonitrile/water system) to obtain compound IV-17.

[0534] MS m/z: 523.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 8.00 (t, J=8.8 Hz, 1H), 7.46 (t, J=8.9 Hz, 1H), 7.05 (ddd, J=11.4, 2.8, 1.4 Hz, 1H), 6.88-6.73 (m, 1H), 4.86 (d, J=7.9 Hz, 2H), 4.49 (p, J=7.1 Hz, 1H), 4.35-4.20 (m, 1H), 3.73 (d, J=18.1 Hz, 3H), 3.46-3.39 (m, 3H), 3.25 (d, J=6.0 Hz, 1H), 2.75 (dtd, J=9.7, 6.7, 3.3 Hz, 2H), 2.23-2.06 (m, 4H), 1.87-1.74 (m, 2H), 1.65-1.41 (m, 4H).

Example 33: Synthesis of Compound VIII-1

##STR00324##

Step 1: Synthesis of Compound 33c

[0535] At room temperature, to a single-necked flask were added 33a (11 g, 63.15 mmol) and dichloromethane (36 mL). Under stirring, 33b (20 g, 57.41 mmol), acetic acid (1.93 g, 32.15 mmol) and tetraethylene glycol dimethyl ether (40 mL) were added. The mixture was reacted at 100 C. for 3 hours. The reaction solution was concentrated under reduced pressure. The crude was purified by flash column chromatography (petroleum ether:ethyl acetate=100:1-10:1) to obtain intermediate 33c. .sup.1H NMR (400 MHz, DMSO) 6.22 (t, J=1.9 Hz, 1H), 4.13 (m, 2H), 1.41 (m, 2H), 1.30-1.26 (m, 2H), 1.22 (t, J=7.1 Hz, 3H).

Step 2: Synthesis of Compound 33e

[0536] At room temperature, to a single-necked flask were added 33c (2.3 g, 17.57 mmol) and toluene (10 mL). Under stirring, 33d (1.0 g, 1.03 mmol) was added. The mixture was reacted at 130 C. for 18 hours. The reaction solution was concentrated under reduced pressure. The crude was purified by flash column chromatography (petroleum ether:ethyl acetate=100:1-7:1) to obtain intermediate 33e. LC-MS: m/z: 269.0 (M+H).sup.+.

Step 3: Synthesis of Compound 33f

[0537] At room temperature, to a single-necked flask were added 33e (2.4 g, 5.36 mmol), potassium fluoride (0.36 g, 8.05 mmol) and methanol (10 mL). The mixture was stirred, and reacted under nitrogen atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure. The crude was purified by flash column chromatography (petroleum ether:ethyl acetate=100:1-5:1) to obtain intermediate 33f. LC-MS: m/z: 197.0 (M+H).sup.+.

Step 4: Synthesis of Compound 33g

[0538] At room temperature, to a single-necked flask were added 33f (877 mg, 1.45 mmol) and methanol (30 mL). Under stirring, acetic acid (80.0 mg, 0.44 mmol) and 2,4-dimethoxybenzylamine (1.76 g, 10.26 mmol) were added. At room temperature, the mixture was reacted for two hours, and then cyano sodiumborohydride (258.03 mg, 6.6 mmol) was added. At room temperature, the resulting mixture was reacted for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude. The crude was purified by flash column chromatography (petroleum ether:ethyl acetate=100:1-5:1) to obtain intermediate 33g. LC-MS: m/z: 348.0 (M+H).sup.+.

Step 5: Synthesis of Compound 33h

[0539] Under ice bath, to a single-necked flask were added 1b (1 g, 0.4 mmol) and dichloromethane (30 mL). Under stirring, oxalyl chloride (600 mg, 0.4 mmol) and three drops of N,N-dimethylformamide were added. At room temperature, the mixture was reacted for 30 minutes, and then the reaction solution was concentrated under reduced pressure to obtain a crude. The crude was dissolved in dichloromethane (20 mL), and then under ice bath, to the reaction solution were added triethylamine (4 mL) and 33g (1.45 g, 4.17 mmol). The mixture was reacted under ice bath for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude. The crude was purified by flash column chromatography (petroleum ether:ethyl acetate=100:1-2:1) to obtain intermediate 33h. LC-MS: m/z: 534.1 (M+H).sup.+.

