Heterocyclic compounds capable of inhibiting PRMT5·MTA and their uses

Abstract

A nitrogen-containing heterocyclic compound represented by formula (Ia), its stereoisomer, deuterated product, solvate, pharmaceutically acceptable salt or co-crystal, and pharmaceutical compositions thereof, and its use in the manufacture of a medicament for treating / preventing a PRMT5·MTA-mediated disease, wherein each group in formula (Ia) is as defined in the specification. [C1] TIFF2025525478000148.tif33156

Description

[Technical Field]

[0001] The present invention relates to inhibitors of the PRMT5·MTA complex and their use in the manufacture of tumor treatments. [Background technology]

[0002] Protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is an important post-translational modification pathway that methylates the nitrogen atom of the arginine side chain of proteins using S-adenosine methionine (SAM) as a methyl group donor. Based on the arginine methylation status, nine identified human PRMTs (PRMT1-9) are further subdivided into types I, II, and III. Type I PRMTs catalyze the formation of monomethylarginine (MMA) and asymmetric dimethylarginine (aDMA) and include PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8. Type II PRMTs catalyze the formation of MMA and symmetric dimethylarginine (sDMA) and include PRMT5 and PRMT9. Type III PRMTs catalyze the formation of MMA and include PRMT7. PRMT5 belongs to type II PRMTs and transfers a methyl group from SAM to the guanido nitrogen of arginine residues to generate MMA and sDMA, thereby regulating the expression of target genes through epigenetic mechanisms or regulating important signaling molecules through post-translational methylation modification pathways.

[0003] Homozygous deletions of pl6 / CDKN2a are ubiquitous in cancer. These mutations are usually associated with the co-deletion of adjacent genes, including the gene encoding methylthioadenosine phosphorylase (MTAP). Estimates suggest that approximately 15% of human cancers harbor homozygous deletions of the MTAP gene (e.g., see Firestone & Schramm (2017) J. Am. Chem Soc. 139(39):13754–13760. doi:10.1021 / jacs.7b05803. Epub 2017 Sep 20).

[0004] In MTAP-deficient cells, excessive accumulation of methylthioadenosine (MTA) occurs, forming a complex with PRMT5, PRMT5·MTA, which partially inhibits PRMT5 enzymatic activity and increases the sensitivity of cell proliferation to PRMT5 deletion or loss of activity. Therefore, MTAP deletion reduces the methylation activity of PRMT5, rendering cells selectively dependent on PRMT5 activity. In MTAP-deficient cancers, inhibition of PRMT5 activity, which synergistically involves MTA, offers therapeutic benefits for various cancers.

[0005] Therefore, there is a need to develop novel MTA-synergistic PRMT5 inhibitors that can inhibit PRMT5 activity when MTA concentrations are elevated, particularly in MTAP-deficient cells. Summary of the Invention

[0006] The present invention provides a compound of formula (Ia), formula (Ib), formula (I), formula (II-a) or formula (II), a stereoisomer, deuterated product, solvate or pharmaceutically acceptable salt thereof, which has excellent effects such as high activity, excellent physicochemical properties, ease of formulation, high bioavailability and low toxic side effects.

[0007] A compound of formula (Ia), formula (Ib), formula (I), formula (II-a) or formula (II), a stereoisomer, a deuterated product, a solvate or a pharmaceutically acceptable salt thereof, [ka] where D is [ka] In some embodiments, D is selected from [ka] In some embodiments, D is selected from [ka] In some embodiments, D is selected from [ka] In some embodiments, D is selected from [ka] In some embodiments, D is selected from [ka] In some embodiments, D is selected from [ka] is selected from In some embodiments, D is [ka] In some embodiments, D is selected from [ka] In some embodiments, D is selected from [ka] In some embodiments, D is selected from [ka] In some embodiments, D is selected from [ka] In some embodiments, D is selected from [ka] In some embodiments, D is selected from [ka] is selected from D1 is [ka] In some embodiments, D1 is selected from: [ka] is selected from Ld, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 In some embodiments, L is selected from the group consisting of C 2-4 Alkenyl group, C 2-4 In some embodiments, L is selected from the group consisting of C 2-4 In some embodiments, L is selected from the group consisting of: [ka] is selected from Rd1 is selected from 5-membered heteroaryl groups, said heteroaryl groups optionally containing halogen, D, CN, OH, C 1-4Alkyl group, C 1-4 In some embodiments, Rd1 is selected from a 5-membered heteroaryl group, and the heteroaryl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, C 1-2 Alkyl group, C 1-2 In some embodiments, Rd1 is selected from a 5-membered heteroaryl group, wherein the heteroaryl group is optionally substituted with 1 or 2 groups selected from NH2; in some embodiments, Rd1 is selected from [ka] is selected from X is selected from CR1 or N, in some embodiments, X is CR1, in some embodiments, X is N, in some embodiments, X is CH; Y, Z, and V are independently CR5, C(R5)2, NR6, N, O, or S, and the sum of O and S is equal to or less than 1; in some embodiments, Y, Z, and V are independently CR5, N, O, or S, and the sum of O and S is equal to or less than 1; in some embodiments, Y, Z, and V are independently CR5, N, or S, and the sum of S is equal to or less than 1; Ring A is a phenyl group, a 5- to 7-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S; in some embodiments, ring A is a phenyl group or a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S; in some embodiments, ring A is a phenyl group, a thienyl group, a thiazolyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, or a pyridazinyl group; Ring B is C 3-12 In some embodiments, ring B is a carbocyclic ring or a 4- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, ring B is C9-12 Parallel cyclic aryl group, C 6-12 In some embodiments, ring B is a phenyl group, C 3-6 a cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, or a 5- to 6-membered aryl group containing 1-3 heteroatoms selected from N, O, and S; in some embodiments, Ring B is a thienyl group, a thiazolyl group, a pyrrolyl group, an imidazolyl group, or a pyrazolyl group; in some embodiments, Ring B is a pyrazolyl group; Ring C is C 3-12 A carbocycle or a 4- to 12-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, ring C is a phenyl group, C 3-6 a cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered aryl group containing 1 to 3 heteroatoms selected from N, O, and S; in some embodiments, ring C is a phenyl group, a thienyl group, a thiazolyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, or a pyridazinyl group; in some embodiments, ring C is a phenyl group; R1 is H, D, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 In some embodiments, R is an alkynyl group, halogen, CN, OH, NH, or COOH, and the alkyl, alkoxy, alkenyl, or alkynyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH; in some embodiments, R is H, D, C 1-4alkyl group, halogen, CN, wherein the alkyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, and OH; in some embodiments, R1 is H, D, C 1-4 an alkyl group, F, Cl, Br, I, or CN, said alkyl group being optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, and OH; R2 is OH, NH2, -CH2NH2, or -NH-OH; in some embodiments, R2 is OH, NH2, or -NH-OH; in some embodiments, R2 is NH2; R3 and R4 are independently H, D, halogen, or C 1-4 Alkyl groups, CN, OH, NH2, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group or C 3-6 and R3, R4 are independently selected from H, D, halogen, C, H, D, H ... 1-4 an alkyl group, CN, OH, or NH2, wherein the alkyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH2; in some embodiments, R3, R4 are independently H, D, F, Cl, Br, I, C 1-4 an alkyl group or CN, wherein the alkyl group is optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, OH, and NH; in some embodiments, R, R are independently H or D; Each R5 is independently H, D, ═O, OH, C 1-4 Alkyl group, CN, halogen, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4an alkynyl group, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C 3-6 and a cycloalkyl group, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, heteroaryl group, or cycloalkyl group is optionally selected from the group consisting of halogen, D, CN, OH, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from alkoxy and NH; in some embodiments, each R is independently H, D, OH, C 1-4 Alkyl group, CN, halogen, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 an alkynyl group, a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C 3-4 and cycloalkyl groups, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, heteroaryl group, heterocycloalkyl group, and cycloalkyl group are optionally selected from the group consisting of halogen, D, CN, OH, C 1-4 Alkyl group, C 1-4 alkoxy, and NH. In some embodiments, each R is independently H, D, OH, C. 1-4 Alkyl groups: CN, F, Cl, Br, I, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 an alkynyl group, a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C 3-4and cycloalkyl groups, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, heteroaryl group, heterocycloalkyl group, and cycloalkyl group are optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, OH, methoxy, and NH. In some embodiments, each R is independently selected from H, D, ═O, OH, C, 1-4 Alkyl group, CN, halogen, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group or C 3-6 and a cycloalkyl group, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, or cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH. In some embodiments, each R is independently selected from H, D, OH, C 1-4 Alkyl group, CN, halogen, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 an alkynyl group, a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C 3-4 and cycloalkyl groups, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, heteroaryl group, heterocycloalkyl group, and cycloalkyl group are optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH. In some embodiments, each R is independently selected from H, D, OH, C, 1-4 Alkyl groups: CN, F, Cl, Br, I, C 1-4 Alkoxy group, C 2-4 Alkenyl group, or C 2-4 an alkynyl group, a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C 3-4and cycloalkyl groups, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, heteroaryl group, heterocycloalkyl group, and cycloalkyl group are optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, OH, and NH. In some embodiments, each R is independently selected from H, D, CN, F, Cl, C, 1-2 Alkoxy group, C 2-4 Alkenyl group, C 2-4 and R is an alkynyl group, a pyrazolyl group, an azetidinyl group, a cyclopropyl group, or a cyclobutyl group, wherein the alkyl group, alkenyl group, alkynyl group, pyrazolyl group, azetidinyl group, cyclopropyl group, or cyclobutyl group is optionally substituted with 1, 2, or 3 groups selected from F, Cl, Br, I, D, CN, OH, and NH; and in some embodiments, each R is independently selected from H, D, OH, C, D, CN ... 1-4 Alkyl group, CN, halogen, C 1-4 Alkoxy group, C 2-4 Alkenyl group, or C 2-4 and an alkynyl group, wherein the alkyl, alkoxy, alkenyl, or alkynyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH. In some embodiments, each R is independently selected from H, D, OH, C, 1-4 Alkyl groups: CN, F, Cl, Br, I, C 1-4 Alkoxy group, C 2-4 Alkenyl group, or C 2-4 an alkynyl group, wherein the alkyl, alkoxy, alkenyl, or alkynyl group is optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, OH, and NH; R6 is H, D, C 1-4 Alkyl group or C 3-6 a cycloalkyl group, wherein the alkyl group or cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH2; in some embodiments, R6 is H; Each R7 is independently H, ═O, D, OH, CN, halogen, C 1-4 Alkyl group, C 1-4Alkoxy group, N(R7')2, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 A cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, or heterocycloalkyl group optionally contains halogen, D, OH, NH, CN, C 1-4 Alkyl group, -C(O)C 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl group, -C(O)NH2, -NHC(O)C 1-4 Alkyl groups and C 1-4 In some embodiments, each R7 is independently substituted with 1 to 3 groups selected from H, ═O, D, OH, CN, halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, N(R7')2, C 2-4 Alkenyl group, or C 2-4 and an alkynyl group, wherein the alkyl, alkoxy, alkenyl, or alkynyl group optionally includes halogen, D, OH, NH, CN, C. 1-4 Alkyl group, -C(O)C 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl group, -C(O)NH2, -NHC(O)C 1-4 Alkyl groups and C 1-4 In some embodiments, each R is independently substituted with 1 to 3 groups selected from H, D, OH, CN, halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, N(R7')2, C 2-4 Alkenyl group, or C 2-4 and an alkynyl group, wherein the alkyl, alkoxy, alkenyl, or alkynyl group optionally includes halogen, D, OH, NH, CN, C. 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Each R8 is independently H, D, a nitro group, an amino group, or C 1-6Alkoxy group, =O, OH, CN, halogen, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -SF5, N3, C 1-6 Alkyl group, -COC 1-4 Alkyl group, -N(R7')2, -C(=O)N(R7')2, -NR7'C(=O)-R7', -C(=O)-R7', -(CH2) r -O-(CH2) r -R8', -SC 1-6 Alkyl group, -S(O)-C 1-6 Alkyl group, -S(O)2-C 1-6 Alkyl group, -S-(CH2) r -R8', -NR7'-(CH2) r -R8' or -(CH2) r -R8', wherein the alkyl, alkenyl, or alkynyl group is optionally selected from the group consisting of R 8’’ In some embodiments, each R is independently substituted with 1 to 5 selected from H, D, ═O, OH, CN, halogen, C 2-4 Alkenyl group, C 2-4 Alkynyl group, N3, C 1-4 Alkyl group, -COC 1-4 Alkyl group, -CONR7'C 1-4 Alkyl group, -NR7'COC 1-4 alkyl group, N(R7')2, -O-(CH2)r-R8', or -(CH2)r-R8', wherein the alkyl group, alkenyl group, or alkynyl group is optionally selected from the group consisting of halogen, D, OH, NH2, CN, C 1-4 Alkyl groups and C 1-4 In some embodiments, each R is independently substituted with 1 to 3 groups selected from D, ═O, OH, CN, halogen, C 2-4 Alkenyl group, C 2-4 Alkynyl group, N3, C 1-4 Alkyl group, -COC 1-4 Alkyl group, -CONR7'C 1-4 Alkyl group, -NR7'COC 1-4alkyl group, N(R7')2, -O-(CH2)r-R8', or -(CH2)r-R8', wherein the alkyl group, alkenyl group, or alkynyl group is optionally selected from the group consisting of halogen, D, OH, NH2, CN, C 1-2 Alkyl groups and C 1-2 In some embodiments, each R is independently substituted with 1 to 3 groups selected from D, CN, F, Cl, Br, C 2-4 Alkenyl group, C 2-4 Alkynyl group, N3, C 1-4 alkyl group, -O-(CH2)r-R8', or -(CH2)r-R8', wherein the alkyl group, alkenyl group, or alkynyl group is optionally selected from the group consisting of halogen, D, OH, NH2, CN, C 1-2 Alkyl groups and C 1-2 substituted with 1 to 3 groups selected from alkoxy groups, or Each R8 is independently H, D, a nitro group, an amino group, or C 1-6 Alkoxy group, =O, OH, CN, halogen, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -SF5, C 1-6 Alkyl group, -COC 1-4 Alkyl group, -N(R7')2, -C(=O)N(R7')2, -NR7'C(=O)-R7', -C(=O)-R7', -(CH2) r -O-(CH2) r -R8', -SC 1-6 Alkyl group, -S(O)-C 1-6 Alkyl group or -S(O)2-C 1-6 Alkyl group, -S-(CH2) r -R8', -NR7'-(CH2) r -R8' or -(CH2) r -R8', wherein the alkyl, alkenyl, or alkynyl group is optionally selected from the group consisting of R 8’’ In some embodiments, each R is independently selected from a halogen, a deuterium, a nitro group, a cyano group, an amino group, a hydroxy group, ═O, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C2-6 Alkynyl groups, -SF5, -(CH2) r -O-(CH2) r -R8', -(CH2) r -C 3-12 Cycloalkyl groups, -(CH2) r -(3-12 membered heterocycloalkyl), -O-(CH2) r -C 3-12 Cycloalkyl groups, -O-(CH2) r -(3- to 12-membered heterocycloalkyl), -NR7'-C 3-12 Cycloalkyl groups, -NR7'- (3- to 12-membered heterocycloalkyl), -SC 3-12 Cycloalkyl groups, -S-(3- to 12-membered heterocycloalkyl), -(CH2) r -(5-12 membered heteroaryl), -(CH2) r -(6-12 membered aryl), -O-(CH2) r -(5-12 membered heteroaryl), -O-(CH2) r -(6- to 12-membered aryl), -NR7'-(CH2) r -(5-12 membered heteroaryl), -NR7'-(CH2) r -(6-12 membered aryl), -N(R7')2, -C(=O)N(R7')2, -NR7'C(=O)-R7', -C(=O)-R7', -SC 1-6 Alkyl group, -S(O)-C 1-6 Alkyl group or -S(O)2-C 1-6 and the alkyl group, alkoxy group, CH, heterocycloalkyl group, cycloalkyl group, heteroaryl group, or aryl group optionally has 1 to 5 R 8’’ or Each R8 is independently H, D, =O, OH, CN, halogen, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -SF5, C 1-4 Alkyl group, -COC 1-4 Alkyl group, -CONR7'C 1-4 Alkyl group, -NR7'COC 1-4 Alkyl group, N(R7')2, -O-(CH2) r -R8', -S-(CH2)r -R8', -NR7'-(CH2) r -R8' or -(CH2) r -R8', wherein the alkyl, alkenyl, or alkynyl group is optionally selected from the group consisting of halogen, D, OH, NH2, CN, C 1-4 Alkyl groups and C 1-4 In some embodiments, each R is independently substituted with 1 to 3 groups selected from H, D, ═O, OH, CN, halogen, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkyl group, -COC 1-4 Alkyl group, -CONR7'C 1-4 Alkyl group, -NR7'COC 1-4 Alkyl group, N(R7')2, -O-(CH2) r -R8', or -(CH2) r -R8', wherein the alkyl, alkenyl, or alkynyl group is optionally selected from the group consisting of halogen, D, OH, NH2, CN, C 1-4 Alkyl groups and C 1-4 In some embodiments, each R is independently substituted with 1 to 3 groups selected from H, D, OH, CN, F, Cl, Br, I, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkyl group, -COC 1-4 Alkyl group, -CONR7'C 1-4 Alkyl group, -NR7'COC 1-4 Alkyl group, N(R7')2, -O-(CH2) r -R8', or -(CH2) r -R8', wherein the alkyl, alkenyl, or alkynyl group is optionally selected from the group consisting of halogen, D, OH, NH2, CN, C 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups, or [ka] Each R7' is independently H, D, an amino group, a hydroxy group, or C 1-6Alkyl group, halo C 1-6 Alkyl groups, deuterated C 1-6 Alkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-12 Heterocycloalkyl groups, -NHC 1-6 Alkyl group, -N(C 1-6 alkyl)2, or deuterated C 1-6 The cycloalkyl group and heterocycloalkyl group may optionally contain deuterium, halogen, cyano, amino, hydroxy, C 1-6 Alkyl group, halo C 1-6 Alkyl groups, deuterated C 1-6 Alkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group or deuterated C 1-6 In some embodiments, each R7' is independently substituted with 1 to 3 groups selected from H, D, an amino group, a hydroxy group, C 1-4 Alkyl group, halo C 1-4 Alkyl groups, deuterated C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-12 Heterocycloalkyl groups, -NHC 1-4 Alkyl group, -N(C 1-4 alkyl)2, or deuterated C 1-4 The cycloalkyl group and heterocycloalkyl group may optionally contain deuterium, halogen, cyano, amino, hydroxy, C 1-4 Alkyl group, halo C 1-4 Alkyl groups, deuterated C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 Alkoxy group or deuterated C 1-4 In some embodiments, each R7' is independently substituted with 1 to 3 groups selected from H, D, an amino group, a hydroxy group, C 1-4 Alkyl group, halo C 1-2Alkyl groups, deuterated C 1-2 Alkyl group, C 1-2 Alkoxy group, haloC 1-2 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-12 Heterocycloalkyl groups, -NHC 1-2 Alkyl group, -N(C 1-2 alkyl)2, or deuterated C 1-2 The cycloalkyl group and heterocycloalkyl group may optionally contain deuterium, halogen, cyano, amino, hydroxy, C 1-2 Alkyl group, halo C 1-2 Alkyl groups, deuterated C 1-2 Alkyl group, C 1-2 Alkoxy group, haloC 1-2 Alkoxy group or deuterated C 1-2 In some embodiments, each R7' is independently substituted with 1 to 3 groups selected from H, D, an amino group, a hydroxy group, C 1-4 is an alkyl group, or Each R7' is independently H, C 1-4 Alkyl or halo C 1-4 In some embodiments, each R is independently H or C. 1-4 is an alkyl group, and in some embodiments, each R is independently H; Each R8' is independently H, D, C 1-6 Alkyl group, C 1-4 Alkoxy group, C 3-12 A 4- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from a carbocycle, N, O, and S, and the alkyl and alkoxy groups are optionally selected from halogen, ═O, D, OH, NH, CN, C 1-6 Alkyl group, halo C 1-6 Alkyl groups, deuterated C 1-6 Alkyl group, -C(O)C 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl group, -C(O)NH2, -NHC(O)C 1-4 Alkyl group, C 1-6 Alkoxy group, haloC 1-6Alkoxy groups and deuterated C 1-6 alkoxy groups, and the carbocyclic or heterocyclic ring is optionally substituted with 1 to 3 groups selected from R 8’’ In some embodiments, each R is independently substituted with 1 to 5 selected from H, C 1-4 Alkoxy group, C 3-6 a cycloalkyl group, a phenyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenyl group, heterocycloalkyl group, or heteroaryl group optionally contains halogen, ═O, D, OH, NH, CN, C 1-4 Alkyl group, halo C 1-4 Alkyl groups, and C 1-4 In some embodiments, each R is independently substituted with 1 to 3 groups selected from H, C 1-4 Alkoxy group, C 3-6 a cycloalkyl group, a phenyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenyl group, heterocycloalkyl group, or heteroaryl group optionally contains halogen, ═O, D, OH, NH, CN, C 1-4 Alkyl group, halo C 1-4 Alkyl groups, and C 1-4 In some embodiments, R is independently substituted with 1 to 3 groups selected from C 1-4 an alkoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a phenyl group, a tetrahydropyrrolyl group, an azetidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, [ka] thienyl, thiazolyl, pyrrolyl, imidazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, optionally F, Cl, Br, I, ═O, D, OH, NH, CN, C 1-4 Alkyl group, halo C 1-2 Alkyl groups, and C 1-2 substituted with 1 to 3 groups selected from alkoxy groups, or Each R8' is independently H, D, C 1-6 Alkyl group, C 1-4 Alkoxy group, C 3-12 A 4- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from a carbocycle, N, O, and S, and the alkyl and alkoxy groups are optionally selected from halogen, ═O, D, OH, NH, CN, C 1-6 Alkyl group, halo C 1-6 Alkyl groups, deuterated C 1-6 Alkyl group, -C(O)C 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl group, -C(O)NH2, -NHC(O)C 1-4 Alkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy groups and deuterated C 1-6 alkoxy groups, and the carbocyclic or heterocyclic ring is optionally substituted with 1 to 3 groups selected from R 8’’ In some embodiments, each R is independently substituted with 1 to 5 selected from H, D, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-12 A 4- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from a carbocycle, N, O, and S, and the alkyl and alkoxy groups are optionally selected from halogen, ═O, D, OH, NH, CN, C 1-4 Alkyl group, halo C 1-4 Alkyl groups, deuterated C 1-4 Alkyl group, -C(O)C 1-2 Alkyl group, -C(O)NHC 1-2 Alkyl group, -C(O)NH2, -NHC(O)C 1-2 Alkyl group, C 1-2 Alkoxy group, haloC1-2 Alkoxy groups and deuterated C 1-2 alkoxy groups, and the carbocyclic or heterocyclic ring is optionally substituted with 1 to 3 groups selected from R 8’’ or substituted with 1 to 5 selected from Each R' is independently H, C 1-4 Alkoxy group, C 3-9 A 4- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from a carbocycle, N, O, and S, wherein the carbocycle or heterocyclic ring is optionally selected from halogen, ═O, D, OH, NH, CN, C 1-4 Alkyl group, -C(O)C 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl group, -C(O)NH2, -NHC(O)C 1-4 Alkyl groups and C 1-4 In some embodiments, each R is independently substituted with 1 to 3 groups selected from H, C 1-4 Alkoxy group, C 3-6 a cycloalkyl group, a phenyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenyl group, heterocycloalkyl group, or heteroaryl group optionally contains halogen, ═O, D, OH, NH, CN, C 1-4 Alkyl groups, and C 1-4 In some embodiments, each R is independently substituted with 1 to 3 groups selected from H, C 1-4 Alkoxy group, C 3-6 a cycloalkyl group, a phenyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenyl group, heterocycloalkyl group, or heteroaryl group optionally contains halogen, ═O, D, OH, NH, CN, C 1-4 Alkyl groups, and C 1-4In some embodiments, R is independently substituted with 1 to 3 groups selected from C 1-4 an alkoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a phenyl group, a tetrahydropyrrolyl group, an azetidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, [ka] thienyl, thiazolyl, pyrrolyl, imidazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, optionally F, Cl, Br, I, ═O, D, OH, NH, CN, C 1-4 Alkyl groups, and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; R 8’’ are halogens, D, OH, NH2, CN, C 1-6 Alkyl groups and C 1-6 alkoxy groups, wherein the alkyl or alkoxy groups are optionally selected from halogen, deuterium, cyano, amino, hydroxy, C 1-6 Alkyl group or C 1-6 and in some embodiments, R 8’’ are halogens, D, OH, NH2, CN, C 1-4 Alkyl groups and C 1-4 alkoxy groups, wherein the alkyl or alkoxy groups are optionally selected from halogen, deuterium, cyano, amino, hydroxy, C 1-2 Alkyl group or C 1-2 In some specific embodiments, R 8’’is selected from deuterium, F, Cl, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, and the methyl, ethyl, propyl, methoxy, ethoxy, or propoxy group is optionally further substituted with 1 to 3 groups selected from F, Cl, deuterium, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy; each r is independently 0, 1, 2, or 3; in some embodiments, each r is independently 0, 1, or 2; p is 0, 1, or 2, and in some embodiments, p is 0 or 1; n and m are independently integers from 0 to 5, and in some embodiments, n is 0, 1, 2, or 3, and in some embodiments, m is 0, 1, 2, 3, or 4; For the compounds of the present invention, where: 1. group [ka] teeth, [ka] Instead, 2. [ka] but [ka] When R3 is H, C 1-4 Alkyl group, C 1-4 is a haloalkyl group, and R5 is H, halogen, or C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 When R3 and R5 are not both H, the group [ka] teeth, [ka] is.

[0008] As a more specific first technical solution of the present invention, there is provided a compound represented by formula (Ia) or (Ib), a stereoisomer thereof, a deuterated product thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, [ka] where: D is [ka] is selected from D1 is [ka] is selected from Ld, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 alkynyl groups, Rd1 is selected from 5-membered heteroaryl groups, said heteroaryl groups optionally containing halogen, D, CN, OH, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group and NH; X is selected from CR1 or N; Y, Z, and V are independently CR5, C(R5)2, NR6, N, O, or S, and the total number of O and S is not more than 1; Ring A is a phenyl group, a 5- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S; Ring B is C 3-12 a carbocyclic ring or a 4- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S; Ring C is C 3-12 a carbocyclic ring or a 4- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S; R1 is H, D, C1-4 Alkyl group, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 an alkynyl group, halogen, CN, OH, NH2, or COOH, wherein the alkyl group, alkoxy group, alkenyl group, or alkynyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH2; R2 is OH, NH2, -CH2NH2 or -NH-OH; R3 and R4 are independently H, D, halogen, or C 1-4 Alkyl groups, CN, OH, NH2, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group or C 3-6 a cycloalkyl group, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, or cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH; In one option, R3 and R4 together form =NH, Each R5 is independently H, D, ═O, OH, C 1-4 Alkyl group, CN, halogen, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 an alkynyl group, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C 3-6 and a cycloalkyl group, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, heteroaryl group, or cycloalkyl group is optionally selected from the group consisting of halogen, D, CN, OH, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group and NH; R6 is H, D, C 1-4 Alkyl group or C 3-6 a cycloalkyl group, wherein the alkyl or cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH; Each R7 is independently H, ═O, D, OH, CN, halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, N(R7')2, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 A cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, or heterocycloalkyl group optionally contains halogen, D, OH, NH, CN, C 1-4 Alkyl group, -C(O)C 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl group, -C(O)NH2, -NHC(O)C 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Each R8 is independently H, D, a nitro group, an amino group, or C 1-6 Alkoxy group, =O, OH, CN, halogen, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -SF5, N3, C 1-6 Alkyl group, -COC 1-4 Alkyl group, -N(R7')2, -C(=O)N(R7')2, -NR7'C(=O)-R7', -C(=O)-R7', -(CH2) r -O-(CH2) r -R8', -SC 1-6 Alkyl group, -S(O)-C 1-6 Alkyl group, -S(O)2-C 1-6 Alkyl group, -S-(CH2) r -R8', -NR7'-(CH2) r -R8' or -(CH2) r -R8', wherein the alkyl, alkenyl, or alkynyl group is optionally selected from the group consisting of R 8’’ and is substituted with 1 to 5 selected from Each R7' is independently H, D, an amino group, a hydroxy group, or C 1-6 Alkyl group, halo C 1-6 Alkyl groups, deuterated C1-6 Alkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-12 Heterocycloalkyl groups, -NHC 1-6 Alkyl group, -N(C 1-6 alkyl)2, or deuterated C 1-6 The cycloalkyl group and heterocycloalkyl group may optionally contain deuterium, halogen, cyano, amino, hydroxy, C 1-6 Alkyl group, halo C 1-6 Alkyl groups, deuterated C 1-6 Alkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group or deuterated C 1-6 substituted with 1 to 3 groups selected from alkoxy groups; Each R8' is independently H, D, C 1-6 Alkyl group, C 1-4 Alkoxy group, C 3-12 A 4- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from a carbocycle, N, O, and S, and the alkyl and alkoxy groups are optionally selected from halogen, ═O, D, OH, NH, CN, C 1-6 Alkyl group, halo C 1-6 Alkyl groups, deuterated C 1-6 Alkyl group, -C(O)C 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl group, -C(O)NH2, -NHC(O)C 1-4 Alkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy groups and deuterated C 1-6 alkoxy groups, and the carbocyclic or heterocyclic ring is optionally substituted with 1 to 3 groups selected from R 8’’ and is substituted with 1 to 5 selected from R 8’’ are halogens, D, OH, NH2, CN, C 1-6 Alkyl groups and C 1-6alkoxy groups, wherein the alkyl or alkoxy groups are optionally selected from halogen, deuterium, cyano, amino, hydroxy, C 1-6 Alkyl group or C 1-6 is further substituted with 1 to 5 groups selected from an alkoxy group; each r is independently 0, 1, 2, or 3; p is 0, 1 or 2; n and m are independently an integer of 0 to 5; As a condition, 1. group [ka] teeth, [ka] Instead, 2. [ka] but [ka] When R3 is H, C 1-4 Alkyl group, C 1-4 is a haloalkyl group, and R5 is H, halogen, or C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 When R3 and R5 are not both H, the group [ka] teeth, [ka] is.

[0009] As a more specific second technical solution of the present invention, there is provided a compound represented by formula (Ia), a stereoisomer, a deuterated product, a solvate, or a pharmaceutically acceptable salt thereof, [ka] where: D is [ka] is selected from X is selected from CR1 or N; Y, Z, and V are independently CR5, C(R5)2, NR6, N, O, or S, and the total number of O and S is not more than 1; Ring A is a phenyl group, a 5- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S; Ring B is C 3-12 a carbocyclic ring or a 4- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S; Ring C is C 3-12 a carbocyclic ring or a 4- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S; R1 is H, D, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 an alkynyl group, halogen, CN, OH, NH2, or COOH, wherein the alkyl group, alkoxy group, alkenyl group, or alkynyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH2; R2 is OH, NH2, -CH2NH2 or -NH-OH; R3 and R4 are independently H, D, halogen, or C 1-4 Alkyl groups, CN, OH, NH2, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group or C 3-6 a cycloalkyl group, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, or cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH; In one option, R3 and R4 together form =NH, Each R5 is independently H, D, ═O, OH, C 1-4 Alkyl group, CN, halogen, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 an alkynyl group, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C 3-6 and a cycloalkyl group, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, heteroaryl group, or cycloalkyl group is optionally selected from the group consisting of halogen, D, CN, OH, C 1-4 Alkyl group, C 1-4 substituted with 1 to 3 groups selected from an alkoxy group and NH; R6 is H, D, C 1-4 Alkyl group or C 3-6 a cycloalkyl group, wherein the alkyl or cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH; Each R7 is independently H, ═O, D, OH, CN, halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, N(R7')2, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 A cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, or heterocycloalkyl group optionally contains halogen, D, OH, NH, CN, C 1-4 Alkyl group, -C(O)C 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl group, -C(O)NH2, -NHC(O)C 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Each R8 is independently H, D, a nitro group, an amino group, or C1-6 Alkoxy group, =O, OH, CN, halogen, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -SF5, C 1-6 Alkyl group, -COC 1-4 Alkyl group, -N(R7')2, -C(=O)N(R7')2, -NR7'C(=O)-R7', -C(=O)-R7', -(CH2) r -O-(CH2) r -R8', -SC 1-6 Alkyl group, -S(O)-C 1-6 Alkyl group, -S(O)2-C 1-6 Alkyl group, -S-(CH2) r -R8', -NR7'-(CH2) r -R8', -(CH2) r -R8' or N3, and the alkyl, alkenyl, or alkynyl group is optionally selected from R 8’’ and is substituted with 1 to 5 selected from Each R7' is independently H, D, an amino group, a hydroxy group, or C 1-6 Alkyl group, halo C 1-6 Alkyl groups, deuterated C 1-6 Alkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-12 Heterocycloalkyl groups, -NHC 1-6 Alkyl group, -N(C 1-6 alkyl)2, or deuterated C 1-6 The cycloalkyl group and heterocycloalkyl group may optionally contain deuterium, halogen, cyano, amino, hydroxy, C 1-6 Alkyl group, halo C 1-6 Alkyl groups, deuterated C 1-6 Alkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group or deuterated C 1-6 substituted with 1 to 3 groups selected from alkoxy groups; Each R8' is independently H, D, C 1-6 Alkyl group, C 1-4 Alkoxy group, C3-12 A 4- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from a carbocycle, N, O, and S, and the alkyl and alkoxy groups are optionally selected from halogen, ═O, D, OH, NH, CN, C 1-6 Alkyl group, halo C 1-6 Alkyl groups, deuterated C 1-6 Alkyl group, -C(O)C 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl group, -C(O)NH2, -NHC(O)C 1-4 Alkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy groups and deuterated C 1-6 alkoxy groups, and the carbocyclic or heterocyclic ring is optionally substituted with 1 to 3 groups selected from R 8’’ and is substituted with 1 to 5 selected from R 8’’ are halogens, D, OH, NH2, CN, C 1-6 Alkyl groups and C 1-6 alkoxy groups, wherein the alkyl or alkoxy groups are optionally selected from halogen, deuterium, cyano, amino, hydroxy, C 1-6 Alkyl group or C 1-6 is further substituted with 1 to 5 groups selected from an alkoxy group; each r is independently 0, 1, 2, or 3; p is 0, 1 or 2; n and m are independently an integer of 0 to 5; As a condition, 1. group [ka] teeth, [ka] Instead, 2. [ka] but [ka] When R3 is H, C 1-4 Alkyl group, C 1-4 is a haloalkyl group, and R5 is H, halogen, or C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 When R3 and R5 are not both H, the group [ka] teeth, [ka] is.

[0010] As a more specific third technical solution of the present invention, the compound of formula (Ia), its stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt has the structure of the following formula (I): [ka] The definitions of other groups are consistent with any of the above technical proposals.

[0011] As a more specific fourth technical solution of the present invention, there is provided a compound represented by formula (I), a stereoisomer, a deuterated product, a solvate, or a pharmaceutically acceptable salt thereof, [ka] wherein X is selected from CR1 or N; Y, Z, and V are independently CR5, C(R5)2, NR6, N, O, or S, and the total number of O and S is not more than 1; Ring A is a phenyl group, a 5- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S; Ring B is C 3-12 a carbocyclic ring or a 4- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S; Ring C is C3-12 a carbocyclic ring or a 4- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S; R1 is H, D, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 an alkynyl group, halogen, CN, OH, NH2, or COOH, wherein the alkyl group, alkoxy group, alkenyl group, or alkynyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH2; R2 is OH, NH2, -CH2NH2 or -NH-OH, or R2 is OH, NH2 or -NH-OH; R3 and R4 are independently H, D, halogen, or C 1-4 Alkyl groups, CN, OH, NH2, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group or C 3-6 a cycloalkyl group, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, or cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH; Each R5 is independently H, D, ═O, OH, C 1-4 Alkyl group, CN, halogen, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group or C 3-6 a cycloalkyl group, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, or cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH; R6 is H, D, C 1-4 Alkyl group or C 3-6 a cycloalkyl group, wherein the alkyl or cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH; Each R7 is independently H, ═O, D, OH, CN, halogen, C 1-4 Alkyl group, C 1-4Alkoxy group, N(R7')2, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 A cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, or heterocycloalkyl group optionally contains halogen, D, OH, NH, CN, C 1-4 Alkyl group, -C(O)C 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl group, -C(O)NH2, -NHC(O)C 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Each R8 is independently H, D, =O, OH, CN, halogen, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -SF5, C 1-4 Alkyl group, -COC 1-4 Alkyl group, -CONR7'C 1-4 Alkyl group, -NR7'COC 1-4 alkyl group, N(R7')2, -O-(CH2)r-R8', -S-(CH2)r-R8', -NR7'-(CH2)r-R8' or -(CH2)r-R8', wherein the alkyl group, alkenyl group, alkynyl group optionally contains halogen, D, OH, NH2, CN, C 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Each R7' is independently H, C 1-4 Alkyl or halo C 1-4 is an alkyl group, Each R' is independently H, C 1-4 Alkoxy group, C 3-9 A 4- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from a carbocycle, N, O, and S, wherein the carbocycle or heterocyclic ring is optionally selected from halogen, ═O, D, OH, NH, CN, C 1-4 Alkyl group, -C(O)C 1-4 Alkyl group, -C(O)NHC 1-4Alkyl group, -C(O)NH2, -NHC(O)C 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; each r is independently 0, 1, 2, or 3; p is 0, 1 or 2; n and m are independently an integer of 0 to 5; As a condition, 1. group [ka] teeth, [ka] Instead, 2. [ka] but [ka] When R3 is H, C 1-4 Alkyl group, C 1-4 is a haloalkyl group, and R5 is H, halogen, or C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 When R3 and R5 are not both H, the group [ka] teeth, [ka] is.

[0012] As a fifth more specific technical solution of the present invention, there is provided a compound represented by formula (Ia), formula (Ib), formula (I), formula (II-a) or formula (II), a stereoisomer, a deuterated product, a solvate or a pharmaceutically acceptable salt thereof, wherein: D is [ka] and D is selected from [ka] and D is selected from [ka] and further selected from D is [ka] and further selected from D is [ka] is selected from The definitions of other groups are consistent with any of the above technical proposals.

[0013] As a more specific sixth technical solution of the present invention, there is provided a compound represented by formula (Ia), formula (Ib), formula (I), formula (II-a) or formula (II), a stereoisomer thereof, a deuterated product thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein: D is [ka] is selected from The definitions of other groups are consistent with any of the above technical proposals.

[0014] As a more specific seventh technical solution of the present invention, there is provided a compound represented by formula (Ia), formula (Ib), formula (I), a stereoisomer thereof, a deuterated product thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein X is selected from CR1 or N; Y, Z, and V are independently CR5, N, O, or S, and the total number of O and S is not more than 1; Ring A is a phenyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S; Ring B is a phenyl group, C 3-6a cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a 5- to 6-membered aryl group containing 1 to 3 heteroatoms selected from N, O and S; Ring C is a phenyl group, C 3-6 a cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a 5- to 6-membered aryl group containing 1 to 3 heteroatoms selected from N, O and S; R1 is H, D, C 1-4 alkyl group, halogen, CN, wherein the alkyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, and OH; R2 is OH, NH2, -CH2NH2 or -NH-OH, or R2 is OH, NH2 or -NH-OH; R3 and R4 are independently H, D, halogen, or C 1-4 an alkyl group, CN, OH, or NH2, said alkyl group being optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH2; Each R5 is independently H, D, OH, C 1-4 Alkyl group, CN, halogen, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 an alkynyl group, a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C 3-4 and cycloalkyl groups, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, heteroaryl group, heterocycloalkyl group, and cycloalkyl group are optionally selected from the group consisting of halogen, D, CN, OH, C 1-4 Alkyl group, C 1-4 alkoxy, and NH. In some embodiments, each R is independently H, D, OH, C. 1-4 Alkyl group, CN, halogen, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4an alkynyl group, a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C 3-4 and wherein the alkyl, alkoxy, alkenyl, alkynyl, heteroaryl, heterocycloalkyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH2, or each R5 is independently selected from H, D, OH, C 1-4 Alkyl group, CN, halogen, C 1-4 Alkoxy group, C 2-4 Alkenyl group, or C 2-4 an alkynyl group, wherein the alkyl, alkoxy, alkenyl, or alkynyl group is optionally substituted with 1 to 3 groups selected from halogen, D, CN, OH, and NH; Each R7 is independently H, ═O, D, OH, CN, halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, N(R7')2, C 2-4 Alkenyl group, or C 2-4 and an alkynyl group, wherein the alkyl, alkoxy, alkenyl, or alkynyl group optionally includes halogen, D, OH, NH, CN, C. 1-4 Alkyl group, -C(O)C 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl group, -C(O)NH2, -NHC(O)C 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Each R8 is independently H, D, =O, OH, CN, halogen, C 2-4 Alkenyl group, C 2-4 Alkynyl group, N3, C 1-4 Alkyl group, -COC 1-4 Alkyl group, -CONR7'C 1-4 Alkyl group, -NR7'COC 1-4alkyl group, N(R7')2, -O-(CH2)r-R8', or -(CH2)r-R8', wherein the alkyl group, alkenyl group, or alkynyl group is optionally selected from the group consisting of halogen, D, OH, NH2, CN, C 1-4 Alkyl groups and C 1-4 or each R8 is independently substituted with 1 to 3 groups selected from H, D, ═O, OH, CN, halogen, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkyl group, -COC 1-4 Alkyl group, -CONR7'C 1-4 Alkyl group, -NR7'COC 1-4 alkyl group, N(R7')2, -O-(CH2)r-R8', or -(CH2)r-R8', wherein the alkyl group, alkenyl group, or alkynyl group is optionally selected from the group consisting of halogen, D, OH, NH2, CN, C 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Each R7' is independently H, C 1-4 Alkyl or halo C 1-4 is an alkyl group, Each R' is independently H, C 1-4 Alkoxy group, C 3-6 a cycloalkyl group, a phenyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenyl group, heterocycloalkyl group, or heteroaryl group optionally contains halogen, ═O, D, OH, NH, CN, C 1-4 Alkyl group, halo C 1-4 Alkyl groups, and C 1-4 or each R8' is independently substituted with 1 to 3 groups selected from H, C 1-4 Alkoxy group, C 3-6a cycloalkyl group, a phenyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenyl group, heterocycloalkyl group, or heteroaryl group optionally contains halogen, ═O, D, OH, NH, CN, C 1-4 Alkyl groups, and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; each r is independently 0, 1, or 2; p is 0 or 1; n and m are independently 0, 1, 2, 3, or 4; Other groups are as described in any one of the first, second, third, fourth, fifth and sixth technical solutions.

[0015] As a more specific eighth technical solution of the present invention, in the compound of the present invention, its stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt, ring B is [ka] is selected from.

[0016] As a more specific ninth technical solution of the present invention, there is provided a compound represented by formula (Ia), formula (I), a stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (II-a), formula (II): [ka] Other groups are as described in the first, second, third, fourth, fifth, sixth, seventh and eighth technical proposals.