Step 6: Synthesis of Compound 33i

[0540] At room temperature, to a single-necked flask were added 33h (1.2 g, 2.24 mmol) and dichloromethane (30 mL). Under stirring, TFA (15 mL) was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude. The crude was purified by flash column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain intermediate 33i (800 mg). LC-MS: m/z: 384.1 (M+H).sup.+.

Step 7: Synthesis of Compound 33j

[0541] At room temperature, to a single-necked flask were added 33i (800 mg, 2.09 mmol), ethanol (20 mL) and water (7 mL). Under stirring, lithium hydroxide (160 mg, 4.10 mmol) was added. The mixture was reacted at room temperature for 3 hours. The reaction solution was adjusted to pH=6 with hydrochloric acid (1 N) and extracted with ethyl acetate (20 mL3). The combined organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain intermediate 33j. LC-MS: m/z: 356.1 (M+H).sup.+.

Step 8: Synthesis of Compound 33k

[0542] At room temperature, to a single-necked flask were added 33j (532 mg, 1.50 mmol) and tetrahydrofuran (20 mL). Under stirring, N,N-carbonyldiimidazole (2.43 g, 15 mmol) and 80% hydrazine hydrate (1.0 mL) were added. The mixture was reacted at 60 C. for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude. The crude was purified by flash column chromatography (petroleum ether:ethyl acetate=100:1-0:1) to obtain intermediate 33k. LC-MS: m/z: 370.1 (M+H).sup.+.

Step 9: Synthesis of Compound 33I

[0543] At room temperature, to a single-necked flask were added 33k (407 mg, 1.1 mmol) and 1,2-dichloroethane (10 mL). Under stirring, N,N-carbonyldiimidazole (891 mg, 5.5 mmol) was added. The mixture was reacted at 80 C. for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude. The crude was purified by flash column chromatography (petroleum ether:ethyl acetate=100:1-0:1) to obtain compound 33I. LC-MS: m/z: 396.0 (M+H).sup.+.

Step 10: Synthesis of Compound VIII-1

[0544] At room temperature, to a single-necked flask were added 33K (356 mg, 0.9 mmol) and N,N-dimethylformamide (3.0 mL). Under stirring, D (132 mg, 0.94 mmol), N,N-diisopropylethylamine (0.19 mL, 1.12 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (166 mg, 0.37 mmol) were added. The mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude. The crude was purified by high performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system) to obtain compound VIII-1. .sup.1H NMR (400 MHz, MeOD) 7.38 (t, J=8.7 Hz, 1H), 6.94 (dd, J=11.0, 2.7 Hz, 1H), 6.85-6.79 (m, 1H), 5.32-5.18 (m, 1H), 4.51 (s, 2H), 4.50-4.46 (m, 2H), 4.25 (dd, J=9.5, 4.1 Hz, 2H), 4.04 (t, J=10.2 Hz, 1H), 3.06 (d, J=7.7 Hz, 1H), 2.14-1.90 (m, 3H), 1.85-1.73 (m, 1H), 1.56 (dd, J=19.2, 10.5 Hz, 1H), 1.39 (d, J=12.8 Hz, 1H), 0.50-0.27 (m, 4H), LC-MS: m/z: 519.1 (M+H).sup.+.

Example 34: Synthesis of Compound III-1

##STR00325## ##STR00326##

Step 1: Synthesis of Compound 34b

[0545] At room temperature, to a 100 mL single-necked flask were added 34a (2.5 g, 9.28 mmol) and ethanol (20 mL). Under stirring, 50% hydrazine hydrate (9.83 g, 139.2 mmol) was added. The mixture was reacted at 80 C. overnight. The reaction solution was concentrated under reduced pressure to obtain a crude. The crude was purified by recrystallization using an acetonitrile solvent, so as to obtain intermediate 34b (2.1 g, 7.02 mmol). LC-MS: m/z: 214.0 (M+H56).sup.+.

Step 2: Synthesis of Compound 34c

[0546] At room temperature, to a 100 mL single-necked flask were added 34b (2.1 g, 7.80 mmol) and 1,2-dichloroethane (25 mL). Under stirring, the compound N,N-carbonyldiimidazole (1.9 g, 11.69 mmol) was sequentially added. The mixture was reacted at room temperature for 18 hours. To the reaction solution was added 50 mL of water, and the mixture was extracted with ethyl acetate. The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain a crude. The crude was purified by a column chromatography machine to obtain intermediate 34c (850 mg, 2.59 mmol). LC-MS: m/z: 240 (M+H56).sup.+.