[0017] As a more specific tenth technical solution of the present invention, there is provided a compound represented by formula (Ia), formula (Ib), formula (I), formula (II-a) or formula (II), a stereoisomer thereof, a deuterated product thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, where: X is selected from CR1 or N; Y, Z, and V are independently CR5, N, O, or S, and the total number of O and S is not more than 1; Ring A is a phenyl group, a thienyl group, a thiazolyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, or a pyridazinyl group; D is [ka] or D is selected from [ka] is selected from Or, D is [ka] is selected from R1 is H, D, C 1-4 an alkyl group, F, Cl, Br, I, or CN, said alkyl group being optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, and OH; R2 is OH, NH2, -CH2NH2 or -NH-OH; R3 and R4 are independently H, D, F, Cl, Br, I, or C 1-4 an alkyl group or CN, wherein the alkyl group is optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, OH, and NH; Each R5 is independently H, D, OH, C 1-4 Alkyl groups: CN, F, Cl, Br, I, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 an alkynyl group, a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C 3-4and cycloalkyl groups, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, heteroaryl group, heterocycloalkyl group, and cycloalkyl group are optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, OH, methoxy, and NH. In some embodiments, each R is independently selected from H, D, OH, C, 1-4 Alkyl groups: CN, F, Cl, Br, I, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 an alkynyl group, a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C 3-4 and wherein the alkyl, alkoxy, alkenyl, alkynyl, heteroaryl, heterocycloalkyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, OH, and NH; or each R is independently selected from H, D, OH, C, 1-4 Alkyl groups: CN, F, Cl, Br, I, C 1-4 Alkoxy group, C 2-4 Alkenyl group, or C 2-4 an alkynyl group, wherein the alkyl, alkoxy, alkenyl, or alkynyl group is optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, OH, and NH; Each R7 is independently H, D, OH, CN, halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, N(R7')2, C 2-4 Alkenyl group, or C 2-4 and an alkynyl group, wherein the alkyl, alkoxy, alkenyl, or alkynyl group optionally includes halogen, D, OH, NH, CN, C. 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Each R8 is independently H, D, OH, CN, F, Cl, Br, I, C 2-4 Alkenyl group, C 2-4Alkynyl group, N3, C 1-4 Alkyl group, -COC 1-4 Alkyl group, -CONR7'C 1-4 Alkyl group, -NR7'COC 1-4 alkyl group, N(R7')2, -O-(CH2)r-R8', or -(CH2)r-R8', wherein the alkyl group, alkenyl group, or alkynyl group is optionally selected from the group consisting of halogen, D, OH, NH2, CN, C 1-4 Alkyl groups and C 1-4 or each R8 is independently substituted with 1 to 3 groups selected from H, D, OH, CN, F, Cl, Br, I, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkyl group, -COC 1-4 Alkyl group, -CONR7'C 1-4 Alkyl group, -NR7'COC 1-4 alkyl group, N(R7')2, -O-(CH2)r-R8', or -(CH2)r-R8', wherein the alkyl group, alkenyl group, or alkynyl group is optionally selected from the group consisting of halogen, D, OH, NH2, CN, C 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Each R7' is independently H, C 1-4 Alkyl or halo C 1-4 is an alkyl group, Each R' is independently H, C 1-4 Alkoxy group, C 3-6 a cycloalkyl group, a phenyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenyl group, heterocycloalkyl group, or heteroaryl group optionally contains halogen, ═O, D, OH, NH, CN, C 1-4 Alkyl group, halo C 1-4 Alkyl groups, and C 1-4 or each R8' is independently substituted with 1 to 3 groups selected from H, C 1-4 Alkoxy group, C3-6 a cycloalkyl group, a phenyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenyl group, heterocycloalkyl group, or heteroaryl group optionally contains halogen, ═O, D, OH, NH, CN, C 1-4 Alkyl groups, and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; each r is independently 0, 1, or 2; p is 0 or 1; n is 0, 1, 2 or 3; m is 0, 1, 2, 3 or 4; Other groups are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth and ninth technical proposals.

[0018] As a more specific eleventh technical solution of the present invention, there is provided a compound represented by formula (Ia), formula (Ib), formula (I), formula (II-a) or formula (II), a stereoisomer thereof, a deuterated product thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein: X is selected from CR1 or N; Y, Z, and V are independently CR5, N, O, or S, and the total number of O and S is not more than 1; Ring A is a phenyl group, a thienyl group, a thiazolyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, or a pyridazinyl group; D is [ka] is selected from R1 is H, D, C 1-4 an alkyl group, F, Cl, Br, I, or CN, said alkyl group being optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, and OH; R2 is OH, NH2, -CH2NH2 or -NH-OH; R3 and R4 are independently H, D, F, Cl, Br, I, or C 1-4 an alkyl group or CN, wherein the alkyl group is optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, OH, and NH; Each R5 is independently H, D, OH, C 1-4 Alkyl groups: CN, F, Cl, Br, I, C 1-4 Alkoxy group, C 2-4 Alkenyl group, or C 2-4 an alkynyl group, wherein the alkyl, alkoxy, alkenyl, or alkynyl group is optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, OH, and NH; Each R7 is independently H, D, OH, CN, halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, N(R7')2, C 2-4 Alkenyl group, or C 2-4 and an alkynyl group, wherein the alkyl, alkoxy, alkenyl, or alkynyl group optionally includes halogen, D, OH, NH, CN, C. 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Each R8 is independently H, D, OH, CN, F, Cl, Br, I, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkyl group, -COC 1-4 Alkyl group, -CONR7'C 1-4 Alkyl group, -NR7'COC 1-4 alkyl group, N(R7')2, -O-(CH2)r-R8', or -(CH2)r-R8', wherein the alkyl group, alkenyl group, or alkynyl group is optionally selected from the group consisting of halogen, D, OH, NH2, CN, C 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Each R7' is independently H, C 1-4 Alkyl or halo C 1-4 is an alkyl group, Each R' is independently H, C1-4 Alkoxy group, C 3-6 a cycloalkyl group, a phenyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenyl group, heterocycloalkyl group, or heteroaryl group optionally contains halogen, ═O, D, OH, NH, CN, C 1-4 Alkyl groups, and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; each r is independently 0, 1, or 2; p is 0 or 1; n is 0, 1, 2 or 3; m is 0, 1, 2, 3 or 4; Other groups are as described in any of the above technical solutions.

[0019] As a more specific twelfth technical solution of the present invention, there is provided a compound represented by formula (Ia), formula (Ib), formula (I), formula (II-a) or formula (II), a stereoisomer thereof, a deuterated product thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, X is selected from CR1 or N; Y, Z, and V are independently CR5, N, O, or S, and the total number of O and S is not more than 1; Ring A is a phenyl group, a thienyl group, a thiazolyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, or a pyridazinyl group; R1 is H, D, C 1-4 an alkyl group, F, Cl, Br, I, or CN, said alkyl group being optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, and OH; R2 is OH, NH2 or -NH-OH; R3 and R4 are independently H, D, F, Cl, Br, I, or C 1-4 an alkyl group or CN, wherein the alkyl group is optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, OH, and NH; Each R5 is independently H, D, OH, C 1-4 Alkyl groups: CN, F, Cl, Br, I, C 1-4 Alkoxy group, C 2-4 Alkenyl group, or C 2-4 an alkynyl group, wherein the alkyl, alkoxy, alkenyl, or alkynyl group is optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, OH, and NH; Each R7 is independently H, D, OH, CN, halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, N(R7')2, C 2-4 Alkenyl group, or C 2-4 and an alkynyl group, wherein the alkyl, alkoxy, alkenyl, or alkynyl group optionally includes halogen, D, OH, NH, CN, C. 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Each R8 is independently H, D, OH, CN, F, Cl, Br, I, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkyl group, -COC 1-4 Alkyl group, -CONR7'C 1-4 Alkyl group, -NR7'COC 1-4 alkyl group, N(R7')2, -O-(CH2)r-R8', or -(CH2)r-R8', wherein the alkyl group, alkenyl group, or alkynyl group is optionally selected from the group consisting of halogen, D, OH, NH2, CN, C 1-4 Alkyl groups and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Each R7' is independently H, C 1-4 Alkyl or halo C 1-4 is an alkyl group, Each R' is independently H, C 1-4 Alkoxy group, C 3-6a cycloalkyl group, a phenyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenyl group, heterocycloalkyl group, or heteroaryl group optionally contains halogen, ═O, D, OH, NH, CN, C 1-4 Alkyl groups, and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; each r is independently 0, 1, or 2; p is 0 or 1; n is 0, 1, 2 or 3; m is 0, 1, 2, 3 or 4; The other groups are as described in any one of the above technical solutions.

[0020] As a more specific thirteenth technical solution of the present invention, there is provided a compound represented by formula (Ia), formula (Ib), formula (I), formula (II-a) or formula (II), a stereoisomer thereof, a deuterated product thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, Each R8 is independently D, CN, F, Cl, Br, C 2-4 Alkenyl group, C 2-4 Alkynyl group, N3, C 1-4 alkyl group, -O-(CH2)r-R8', or -(CH2)r-R8', wherein the alkyl group, alkenyl group, or alkynyl group is optionally selected from the group consisting of halogen, D, OH, NH2, CN, C 1-2 Alkyl groups and C 1-2 substituted with 1 to 3 groups selected from alkoxy groups; The definitions of other groups are as in the above optional technical proposals.

[0021] As a more specific 14th technical solution of the present invention, there is provided a compound represented by formula (Ia), formula (Ib), formula (I), formula (II-a) or formula (II), a stereoisomer, a deuterated product, a solvate or a pharmaceutically acceptable salt thereof, wherein: R8' is independently C 1-4an alkoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a phenyl group, a tetrahydropyrrolyl group, an azetidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, [ka] thienyl, thiazolyl, pyrrolyl, imidazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, optionally F, Cl, Br, I, ═O, D, OH, NH, CN, C 1-4 Alkyl group, halo C 1-2 Alkyl groups, and C 1-2 substituted with 1 to 3 groups selected from alkoxy groups, or R8' is independently C 1-4 an alkoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a phenyl group, a tetrahydropyrrolyl group, an azetidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, [ka] thienyl, thiazolyl, pyrrolyl, imidazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, optionally F, Cl, Br, I, ═O, D, OH, NH, CN, C 1-4 Alkyl groups, and C 1-4 substituted with 1 to 3 groups selected from alkoxy groups; Other groups are as described in any of the above technical solutions.

[0022] As a more specific fifteenth technical solution of the present invention, there is provided a compound represented by formula (Ia), formula (Ib), formula (I), formula (II-a) or formula (II), a stereoisomer thereof, a deuterated product thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein D is [ka] is selected from D is [ka] is selected from The definitions of other groups are consistent with any one of the above technical solutions.

[0023] As a more specific 16th technical solution of the present invention, there is provided a compound represented by formula (Ia), formula (Ib), formula (I), formula (II-a) or formula (II), a stereoisomer, a deuterated product, a solvate or a pharmaceutically acceptable salt thereof, wherein: R8 is -O-(CH2) r -R 8’ , 3 to 12-membered heterocycloalkyl group, C 3-12 Cycloalkyl groups, -O-(CH2) r -C 3-12 Cycloalkyl groups, -O-(CH2) r -(3- to 12-membered heterocycloalkyl group) or -N(R 7’ )2, wherein the CH2, cycloalkyl group, and heterocycloalkyl group are optionally selected from 1 to 3 R 8’’ Preferably, the cycloalkyl group is further substituted with 1 to 3 R 8’’ is further substituted with Each R 7’ are each independently hydrogen, deuterium, an amino group, a hydroxy group, or C 1-4 Alkyl group, halo C 1-4 Alkyl groups, deuterated C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 Alkoxy group or deuterated C 1-4 alkoxy groups, R 8’ is C 1-4 Alkyl group or C 1-4 alkoxy groups, wherein the alkyl or alkoxy groups are optionally selected from deuterium, halogen, C 1-4 Alkyl group, halo C 1-4 Alkyl groups, deuterated C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC1-4 Alkoxy group or deuterated C 1-4 is further substituted with 1 to 5 groups selected from an alkoxy group; Each R 8’’ are independently deuterium, ═O, halogen, C 1-4 Alkyl group or C 1-4 alkoxy groups, wherein the alkyl or alkoxy groups are optionally selected from halogen, deuterium, hydroxyl groups, C 1-4 Alkyl group or C 1-4 is further substituted with 1 to 3 groups selected from an alkoxy group; The definitions of the other groups are the same as above.

[0024] As a more specific 17th technical solution of the present invention, there is provided a compound represented by formula (Ia), formula (Ib), formula (I), formula (II-a) or formula (II), a stereoisomer, a deuterated product, a solvate or a pharmaceutically acceptable salt thereof, wherein: R8 is -O-(CH2) r -O(CH2) r CH3, 4-6 membered monocyclic heterocycloalkyl group, 5-8 membered parallel cyclic heterocycloalkyl group, 5-11 membered spirocyclic heterocycloalkyl group, 5-8 membered bridged cyclic heterocycloalkyl group, -O-(CH2) r -C 3-8 Monocyclic cycloalkyl groups, -O-(CH2) r -4-6 membered monocyclic heterocycloalkyl group, -O-(CH2) r -5-8 membered parallel cyclic heterocycloalkyl group, -O-(CH2) r -5-8 membered spirocyclic heterocycloalkyl group, -O-(CH2) r -5 to 8-membered bridged cyclic heterocycloalkyl group or -N(CH3)2, and the heterocycloalkyl group or cycloalkyl group may optionally be selected from 1 to 3 R 8’’ Preferably, the cycloalkyl group is further substituted with 1 to 3 R 8’’ is further substituted with R 8’’are each independently selected from deuterium, ═O, F, Cl, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, and the methyl, ethyl, propyl, methoxy, ethoxy, or propoxy groups are optionally further substituted with 1 to 3 groups selected from F, Cl, deuterium, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy; The definitions of the other groups are the same as above.

[0025] As a more specific eighteenth technical solution of the present invention, there is provided a compound represented by formula (Ia), formula (Ib), formula (I), formula (II-a) or formula (II), a stereoisomer, a deuterated product, a solvate or a pharmaceutically acceptable salt thereof, wherein: [ka] R8 is -O-CH2CH2-OCH3, -N(CH3)2, [ka] is selected from The definitions of the other groups are the same as above.

[0026] As a more specific 19th technical solution of the present invention, there is provided a compound of formula (Ib), its stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt, wherein: D1 is [ka] is selected from Ld, C 2-4 In some embodiments, L is selected from the group consisting of: [ka] is selected from Rd1 is selected from a 5-membered heteroaryl group, said heteroaryl group optionally substituted with 1-2 groups selected from NH2, and in some embodiments, Rd1 is [ka] is selected from.

[0027] As a more specific twentieth technical solution of the present invention, there is provided a compound of the present invention, its stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt, wherein the compound is selected from the structures in Table 1 below.

[0028] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

[0029] As a more specific 21st technical solution of the present invention, there is provided a pharmaceutical composition, which contains a compound according to any one of the 1st to 20th technical solutions, its stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

[0030] As a more specific 22nd technical solution of the present invention, there is provided a use, namely, a use of a compound described in any one of technical solutions 1 to 20, its stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt, or a composition described in technical solution 21, in the manufacture of a pharmaceutical for treating / preventing PRMT5·MTA-mediated diseases.

[0031] Furthermore, the PRMT5·MTA-mediated disease is selected from liver cancer, breast cancer, skin cancer, bladder cancer, pancreatic cancer, or head and neck cancer.

[0032] The present invention further provides a composition or pharmaceutical formulation comprising a compound according to any one of the preceding methods, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (a unit dosage form is also referred to as a "formulation specification").

[0033] The present invention also provides a composition or pharmaceutical formulation comprising 1 to 1500 mg of any one of the compounds described above, its stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

[0034] The present invention further provides a use of the compound, stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof according to any one of the above methods in the manufacture of a medicament for treating / preventing a PRMT5·MTA-mediated disease, wherein the PRMT5·MTA-mediated disease is liver cancer, breast cancer, skin cancer, bladder cancer, pancreatic cancer, or head and neck cancer.

[0035] The present invention further provides a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of any one of the compounds described above, or a stereoisomer, deuterated salt, solvate, or pharmaceutically acceptable salt thereof, wherein the disease is preferably liver cancer, breast cancer, skin cancer, bladder cancer, pancreatic cancer, or head and neck cancer, and the therapeutically effective amount is preferably 1 to 1500 mg. In some embodiments, the mammal described in the present invention includes a human.

[0036] As used herein, an "effective amount" or "therapeutically effective amount" includes administering a sufficient amount of a compound disclosed herein that relieves to some extent one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is necessary to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 1-50 mg, 1-1 ... 500mg, 5~1000mg, 5~900mg, 5~800mg, 5~700mg, 5~600mg, 5~500mg, 5~400mg, 5~300mg, 5~250mg, 5~200mg, 5~150mg, 5~1 25mg, 5~100mg, 5~90mg, 5~70mg, 5~80mg, 5~60mg, 5~50mg, 5~40mg, 5~30mg, 5~25mg, 5~20mg, 10~1500mg, 10~1000mg, 10 ~900mg, 10~800mg, 10~700mg, 10~600mg, 10~500mg, 10~450mg, 10~400mg, 10~300mg, 10~250mg, 10~200mg, 10~150mg, 1 0~125mg, 10~100mg, 10~90mg, 10~80mg, 10~70mg, 10~60mg, 10~50mg, 10~40mg, 10~30mg, 10~20mg, 20~1500mg, 20~1000 mg, 20~900mg, 20~800mg, 20~700mg, 20~600mg, 20~500mg, 20~400mg, 20~350mg, 20~300mg, 20~250mg, 20~200mg, 20~15 0mg, 20~125mg, 20~100mg, 20~90mg, 20~80mg, 20~70mg, 20~60mg, 20~50mg, 20~40mg, 20~30mg, 50~1500mg, 50~1000mg,Including, but not limited to, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 50-100mg, 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg In some embodiments, the pharmaceutical composition or formulation of the invention comprises a therapeutically effective amount of a compound of the invention or a stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt thereof, The present invention relates to a pharmaceutical composition or formulation comprising a therapeutically effective amount of a compound according to the present invention or a stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt thereof and a carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of active ingredient in a unit dosage form is also referred to as the "formulation specification"). In some embodiments, the pharmaceutical composition contains 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, including, but not limited to, 5 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of a compound of the present invention or a stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt thereof.

[0037] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably liver cancer, breast cancer, skin cancer, bladder cancer, pancreatic cancer, or head and neck cancer.

[0038] A method for treating a disease in a mammal, the method comprising administering to a subject a pharmaceutical compound of the present invention, a stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, in a daily dose of 1 to 1500 mg / day, which may be a single dose or divided doses, and in some embodiments, the daily dose is 10 to 1500 mg / day, 20 to 1500 mg / day, 25 to 1500 mg / day, 50 to 1500 mg / day, 75 to 1500 mg / day, 100 to 1500 mg / day, 200 to 1500 mg / day, 10 to 1000 mg / day, 20 to 1000 mg / day, 25 to 1000 mg / day, 50 to 1000 mg / day, 75 to 1500 mg / day, In some embodiments, the daily dose includes, but is not limited to, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, and 200-400 mg / day. Amounts include, but are not limited to, 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, and 1500 mg / day.

[0039] The present invention relates to a kit, which may contain a composition in single-dose or multi-dose form, comprising a compound of the present invention or a stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt thereof, wherein the amount of the compound of the present invention or a stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt thereof is the same as the amount in the pharmaceutical composition.

[0040] In the present invention, the amounts of the compounds of the invention or their stereoisomers, deuterated forms, solvates or pharmaceutically acceptable salts are in each case calculated in terms of the free base form.

[0041] "Preparation specifications" refers to the weight of the active ingredient contained in one unit dosage form, one tablet, or each other unit dosage form.

[0042] Synthetic Route Those skilled in the art can combine known organic synthesis techniques to prepare the compounds of the present invention, and the starting materials are commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are those obtained from legitimate commercial sources, including companies such as Taitan Technology, Ananji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical, Nanjing Yaoshi, Yaoming Kangde, and Bailingwei Technology.

[0043] Specific and similar reactants can be selectively identified through indexes of known chemicals produced by the American Chemical Society's Chemical Information Retrieval Service, which are available in many public and university libraries and online. Known chemicals not available in catalogs may optionally be produced by custom chemical synthesis businesses, many of which offer custom synthesis services (e.g., the companies listed above).

[0044] term Unless otherwise specified in the present invention, the terms used in the present invention have the following meanings.

[0045] Carbon, hydrogen, oxygen, sulfur, nitrogen or halogen in the groups and compounds described in the present invention include any of their isotopes, and carbon, hydrogen, oxygen, sulfur, nitrogen or halogen in the groups and compounds described in the present invention are optionally further substituted by one or more corresponding isotopes, where the carbon isotope is: 12 C and 13 C and 14 C, isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called tritium), and isotopes of oxygen include 16 O and 17 O and 18 Isotopes of sulfur include O and 32 S and 33 S and 34 S and 36 S and nitrogen isotopes include 14 N and 15 N and fluorine isotopes include 19 F, and the chlorine isotope is 35 Cl and 37 The isotopes of bromine include Cl and 79 Br and 81 Contains Br.

[0046] As used herein, "halogen" refers to F, Cl, Br, I, or an isotope thereof.

[0047] "Halogenated" or "halogen substituted" refers to substitution with one or more selected from F, Cl, Br, I, or isotopes thereof, and the upper limit of the number of halogen substituents is equal to the sum of the substitutable hydrogen atoms of the group to be substituted. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, and when the number of halogen substituents is greater than 1, they may be substituted with the same or different halogens. Usually, cases of 1 to 5 halogen substitutions, 1 to 3 halogen substitutions, 1 to 2 halogen substitutions, and 1 halogen substitution are included.

[0048] "Deuterium" refers to heavy hydrogen, an isotope of hydrogen (H), and has the same meaning as "D."

[0049] The term "deuterated" or "deuteride" refers to a group such as an alkyl group, a cycloalkyl group, an alkylene group, an aryl group, a heteroaryl group, a mercapto group, a heterocycloalkyl group, an alkenyl group, or an alkynyl group, in which a hydrogen atom is substituted with at least one deuterium atom, and the upper limit of the number of deuteration is equal to the sum of the numbers of hydrogen atoms that can be substituted in the substituted groups. Unless otherwise specified, the number of deuteration is any integer between 1 and the upper limit, such as 1 to 20 deuterium atom substitutions, 1 to 10 deuterium atom substitutions, 1 to 6 deuterium atom substitutions, 1 to 3 deuterium atom substitutions, 1 to 2 deuterium atom substitutions, or 1 deuterium atom substitution.

[0050] "C x-y " group refers to a group containing x to y carbon atoms, e.g., "C 1-6 "Alkyl group" refers to an alkyl group containing from 1 to 6 carbon atoms.

[0051] "Alkyl group" refers to a monovalent linear or branched saturated aliphatic hydrocarbon group. Typically, the alkyl group has 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like, and the alkyl group may be further substituted with a substituent.

[0052] "Alkylene group" refers to divalent straight and branched chain saturated alkyl groups. Examples of alkylene groups include, but are not limited to, methylene groups, ethylene groups, and the like.

[0053] A "haloalkyl group" refers to an alkyl group in which one or more hydrogen atoms are replaced with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine, or isotopes thereof), and the upper limit of the number of halogen substituents is equal to the sum of the replaceable hydrogen atoms in the alkyl group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. Typically, the alkyl group is substituted with 1 to 5 halogen atoms, or 1 to 3 halogen atoms, or 1 to 2 halogen atoms, or 1 halogen atom. When the number of halogen substituents is greater than 1, they may be substituted with the same or different halogen atoms. Specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0054] An "alkoxy group" or "alkyloxy group" refers to an -O-alkyl group. For example, -OC 1-8 Alkyl group, -OC 1-6 Alkyl group, -OC 1-4 Alkyl group or -OC 1-2 Specific non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy, and cyclobutoxy groups, and the alkoxy groups may be optionally substituted with a substituent.

[0055] A "haloalkoxy group" refers to an -O-haloalkyl group. For example, -O-haloC 1-8 Alkyl group, -O-haloC 1-6 Alkyl group, -O-haloC 1-4 Alkyl group or -O-haloC 1-2It is an alkyl group, and the upper limit of the number of halogen substituents is equal to the sum of the substitutable hydrogen atoms in the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, and preferably 1 to 5 halogen substituents, 1 to 3 halogen substituents, 1 to 2 halogen substituents, or 1 halogen substituent. When the number of halogen substituents is more than 1, they may be substituted with the same or different halogens. Non-limiting examples include a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, and a difluoroethyloxy group.

[0056] The term "alkenyl group" refers to a straight-chain or branched-chain hydrocarbon group containing at least one carbon-carbon double bond (C=C), and typically contains 2 to 18 carbon atoms, for example, 2 to 8 carbon atoms, further for example, 2 to 6 carbon atoms, and even further for example, 2 to 4 carbon atoms. Examples of alkenyl groups include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, and 2-methyl-3-butenyl. Examples of alkenyl groups include, but are not limited to, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, wherein the alkenyl groups may be optionally further substituted with substituents.

[0057] An "alkenylene group" refers to a straight-chain or branched-chain divalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, for example, 2 to 8 carbon atoms, further for example, 2 to 6 carbon atoms, and even further for example, 2 to 4 carbon atoms; a non-limiting embodiment includes an ethynylene group, which alkenylene group may be optionally substituted with a substituent.

[0058] The term "alkynyl group" refers to a straight-chain or branched-chain hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically containing 2 to 18 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentyl, 3-pentyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, and 4-decynyl groups, and the alkynyl group may be optionally substituted.

[0059] "Alkynylene group" refers to a straight or branched chain divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond (C≡C), typically containing 2 to 18 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms; non-limiting examples include ethynylene, propynylene, and butynylene groups, which alkynylene groups may be optionally substituted.

[0060] "Cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain a cycloheteroatom. Cycloalkyl groups can be monocyclic, bicyclic, or polycyclic, and bicyclic or polycyclic rings can be parallel, spirocyclic, bridged, or combinations thereof. Bicyclic or polycyclic rings can contain one or more aromatic rings, but the ring system as a whole does not possess aromatic character, and the linking site can be on an aromatic or non-aromatic ring. Typically, cycloalkyl groups contain 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms; if monocyclic, 3 to 15 carbon atoms, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms; if bicyclic or polycyclic, 5 to 12 carbon atoms, or 5 to 11 carbon atoms, or 6 to 10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, [ka] and the like, and cycloalkyl groups may be optionally substituted with substituents.

[0061] A "cycloalkylene group" is a divalent group of a cycloalkyl group.

[0062] "Aryl group" refers to a carbon ring having aromatic character and containing no heteroatoms, including monocyclic aryl groups and fused-ring aryl groups. Typically, they contain 6 to 14 carbon atoms, and even 6 to 10 carbon atoms. Non-limiting examples include phenyl, naphthyl, anthryl, and phenanthryl groups, and aryl groups may optionally be substituted with substituents.

[0063] "Carbocycle" or "carbocyclic group" refers to a saturated, partially unsaturated, or aromatic carbon ring, and includes aryl and cycloalkyl groups. Carbocycles can be monocyclic, bicyclic, or polycyclic, and bicyclic or polycyclic rings include bridged, parallel, and spiro rings, as well as combinations thereof. Carbocycles typically have 3 to 12 carbon atoms, or 3 to 10 carbon atoms, or 3 to 6 carbon atoms. In non-limiting examples, monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, and bicyclic bridged rings include [ka] and the like, and the bicyclic parallel ring is [ka] and the like, and bicyclic spiro rings include [ka] etc., and carbocycles may be optionally substituted with substituents.

[0064] A "heterocycloalkyl group" refers to a saturated or partially unsaturated non-aromatic carbocyclic ring containing one, two, three, or four heteroatoms selected from N, S, and O. A heterocycloalkyl group may be monocyclic, bicyclic, or polycyclic, and the bicyclic or polycyclic ring may be bridged, parallel, spiro, or a combination thereof. A bicyclic or polycyclic ring may contain one or more aromatic or heteroaromatic rings, but the ring system as a whole does not possess aromaticity, and the linking site may be on an aromatic or non-aromatic ring. A heterocycloalkyl group typically has 3 to 20 ring members. When it is a monocyclic heterocycloalkyl group, it is typically a 3 to 15-, 3 to 10-, 3 to 8-, or 3 to 6-membered ring. When it is a bicyclic or polycyclic heterocycloalkyl group, it is typically a 5 to 12-, 5 to 11-, or 6 to 9-membered ring. Here, the heteroatoms N and S include their oxidation states. Non-limiting examples of heterocycloalkyl groups include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, pyranyl, azacyclopentenyl, azacyclohexenyl, oxolyl, oxynyl, and the like, and heterocycloalkyl groups may be optionally substituted.

[0065] "Heteroaromatic ring" or "heteroaryl group," unless otherwise specified, refers to a ring containing 1 to 4 heteroatoms selected from N, O, or S and their oxidation states, and having aromatic properties. The ring may be monocyclic, bicyclic, or polycyclic, and the bicyclic or polycyclic ring may be a bridged ring, a parallel ring, a spiro ring, or a combination thereof. If bicyclic or polycyclic, the heteroaryl group may be fused with an aryl group, or a heteroaryl group may be fused with a heteroaryl group, where both the heteroaryl group and the aryl group may be linking moieties. Non-limiting examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, purinyl, [ka] and the like, wherein said heteroaryl groups may be optionally substituted with substituents.

[0066] "Heterocyclo" or "heterocyclo group" refers to a saturated or unsaturated, aromatic or non-aromatic ring containing 1 to 4 heteroatoms selected from N, O, or S and their oxidation states, including heteroaryl and heterocycloalkyl groups. Heterocyclo includes monocyclic heterocyclos, bridged bicyclic heterocyclos, fused bicyclic heterocyclos, and spiro bicyclic heterocyclos, or combinations thereof. Typically, the heterocyclo is a 3- to 12-membered heterocyclo, a 5- to 12-membered heterocyclo, or a 5- to 7-membered heterocyclo. Heterocyclo groups may be attached at a heteroatom or a carbon atom, and non-limiting examples include oxiranyl, azacyclopropyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, piperazinyl, azacycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihybridyl, methyl ... a thiazolyl group, a benzopyridyl group, a dihydropyranyl group, a dithiolanyl group, a tetrahydrofuranyl group, a tetrahydropyrrolyl group, a tetrahydroimidazolyl group, an oxazolyl group, a dihydrooxazolyl group, a tetrahydrooxazolyl group, a tetrahydrothiazolyl group, a tetrahydropyranyl group, a benzimidazolyl group, a benzopyridyl group, a pyrrolopyridyl group, a benzodihydrofuryl group, an azabicyclo[3.2.1]octyl group, an azabicyclo[5.2.0]nonyl group, an oxatricyclo[5.3.1.1]dodecyl group, an azaadamantyl group, and an oxaspiro[3.3]heptyl group; [ka] and the like, wherein heterocyclos may be optionally substituted with substituents.

[0067] A "heterocyclylene group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic divalent heterocyclo group. Non-limiting examples include: [ka] Includes:

[0068] "Spiro ring" refers to a polycyclic group in which the rings share one carbon atom (called a spiro atom), which may contain zero or more double or triple bonds and zero to five heteroatoms selected from N, O, S, P, Si, and their oxidation states. Typically, the spiro ring is a 6- to 14-membered ring, or a 6- to 12-membered ring, or a 6- to 10-membered ring. Typically, the spiro ring is a 3-spiro3 (representing a 3-membered spiro3 ring), a 3-spiro4, a 3-spiro5, a 3-spiro6, a 4-spiro4, a 4-spiro5, a 4-spiro6, a 5-spiro5, or a 5-spiro6. Non-limiting examples of spiro rings are: [ka] wherein the spiro ring may be optionally substituted with a substituent.

[0069] "Parallel ring" or "fused ring" refers to a polycyclic group in which rings share two adjacent ring atoms and one chemical bond, and may contain one or more double or triple bonds. The parallel rings may contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Typically, the parallel rings are 5 to 20-membered, 5 to 14-membered, 5 to 12-membered, or 5 to 10-membered rings. Typically, the parallel rings are 3-parallel 4-rings (representing parallel rings formed by a 3-membered ring and a 4-membered ring; based on the IUPC nomenclature rules, parallel rings with a 3-membered ring as the base ring are possible, and parallel rings with a 4-membered ring as the base ring are also possible, and the same applies below), 3-parallel 5-rings, 3-parallel 6-rings, 4-parallel 4-rings, 4-parallel 5-rings, 4-parallel 6-rings, 5-parallel 5-rings, 5-parallel 6-rings, or 6-parallel 6-rings. Non-limiting examples of parallel rings include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, [ka] wherein the parallel rings may be aromatic or non-aromatic and are optionally substituted with substituents.

[0070] A "bridged ring" refers to two rings that share two non-adjacent ring atoms and may contain one or more double or triple bonds. The bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Typically, the bridged ring has 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10 ring atoms. Non-limiting examples of bridged rings include adamantane, [ka] Includes.

[0071] "Substituted" or "substituent" means, unless otherwise specified, that optional substitution occurs in chemically permissible positions and the number of substituents complies with the rules of chemical bonding. Exemplary substituents are C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Heteroalkyl groups, C 5-12 Aryl group, 5- to 12-membered heteroaryl group, hydroxy group, C 1-6 Alkoxy group, C 5-12 Aryloxy group, thiol group, C 1-6 Alkylthio group, cyano group, halogen, C 1-6 Alkylthiocarbonyl group, C 1-6 Alkylcarbamoyl group, N-carbamoyl group, nitro group, silyl group, sulfinyl group, sulfonyl group, sulfoxide, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, amino group, phosphonic acid, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -HC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Examples include, but are not limited to, alkyl groups and the like.

[0072] "Optionally" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and the description includes both cases where the event or circumstance occurs and cases where it does not occur. For example, "an alkyl group optionally substituted with F" means that the alkyl group may be substituted with F, but is not necessarily substituted with F, and indicates that the alkyl group is substituted with F and the alkyl group is not substituted with F are included.

[0073] "Pharmaceutically acceptable salts" refers to salts in which the compounds of the present invention retain the biological effectiveness and properties of the free acids or free bases and which are obtained by reaction of said free acids with non-toxic inorganic or organic bases, or by reaction of said free bases with non-toxic inorganic or organic acids.

[0074] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein or stereoisomers, deuterated forms, solvates, pharmaceutically acceptable salts, or co-crystals thereof with other components, wherein the other components include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0075] The term "carrier" refers to a system that does not significantly stimulate the living body, does not eliminate the biological activity and properties of a given compound, and can change the drug's administration form and distribution in the body, control the drug release rate, and deliver the drug to the target organ; non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0076] "Excipient" refers to a substance that is not itself a therapeutic agent, but is added to a pharmaceutical composition as a diluent, excipient, adhesive, and / or vehicle to improve its processing or storage properties, or to allow or facilitate the compound or pharmaceutical composition to form a dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can serve a variety of functions and may be described as wetting agents, buffers, suspending aids, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to, the following: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, goa oil, and olive oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) water for endotoxin testing; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other non-toxic, compatible substances used in pharmaceutical formulations.

[0077] "Stereoisomer" refers to isomers that result from differences in the way atoms in molecules are arranged in space, and includes cis-trans isomers, enantiomers, and conformational isomers.

[0078] The compounds of the present invention further include tautomers thereof, for example, when a left-hand compound in which the pyrimidine ring is substituted with OH is described in the present invention, the right-hand tautomeric compound is also included. [ka]

[0079] The term "solvate" refers to a substance formed by intermolecular non-covalent bonding of the compound of the present invention or a salt thereof with a stoichiometric or non-stoichiometric solvent. When the solvent is water, it becomes a hydrate.

[0080] A "cocrystal" refers to a crystalline body formed by the association of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) through hydrogen bonding or other non-covalent bonds, where the API and CCF are both solids in their pure states at room temperature and there is a fixed stoichiometric ratio between the components. Cocrystals are multi-component crystalline bodies, and include not only binary cocrystals formed between two neutral solids, but also multi-component cocrystals formed between a neutral solid and a salt or solvate. [Brief explanation of the drawings]

[0081] [Figure 1] 1 shows the in vivo efficacy results of Compound 30 (tumor volume (a in the figure) and mouse body weight (b in the figure)). [Figure 2] 1 shows the in vivo efficacy results (tumor weight) of Compound 30. DETAILED DESCRIPTION OF THE INVENTION

[0082] The following describes in detail the technical solution of the present invention in conjunction with the drawings and embodiments, and the protection scope of the present invention includes but is not limited to the above.

[0083] Test Method The structure of the compound is confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR displacements (δ) are 10 -6The NMR data are given in ppm (ppm). NMR measurements were performed using Bruker Avance III 400 and Bruker Avance 300 nuclear magnetic resonance spectrometers, with deuterated dimethyl sulfoxide (DMSO-d), deuterated chloroform (CDCl), and deuterated methanol (CD3OD) as solvents, and tetramethylsilane (TMS) as the internal standard. MS measurements were performed using Agilent 6120B (ESI) and Agilent 6120B (APCI). HPLC measurements were performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C 18 100 × 4.6 mm, 3.5 μM) Thin layer chromatography silica gel plates are Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for thin layer chromatography (TLC) are 0.15mm to 0.20mm in diameter, and the separation and purification of products by thin layer chromatography are 0.4mm to 0.5mm in diameter. Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0084] Example 1 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (Compound 1) [ka]

[0085] Step 1: 1-Hydroxy-6-chloroisoquinoline (compound 1A) (5.00 g, 27.84 mmol, CAS number: 131002-09-0, supplier: Shanghai Taitan Technology Co., Ltd.) was added to a mixture of tetrahydrofuran (120 mL) and dichloromethane (80 mL). After stirring for 15 minutes, the temperature was controlled below 30°C, and N-bromosuccinimide (5.45 g, 30.62 mmol) was added. After the addition was completed, the reaction was allowed to proceed at room temperature for 8 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and dichloromethane (50 mL) was added. The mixture was stirred for 1 hour and then filtered to obtain compound 1B (6.20 g, yield: 86.11%), which was used directly in the next step.

[0086] LC-MS (ESI): m / z=260.0 [M+H] + .

[0087] Step 2: Compound 1B (5.00 g, 19.34 mmol), zinc cyanide (1.14 g, 9.67 mmol), and 1,1'-bis(diphenylphosphine)ferrocene (1.08 g, 1.93 mmol) were added to N,N-dimethylformamide (150 mL). The mixture was purged with nitrogen three times, and then tris(dibenzylideneacetone)dipalladium (0.89 g, 0.97 mmol) was added. The mixture was purged with nitrogen three times, and then heated to 100 °C and reacted for 2 hours. After completion of the reaction, the reaction mixture was concentrated to dryness, dichloromethane (50 mL) was added, and the mixture was again concentrated to dryness. Dichloromethane (30 mL) was added, stirred for 1 hour, and filtered to give compound 1C (3.3 g, yield: 83.39%).

[0088] LC-MS (ESI): m / z=203.1 [MH] - .

[0089] Step 3: Compound 1C (1.00 g, 4.84 mmol) was dissolved in methanol (100 mL), and cobalt chloride (0.63 g, 4.84 mmol) was added. After stirring for 15 minutes, sodium borohydride (0.46 g, 12.10 mmol) was slowly added and the mixture was stirred at room temperature for 2 hours. Di-tert-butyl dicarbonate (1.27 g, 5.81 mmol) was added and the mixture was allowed to react overnight at room temperature. After completion of the reaction, the mixture was filtered, washed with methanol, and concentrated to dryness. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 100% to 90%) to give compound 1D (600 mg, yield: 39.89%).

[0090] LC-MS (ESI): m / z=309.1 [M+H] + .

[0091] Step 4: Compound 1D (700 mg, 2.27 mmol), bis(pinacolato)diboron (1.15 g, 4.54 mmol), and potassium acetate (1.11 g, 11.35 mmol) were added to 1,4-dioxane (150 mL) in that order, and the mixture was purged with nitrogen gas three times. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.18 g, 0.23 mmol) was added, and the mixture was again purged with nitrogen gas three times. The mixture was heated to 105°C and reacted for 1 hour. After cooling, the reaction solution was concentrated to dryness, and the residue was separated by silica gel column chromatography (dichloromethane:methanol (v:v) = 100% to 90%) to obtain compound 1E (800 mg, yield: 88.04%).

[0092] LC-MS (ESI): m / z=309.1 [M+H] + .

[0093] Step 5: Compound 1F (100 mg, 0.27 mmol) (see patent WO2021050915A1 for synthesis method), compound 1E (110 mg, 0.27 mmol), sodium bicarbonate (45 mg, 0.54 mmol) were added sequentially to a solution of 1,4-dioxane (9 mL) and water (3 mL). After purging with nitrogen gas three times, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.027 mmol) was added, and the atmosphere was purged with nitrogen gas three times again. The mixture was heated to 60 ° C and reacted for 1 hour. After completion of the reaction, the reaction solution was concentrated to dryness, and the residue was separated by silica gel column chromatography (dichloromethane:methanol (v:v) = 100% to 90%) to obtain compound 1G (90 mg, yield: 59.10%).

[0094] LC-MS (ESI): m / z=564.2 [M+H] + .

[0095] Step 6: Compound 1G (90 mg, 0.16 mmol) was added to a 4 mol / L solution of hydrochloric acid in methanol (10 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated to dryness. The residue was separated by reverse-phase column chromatography (instrument: Biotage Isolera One, chromatography column: Agela C18 reverse-phase column, mobile phase: acetonitrile:water (v:v) = 98% to 30%) to give compound 1 (6 mg, yield: 8.08%).

[0096] 1 H NMR (400MHz,DMSO-d6) δ 11.06 (s,1H),8.18 (s,1H),8.13 (d,1H),7.99 (d,1H),7.45 - 7.38 (m,2H),7.04 (s,1H),4.21-4.18 (m,1H),3.77 (s,3H),3.52 (s,2H),0.96 - 0.76 (m,4H), LC-MS (ESI): m / z=462.1 [MH] - .

[0097] Example 2 4-Chloro-6-cyclopropoxy-3-fluoro-2-(4-(4-(hydroxymethyl)-7-oxo-6,7-dihydrothieno[2,3-d]pyridazin-2-yl)-1-methyl-1H-pyrazol-5-yl)benzonitrile (Compound 2) [ka]

[0098] Step 1: Compound 1F (2.0 g, 4.8 mmol), pinacolborane (896 mg, 7.0 mmol), tetrakis(triphenylphosphine)palladium (554 mg, 0.48 mmol), and triethylamine (960 mg, 9.6 mmol) were dissolved in 1,4-dioxane (20 mL), purged with nitrogen gas three times, heated to 90 °C, and reacted overnight. The mixture was cooled to room temperature, passed through a short silica gel column, and rinsed with ethyl acetate (50 mL). The filtrate was collected and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 10:1) to give compound 2B (1.5 g, yield: 75%).

[0099] LC-MS (ESI): m / z=418.1 [M+H] + .

[0100] Step 2: Methyl 3-bromothiophene-2-carboxylate (compound 2C) (10.1 g, 45.7 mmol) was dissolved in 1,4-dioxane (150 mL) and water (10 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (1.7 g, 2.3 mmol), cesium carbonate (29.3 g, 90.0 mmol), and potassium vinyltrifluoroborate (6.7 g, 50.0 mmol) were added. The mixture was purged with nitrogen gas three times, heated to 90 °C, and reacted for 2 h. The mixture was cooled to room temperature, passed through a short silica gel column, rinsed with ethyl acetate, and the filtrate was collected and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 20:1) to give compound 2D (6.1 g, 80% yield).

[0101] LC-MS (ESI): m / z=168.1 [M+H] + .

[0102] Step 3: Compound 2D (6.1 g, 36.5 mmol) was dissolved in tetrahydrofuran (250 mL) and lithium bis(trimethylsilyl)amide (40 mL, 1.0 M tetrahydrofuran solution, 40.0 mmol) was slowly added in an ice bath. The reaction was continued for 0.5 h, followed by the addition of iodine (10.1 g, 40.0 mmol). The mixture was allowed to warm to room temperature and react overnight. The reaction was quenched by the addition of aqueous sodium thiosulfate (100 mL). The mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 15:1) to give compound 2E (8.5 g, 81% yield).

[0103] LC-MS (ESI): m / z=294.9 [M+H] + .

[0104] Step 4: Compound 2E (8.5 g, 29.5 mmol) was dissolved in acetone (50 mL), and potassium osmate dihydrate (0.9 g, 2.9 mmol) and 4-methylmorpholine-N-oxide (7.0 g, 60.0 mmol) were dissolved in water (10 mL). The mixture was then added to the above system and reacted at room temperature for 2 h. The reaction was quenched with saturated aqueous sodium sulfite solution, concentrated to remove acetone, and extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (dichloromethane:methanol (v:v) = 10:1) to give compound 2F (7.2 g, yield: 74%).

[0105] LC-MS (ESI): m / z=328.9 [M+H] + .

[0106] Step 5: Compound 2F (7.2 g, 21.9 mmol) was dissolved in N,N-dimethylformamide (100 mL), imidazole (3.0 g, 44.0 mmol), and tert-butyldimethylchlorosilane (3.3 g, 22.0 mmol) were added, and the mixture was allowed to react at room temperature for 2 h. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 2G (7.4 g crude), which was used directly in the next step.

[0107] LC-MS (ESI): m / z=443.0 [M+H] + .

[0108] Step 6: Compound 2G (7.4 g, 16.7 mmol) was dissolved in ethyl acetate (100 mL), and 2-iodoacylbenzoic acid (9.8 g, 35.0 mmol) was added. The mixture was heated to 80° C. and reacted overnight. The mixture was cooled to room temperature, filtered to remove the solids, and the filtrate was collected and concentrated to give compound 2H (6.4 g crude), which was used directly in the next step of the reaction.

[0109] LC-MS (ESI): m / z=441.0 [M+H] + .

[0110] Step 7: Compound 2H (6.4 g, 14.5 mmol) was dissolved in ethanol (20 mL), and hydrazine hydrate (6.0 mL) was slowly added. After about 5 min, a solid appeared. Stirring was continued for 10 min. The mixture was filtered, the filter cake was rinsed with ethanol (5.0 mL), and the filtrate was collected and concentrated to give compound 2I (4.5 g crude), which was used directly in the next step.

[0111] LC-MS (ESI): m / z=423.0 [M+H] + .