Step 3: Synthesis of Compound 34e

[0547] Under ice bath, to a 50 mL single-necked flask were added 34d (611 mg, 3.46 mmol) and dimethylformamide (10.0 mL). Under stirring, 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.93 g, 4.61 mmol), diisopropylethylamine (1.87 mg, 14.38 mmol) and compound 34c (850 mg, 2.88 mmol) were sequentially added. At room temperature, the mixture was reacted overnight. To the reaction solution was added 25 mL of water, and the mixture was extracted with ethyl acetate. The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain a crude. The crude was purified by a column chromatography machine to obtain intermediate 34e as a colorless oil. LC-MS: m/z: 419 (M+H).sup.+.

Step 4: Synthesis of Compound 34f

[0548] At room temperature, to a 100 mL single-necked flask were added 34e (220 mg, 0.53 mmol) and dichloromethane (8 mL). Under stirring, trifluoroacetic acid (3.0 mL) was added. The mixture was reacted at room temperature for 1 hour and concentrated under reduced pressure to obtain the crude 34f. LC-MS: m/z: 319 (M+H).sup.+.

Step 4: Synthesis of Compound III-1

[0549] Under ice bath, to a 50 mL single-necked flask were added 1b (115 mg, 0.56 mmol) and dimethylformamide (5.0 mL). Under stirring, 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (268 mg, 0.71 mmol) and diisopropylethylamine (245 mg, 1.88 mmol) were sequentially added. The mixture was reacted at room temperature for half an hour, and then compound 34f (150 mg, 0.47 mmol) was added to the reaction solution. At room temperature, the mixture was reacted overnight. To the reaction solution was added 25 mL of water, and the mixture was extracted with ethyl acetate. The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain a crude. The crude was purified by high performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system) to obtain compound III-1.

[0550] .sup.1H NMR (400 MHz, DMSO-d6) 8.30-8.28 (m, 1H), 7.52-7.47 (m, 1H), 7.09-7.05 (m, 1H), 6.86-6.83 (m, 1H), 5.33-5.30 (m, 1H), 4.48-4.44 (m, 4H), 4.21-4.13 (m, 3H), 3.48-3.44 (m, 1H), 2.51-2.43 (m, 2H), 2.33-2.23 (m, 4H), 2.07-2.01 (m, 2H), LC-MS: m/z: 505.0 (M+H).sup.+.

Example 35: Synthesis of Compound VI-1

##STR00327##

Step 1: Synthesis of Compound 35c

[0551] Under ice bath, to a single-necked flask were added 35a (3 g, 17.83 mmol), a zinc copper reagent (4.6 g, 35.66 mmol) and tetrahydrofuran (50 mL). Under stirring, 35b (6.04 mL, 53.50 mmol) was slowly added dropwise for 20 minutes. The mixture was reacted at 35 C. for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude. The crude was separated by flash column chromatography (petroleum ether:ethyl acetate=100:1-5:1) to obtain intermediate 35c.

Step 2: Synthesis of Compound 35d

[0552] At room temperature, to a single-necked flask were added 35c (4.7 g, 16.84 mmol) and acetic acid (10 mL). Under stirring, zinc powder (4.4 g, 67.34 mmol) was added. The mixture was reacted at 100 C. for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude. The crude was separated by flash column chromatography (petroleum ether:ethyl acetate=100:1-4:1) to obtain intermediate 35d. LC-MS: m/z: 211.0 (M+H).sup.+.

Step 3: Synthesis of Compound 35e

[0553] At room temperature, to a single-necked flask were added 35d (1 g, 4.76 mmol) and methanol (35 mL). Under stirring, 2,4-dimethoxybenzylamine (0.86 mL, 5.71 mmol) was added. At room temperature, the mixture was reacted for 16 hours, and then cyano sodiumborohydride (597 mg, 9.51 mmol) was added to the reaction solution. At room temperature, the mixture was reacted for 6 hours. The reaction solution was concentrated under reduced pressure to obtain a crude. The crude was separated by flash column chromatography (dichloromethane:methanol=100:1-10:1) to obtain intermediate 35e. LC-MS: m/z: 362.2 (M+H).sup.+.