[0112] Step 8: Compound 2I (590.0 mg, 1.4 mmol), compound 2B (600.0 mg, 1.4 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (91.0 mg, 0.14 mmol), and sodium bicarbonate (403.2 mg, 4.8 mmol) were dissolved in 1,4-dioxane (10.0 mL) and water (3.0 mL), purged with nitrogen gas three times, heated to 80 °C, and reacted for 2 h. After cooling to room temperature, the reaction mixture was filtered through a short silica gel column. The filter cake was rinsed with ethyl acetate (50.0 mL). The filtrate was collected and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1) to give compound 2J (690.0 mg, 84% yield).

[0113] LC-MS (ESI): m / z=586.1 [M+H] + .

[0114] Step 9: Compound 2J (690.0 mg, 1.1 mmol) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 1.5 mL) was added slowly. The mixture was allowed to react at room temperature for 1 h. The mixture was concentrated directly, and the residue was purified by column chromatography (dichloromethane:methanol (v:v) = 10:1) to give compound 2 (480.0 mg, yield: 99%).

[0115] 1 H NMR (400MHz,DMSO-d6) δ 12.70 (s,1H),8.28 (s,1H),8.09 (d,1H),7.69 (s,1H),5.44 (s,1H),4.57 (d,2H),4.38 - 4.09 (m,1H),3.78 (s,3H),0.95 - 0.92 (m,2H),0.88 - 0.74 (m,2H), LC-MS (ESI): m / z=472.0 [M+H] + .

[0116] Example 3 2-(4-(4-(aminomethyl)-7-oxo-6,7-dihydrothieno[2,3-d]pyridazin-2-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (compound 3) [ka]

[0117] Step 1: Compound 2 (420.0 mg, 0.9 mmol) was dissolved in ethyl acetate (10 mL), and 2-iodoacylbenzoic acid (504.0 mg, 1.8 mmol) was added. The mixture was heated to reflux and reacted overnight. The mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate. The filtrate was collected and concentrated. The resulting residue was purified by column chromatography (dichloromethane:methanol (v:v) = 10:1) to give compound 3A (400.0 mg, yield: 95%).

[0118] LC-MS (ESI): m / z=470.0 [M+H] + .

[0119] Step 2: Compound 3A (400.0 mg, 0.8 mmol) was dissolved in methanol (10 mL), ammonium acetate (246.0 mg, 3.2 mmol) was added, and the mixture was heated to reflux for 1 h. After that, sodium cyanoborohydride (201.0 mg, 3.2 mmol) was added and the mixture was allowed to react for 4 h. The mixture was cooled to room temperature and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 10:1) to give compound 3 (70.0 mg, 17% yield).

[0120] 1H NMR (400MHz,DMSO-d6) δ 12.66 (s,1H),8.30 (s,1H),8.09 (d,1H),7.85 (s,1H),4.42 - 4.15 (m,3H),3.87 (s,2H),3.77 (s,3H),0.95 - 0.93 (m,2H),0.90 - 0.73 (m,2H), LC-MS (ESI): m / z=471.0 [M+H] + .

[0121] Example 4 2-(4-(5-(aminomethyl)-8-oxo-7,8-dihydropyrido[2,3-d]pyridazin-3-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (Compound 4) [ka]

[0122] Step 1: Compound 4A (15 g, 59.89 mmol), isopropenylboronic acid pinacol ester (10.57 g, 62.88 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (2.19 g, 2.99 mmol), and potassium carbonate (20.69 g, 149.72 mmol) were dissolved in 1,4-dioxane (125 mL) and water (25 mL). The mixture was purged with nitrogen gas three times and reacted at 80°C for 2 h. The mixture was quenched with water (150 mL) and ethyl acetate (100 mL), filtered, and the filtrate was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give compound 4B (12.0 g, yield: 94.67%).

[0123] LCMS (ESI): m / z=212.1 [M+H] + .

[0124] Step 2: Compound 4B (12 g, 56.70 mmol) was dissolved in tetrahydrofuran (120 mL) and water (120 mL). Potassium osmate dihydrate (420 mg, 1.13 mmol) and sodium periodate (42.45 g, 198.45 mmol) were added and the mixture was allowed to react at room temperature overnight. After filtration, the filtrate was quenched with sodium thiosulfate solution (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 2:1) to give compound 4C (8.8 g, yield: 72.65%).

[0125] LCMS (ESI): m / z=214.1 [M+H] + .

[0126] Step 3: Compound 4C (8.8 g, 41.19 mmol) was dissolved in ethanol (130 mL), and hydrazine hydrate (3.75 mL, 61.73 mmol) was added, followed by refluxing at 80° C. for 2 hours. The mixture was cooled to room temperature and filtered. The filter cake was rinsed with ethanol once, and the filter cake was collected and dried to obtain compound 4D (6.5 g, yield: 80.67%).

[0127] LCMS (ESI): m / z=196.0 [M+H] + .

[0128] Step 4: Compound 4D (2.0 g, 10.22 mmol) was dissolved in acetonitrile (25 mL), and phosphorus oxychloride (7.84 g, 51.06 mmol) was added. The mixture was reacted at 80° C. for 1.5 hours. After cooling, the mixture was concentrated under reduced pressure to remove excess phosphorus oxychloride and acetonitrile. The residue was dissolved in dichloromethane (200 mL) and washed with saturated sodium bicarbonate (200 mL). The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 4E (2.0 g crude), which was used directly in the next step.

[0129] Step 5: Compound 4E (2.0 g, 9.34 mmol) was dissolved in acetonitrile (25 mL), and azodiisobutyronitrile (0.31 g, 1.89 mmol) and N-bromosuccinimide (2.49 g, 14.04 mmol) were added, followed by a reaction at 80° C. for 16 hours. After cooling, the mixture was concentrated under reduced pressure to remove acetonitrile, and the residue was dissolved in dichloromethane (20 mL) and purified by column chromatography to give compound 4F (0.73 g, yield: 26.68%).

[0130] LCMS (ESI): m / z=291.9 [M+H] + .

[0131] Step 6: Compound 4F (0.73 g, 2.49 mmol) was dissolved in N,N-dimethylformamide (6 mL), and potassium phthalimide (0.48 g, 2.61 mmol) was added portionwise at room temperature. The mixture was allowed to react for 1 hour. After the reaction was completed, water (60 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with water (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 4G (0.80 g crude), which was used directly in the next step.

[0132] LCMS (ESI): m / z=359.0 [M+H] + .

[0133] Step 7: Compound 4G (0.8 g, 2.23 mmol) was dissolved in acetic acid (8 mL), and potassium acetate hydrate (1.3 g, 11.19 mmol) was added, followed by reaction at 100° C. for 1 hour. After cooling, the mixture was concentrated under reduced pressure to remove acetic acid, and the residue was added with water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4H (0.80 g crude), which was used directly in the next step.

[0134] LCMS (ESI): m / z=341.0 [M+H] + .

[0135] Step 8: Compound 4H (0.8 g) was dissolved in ethanol (15 mL), and hydrazine hydrate (0.18 g, 3.6 mmol) was added and reacted at 80° C. for 2 hours. After cooling, the mixture was concentrated under reduced pressure to give compound 4I (0.6 g crude), which was used directly in the next step.

[0136] LCMS (ESI): m / z=211.1 [M+H] + .

[0137] Step 9: Compound 4I (0.8 g, 2.85 mmol) was dissolved in dichloromethane (12 mL), and triethylamine (0.87 g, 8.61 mmol) and di-tert-butyl dicarbonate (1.24 g, 5.7 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was filtered, and the filter cake was collected to give compound 4J (0.55 g crude), which was used directly in the next step.

[0138] LCMS (ESI): m / z = 311.1 [M+H] + .

[0139] Step 10: Compound 4J (0.25 g, 0.80 mmol), compound 2B (0.37 g, 0.89 mmol), potassium acetate (0.39 g, 3.98 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.065 g, 0.079 mmol) were dissolved in acetonitrile (3 mL) and water (1 mL). The mixture was purged with nitrogen gas three times and reacted at 130 °C for 1 h. The mixture was concentrated directly, dichloromethane (10 mL) was added, filtered, and the filtrate was collected and concentrated. The resulting residue was purified by column chromatography (dichloromethane:methanol (v:v) = 25:1) to give compound 4K (0.15 g, yield: 33.13%).

[0140] LCMS (ESI): m / z=566.1 [M+H] + .

[0141] Step 11: Compound 4K (0.15 g, 0.27 mmol) and dichloromethane (4 mL) were added to a 25 mL single-neck flask, and trifluoroacetic acid (1 mL) was added dropwise. After completion, the mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated at 35 °C, and dichloromethane (10 mL) and triethylamine (0.3 g) were added. The mixture was stirred for five minutes, and the reaction mixture was concentrated. The resulting crude product was separated and purified by preparative HPLC. Separation method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% NH₃·H₂O); b. Gradient elution, with the content of mobile phase A ranging from 20% to 70%; c. Flow rate: 20 mL / min; d. Elution time: 15 min. Retention time: 3.10 min. Compound 4 (0.032 g, yield: 25.44%) was obtained.

[0142] 1 H NMR (400MHz,DMSO-d6) δ 12.66 (s,1H),8.90 (d,1H),8.39 (s,1H),8.22 (d,1H),8.00 (d,1H),4.24 - 4.15 (m,1H),3.84 (d,2H),3.81 (s,3H),0.90 (dd,2H),0.81 (dd,2H), LC-MS (ESI): m / z=466.1 [M+H] + .

[0143] Example 5 2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (Compound 5) [ka]

[0144] Step 1: Compound 5A (4 g, 16.7 mmol, CAS number: 403850-89-5, supplier: Shanghai BiDe Pharmaceutical Technology Co., Ltd.) and 1-bromopyrrolidine-2,5-dione (2.96 g, 16.7 mmol) were dissolved in N,N-dimethylformamide (60 mL) and stirred at 40 °C for 12 hours. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by column chromatography (dichloromethane:ethyl acetate (v:v) = 17:100) to give compound 5B (1.9 g, yield: 36%).

[0145] 1 H NMR (400MHz,DMSO-d6) δ 12.72 (s,1H),8.03 (d,1H),7.91-7.88 (m,1H),7.71-7.69 (m,1H),4.54 (s,2H).

[0146] Step 2: Compound 5B (0.75 g, 2.36 mmol), (2,4-dimethoxyphenyl)methylamine (0.51 g, 3.05 mmol), and potassium carbonate (0.65 g, 4.72 mmol) were dissolved in N,N-dimethylformamide (20 mL) and stirred at room temperature for 1 hour. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by preparative HPLC. Purification Method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water; b. Gradient elution, mobile phase A content: 10% to 40%; c. Flow rate: 80 mL / min; d. Elution time: 20 min. Retention time: 10.50 min. Compound 5C (0.27 g, yield: 28%) was obtained.

[0147] LC-MS (ESI): m / z=404.2 [M+H] + .

[0148] Step 3: Compound 5C (0.2 g, 0.49 mmol), compound 2B (0.37 g, 0.89 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.036 g, 0.049 mmol), and potassium acetate (0.096 g, 0.98 mmol) were dissolved in a mixture of acetonitrile (9 mL) and water (3 mL). The mixture was purged with nitrogen three times, heated to 130 °C in a microwave oven, and stirred for 1 h. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (dichloromethane:methanol (v:v) = 100:8) to give compound 5D (0.13 g, 43% yield).

[0149] LC-MS (ESI): m / z=615.1 [M+H] + .

[0150] Step 4: Compound 5D (0.1 g, 0.16 mmol) was dissolved in a mixture of trifluoroacetic acid (4 mL) and concentrated hydrochloric acid (1 mL) and reacted at 50 °C for 3 hours. After completion of the reaction, the mixture was directly concentrated, and the resulting residue was purified by preparative HPLC. Separation method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to produce the sample solution. 3. Preparative Chromatography Conditions: a. Composition of Mobile Phases A and B: Mobile Phase A: acetonitrile, Mobile Phase B: water (containing 0.1% NH₃H₂O); b. Gradient elution, with the content of Mobile Phase A ranging from 5% to 50%; c. Flow rate: 20 mL / min; d. Elution time: 20 min; Retention time: 15 min. Compound 5 (0.0015 g, yield: 2%) was obtained.

[0151] 1H NMR (400MHz,DMSO-d6) δ 12.31 (s,1H),8.13 (s,1H),8.05 - 7.97 (m,2H),7.43 (d,1H),7.27-7.24 (m,1H),4.20-4.16 (m,1H),4.04 (s,2H),3.76 (s,3H),0.95-0.90 (m,2H),0.84 - 0.76 (m,2H), LC-MS (ESI): m / z=465.1 [M+H] + .

[0152] Example 6 7-(5-(3-chloro-6-cyano-5-cyclopropoxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazine-1-carboximidamide (Compound 6) [ka]

[0153] Step 1: Compound 6A (1.3 g, 4.59 mmol, synthesis reference: US202178994) was added to a sealed tube, and ammonia solution (20 mL, 7 M in methanol) was added, heated to 100 °C, and reacted for 16 hours. The reaction was cooled, filtered, and the filter cake was collected to obtain compound 6B (1.1 g crude), which was used directly in the next step reaction.

[0154] LC-MS (ESI): m / z=265.9 [MH] - .

[0155] Step 2: Compound 6B (1.1 g crude, 4.10 mmol) and dioxane (20 mL) were added to a flask, and phosphorus oxychloride (1.87 mL, 20.46 mmol) was added. The mixture was reacted at 120° C. for 6 hours. The reaction mixture was concentrated, diluted with dichloromethane, dissolved in 30 mL of water and saturated aqueous sodium carbonate, the pH was adjusted to about 8, and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give compound 6C (690 mg, yield: 67.3%).

[0156] LC-MS (ESI): m / z=248.0 [MH] - .

[0157] Step 3: Ammonium chloride (612 mg, 11.45 mmol) and xylene (10 mL) were added to a flask, and trimethylaluminum (5.4 mL, 10.80 mmol, 2 M hexane solution) was added dropwise under ice bath conditions. The mixture was then reacted at room temperature for 1 hour. Compound 6C (540 mg, 2.16 mmol) was then added, and the mixture was heated to 120°C and reacted for 24 hours. Diethylene glycol dimethyl ether (10 mL) was then added, and the mixture was heated to 160°C and reacted for 8 hours. After cooling, methanol (5 mL) was added, and the mixture was stirred for 1 hour. The mixture was filtered, and the filter cake was washed with ethyl acetate / methanol (10 mL / 10 mL). The filtrate was collected, dried over anhydrous sodium sulfate, and concentrated to give compound 6D (3 g crude), which was used directly in the next step.

[0158] LC-MS (ESI): m / z=266.9 [M+H] + .

[0159] Step 4: Compound 6D (3 g crude, 11.23 mmol), methanol (30 mL), and water (10 mL) were added to a flask. Potassium carbonate (4.66 g, 33.69 mmol) and di-tert-butyl dicarbonate (4.9 g, 22.46 mmol) were added, and the mixture was allowed to react at room temperature for 4 hours. Ethyl acetate (50 mL) and saturated sodium chloride solution (50 mL) were added to the mixture, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1) to give compound 6E (380 mg, two-step yield: 47.91%).

[0160] LCMS (ESI): m / z=367.0 [M+H] + .

[0161] Step 5: Compound 6E (180 mg, 0.49 mmol), compound 2B (250 mg, 0.60 mmol), and sodium bicarbonate (164 mg, 1.96 mmol) were dissolved in 1,4-dioxane (9 mL) and water (3 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (18 mg, 0.025 mmol) was added and the mixture was reacted under nitrogen gas protection at 80 °C for 2 hours. After cooling, the mixture was directly concentrated, and the resulting residue was separated by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:4) to give compound 6F (80 mg, yield: 28.25%).

[0162] LCMS (ESI): m / z=578.2 [M+H] + .

[0163] Step 6: Compound 6F (80 mg, 0.14 mmol) and dichloromethane (6 mL) were added to a flask, and trifluoroacetic acid (1 mL) was added. The mixture was allowed to react at 35 °C for 2 hours. The mixture was then directly concentrated, and the resulting residue was purified by preparative HPLC. Separation method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative Chromatography Conditions: a. Composition of Mobile Phases A and B: Mobile Phase A: acetonitrile, Mobile Phase B: water (containing 0.1% NH₃.H₂O). b. Gradient elution was performed, with the content of Mobile Phase A ranging from 10% to 40%. c. Flow rate: 20 mL / min. d. Elution time: 10 min. Retention time: 3.28 min. Compound 6 (23 mg, yield: 34%) was obtained.

[0164] 1 H NMR (400MHz,CD3OD) δ 8.33 (d,1H),8.10 (s,1H),7.89 (d,1H),7.85 (s,1H),7.80 (t,1H),4.09-4.07 (m,1H),3.81 (s,3H),0.94-0.91 (m,2H),0.87-0.84 (m,2H), LC-MS (ESI): m / z=478.4 [M+H] + .

[0165] Example 7 2-(4-(4-(aminomethyl)-8-(1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (Compound 7) [ka]

[0166] Step 1: Compound 7A (100 g, 410 mmol) was dissolved in acetonitrile (1.1 L) and triethylamine (110 mL, 820 mmol) was added. Di-tert-butyl dicarbonate (119 g, 533 mmol) and 4-dimethylaminopyridine (5.0 g, 41 mmol) were then added, and the mixture was heated to 50° C. and stirred for 2 hours. After cooling, the mixture was directly concentrated, water (1 L) was added, and the mixture was extracted with ethyl acetate (1 L × 3). The organic phases were combined, dried, and concentrated to give compound 7B (123 g, yield: 87.23%).

[0167] 1 H NMR (400MHz,DMSO-d6) δ 8.88 (s,1H),7.74 (t,1H),7.63 (d,1H),3.84 (s,3H),2.27 (s,3H),1.48 (s,9H).

[0168] Step 2: Compound 7B (123 g, 358 mmol) and lithium hydroxide monohydrate (45 g, 1.07 mol) were dissolved in tetrahydrofuran (800 mL) and water (250 mL) and stirred at room temperature for 18 h. The mixture was concentrated directly, and the resulting residue was diluted with water (300 mL). The pH was adjusted to 2-3 with 2 mol / L dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (1 L x 3). The organic phase was collected, dried, and concentrated to give compound 7C (102 g, 86.45% yield).

[0169] 1 H NMR (400MHz,DMSO-d6) δ 8.82 (s,1H),7.65 (d,1H),7.57 (d,1H),2.27 (s,3H),1.47 (s,9H).

[0170] Step 3: Compound 7C (102 g, 308.9 mmol) was dissolved in N,N-dimethylformamide (1.0 L). N,N-diisopropylethylamine (102 mL, 620 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (153 g, 403 mmol) were added at room temperature. The mixture was stirred at room temperature for 30 min. Finally, dimethanohydroxylamine hydrochloride (45.6 g, 465 mmol) was added and the mixture was allowed to react at room temperature for 2 h. The reaction mixture was poured into 2 L of water and extracted three times with ethyl acetate (1 L × 3). The organic phase was collected, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give compound 7D (82 g, yield: 71.12%).

[0171] 1 H NMR (400MHz,DMSO-d6) δ 8.78 (s,1H),7.63 (s,1H),7.24 (d,1H),3.43 (s,3H),3.26 (s,3H),2.04 (s,3H),1.47 (s,9H).

[0172] Step 4: Compound 7D (82 g, 220 mmol) was dissolved in tetrahydrofuran (800 mL), and methylmagnesium bromide (220 mL, 660 mmol, 3 M ether solution) was added at 0 °C. The mixture was allowed to warm to room temperature and react for 16 hours. Saturated ammonium chloride solution (1 L) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The mixture was then extracted with ethyl acetate (500 mL × 3). The organic phase was collected, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give compound 7E (70 g, yield: 97.08%).

[0173] 1 H NMR (400MHz,DMSO-d6) δ 8.84 (s,1H),7.67 (d,1H),7.62 (d,1H),2.53 (s,3H),2.13 (s,3H),1.47 (s,9H).

[0174] Step 5: Compound 7E (53 g, 160 mmol) was dissolved in tert-butanol (500 mL) and water (500 mL). Anhydrous potassium carbonate (44 g, 320 mmol) was added, and the mixture was heated to 70 °C with stirring. Finally, potassium permanganate (179 g, 1.13 mol) was added to the reaction mixture in six portions at 30 min intervals. After the addition was completed, the reaction was continued at 70 °C for 1 hour. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was collected. The pH was adjusted to 2-3 with 2 mol / L dilute hydrochloric acid and extracted with a mixture of ethyl acetate and tetrahydrofuran (v:v = 10:1) (700 mL × 3). The organic phase was collected, dried, and concentrated to give compound 7F (39 g crude), which was used directly in the next step.

[0175] LC-MS (ESI): m / z=388.1 [M+H] + .

[0176] Step 6: Compound 7F (39 g, 100 mmol) was dissolved in ethanol (200 mL), and hydrazine hydrate (7.24 mL, 120 mmol) was added, and the mixture was heated to 75° C. and reacted for 15 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with ethanol (100 mL). The filter cake was collected and dried to obtain compound 7G (17 g, yield: 43.81%).

[0177] 1 H NMR (400MHz,DMSO-d6) δ 12.00 (s,1H),8.63 (s,1H),8.05 (s,1H),1.50 (s,9H).

[0178] Step 7: Compound 7G (17 g, 44.2 mmol) was dissolved in methanol (150 mL), and a solution of hydrochloric acid in methanol (4 mol / L, 240 mL) was added. The mixture was heated to 70° C. and reacted for 2 hours. After cooling, the mixture was directly concentrated. Water (200 mL) was added to the residue, and the pH was adjusted to 8 with sodium bicarbonate. The mixture was filtered. The filter cake was washed with water (100 mL). The filter cake was collected and dried to obtain compound 7H (13 g, yield: 98.56%).

[0179] 1 H NMR (400MHz,DMSO-d6) δ 12.87 (s,1H),7.58 (s,2H),7.13 (s,1H),3.87 (s,3H), LC-MS (ESI): m / z=298.0 [M+H] + .

[0180] Step 8: Compound 7H (13 g, 43.6 mmol) and p-toluenesulfonic acid (33 g, 174.4 mmol) were dissolved in acetonitrile (2.0 L) and purged with nitrogen gas twice. Sodium nitrite (7.5 g, 109 mmol) was dissolved in water (20 mL) and added dropwise to the reaction mixture. The temperature was maintained at this level for 1 h. Finally, potassium iodide (21.7 g, 130.8 mmol) was dissolved in water (20 mL) and added dropwise to the reaction mixture. After completion, the mixture was warmed to room temperature and allowed to react for 2 h. Saturated sodium thiosulfate solution (200 mL) was added to the reaction mixture and stirred for 10 minutes. The mixture was then concentrated, the organic phase was removed, filtered, and the filter cake was washed with clean water (300 mL). The filter cake was collected and dried to give compound 7I (8.2 g, yield: 45.98%).

[0181] 1 H NMR (400MHz,DMSO-d6) δ 13.24 (s,1H),8.73 (d,1H),8.61 (d,1H),3.90 (s,3H), LC-MS (ESI): m / z=409.1 [M+H] + .

[0182] Step 9: Compound 7I (8.2 g, 20 mmol) was dissolved in a mixture of tetrahydrofuran (240 mL) and ethanol (240 mL). Anhydrous calcium chloride (2.5 g, 2.4 mmol) was added at 0 °C, and sodium borohydride (1.47 g, 40 mmol) was added to the reaction mixture in four portions at 10 min intervals. After the addition was completed, the reaction mixture was allowed to react for another 10 min. Saturated ammonium chloride solution (100 mL) was added to the mixture, and the mixture was stirred at room temperature for 10 min. The mixture was then filtered. The filter cake was washed with water (100 mL), collected, and dried. The solid was then homogenously mixed with methanol (200 mL), stirred for 3 h, filtered, and the filter cake was collected and dried to obtain compound 7J (4.8 g, yield: 62.84%).

[0183] 1 H NMR (400MHz,DMSO-d6) δ 12.61 (s,1H),8.55 (d,1H),8.28 (d,1H),5.55 (t,1H),4.61 (d,2H), LC-MS (ESI): m / z=381.1 [M+H] + .

[0184] Step 10: Compound 7J (0.95 g, 2.5 mmol) was dissolved in thionyl chloride (10 mL), heated to 70 °C, and reacted for 2 hours. After cooling, the mixture was directly concentrated. Petroleum ether (20 mL) was added to the resulting residue, mixed homogeneously, stirred for 20 minutes, filtered, and the filter cake was washed with petroleum ether (30 mL). The filter cake was collected and dried to give compound 7K (0.92 g, yield: 89.93%).

[0185] 1 H NMR (400MHz,DMSO-d6) δ 12.86 (s,1H),8.60 (d,1H),8.27 (d,1H),5.01 (s,2H).

[0186] Step 11: Compound 7K (0.92 g, 2.24 mmol) was dissolved in N,N-dimethylformamide (20 mL), and potassium phthalimide (0.42 g, 2.24 mmol) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was poured into water (200 mL), stirred for 10 minutes, and then filtered. The filter cake was washed with water (50 mL). The filter cake was collected and dried to give compound 7L (1.1 g, yield: 96.32%).

[0187] 1 H NMR (400MHz,DMSO-d6) δ 12.54 (s,1H),8.61 (d,1H),8.40 (d,1H),7.96 - 7.94 (m,2H),7.90 - 7.88 (m,2H),5.12 (s,2H), LC-MS (ESI): m / z=510.3 [M+H] + .

[0188] Step 12: Compound 7L (300 mg, 0.59 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (110 mg, 0.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (43 mg, 0.059 mmol), and sodium bicarbonate (200 mg, 2.36 mmol) were dissolved in a mixture of N,N-dimethylformamide and water (v:v = 2:1, 12 mL), purged with nitrogen gas three times, heated to 70 °C, and reacted for 5 h. After cooling to room temperature and direct concentration, the residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 20:1 to 10:1) to give compound 7M (180 mg, yield: 65.72%).

[0189] LC-MS (ESI): m / z=466.1 [M+H] + .

[0190] Step 13: Compound 7M (180 mg, 0.38 mmol), bis(pinacolato)diboron (190 mg, 0.76 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (27 mg, 0.038 mmol), and potassium acetate (88 mg, 1.8 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was purged with nitrogen three times and heated to 80 °C for 16 h. After cooling and direct concentration, the resulting residue was homogenized with a mixture of petroleum ether and ethyl acetate (v:v = 10:1, 20 mL). The mixture was stirred at room temperature for 1 h, filtered, and the filter cake was washed once with a mixture of petroleum ether and ethyl acetate (v:v = 10:1, 20 mL). The filter cake was collected and dried to give compound 7N (300 mg crude), which was used directly in the next step.

[0191] LC-MS (ESI): m / z=430.1 [M+H] + .

[0192] Step 14: Compound 7N (300 mg, 0.58 mmol), compound 1F (242 mg, 0.58 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (42 mg, 0.058 mmol), and sodium bicarbonate (101 mg, 1.2 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (v:v = 5:1, 18 mL), purged with nitrogen gas three times, heated to 80 °C, and reacted for 5 hours. After cooling, the mixture was directly concentrated to give compound 7O (600 mg crude), which was used directly in the next step.

[0193] LC-MS (ESI): m / z=676.1 [M+H] + .

[0194] Step 15: Compound 7O (600 mg) was dissolved in ethanol (30 mL) and hydrazine hydrate (0.1 mL) was added. The mixture was allowed to react at 80 °C for 1 hour. After cooling, the mixture was directly concentrated, and the resulting residue was purified by preparative HPLC. Preparative Method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to produce the sample solution. 3. Preparative Chromatography Conditions: a. Composition of Mobile Phases A and B: Mobile Phase A: acetonitrile, Mobile Phase B: water (containing 0.1% NH₃·H₂O). b. Gradient elution was performed, with the content of Mobile Phase A ranging from 20% to 60%. c. Flow rate: 20 mL / min. d. Elution time: 20 min. Retention time: 3.26 min. Compound 7 (26 mg, yield: 12.58%) was obtained.

[0195] 1 H NMR (400MHz,DMSO-d6) δ 12.18 (s,1H),8.35 (s,1H),8.05 (d,1H),7.84 (s,1H),7.59 (s,1H),7.50 (s,1H),7.40 (s,1H),4.21 (s,1H),3.86 (s,3H),3.79 (s,3H),3.75 (s,2H),0.92 (d,2H),0.84 - 0.74 (m,2H), LC-MS (ESI): m / z=545.1 [M+H] + .

[0196] Examples 8 and 9 (2S)-2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(3-methylazetidin-1-yl)benzonitrile and (2R)-2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(3-methylazetidin-1-yl)benzonitrile (Compound 8, Compound 9) [ka]

[0197] Step 1: Compound 8A (30 g, 118.84 mmol, synthetic method reference: US202178994), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40 g, 190.2 mmol), cesium fluoride (30 g, 202 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (8.7 g, 11.9 mmol) were weighed into a three-neck flask, and cyclopentyl methyl ether was added. The mixture was reacted under nitrogen gas protection at 90 °C for 3 h. A mixture of petroleum ether and ethyl acetate (v:v = 1:1, 250 mL) was added, stirred, and filtered. The filtrate was collected. The filter cake was washed twice with a mixed solvent of petroleum ether and ethyl acetate (v:v=1:1, 250 mL), the filtrates were combined and concentrated, and the resulting residue was separated by column chromatography (petroleum ether:ethyl acetate (v:v)=10:1) to obtain compound 8B (18.80 g, yield: 62%).

[0198] LC-MS (ESI): m / z=254.0 [M+H] + .

[0199] Step 2: Compound 8B (3.00 g, 11.83 mmol) was dissolved in acetonitrile (80 mL), N-iodosuccinimide (5.32 g, 23.66 mmol) and trifluoroacetic acid (0.67 g, 5.92 mmol) were added, and the mixture was stirred at 50° C. for 4 h. After direct concentration, the resulting residue was separated by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:5) to give compound 8C (4.30 g, yield: 95%).

[0200] LC-MS (ESI): m / z=379.9 [M+H] + .

[0201] Step 3: Compound 8C (1.14 g, 3.00 mmol), compound 1E (1.00 g, 2.50 mmol), and sodium bicarbonate (0.63 g, 7.50 mmol) were added sequentially to a solution of 1,4-dioxane (75 mL) and water (25 mL). After purging with nitrogen gas three times, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.18 g, 0.25 mmol) was added. After purging with nitrogen gas three times again, the mixture was heated to 60 °C and reacted for 1 h. After cooling, the mixture was directly concentrated. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 100% to 90%) to give compound 8D (680 mg, yield: 51.72%).

[0202] LC-MS (ESI): m / z=526.2 [M+H] + .

[0203] Step 4: Compound 8D (400 mg, 0.76 mmol), potassium carbonate (0.32 g, 2.32 mmol), and 3-methylazetidine (65 mg, 0.91 mmol) were added to N,N-dimethylformamide (20 mL) in that order, heated to 80 °C, and reacted for 1 h. After cooling, the mixture was filtered. Ethyl acetate (50 mL) and water (50 mL) were added to the filtrate, and the mixture was separated. The organic phase was collected, dried, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 100% to 90%) to give compound 8E (79 mg, yield: 18.01%).

[0204] LC-MS (ESI): m / z=575.0 [MH] - .

[0205] Step 5: Compound 8E (79 mg, 0.13 mmol) was subjected to SFC separation to obtain P1 (retention time 1.404 min, designated compound 8E-1) and P2 (retention time 2.049 min, designated compound 8E-2). The separation conditions were as follows: Instrument: WATERS 150 preparative SFC (SFC-26); Chromatography column: ChiralCel OX, 250 × 30 mm ID, 5 μm; Mobile phase: A = CO2, B = isopropanol and acetonitrile (containing 0.1% aqueous ammonia); Gradient: B 50%; Flow rate: 120 mL / min; Column pressure: 100 bar; Column temperature: 25 °C; Wavelength: 220 nm; Cycle time: 4.5 min; Sample preparation: The compound was dissolved in acetonitrile; Injection: 3 mL of sample was injected at a time. Treatment: After separation, the mixture was concentrated using a rotary evaporator at 35° C., and the solvent was dried using a freeze dryer at −80° C. Compound 8E-1 (38 mg, 48.1%) and Compound 8E-2 (40 mg, 50.6%) were obtained.

[0206] Compound 8E-1:LC-MS (ESI):m / z=577.5[M+H] + .

[0207] Compound 8E-2:LC-MS (ESI):m / z=577.5[M+H] + .

[0208] Step 6: Compound 8E-1 (38 mg, 0.066 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was then directly concentrated, and the resulting residue was purified by preparative HPLC. Separation method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative Chromatography Conditions: a. Composition of Mobile Phases A and B: Mobile Phase A: acetonitrile, Mobile Phase B: water (containing 0.1% NH₃·H₂O). b. Gradient elution was performed, with the content of Mobile Phase A ranging from 10% to 70%. c. Flow rate: 20 mL / min. d. Elution time: 15 min. Retention time: 11.0 min. Compound 8 (14 mg, yield: 44%) was obtained.

[0209] Compound 8: 1 H NMR (400MHz,CDCl3) δ 8.23 (s,1H),7.92 (s,1H),7.55 (s,1H),7.14 (s,2H),6.56 (d,1H),4.31-4.23 (m,3H),3.81 (s,4H),3.77-3.73 (m,1H),3.70-3.66 (m,1H),2.79 (s,1H),1.26 (s,3H), LC-MS (ESI):m / z=475.0[MH] - .

[0210] Compound 8E-2 (40 mg, 0.069 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated directly, and the resulting residue was purified by preparative HPLC. Separation method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative Chromatography Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% NH₃·H₂O). b. Gradient elution, with the content of mobile phase A ranging from 10% to 70%. c. Flow rate: 20 mL / min. d. Elution time: 15 min. Retention time: 12.5 min. Compound 9 (14.6 mg, yield: 44%) was obtained.

[0211] Compound 9: 1 H NMR (400MHz,CDCl3) δ 8.23 (s,1H),7.92 (s,1H),7.54 (s,1H),7.15 (s,2H),6.56 (d,1H),4.30-4.23(m,3H),3.82 (s,4H),3.77-3.73 (m,1H),3.70-3.66 (m,1H),2.79 (s,1H),1.25 (s,3H), LC-MS (ESI):m / z=475.0[MH] - .

[0212] Example 10 2-(4-(4-(2-aminoethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (Compound 10) [ka]

[0213] Step 1: Compound 10A (2.98 g, 11 mmol; see synthesis method: Journal of Medicinal Chemistry, 2022, vol. 65, #3, pp. 1749-1766) was dissolved in anhydrous acetonitrile (30 mL), cyanotrimethylsilane (2.75 mL, 22 mmol) was added, and the mixture was purged with nitrogen gas. After that, tetrabutylammonium fluoride (11.51 g, 44 mmol) was added, heated to 80 °C, and stirred for 3 h. After cooling to room temperature, the reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by trituration with a mixture of petroleum ether and dichloromethane (v:v = 10:1) to give compound 10B (2.6 g, yield: 90%).

[0214] 1 H NMR (400MHz,DMSO-d6) δ 12.86 (s,1H),8.17 (dd,2H),8.06 (dd,1H),4.49 (s,2H), LC-MS (ESI): m / z=264.0 [M+H] + .

[0215] Step 2: Compound 10B (1.0 g, 3.8 mmol) was dissolved in ethanol (15 mL), and nickel chloride (0.41 g, 3.1 mmol) and sodium borohydride (11.51 g, 30.4 mmol) were added, followed by heating to 45° C. and stirring for 3 hours to obtain an ethanol solution of compound 10C, which was used directly in the next step.

[0216] LC-MS (ESI): m / z=268.0 [M+H] + .

[0217] Step 3: To a solution of compound 10C in ethanol (15 mL), triethylamine (0.16 g, 15.2 mmol) and di-tert-butyl dicarbonate (6.63 g, 30.4 mmol) were slowly added dropwise and allowed to react at room temperature overnight. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give compound 10D (0.068 g, 4.9% yield).

[0218] LC-MS (ESI): m / z=368.2 [M+H] + .

[0219] Step 4: Compound 10D (68 mg, 0.18 mmol), compound 2B (150 mg, 0.36 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (29 mg, 0.036 mmol), and sodium bicarbonate (53 mg, 0.63 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). The mixture was purged with nitrogen gas three times, heated to 80 °C, and stirred for 2 h. After cooling, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was separated by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:5) to give compound 10E (87 mg, yield: 83%).

[0220] LC-MS (ESI): m / z=579.3 [M+H] + .

[0221] Step 5: Compound 10E (87 mg, 0.15 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the resulting residue was purified by preparative HPLC. Separation method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to produce the sample solution. 3. Preparative Chromatography Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content: 10% to 40%; c. Flow rate: 20 mL / min; d. Elution time: 10 min. Compound 10 (5 mg, yield: 7%) was obtained.

[0222] 1 H NMR (400MHz,DMSO-d6) δ 12.44 (s,1H),8.26 (s,1H),8.16 (t,1H),8.02 (t,1H),7.67 (d,1H),7.56 (s,1H),4.24 - 4.13 (m,1H),3.77 (d,3H),2.80 (dd,4H),0.90 (t,2H),0.83 (d,2H), LC-MS (ESI): m / z=479.50 [M+H] + .

[0223] Examples 11 and 12 (2S)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile and (2R)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (Compound 11, Compound 12) [ka]

[0224] Step 1: Compound 5C (4 g, 9.89 mmol) was dissolved in trifluoroacetic acid (20 mL), heated to 50° C., and stirred for 1 hour. Directly concentrated, saturated aqueous sodium carbonate solution (50 mL) was added to the resulting residue, stirred for 30 minutes, filtered, and the filter cake was collected, washed twice with water, and dried to give compound 11A (2.4 g crude), which was used directly in the next step of the reaction.

[0225] LC-MS (ESI): m / z=254.0 [M+H] + .

[0226] Step 2: Compound 11A (2.5 g, 9.84 mmol) was dissolved in methanol (20 mL) and dichloromethane (20 mL), and di-tert-butyl dicarbonate (6.5 g, 29.51 mmol) was added and stirred at room temperature for 1 hour. The mixture was then directly concentrated, water (50 mL) was added, the mixture was stirred uniformly, and the mixture was filtered. The filter cake was collected, washed with petroleum ether three times, and dried to give compound 11B (1.6 g crude), which was used directly in the next step.

[0227] LC-MS (ESI): m / z=354.0 [M+H] + .

[0228] Step 3: Compound 11B (0.1 g, 0.24 mmol), compound 2B (0.16 g, 0.24 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.018 g, 0.024 mmol), and sodium bicarbonate (0.06 g, 0.72 mmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL), purged with nitrogen three times, heated to 80 °C, and stirred for 1 h. After cooling, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (dichloromethane:methanol (v:v) = 100:8) to give compound 11C (0.08 g, yield: 59.00%).

[0229] LC-MS (ESI): m / z=565.2 [M+H] + .

[0230] Step 4: Compound 11C (320 mg) was subjected to chiral SFC separation to give P1 (retention time: 1.891 min, designated as compound 11C-1) and P2 (retention time: 2.139 min, designated as compound 11C-2). Separation method: Instrument: Waters 150 SFC, Chromatography column: Chiralcel OD-Column, Mobile phase: A for CO₂ and B for EtOH (0.1% NH₃·H₂O), Gradient: 35% phase B isocratic elution, Flow rate: 80 mL / min, Column pressure: 100 bar, Column temperature: 25 °C, Absorption wavelength: 220 nm, Cycle time: 3 min. Sample preparation: The compound was dissolved in acetonitrile to a concentration of 5 mg / mL. Injection: 3 mL of sample was injected once. Processing: After separation, the compound was concentrated at 35°C using a rotary evaporator, and the solvent was dried at -80°C using a freeze dryer to obtain compounds 11C-1 (93.6 mg, 29.25%) and 11C-2 (100 mg, 31.25%).

[0231] Step 5: Compound 11C-1 (93.6 mg, 0.17 mmol) was dissolved in a solution of hydrogen chloride in dioxane (5 mL, 4 M) and stirred at room temperature for 2 hours. The reaction mixture was concentrated and then diluted with dichloromethane. Sodium bicarbonate solution was then added to adjust the pH to alkaline. Extraction with dichloromethane was performed, and the organic phase was collected, dried, and concentrated. The resulting residue was separated by reverse-phase column chromatography (water:acetonitrile (v / v) = 67:33) to give compound 11 (38 mg, yield: 48.08%).

[0232] Compound 11: 1 H NMR (400MHz,DMSO-d6) δ 8.16 (s,1H),8.00 (dd,2H),7.37 (d,1H),7.21 (dd,1H),4.25 - 4.15 (m,1H),3.76 (s,3H),3.63 (s,2H),0.94 - 0.75 (m,4H), LC-MS (ESI): m / z=465.4 [M+H] + .

[0233] Compound 11C-2 (100 mg, 0.18 mmol) was dissolved in a solution of hydrogen chloride in dioxane (5 mL, 4 M) and stirred at room temperature for 2 hours. The reaction mixture was concentrated and then diluted with dichloromethane. Sodium bicarbonate solution was then added to adjust the pH to alkaline. The mixture was extracted with dichloromethane, separated, and the organic phase was collected, dried, and concentrated. The crude product was purified by reverse-phase column chromatography (water:acetonitrile (v / v) = 67:33) to give compound 12 (40 mg, yield: 47.80%).

[0234] Compound 12: 1 H NMR (400MHz,DMSO-d6) δ 8.16 (s,1H),8.00 (dd,2H),7.37 (d,1H),7.21 (dd,1H),4.26 - 4.16 (m,1H),3.76 (s,3H),3.65 (s,2H),0.97 - 0.74 (m,4H), LC-MS (ESI): m / z=465.5 [M+H] + .

[0235] Example 13 1-(aminomethyl)-7-(5-(3-chloro-6-cyano-5-cyclopropoxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazine-5-carbonitrile (Compound 13) [ka]

[0236] Step 1: Compound 7L (300 mg, 0.59 mmol), zinc cyanide (70 mg, 0.53 mmol), and tetrakis(triphenylphosphine)palladium (68 mg, 0.059 mmol) were dissolved in N,N-dimethylformamide (8 mL), purged with nitrogen gas three times, heated to 80 °C, and reacted for 4 h. After cooling, the mixture was directly concentrated, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1 to 1:2) to give compound 13A (130 mg, yield: 53.85%).

[0237] 1 H NMR (400MHz,DMSO-d6) δ 12.86 (s,1H),8.73 (d,1H),8.65 (d,1H),7.95 (dd,2H),7.90 (dd,2H),5.21 (s,2H), LC-MS (ESI): m / z=409.0 [M+H] + .

[0238] Step 2: Compound 13A (130 mg, 0.32 mmol), bis(pinacolato)diboron (163 mg, 0.64 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (23 mg, 0.032 mmol), and potassium acetate (76 mg, 0.8 mmol) were dissolved in 1,4-dioxane (6 mL), purged with nitrogen three times, heated to 80 °C, and reacted for 16 h. After cooling and direct concentration, the resulting residue was added to a mixture of petroleum ether and ethyl acetate (v:v = 10:1, 20 mL), stirred for 1 h, filtered, and the filter cake was washed once with a mixture of petroleum ether and ethyl acetate (v:v = 10:1, 20 mL). The filter cake was collected and dried to give compound 13B (210 mg crude), which was used directly in the next step.

[0239] LC-MS (ESI): m / z=375.30 [M+H] + .

[0240] Step 3: Compound 13B (210 mg, 0.46 mmol), compound 1F (191 mg, 0.46 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (33 mg, 0.046 mmol), and sodium bicarbonate (77 mg, 0.92 mmol) were dissolved in a mixture of 1,4-dioxane and water (v:v = 5:1, 12 mL), purged with nitrogen gas three times, heated to 80 °C, and reacted for 5 h. After cooling, the mixture was directly concentrated to give compound 13C (400 mg crude), which was used directly in the next step.

[0241] Step 4: Compound 13C (400 mg) was dissolved in ethanol (20 mL), and hydrazine hydrate (0.1 mL) was added. The mixture was heated to 80 °C and reacted for 1 hour. After cooling, the mixture was directly concentrated, and the resulting residue was purified by preparative HPLC. Preparative method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography; Chromatography column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to produce the sample solution. 3. Preparative Chromatography Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% NH₃·H₂O); b. Gradient elution, with the content of mobile phase A ranging from 50% to 90%; c. Flow rate: 20 mL / min; d. Elution time: 20 min. Retention time: 4.91 min. Compound 13 (18 mg, yield: 11.48%) was obtained.

[0242] 1 H NMR (400MHz,DMSO-d6) δ 12.79 (s,1H),8.42 (s,1H),8.35 (s,1H),8.03 (d,1H),7.91 (s,1H),4.21 (s,1H),3.80 (s,3H),3.73 (s,2H),0.91 (d,2H),0.80 (d,2H), LC-MS (ESI): m / z=490.50 [M+H] + .