Step 4: Synthesis of Compound 35f

[0554] At room temperature, to a single-necked flask were added 35e (400 mg, 1.11 mmol) and ethanol (5 mL). Under stirring, 80% hydrazine hydrate (5 mL) was added. The mixture was reacted under reflux for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude. The crude was separated by high performance liquid chromatography (aqueous ammonia/acetonitrile/water system) to obtain intermediate 35f (360 mg). LC-MS: m/z: 348.2 (M+H).sup.+.

Step 5: Synthesis of Compound 35g

[0555] At room temperature, to a single-necked flask were added 35f (360 mg, 1.04 mmol) and 1,2-dichloroethane (10 mL). Under stirring, N,N-carbonyldiimidazole (252 mg, 1.55 mmol) was added. The mixture was reacted at room temperature for 16 hours. The reaction solution was poured into 20 mL of water and extracted with dichloromethane (10 mL3). The organic phase was washed with 10 mL of saturated brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain a crude. The crude was separated by flash column chromatography (dichloromethane:methanol=100:1-10:1) to obtain intermediate 35g. LC-MS: m/z: 374.1 (M+H).sup.+.

Step 6: Synthesis of Compound 35h

[0556] At room temperature, to a single-necked flask were added 35g (70 mg, 0.19 mmol) and N,N-dimethylformamide (3.0 mL). Under stirring, 34d (132 mg, 0.94 mmol), N,N-diisopropylethylamine (0.19 mL, 1.12 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (166 mg, 0.37 mmol) were added. The mixture was reacted at room temperature for 18 hours. The reaction solution was poured into 20 mL of water and extracted with ethyl acetate (20 mL3). The organic phase was washed with 30 mL of saturated brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain a crude. The crude was separated by high performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system) to obtain intermediate 35h. LC-MS: m/z: 497.2 (M+H).sup.+.

Step 7: Synthesis of Compound 35i

[0557] Under ice bath, to a single-necked flask were added 1b (10 mg, 0.04 mmol) and dichloromethane (3.0 mL). Under stirring, oxalyl chloride (6 mg, 0.04 mmol) and a drop of N,N-dimethylformamide were added. At room temperature, the mixture was reacted for 30 minutes, and then triethylamine (12 mg, 0.12 mmol) and 35h (20 mg, 0.04 mmol) were added to the reaction solution. At room temperature, the mixture was reacted for one hour. The reaction solution was diluted with 20 mL of saturated aqueous ammonium chloride solution and extracted with dichloromethane (20 mL3). The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain the crude intermediate 35i. The crude was used directly in the next step without purification. LC-MS: m/z: 683.2 (M+H).sup.+.

Step 8: Synthesis of Compound VI-1

[0558] Under ice bath, to a single-necked flask were added 35i (30 mg, 0.04 mmol) and dichloromethane (3.0 mL). Under stirring, trifluoroacetic acid (1.5 mL) was added. At room temperature, the mixture was reacted for 10 minutes. To the reaction solution was added 25 mL of water, and the mixture was extracted with dichloromethane (20 mL1). The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain a crude. The crude was purified by high performance liquid chromatography (trifluoroacetic acid/acetonitrile/water system) to obtain compound VI-1. .sup.1H NMR (400 MHz, DMSO) 8.31 (d, J=7.7 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.08 (dd, J=11.4, 2.8 Hz, 1H), 6.85 (ddd, J=9.0, 2.8, 1.0 Hz, 1H), 5.36-5.27 (m, 1H), 4.49 (s, 2H), 4.45 (m, 2H), 4.23 (m, 1H), 4.18 (m, 2H), 2.76-2.66 (m, 1H), 2.20-2.11 (m, 1H), 2.07-1.96 (m, 1H), 1.84 (m, 1H), 1.76 (m, 3H), 1.71-1.60 (m, 2H), 1.57-1.36 (m, 4H), LC-MS: m/z: 533.0 (M+H).sup.+.

Example 36: Synthesis of Compound IV-1

##STR00328##

Step 1: Synthesis of Compound 36a

[0559] At room temperature, to a single-necked flask were added 17c (1.3 g, 3.98 mmol) and tetrahydrofuran (15.0 mL). Under stirring, the compound N,N-carbonyldiimidazole (1.29 g, 7.96 mmol) was added. The mixture was reacted at room temperature for 2 hours, and then diisopropylethylamine (2.59 g, 19.89 mmol) and 80% hydrazine hydrate (1.59 g, 15.91 mmol) were sequentially added. The mixture was reacted at 45 C. overnight. To the reaction solution was added 50 mL of water, and the mixture was extracted with ethyl acetate (50 mL2). The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain a crude. The crude was slurried by using an acetonitrile solvent to obtain intermediate 36a. LC-MS: m/z: 385.2 (M+H).sup.+.