[0243] Examples 14 and 15 (2S)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropoxy)benzonitrile and (2R)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropoxy)benzonitrile (Compound 14, Compound 15) [ka]

[0244] Step 1: Compound 11B (0.1 g, 0.28 mmol), bis(pinacolato)diboron (0.078 g, 0.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.02 g, 0.028 mmol), and potassium acetate (0.082 g, 0.84 mmol) were dissolved in 1,4-dioxane (5 mL), purged with nitrogen three times, heated to 80 °C, and reacted for 16 h. After cooling and direct concentration, the resulting residue was added to a mixture of petroleum ether and ethyl acetate (v:v = 10:1, 20 mL), stirred for 1 h, filtered, and the filter cake was washed once with a mixture of petroleum ether and ethyl acetate (v:v = 10:1, 20 mL). The filter cake was collected and dried to give compound 14A (0.2 g crude), which was used directly in the next step.

[0245] LC-MS (ESI): m / z=402.2 [M+H] + .

[0246] Step 2: 1-Methylcyclopropanol (5.7 g, 79.05 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydride (3.15 g, 79.05 mmol) was added portionwise, and the mixture was heated to 40 °C and stirred for 2 h. After cooling to room temperature, compound 8C (10 g, 26.35 mmol) was added and the mixture was allowed to react at room temperature for 8 h. The reaction was quenched by the addition of methanol and directly concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v:v) = 1:5) to give compound 14B (2.5 g, yield: 21.98%).

[0247] LC-MS (ESI): m / z=432.3 [M+H] + .

[0248] Step 3: Compound 14B (0.5 g, 1.16 mmol), compound 14A (0.47 g, 1.16 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.085 g, 0.12 mmol), and sodium bicarbonate (0.29 g, 3.48 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (2 mL). The mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 2 h. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was collected, washed, dried, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 100:8) to give compound 14C (0.3 g, yield: 44.67%).

[0249] LC-MS (ESI): m / z=579.6 [M+H] + .

[0250] Step 4: Compound 14C (100 mg) was subjected to chiral SFC separation to give P1 (retention time: 1.754 min, designated as compound 14C-1) and P2 (retention time: 2.035 min, designated as compound 14C-2). Separation method: Instrument: Waters 150 SFC, Chromatography column: Chiralcel OD-Column, Mobile phase: A for CO₂ and B for MeOH (0.1% NH₃·H₂O), Gradient: 35% phase B isocratic elution, Flow rate: 100 mL / min, Column pressure: 100 bar, Column temperature: 25 °C, Absorption wavelength: 220 nm, Cycle time: 2 min). Sample preparation: The compound was dissolved in acetonitrile to a concentration of 2 mg / mL. Injection: 2.5 mL of sample was injected once. Processing: After separation, the compound was concentrated at 35°C using a rotary evaporator, and the solvent was dried at -80°C using a freeze dryer to obtain compounds 14C-1 (24 mg, 23.51%) and 14C-2 (22 mg, 22.12%).

[0251] Step 5: Compound 14C-1 (20 mg, 0.035 mmol) was dissolved in 4 M hydrogen chloride in dioxane (2 mL) and reacted at 25 °C for 2 hours. The reaction mixture was concentrated and then diluted with dichloromethane. Sodium bicarbonate solution was then added to adjust the pH to alkaline. The mixture was extracted with dichloromethane, separated, and the organic phase was collected, dried, and concentrated. The residue was purified by reverse-phase column chromatography (water:acetonitrile (v / v) = 67:33) to give compound 14 (8 mg, yield: 47.73%).

[0252] Compound 14: 1 H NMR (400MHz,DMSO-d6) δ 8.15 (s,1H),7.98 (d,1H),7.82 (d,1H),7.38 (d,1H),7.20 (dd,1H),3.76 (s,3H),3.71 (s,2H),1.58 (s,3H),1.05-1.02 (m,2H),0.90 (t,2H), LC-MS (ESI):m / z=479.4[M+H] + .

[0253] Compound 14C-2 (20 mg, 0.035 mmol) was dissolved in 4 M hydrogen chloride in dioxane (2 mL) and reacted at 25 °C for 2 hours. The reaction mixture was concentrated and then diluted with dichloromethane. Sodium bicarbonate solution was then added to adjust the pH to alkaline. The mixture was extracted with dichloromethane, separated, and the organic phase was collected, dried, and concentrated. The residue was purified by reverse-phase column chromatography (water:acetonitrile (v / v) = 67:33) to give compound 15 (8 mg, yield: 47.73%).

[0254] Compound 15: 1 H NMR (400MHz,DMSO-d6) δ 8.16 (s,1H),7.98 (d,1H),7.82 (d,1H),7.37 (d,1H),7.20 (dd,1H),3.76 (s,3H),3.66 (s,2H),1.58 (s,3H),1.05-1.02 (m,2H),0.90 (t,2H), LC-MS (ESI):m / z=479.5[M+H] + .

[0255] Examples 16 and 17 (2S)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(3-methylazetidin-1-yl)benzonitrile and (2R)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(3-methylazetidin-1-yl)benzonitrile (Compound 16, Compound 17) [ka]

[0256] Step 1: Compound 8C (10 g, 26.35 mmol), 14A (12.7 g, 31.62 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (1.93 g, 2.64 mmol), and potassium acetate (6.64 g, 79.05 mmol) were dissolved in 1,4-dioxane (100 mL) and water (20 mL). The mixture was purged with nitrogen three times and heated to 80 °C for 4 h. After cooling and direct concentration, the resulting residue was added to a mixture of petroleum ether and ethyl acetate (v:v = 10:1, 20 mL), stirred for 1 h, filtered, and the filter cake was collected and purified by column chromatography (methanol:dichloromethane (v:v) = 1:20) to give compound 16A (9 g, yield: 64.82%).

[0257] LC-MS (ESI): m / z=527.1 [M+H] + .

[0258] Step 2: 3-(Methoxymethyl)azetidine hydrochloride (0.31 g, 2.89 mmol), compound 16A (1 g, 1.90 mmol), and potassium carbonate (0.78 g, 5.63 mmol) were dissolved in N,N-dimethylformamide (20 mL), heated to 80 °C, and stirred for 2 h. After cooling to room temperature and direct concentration, the residue was purified by silica gel column chromatography (methanol:dichloromethane (v:v) = 1:20) to give compound 16B (0.8 g, yield: 72.84%).

[0259] LC-MS (ESI): m / z=578.6 [M+H] + .

[0260] Step 3: Compound 16B (600 mg) was subjected to chiral SFC separation to give P1 (retention time: 2.025 min, designated as compound 16B-1) and P2 (retention time: 2.288 min, designated as compound 16B-2). Separation method: Instrument: Waters 150 SFC, Chromatography column: Chiralcel OJ-Column, Mobile phase: A for CO₂ and B for MeOH (0.1% NH₃·H₂O), Gradient: 45% phase B isocratic elution, Flow rate: 120 mL / min, Column pressure: 100 bar, Column temperature: 25 °C, Absorption wavelength: 220 nm, Cycle time: 3.5 min. Sample preparation: The compound was dissolved in methanol to a concentration of 10 mg / mL. Injection: 3 mL of sample was injected at a time. Processing: After separation, the compound was concentrated at 35°C using a rotary evaporator, and the solvent was dried at -80°C using a freeze dryer to obtain compounds 16B-1 (80 mg, 13.33%) and 16B-2 (80 mg, 13.33%).

[0261] Step 5: 16B-1 (80 mg, 0.14 mmol) was dissolved in 4 M hydrogen chloride in dioxane (2 mL) and reacted at 25 °C for 2 hours. The reaction mixture was concentrated and then diluted with dichloromethane. Sodium bicarbonate solution was added to adjust the pH to alkaline. Extraction with dichloromethane was performed, and the organic phase was collected, dried, and concentrated. The residue was purified by reverse-phase column chromatography (water:acetonitrile (v / v) = 67:33) to give compound 16 (40 mg, yield: 59.78%).

[0262] Compound 16: 1 H NMR (400MHz,DMSO-d6) δ 8.14 (d,1H),7.99 (d,1H),7.38- 7.35 (m,1H),7.34 - 7.25 (m,2H),6.64-6.61 (m,1H),3.75 (s,3H),3.72 - 3.57 (m,4H),3.15 - 3.12 (m,2H),1.10-0.95 (m,4H), LC-MS (ESI): m / z=514.5[M+HCl+H]+ .

[0263] 16B-2 (80 mg, 0.14 mmol) was dissolved in 4 M hydrogen chloride in dioxane (2 mL) and reacted at 25 °C for 2 hours. The reaction mixture was concentrated and then diluted with dichloromethane. Sodium bicarbonate solution was then added to adjust the pH to alkaline. The mixture was extracted with dichloromethane, separated, and the organic phase was collected, dried, and concentrated. The residue was purified by reverse-phase column chromatography (water:acetonitrile (v / v) = 67:33) to give compound 17 (41 mg, yield: 60.05%).

[0264] Compound 17: 1 H NMR (400MHz,DMSO-d6) δ 8.14 (d,1H),7.99 (d,1H),7.37 - 7.33 (m,1H),7.33 - 7.27 (m,2H),6.64-6.61 (m,1H),3.75 (s,3H),3.72 - 3.57 (m,4H),3.18 - 3.09 (m,2H),1.10-0.95 (m,4H), LC-MS (ESI): m / z=514.5[M+HCl+H] + .

[0265] Examples 18 and 19 (2S)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-azido-4-chloro-3-fluorobenzonitrile and (2R)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-azido-4-chloro-3-fluorobenzonitrile (Compound 18, Compound 19) [ka]

[0266] Step 1: Compound 16A (0.5 g, 0.95 mmol) was dissolved in N,N-dimethylformamide (10 mL) and cooled to -20 °C. Sodium azide (0.068 g, 1.04 mmol) was added, and the mixture was allowed to warm to room temperature and react for 5 h. The mixture was then directly concentrated, and the resulting residue was purified by silica gel column chromatography (methanol:dichloromethane (v:v) = 1:20) to give compound 18A (0.4 g, yield: 76.56%).

[0267] LC-MS (ESI): m / z=550.1 [M+H] + .

[0268] Step 2: Compound 18A (400 mg) was subjected to chiral SFC separation to give P1 (retention time: 1.156 min, designated compound 18A-1) and P2 (retention time: 1.479 min, designated compound 18A-2). Separation method: Instrument: Waters 150 SFC, Chromatography column: Chiralcel IC-Column, Mobile phase: A for CO₂ and B for EtOH (0.1% NH₃·H₂O), Gradient: 45% phase B isocratic elution, Flow rate: 70 mL / min, Column pressure: 100 bar, Column temperature: 25 °C, Absorption wavelength: 220 nm, Cycle time: 9 min. Sample preparation: The compound was dissolved in acetonitrile to a concentration of 2 mg / mL. Injection: 2.5 mL of sample was injected once. Treatment: After separation, the compound was concentrated at 35°C using a rotary evaporator, and the solvent was dried at -80°C using a freeze dryer to obtain compounds 18A-1 (128 mg, 32.00%) and 18A-2 (126 mg, 31.5%).

[0269] Step 3: Compound 18A-1 (128 mg, 0.23 mmol) was dissolved in 4 M hydrogen chloride in dioxane (2 mL) and reacted at 25 °C for 2 hours. The reaction mixture was concentrated and then diluted with dichloromethane. Sodium bicarbonate solution was then added to adjust the pH to alkaline. Extraction with dichloromethane was performed, and the organic phase was collected, dried, and concentrated. The resulting residue was purified by reverse-phase column chromatography (water:acetonitrile (v / v) = 67:33) to give compound 18 (50 mg, yield: 48.33%).

[0270] Compound 18: 1 H NMR (400MHz,DMSO-d6) δ 8.21 (d,1H),8.16 (s,1H),7.97 (d,1H),7.39 (d,1H),7.23 - 7.16 (m,1H),3.76 (s,3H),3.61 (s,2H), LC-MS (ESI): m / z=450.5 [M+H] + .

[0271] Compound 18A-2 (126 mg, 0.32 mmol) was dissolved in 4 M hydrogen chloride in dioxane (2 mL) and reacted at 25 °C for 2 hours. The reaction mixture was concentrated and then diluted with dichloromethane. Sodium bicarbonate solution was then added to adjust the pH to alkaline. The mixture was extracted with dichloromethane, separated, and the organic phase was collected, dried, and concentrated. The residue was purified by reverse-phase column chromatography (water:acetonitrile (v / v) = 67:33) to give compound 19 (50 mg, yield: 48.32%).

[0272] Compound 19: 1 H NMR (400MHz,DMSO-d6) δ 8.20 (d,1H),8.16 (s,1H),7.97 (d,1H),7.39 (d,1H),7.23 - 7.16 (m,1H),3.76 (s,3H),3.60 (s,2H), LC-MS (ESI): m / z=450.5 [M+H] + .

[0273] Example 20 2-(4-(4-(aminomethyl)-1-oxo-8-vinyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (Compound 20) [ka]

[0274] Step 1: Compound 7L (5.0 g, 9.8 mmol) was added to a reaction flask and mixed homogeneously with absolute ethanol (25 mL). Hydrazine hydrate (3 mL, 39.2 mmol) was added and reacted at 80° C. for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed once with absolute ethanol (25 mL) and once with water (50 mL). The filter cake was collected and dried to obtain compound 20A (3.5 g, yield: 94.59%).

[0275] LC-MS (ESI): m / z=382.0 [M+H] + .

[0276] Step 2: Compound 20A (3.5 g, 9.2 mmol) and triethylamine (3.8 mL, 27.6 mmol) were added to a reaction flask and dissolved in dichloromethane (60 mL). Di-tert-butyl dicarbonate (4.0 g, 18.4 mmol) was added and reacted at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 2:1 to 1:2) to give compound 20B (1.0 g, yield: 22.73%).

[0277] 1 H NMR (400MHz,DMSO-d6) δ 12.64 (s,1H),8.56 (d,1H),8.23 (s,1H),7.40 (s,1H),4.35 (d,2H),1.40 (s,9H), LC-MS (ESI): m / z=480.3 [M+H] + .

[0278] Step 3: Compound 20B (400 mg, 0.83 mmol), bistriphenylphosphine palladium dichloride (57 mg, 0.083 mmol), and tetraethylammonium chloride (270 mg, 1.63 mmol) were added to a reaction flask and dissolved in N,N-dimethylformamide (15 mL). The mixture was purged with nitrogen three times, and tributylvinyltin (260 mg, 0.83 mmol) was added. The mixture was then reacted at 110 °C for 2 h. After cooling, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed once with saturated brine and further dried over anhydrous sodium sulfate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 2:1 to 0:1) to give compound 20C (200 mg, yield: 63.49%).

[0279] 1 H NMR (400MHz,DMSO-d6) δ 12.57 (s,1H),8.15 (s,1H),8.13 - 8.07 (m,1H),8.06 (d,1H),7.36 - 7.30 (m,1H),5.83 (d,1H),5.45 (d,1H),4.38 (t,2H),1.40 (s,9H), LC-MS (ESI): m / z=382.1 [M+H] + .

[0280] Step 4: Compound 20C (100 mg, 0.26 mmol), compound 2B (109 mg, 0.26 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (21 mg, 0.026 mmol), and sodium bicarbonate (45 mg, 0.53 mmol) were added to a reaction flask. 1,4-Dioxane and water (v:v = 10:1, 10 mL) were added, and the mixture was purged with nitrogen gas three times. The reaction mixture was then heated at 90 °C for 2 h. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 4:1 to 1:1) to give compound 20D (56 mg, yield: 36.51%).

[0281] LC-MS (ESI): m / z=591.3 [M+H] + .

[0282] Step 5: Compound 20D (56 mg, 0.095 mmol) was added to a reaction flask and dissolved in dichloromethane (2 mL). Trifluoroacetic acid (0.6 mL) was added and the mixture was allowed to react at room temperature for 30 min. The mixture was then concentrated under reduced pressure to remove the organic solvent, and the residue was purified by preparative HPLC. Method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to produce the sample solution. 3. Preparative Chromatography Conditions: a. Composition of Mobile Phases A and B: Mobile Phase A: acetonitrile, Mobile Phase B: water (containing 0.1% TFA); b. Gradient elution was performed, with the content of Mobile Phase A ranging from 20% to 60%; c. Flow rate: 20 mL / min; d. Elution time: 20 min; Retention time: 3.45 min. Compound 20 (19 mg, yield: 33.04%) was obtained.

[0283] 1H NMR (400MHz,DMSO-d6) δ 12.81 (s,1H),8.43 (s,1H),8.14 - 8.04 (m,2H),7.79 (s,1H),7.38 (s,1H),5.30 (d,1H),5.11 (d,1H),4.38 (d,2H),4.26 - 4.20 (m,1H),3.81 (s,3H),0.94 - 0.93 (m,2H),0.85 - 0.72 (m,2H), LC-MS (ESI): m / z=491.5 [M+H] + .

[0284] Example 21 2-(4-(4-(aminomethyl)-8-ethynyl-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (Compound 21) [ka]

[0285] Step 1: Compound 20B (0.1 g, 0.21 mmol), trimethylethynylsilane (41 mg, 0.42 mmol), cuprous iodide (8 mg, 0.42 mmol), and triethylamine (42 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (5 mL) and purged with nitrogen for 1 minute. Bistriphenylphosphine palladium dichloride (15 mg, 0.021 mmol) was added, followed by purifying with nitrogen for 0.5 minutes and stirring in an ice bath for 1 hour. After filtration, the filtrate was diluted with water and extracted with ethyl acetate. The organic phase was washed successively with sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:2) to give compound 21A (30 mg, 32% yield).

[0286] LCMS (ESI): m / z=450.1 [M+H] + .

[0287] Step 2: Compound 21A (80 mg, 0.18 mmol), compound 2B (110 mg, 0.27 mmol), sodium bicarbonate (30 mg, 0.36 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (14 mg, 0.018 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). The mixture was heated to 90 °C under nitrogen gas protection and stirred for 2 h. After cooling, the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0 to 1:1) to give compound 21B (40 mg, 34% yield).

[0288] LCMS (ESI): m / z=661.2 [M+H] + .

[0289] Step 3: Compound 21B (40 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.6 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was directly concentrated to dryness, and the solid crude was added to anhydrous methanol (3 mL). Potassium carbonate (17 mg, 0.12 mmol) was added and stirred at room temperature for 2 hours. After filtration, the filtrate was concentrated to dryness, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0 to 9:1) to give compound 21 (8 mg, yield: 27%).

[0290] 1 H NMR (400MHz,CD3OD) δ 8.18 (s,1H),7.95 (d,1H),7.72 (d,1H),7.68 (dd,1H),4.15-4.11 (m,1H),3.95 (s,1H),3.93 (d,2H),3.85 (s,3H),0.97-0.93 (m,2H),0.89-0.85 (m,2H), LCMS (ESI): m / z=489.1 [M+H] + .

[0291] Example 22 2-(4-(4-(aminomethyl)-8-(azetidin-1-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (Compound 22) [ka]

[0292] Step 1: Compound 7L (0.25 g, 0.49 mmol), anhydrous potassium phosphate (310 mg, 1.47 mmol), cuprous iodide (47 mg, 0.24 mmol), and azetidine (56 mg, 0.98 mmol) were dissolved in N,N-dimethylformamide (5 mL), bubbled with nitrogen gas for 1 minute, and stirred at 90 °C for 2 h. After cooling, the mixture was filtered and the filtrate was diluted with water and extracted with ethyl acetate. The organic phase was collected, washed successively with sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1) to give compound 22A (30 mg, yield: 14%).

[0293] LCMS (ESI): m / z=439.0 [M+H] + .

[0294] Step 2: Compound 22A (30 mg, 0.068 mmol), compound 2B (43 mg, 0.10 mmol), sodium bicarbonate (17 mg, 0.20 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (5 mg, 0.0068 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). The mixture was heated to 90 °C under nitrogen gas protection and stirred for 2 h. After cooling, the mixture was filtered, and the filtrate was collected and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to give compound 22B (40 mg, yield: 94%).

[0295] LCMS (ESI): m / z=650.2 [M+H] + .

[0296] Step 3: Compound 22B (40 mg, 0.062 mmol) was dissolved in anhydrous methanol (3 mL), and then methylamine aqueous solution (0.3 mL) was added. The mixture was heated to 45 °C and reacted for 3 hours. After cooling, the mixture was directly concentrated to dryness. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0 to 9:1) to give compound 22 (10 mg, yield: 31%).

[0297] 1 H NMR (400MHz,CD3OD) δ 8.01 (s,1H),7.82 (d,1H),6.92 (s,1H),6.27 (s,1H),4.02 -3.97 (m,3H),3.84 - 3.78 (m,4H),3.71 (s,3H),2.21 - 2.15 (m,2H),0.85 - 0.80 (m,2H),0.79 - 0.73 (m,2H), LCMS (ESI): m / z=520.2 [M+H] + .

[0298] Examples 23 and 24 (2S)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-vinylbenzonitrile and (2R)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-vinylbenzonitrile (Compound 23, Compound 24) [ka]

[0299] Step 1: Compound 14A (2.00 g, 3.80 mmol) was dissolved in tetrahydrofuran (10 mL), and aqueous ammonia (40%, 50 mL) was added. The mixture was sealed and heated to 100° C. and stirred for 6 hours. After cooling, ethyl acetate (200 mL) and water (200 mL) were added, and the layers were separated. The organic phase was collected, washed with saturated brine (200 mL×3), dried over anhydrous sodium sulfate, and concentrated to give compound 23A (1.86 g crude), which was used directly in the next step.

[0300] LC-MS (ESI): m / z=525.2 [M+H] + .

[0301] Step 2: Compound 23A (1.86 g, 3.55 mmol) was dissolved in acetonitrile (50 mL), copper bromide (0.87 g, 3.91 mmol) was added, and the mixture was cooled to -15 to -10 °C under nitrogen gas protection. tert-Butyl nitrite (0.50 g, 4.85 mmol) was slowly added, and the mixture was allowed to warm to 30 °C and stirred for 1 h. Ethyl acetate (200 mL) and water (200 mL) were added, and the mixture was separated. The organic phase was washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, and concentrated to give compound 23B (2.00 g crude), which was used directly in the next step.

[0302] LC-MS (ESI): m / z=587.2 [M+H] + .

[0303] Step 3: Compound 23B (2.00 g, 3.40 mmol), potassium vinyltrifluoroborate (0.68 g, 5.10 mmol), and potassium carbonate (2.82 g, 20.40 mmol) were added to a mixture of 1,4-dioxane (100 mL) and water (20 mL). The mixture was purged with nitrogen gas, and then [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.12 g, 0.17 mmol) was added. The mixture was then purged with nitrogen gas again, and the temperature was raised to 90 °C for 2 h. After cooling and filtration, the filtrate was added with ethyl acetate (200 mL) and water (200 mL). The organic phase was washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, and concentrated to give compound 23C (1.50 g crude), which was used directly in the next step.