Step 2: Synthesis of Compound 36b

[0560] Under ice bath, to a single-necked flask were added 36a (200 mg, 0.52 mmol), 1,4-dioxane (5.0 mL) and water (0.5 mL). Under stirring, sodium bicarbonate (65 mg, 1.49 mmol) and bromoacetonitrile (60 mg, 0.57 mmol) were sequentially added. The mixture was warmed to room temperature and reacted overnight. To the reaction solution was added 25 mL of water, and the mixture was extracted with ethyl acetate (20 mL2). The organic phase was washed with 30 mL of saturated brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain the crude compound 36b, which was used directly in the next step without purification. LC-MS: m/z: 410.2 (M+H).sup.+.

Step 3: Synthesis of Compound 36c

[0561] At room temperature, to a single-necked flask were added 36b (180 mg, 0.44 mmol) and anhydrous acetonitrile (5 mL). Under stirring, cuprous bromide (126.0 mg, 0.88 mmol) was added. After 5 minutes, tert-butyl nitrite (25 mg, 0.24 mmol) was added. The mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain a crude. The crude was purified by flash column chromatography (petroleum ether:ethyl acetate=100:1-3:1) to obtain intermediate 36c. LC-MS: m/z: 473.1 (M+H).sup.+.

Step 4: Synthesis of Compound VI-1

[0562] Under ice bath, to a single-necked flask were added 36c (50 mg, 0.11 mmol) and tetrahydrofuran (5.0 mL). Under stirring, potassium carbonate (15 mg, 0.11 mmol) and compound B (22 mg, 0.16 mmol) were sequentially added. The mixture was reacted at 80 C. overnight. To the reaction solution was added 25 mL of water, and the mixture was extracted once with 25 mL of ethyl acetate. The organic phase was washed with 25 mL of saturated brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain a crude. The crude was purified by high performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system) to obtain compound IV-1. .sup.1HNMR (400 MHz, MeOD) =7.38 (t, J=8.7 Hz, 1H), 7.00-6.92 (m, 1H), 6.87-6.79 (m, 1H), 4.67-4.56 (m, 2H), 4.50 (s, 2H), 4.46-4.39 (m, 2H), 4.18 (dd, J=4.4, 9.5 Hz, 2H), 3.39-3.34 (m, 2H), 3.30-3.25 (m, 2H), 2.31 (br t, J=10.5 Hz, 2H), 1.87 (br t, J=10.2 Hz, 2H), 1.78-1.53 (m, 4H), LC-MS: m/z: 534.2 (M+H).sup.+.

[0563] It should be noted that other compounds in the present application can be prepared by methods similar to those in the above examples (if necessary, appropriate adjustments such as replacing reaction raw materials can be made).

Biological Test

[0564] The ATF4 luciferase reporter plasmid consists of two parts, i.e., the 5 untranslated region sequence of the ATF4 gene and the luciferase coding sequence. Specifically, the ATF4 5 untranslated region sequence (NCBI database number BC022088.2) containing two upstream open reading frames (uORFs), and the firefly luciferase encoding gene were cloned into the pLVX-Puro vector (YouBio, VT1465). The packaging plasmids of lentivirus were psPAX2 (YouBio, VT1444) and pMD2.G (YouBio, VT1443). 650,000 HEK293T cells were seeded per well of a 6-well plate and cultured overnight in a 5% CO.sub.2 incubator. The cells were transfected with the packaged lentivirus for 48 hours and then centrifuged, and the supernatant was discarded. The medium was replaced and changed to the DMEM complete medium containing 0.8 g/ml puromycin, and the cells were resuspended and then cultured. After one week of cell screening with puromycin, the surviving cells were HEK293T-ATF4 uORF-Luc-Puro polyclonal cells. 200 polyclonal cells were taken and subjected to limiting gradient dilution by using a 96-well plate, so as to obtain monoclonal cells.

[0565] The specific method for screening the monoclonal cells involves: placing the 200 polyclonal cells in well A1 of the 96-well plate; step one: performing gradient dilution from columns A1 to H1 at a ratio of 1:2; step two: performing gradient dilution from rows A to H, with each row from wells 1 to 12 at a ratio of 1:2; marking the wells with a theoretical cell number less than 0.5 and observing one by one under a microscope; marking the wells with only one cell; and culturing the cells for two weeks to obtain the monoclonal cells.

[0566] By using this cell line and the cold fluorescence readings, the translational regulation of ATF4 can be detected, and the activity of eIF2B activated by the compounds can be tested.

[0567] The specific experimental process is as follows: 6000 HEK293T/17-ATF4 uORF-Luc-Puro monoclonal cells were plated in a 384-well plate and allowed to adhere overnight. The test compounds were dissolved in DMSO and diluted to 10 different concentrations, which were respectively added together with 50 nM thapsigargin to the cell culture medium and incubated for 6 hours, wherein the thapsigargin was used to cause cellular stress and upregulate the protein translation of ATF4. Six hours after the addition, the cells were lysed using the One-Glo Luciferase Assay Kit (Promega #E6120), and then the cold fluorescence values were read using the LUM program of the EnVision 2104 plate reader.

[0568] EC.sub.50 was calculated based on the fluorescence values at 9 concentrations (0.1 nM, 0.3 nM, 1.0 nM, 3.0 nM, 10.0 nM, 30.0 nM, 100.0 nM, 300.0 nM and 1000.0 nM) of each compound and recorded in Table 1.

[0569] The ATF4 reporter expression was calculated as follows:

ATF4 reporter expression=(ave_sample-ave_vc)/(ave_pc-ave_vc)

where ave_vc represents the average signal value of negative controls, ave_pc represents the average signal value of positive controls, and ave_sample represents the average signal value of samples.

[0570] The dose-response curves were fitted, and the EC.sub.50 values were calculated.

[0571] The nonlinear regression log(inhibitor) vs. responsevariable slope (four parameters) method of GraphPad 9 software was used to fit the corresponding relationship between the ATF4 reporter expression and the compound concentration.

[0572] The X-axis represents the log value of the compound concentration; and the Y-axis represents the ATF4 reporter expression.

[00001]$\begin{array}{cc}& \mathrm{Formula}:\end{array}$$Y=\mathrm{Bottom}+\left(\mathrm{Top}-\mathrm{Bottom}\right)/\left(1+10^\left(\left(\mathrm{Log}{\mathrm{EC}}_{50}-X\right)*\mathrm{HillSlope}\right)\right)$

TABLE-US-00001 TABLE 1 EC.sub.50 values of exemplary compounds of the present disclosure in ATF4-Luc assay Compound ATF4-luc EC.sub.50 Compound structure No. (nM).sup.a [00329] I-1 + [00330] I-2 + [00331] I-3 + [00332] I-4 + [00333] I-5 + [00334] I-6 + [00335] I-7 + [00336] I-8 + [00337] I-9 + [00338] I-10 ++ [00339] II-10 + [00340] II-11 + [00341] II-12 ++ [00342] II-13 + [00343] II-14 + [00344] III-1 +++ [00345] III-10 + [00346] III-11 + [00347] III-12 + [00348] III-13 ++ [00349] IV-1 ++ [00350] IV-11 ++ [00351] IV-12 + [00352] IV-13 +++ [00353] IV-14 ++ [00354] IV-15 + [00355] IV-16 + [00356] IV-17 + [00357] IV-18 ++ [00358] IV-19 ++ [00359] IV-20 +++ [00360] V-10 ++ [00361] V-11 + [00362] V-12 + [00363] VI-1 ++ [00364] VIII-1 +++ + indicates the ATF4-luc EC.sub.50 being greater than 100 nM; ++ indicates the ATF4-luc EC.sub.50 ranging from 10 nM and 100 nM; +++ indicates the ATF4-luc EC.sub.50 being less than 10 nM.

[0573] The experimental results (partially not shown) show that the compounds of the present application can enhance the activity of eIF2B and reduce the expression of ATF4, thereby weakening the fluorescence intensity. It is indicated that the compounds of the present application can significantly alleviate the cellular stress caused by thapsigargin and weaken the integrated stress response of cells, so that proteins in the cells tend to be synthesized normally.

2. Kinetic Solubility Evaluation

[0574] The test compounds were dissolved in DMSO to prepare 10 mM stock solutions. 8.71 g of K.sub.2HPO.sub.4 was added to 500 mL of deionized water to prepare a 100 mM K.sub.2HPO.sub.4 solution. 2.05 g of potassium dihydrogen phosphate was added to 150 mL of deionized water to prepare a 100 mM potassium dihydrogen phosphate solution. 405 mL of 100 mM K.sub.2HPO.sub.4 and 95 mL of 100 mM KH.sub.2PO.sub.4 were mixed, and the mixed solution was adjusted to pH 7.4 by a 100 mM K.sub.2HPO.sub.4/KH.sub.2PO.sub.4 solution. 10.41 g of FaSSIF buffer concentrate was added to 240.3 g of deionized water to prepare a buffer solution (fasted-state simulated intestinal fluid, pH=6.5). 4.071 g of FeSSIF buffer concentrate was added to 45.97 g of deionized water to prepare a buffer solution (fasted-state simulated intestinal fluid, pH=5.0).

[0575] 16 L of the 10 mM stock solution of the compound was added to 784 L of different buffer solutions (n=3) in a 96-well plate, and the plate was sealed and shaken at 1000 rpm for 1.5 h at 25 C. (for PBS) or 37 C. (for others). After the incubation, the solution was transferred to a filter plate. All samples were filtered. 5 L of the filtrate was added to 5 L of DMSO, and 490 L of an aqueous acetonitrile solution containing the internal standard (1:1), and the mixture was mixed evenly. Based on the properties of the compound and its response in mass spectrometry, dilution with an aqueous acetonitrile solution containing the internal standard (1:1) was performed. The dilution factor was varied according to the solubility value and UPLC-MS/MS signal response.

[0576] The experiments show that at least some of the compounds of the present application have good solubility in the above-mentioned different simulated environments.

3. Evaluation of Cell Membrane Permeability

[0577] The test compounds were diluted from 10 mM stock solutions to a concentration of 10 M using the transport buffer (HBSS+BSA) and applied to the apical or basolateral side of the cell monolayer. After the incubation at 37 C., 5% CO.sub.2 and 95% relative humidity for 120 minutes, the permeability of the test compounds in the A to B direction or the B to A direction was dually determined. In addition, the efflux ratio (Papp B to A/Papp A to B) of each compound was determined. The test substances and reference substances were quantitatively analyzed by the LC-MS/MS method based on the analyte/IS peak area ratio.

TABLE-US-00002 TABLE 2 Cell membrane permeability of exemplary compounds Papp (10.sup.6 cm/s) Efflux Compound No. A to B B to A Ratio Atenolol 0.41 0.61 Propranolol 32.43 20.14 Digoxin 0.25 11.17 44.68 III-1 17.72 18.63 1.05

[0578] The experimental results show that at least some of the compounds of the present application (such as Ill-1) have good cell membrane permeability and are not P-glycoprotein substrates.

4. Pharmacokinetic Evaluation in Mice

[0579] The test compounds were dissolved in vehicles to prepare clear solutions or homogeneous suspensions. Three mice were placed in each group and received an intravenous (IV) administration via the tail vein at 1 mg/kg and an oral (PO) administration at 30 mg/kg. Blood samples were collected at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after the intravenous administration, and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after the oral administration. Plasma samples were centrifuged, and the supernatant was collected to prepare samples, which were then quantitatively analyzed by LC/MS/MS.

TABLE-US-00003 TABLE 3 PK properties of exemplary compounds in mice mouse IV C.sub.0 (ng/mL) 1344 (1 mg/kg) T.sub.1/2 (h) 2.07 Cl (mL/h/kg) 450 V.sub.ss (L/kg) 1.18 AUC.sub.(0-inf) (ng*h/ml) 2230.64 mouse PO C.sub.max (ng/mL) 21541.07 (30 mg/kg) T.sub.1/2 (h) 1.93 T.sub.max (h) 1.33 AUC.sub.(0-inf) (ng*h/ml) 110833.28 F % 177.04

[0580] The experimental results show that at least some of the compounds of the present application (such as III-1) have excellent pharmacokinetic properties in mice (including but not limited to C.sub.0 (initial drug concentration), CL (clearance), AUC, t (half-life), C.sub.max (peak concentration), T.sub.max (time to reach peak concentration), AUC (area under the plasma drug concentration-time curve), F (bioavailability) and Vss (apparent volume of distribution at steady state)).

[0581] The technical solutions of the present disclosure are not limited to the above-mentioned specific examples. All technical variations made according to the technical solutions of the present disclosure fall within the protection scope of the present disclosure.