[0304] LC-MS (ESI): m / z=535.1 [M+H] + .

[0305] Step 4: Compound 23C (1.50 g) was subjected to chiral SFC separation to give P1 (retention time: 1.927 min, designated as compound 23C-1) and P2 (retention time: 2.093 min, designated as compound 23C-2). Separation method: Instrument: Waters 150 SFC, Chromatography column: Chiralcel OD-Column, Mobile phase: A for CO₂ and B for MeOH (0.1% NH₃·H₂O), Gradient: 35% phase B isocratic elution, Flow rate: 100 mL / min, Column pressure: 100 bar, Column temperature: 25 °C, Absorption wavelength: 220 nm, Cycle time: 5 min). Sample preparation: The compound was dissolved in methanol to a concentration of 10 mg / mL. Injection: 3.5 mL of sample was injected at a time. Processing: After separation, the compound was concentrated at 35°C using a rotary evaporator, and the solvent was dried at -80°C using a freeze dryer to obtain Compound 23C-1 (211 mg, 14.1%) and Compound 23C-2 (121 mg, 8.1%).

[0306] Step 5: Compound 23C-1 (211 mg) was dissolved in 20% trifluoroacetic acid in dichloromethane (5 mL) and stirred at room temperature for 2 hours. The mixture was then concentrated to dryness, and methanol (15 mL) and solid sodium bicarbonate were added to adjust the pH to alkaline. The reaction mixture was then directly separated by reverse-phase column chromatography (acetonitrile:water (v / v) = 5% to 50%) to obtain compound 23 (123 mg, yield: 76.5%).

[0307] Compound 23: 1 H NMR (400MHz,CDCl3) δ 8.14 (d,1H),7.90 (s,1H),7.85 (d,1H),7.46 (s,1H),7.15 (d,1H),6.98-6.88 (m,1H),5.94 (d,1H),5.63 (d,1H),3.93(s,2H),3.82 (s,3H), LC-MS (ESI):m / z=435.5[M+H] + .

[0308] Compound 23C-2 (121 mg) was dissolved in 20% trifluoroacetic acid in dichloromethane (5 mL) and stirred at room temperature for 2 hours. The mixture was then concentrated to dryness, and the pH was adjusted to alkaline by adding methanol (15 mL) and solid sodium bicarbonate. The reaction mixture was then directly separated by reverse-phase column chromatography (acetonitrile:water (v / v) = 5% to 50%) to obtain compound 24 (19 mg, yield: 19.9%).

[0309] Compound 24: 1 H NMR (400MHz,CDCl3) δ 8.14 (d,1H),7.91 (s,1H),7.85 (d,1H),7.46 (s,1H),7.15 (d,1H),6.96-6.92 (m,1H),5.94 (d,1H),5.63 (d,1H),3.94(s,2H),3.83 (s,3H), LC-MS (ESI):m / z=435.5[M+H] + .

[0310] Examples 25 and 26 (2S)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3,3-difluoroazetidin-1-yl)-3-fluorobenzonitrile and (2R)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3,3-difluoroazetidin-1-yl)-3-fluorobenzonitrile (Compound 25, Compound 26) [ka]

[0311] Step 1: Compound 8C (3.8 g, 10.01 mmol), 3,3-difluoroazetidine hydrochloride (1.56 g, 12 mmol), and potassium carbonate (2.77 g, 20 mmol) were dissolved in dimethyl sulfoxide (40 mL) and reacted with stirring at 80 °C for 4 hours. After cooling, ethyl acetate (100 mL) and water (100 mL) were added, followed by extraction. The organic phase was collected and concentrated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v:v) = 0-25%) to give compound 25A (2.5 g, yield: 55.2%).

[0312] LC-MS (ESI): m / z=453.2 [M+H] + .

[0313] Step 2: Compound 14A (0.64 g, 1.77 mmol), compound 25A (800 mg, 1.77 mmol), and sodium bicarbonate (0.45 g, 5.31 mmol) were added to a mixture of 1,4-dioxane (90 mL) and water (30 mL). The mixture was purged with nitrogen three times, and then [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.13 g, 0.18 mmol) was added. The mixture was then purged with nitrogen again, and the temperature was raised to 60 °C for 2 h. After cooling, the mixture was filtered. Ethyl acetate (300 mL) and water (300 mL) were added to the filtrate, and the layers were separated. The organic phase was washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, and concentrated to dryness to give compound 25B (389 mg crude), which was used directly in the next step.

[0314] LC-MS (ESI): m / z=600.2 [M+H] + .

[0315] Step 3: Compound 25B (380 mg) was subjected to chiral SFC separation to give P1 (retention time: 1.284 min, designated as compound 25B-1) and P2 (retention time: 1.335 min, designated as compound 25B-2). Separation method: Instrument: Waters 150 SFC, Chromatography column: Chiralpak AS Column, Mobile phase: A for CO₂ and B for EtOH (0.1% NH₃·H₂O), Gradient: 15% phase B isocratic elution, Flow rate: 100 mL / min, Column pressure: 100 bar, Column temperature: 25 °C, Absorption wavelength: 220 nm, Cycle time: 2.5 min. Sample preparation: The compound was dissolved in ethanol to a concentration of 8.0 mg / mL. Injection: 2 mL of sample was injected at a time. Processing: After separation, the compound was concentrated at 35°C using a rotary evaporator, and the solvent was dried at -80°C using a freeze dryer to obtain Compound 25B-1 (49 mg, 12.9%) and Compound 25B-2 (41 mg, 10.8%).

[0316] Step 4: Compound 25B-1 (49 mg) was dissolved in 20% trifluoroacetic acid in dichloromethane (3 mL) and stirred at room temperature for 2 hours. The mixture was then concentrated to dryness, and a methanol solution (15 mL) was added. Solid sodium bicarbonate was added to adjust the pH to alkaline. The reaction mixture was then directly separated by reverse-phase column chromatography (acetonitrile:water (v / v) = 5% to 50%) to give compound 25 (11 mg, yield: 26.9%).

[0317] Compound 25: 1 H NMR (400MHz,DMSO-d6) δ 8.16 (s,1H),7.99 (d,1H),7.40 (d,1H),7.32 - 7.23 (m,2H),4.77-4.55 (m,4H),3.76 (s,3H),3.60 (s,2H), LC-MS (ESI):m / z=500.5[M+H] + .

[0318] Compound 25B-2 (41 mg) was dissolved in 20% trifluoroacetic acid in dichloromethane (3 mL) and stirred at room temperature for 2 hours. The mixture was then concentrated to dryness, and a methanol solution (15 mL) was added. Solid sodium bicarbonate was added to adjust the pH to alkaline. The reaction mixture was directly separated by reverse-phase column chromatography (acetonitrile:water (v / v) = 5% to 50%) to obtain compound 26 (13 mg, yield: 19.9%).

[0319] Compound 26: 1 H NMR (400MHz,DMSO-d6) δ 8.16 (s,1H),7.99 (d,1H),7.40 (d,1H),7.32 - 7.25 (m,2H),4.71-4.55 (m,5H),3.76 (s,4H),3.60 (s,2H), LC-MS (ESI):m / z=500.5[M+H] + .

[0320] Example 27 6-(5-(3-chloro-6-cyano-5-cyclopropoxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)quinoline-3-carboxamide (Compound 27) [ka]

[0321] Step 1: 6-Bromoquinoline-3-carboxamide (250.0 mg, 1.0 mmol), compound 2B (583.0 mg, 1.4 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (73.0 mg, 0.1 mmol), and sodium bicarbonate (385.2 mg, 4.0 mmol) were dissolved in 1,4-dioxane (10.0 mL) and water (3.0 mL). The mixture was purged with nitrogen gas three times, heated to 80 °C, and reacted for 2 h. After cooling to room temperature, the mixture was filtered through a silica gel funnel. The filter cake was rinsed with ethyl acetate (50.0 mL). The filtrate was collected and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1) to give compound 27 (690.0 mg, 84% yield).

[0322] 1 H NMR (400MHz,DMSO-d6) δ 9.23 (d,1H),8.70 (d,1H),8.27 (s,1H),8.15 (s,1H),8.07 - 7.94 (m,2H),7.81 (d,1H),7.75 - 7.59 (m,2H),4.26 - 4.11 (m,1H),3.78 (s,3H),0.91 - 0.89 (m,2H),0.85 - 0.74 (m,2H), LC-MS (ESI): m / z=462.1 [M+H] + .

[0323] Example 28 2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropoxy)benzonitrile (Compound 28) [ka]

[0324] Step 1: Compound 14B (2 g, 4.63 mmol), bis(pinacolato)diboron (2.96 g, 23.17 mmol), triethylamine (2.81 g, 27.77 mmol), and tetrakis(triphenylphosphine)palladium (0.54 g, 0.46 mmol) were dissolved in 1,4-dioxane (25 mL). The mixture was purged with nitrogen three times, maintained under a nitrogen atmosphere, heated to 90 °C, and stirred for 12 h. After cooling, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was collected, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v:v) = 10-13%) to give compound 28A (1.25 g, 63% yield).

[0325] LC-MS (ESI): m / z=432.20 [M+H] + .

[0326] Step 2: Sodium metal (0.27 g, 11.7 mmol) was added portionwise to methanol (50 mL) and completely dissolved. 2-Chloroacetonitrile (13.1 g, 173.5 mmol) was added and stirred at room temperature for 40 minutes. 2-Amino-6-chloropyridine-3-carboxylic acid (compound 28B) (10 g, 57.9 mmol) was then dissolved in methanol (50 mL) and added to the reaction mixture. The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated directly, and the residue was purified by silica gel column chromatography (methanol:dichloromethane (v:v) = 3%) to give compound 28C (3.6 g, yield: 27%).

[0327] LC-MS (ESI): m / z=230.1 [M+H] + .

[0328] Step 3: Compound 28C (2.2 g, 9.56 mmol) was dissolved in aqueous ammonia (20 mL) and stirred at room temperature for 2 hours until dissolved. The reaction mixture was directly concentrated, and the resulting crude product was dissolved in methanol (15 mL). Triethylamine (3.87 g, 38.24 mmol) and di-tert-butyl dicarbonate (3.13 g, 14.3 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was directly concentrated, and the resulting residue was purified by silica gel column chromatography (methanol:dichloromethane (v:v) = 3-6%) to give compound 28D (2.8 g, yield: 94%).

[0329] LC-MS (ESI): m / z=311.3 [M+H] + .

[0330] Step 4: Compound 28A (0.4 g, 0.93 mmol), compound 28D (0.40 g, 1.30 mmol), potassium carbonate (0.32 g, 2.33 mmol), and [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.068 g, 0.093 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2.5 mL). The mixture was purged with nitrogen three times, maintained under nitrogen, heated to 100 °C, and stirred for 2 h. After cooling, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was collected, dried, and concentrated. The residue was purified by silica gel column chromatography (methanol:dichloromethane (v:v) = 10-12%) to give compound 28E (0.52 g, 96% yield).

[0331] LC-MS (ESI): m / z=580.2 [M+H] + .

[0332] Step 5: Compound 28E (0.15 g, 0.26 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated directly, and the resulting residue was purified by preparative HPLC. Method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative Chromatography Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate). b. Gradient elution, with the content of mobile phase A ranging from 30% to 80%. c. Flow rate: 15 mL / min. d. Elution time: 40 min. Retention time: 30 min. Compound 28 (14 mg, yield: 11%) was obtained.

[0333] 1 H NMR (400MHz,DMSO-d6) δ 8.43 (s,1H),8.36 (d,1H),7.78 (d,1H),7.67 (d,1H),3.78 (s,3H),3.58 (s,2H),1.62 (s,3H),1.03 (dd,2H),0.92 (s,2H). LC-MS (ESI): m / z=480.1 [M+H] + .

[0334] Examples 29 and 30 (2S)-2-(4-(4-(aminomethyl)-1-oxo-8-vinyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropoxy)benzonitrile and (2R)-2-(4-(4-(aminomethyl)-1-oxo-8-vinyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropoxy)benzonitrile (Compound 29, Compound 30) [ka]

[0335] Step 1: Compound 20C (1.0 g, 2.63 mmol), compound 28A (1.13 g, 2.63 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (190 mg, 0.26 mmol), and potassium carbonate (1.09 g, 7.89 mmol) were dissolved in a 1,4-dioxane / water mixture (v:v = 6:1, 70 mL), purged with nitrogen gas three times, and reacted at 85 °C for 6 h. After cooling, the mixture was directly concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 4:1 to 1:1) to give compound 29A (690 mg, yield: 43.40%).

[0336] LC-MS (ESI): m / z=605.7 [M+H] + .

[0337] Step 2: Compound 29A (0.69 g, 1.14 mmol) was subjected to SFC separation to give P1 (retention time 1.142 min, designated as compound 29A-1) and P2 (retention time 1.195 min, designated as compound 29A-2). Method: Instrument: Waters 150 SFC; Chromatography column: Chiralcel AS Column (250 × 30 mm × 10 μm); Mobile phase: A for CO₂; B for 0.1% NH₃·H₂O in MeOH; Gradient: B 15%; Flow rate: 100 mL / min; Column pressure: 100 bar; Column temperature: 25 °C; Absorption wavelength: 220 nm; Cycle time: 6.3 min. Sample preparation: The compound was dissolved in acetonitrile to a concentration of 10 mg / mL. Injection: 3 mL of sample was injected at a time. Treatment: After separation, the compound was concentrated at 35°C using a rotary evaporator, and the solvent was dried at -80°C using a freeze dryer to obtain compounds 29A-1 (92.8 mg, 13.45%) and 29A-2 (66.9 mg, 9.96%).

[0338] Compound 29A-1:LC-MS (ESI):m / z=605.7[M+H] + .

[0339] Compound 29A-2:LC-MS (ESI):m / z=605.7[M+H] + .

[0340] Step 3: Compound 29A-1 (92.8 mg, 0.15 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (1.6 mL) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was then concentrated, and the residue was dissolved in dichloromethane (50 mL). The solution was then adjusted to alkaline with saturated sodium bicarbonate solution (50 mL). The mixture was then allowed to stand, separated, and the dichloromethane phase was separated. The aqueous phase was further extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 20:1) to give compound 29 (75 mg, yield: 96.87%).

[0341] Compound 29: 1 H NMR (400MHz,DMSO-d6) δ 12.36 (s,1H),8.39 (s,1H),8.13 (dd,1H),7.85 (d,1H),7.71 (s,1H),7.61 (s,1H),5.38 (d,1H),5.31 (d,1H),3.82 - 3.77 (m,5H),1.59 (s,3H),1.05 - 1.00 (m,2H),0.95 - 0.90 (m,2H), LC-MS (ESI): m / z=505.9 [M+H] + .

[0342] Compound 29A-2 (66.9 mg, 0.11 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.2 mL) was added, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was then concentrated, the residue was dissolved in dichloromethane (50 mL), and the solution was adjusted to alkaline with saturated sodium bicarbonate solution (50 mL). The mixture was then allowed to stand, the layers were separated, the dichloromethane phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 20:1) to give compound 30 (43 mg, yield: 77.25%).

[0343] Compound 30: 1 H NMR (400MHz,DMSO-d6) δ 12.35 (s,1H),8.39 (s,1H),8.13 (dd,1H),7.85 (d,1H),7.71 (s,1H),7.61 (s,1H),5.38 (d,1H),5.31 (d,1H),3.81 - 3.77 (m,5H),1.59 (s,3H),0.94 - 0.91 (m,,2H),0.87 - 0.83 (m,2H), LC-MS (ESI): m / z=505.9 [M+H] + .

[0344] Examples 31 and 32 (2S)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropoxy)benzonitrile and (2R)-2-(4-(2-(aminomethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropoxy)benzonitrile (Compound 31, Compound 32) [ka]

[0345] Step 1: Compound 28E (1.6 g, 2.76 mmol) was subjected to chiral SFC separation to give P1 (retention time: 2.590 min, designated as compound 28E-1) and P2 (retention time: 3.949 min, designated as compound 28E-2). Separation method: Instrument: MG II preparative SFC (SFC-14); Chromatography column: ChiralPak IE, 250 × 30 mm ID, 10 μm; Mobile phase: A for CO₂ and B for EtOH; Gradient: 30% phase B; Flow rate: 80 mL / min; Column pressure: 100 bar; Column temperature: 38 °C; Absorption wavelength: 220 nm; Cycle time: 2.5 min. Sample preparation: The compound was dissolved in ethanol. Injection: 2 mL of sample was injected at a time. Processing: After separation, the solution was concentrated at 35°C using a rotary evaporator, and the solvent was dried at -80°C using a freeze dryer to obtain Compound 28E-1 (0.45 g, 28%) and Compound 28E-2 (0.53 g, 33%).

[0346] Step 2: Compound 28E-1 (0.45 g, 0.78 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated directly, and the resulting residue was purified by preparative HPLC. Method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative Chromatography Conditions: a. Composition of Mobile Phases A and B: Mobile Phase A: acetonitrile, Mobile Phase B: water (containing 0.5% NH₃.H₂O). b. Gradient elution, with the content of Mobile Phase A ranging from 5% to 60%. c. Flow rate: 20 mL / min. d. Elution time: 15 min. Retention time: 10.0 min. Compound 31 (19 mg, yield: 5%) was obtained.

[0347] Compound 31: 1H NMR (400MHz,DMSO-d6) δ 8.41 (s,1H),8.36 (d,1H),7.78 (d,1H),7.64 (d,1H),3.78 (s,3H),3.64 (s,2H),1.62 (s,3H),1.11-1.00 (m,2H),0.98-0.89 (m,2H), LC-MS (ESI): m / z=480.5 [M+H] + .

[0348] Compound 28E-2 (0.53 g, 0.91 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated directly, and the resulting residue was purified by preparative HPLC. Method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative Chromatography Conditions: a. Composition of Mobile Phases A and B: Mobile Phase A: acetonitrile, Mobile Phase B: water (containing 0.5% NH₃.H₂O). b. Gradient elution was performed, with the content of Mobile Phase A ranging from 5% to 60%. c. Flow rate: 20 mL / min. d. Elution time: 15 min. Retention time: 10.0 min. Compound 32 (51 mg, yield: 11%) was obtained.

[0349] Compound 32: 1 H NMR (400MHz,DMSO-d6) δ 8.42 (s,1H),8.36 (d,1H),7.78 (d,1H),7.65 (d,1H),3.78 (s,3H),3.63 (s,2H),1.62 (s,3H),1.11-1.01 (m,2H),0.96-0.90 (m,2H), LC-MS (ESI): m / z=480.5 [M+H] + .

[0350] Example 33 2-(4-(4-(aminomethyl)-8-vinyl-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-fluorocyclobutyl)benzonitrile (Compound 33) [ka]

[0351] Step 1: Compound 8C (7 g, 27.6 mmol) was weighed into a flask, N,N-dimethylformamide (70 mL) was added, diethyl malonate (8.84 g, 55.20 mmol), and sodium hydride (3.31 g, 82.81 mmol) was slowly added, and the mixture was heated to 80 °C and reacted for 15 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to give compound 33A (4.1 g, yield: 37.7%).

[0352] LC-MS (ESI): m / z=394.2 [M+H] + .

[0353] Step 2: Compound 33A (4.1 g, 10.43 mmol) was dissolved in dimethyl sulfoxide (40 mL), lithium chloride (1.33 g, 31.28 mmol) was added, and the mixture was heated to 100° C. and reacted for 15 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give compound 33B (2 g, yield: 59.6%).

[0354] LC-MS (ESI): m / z=322.3 [M+H] + .

[0355] Step 3: Compound 33B (1.7 g, 5.28 mmol) was dissolved in dimethyl sulfoxide (10 mL), diphenyl(vinyl)sulfonium trifluoromethanesulfonate (2.3 g, 6.34 mmol) was added, and the mixture was allowed to react at 25 °C for 5 minutes. 1,8-diazabicyclo[5.4.0]undec-7-ene (2.4 g, 15.84 mmol) was added, and the mixture was allowed to react at 25 °C for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give compound 33C (1.6 g, 87% yield).

[0356] LC-MS (ESI): m / z=348.2 [M+H] + .

[0357] Step 4: Compound 33C (1.1 g, 3.16 mmol) was weighed into a flask, tetrahydrofuran (10 mL) was added, lithium borohydride (137.8 mg, 6.33 mmol) was added, and the mixture was stirred at 25°C. Water (1 mL) was then slowly added. The mixture was then reacted at 25°C for 15 hours. The reaction mixture was extracted with ethyl acetate, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was collected and concentrated, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give compound 33D (890 mg, yield: 92%).

[0358] LC-MS (ESI): m / z=306.1 [M+H] + .

[0359] Step 5: Compound 33D (300 mg, 0.98 mmol) was dissolved in dichloromethane (10 mL) and cooled to -78 °C. Diethylamine sulfur trifluoride (315.9 mg, 1.96 mmol) was added with stirring, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was slowly added to saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 8:1) to give Compound 33E (240 mg, yield: 79.7%).

[0360] LC-MS (ESI): m / z=308.2 [M+H] + .

[0361] Step 6: Compound 33E (0.22 g, 0.71 mmol), N-iodosuccinimide (0.24 g, 1.06 mmol), and acetonitrile (5 mL) were added to a one-neck flask, trifluoroacetic acid (16 mg, 0.14 mmol) was added, and the mixture was heated to 50° C. and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give compound 33F (0.24 g, yield: 78.0%).

[0362] LC-MS (ESI): m / z=434.0[M+H]+.

[0363] Step 7: Compound 33F (0.2 g, 0.46 mmol), pinacolborane (0.35 g, 2.77 mmol), triethylamine (0.28 g, 2.77 mmol), and tetrakis(triphenylphosphine)palladium (0.05 g, 0.05 mmol) were weighed into a flask, and 1,4-dioxane (3 mL) was added. The mixture was heated to 90 °C under nitrogen gas protection and reacted for 16 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give compound 33G (130 mg, 65.0% yield).

[0364] LC-MS (ESI): m / z=434.1 [M+H] + .

[0365] Step 8: Compound 33G (0.13 g, 0.30 mmol), compound 20C (0.11 g, 0.30 mmol), sodium bicarbonate (0.06 g, 0.75 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.02 g, 0.03 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.5 mL). The mixture was heated to 90 °C under nitrogen gas protection and stirred for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1) to give compound 33H (0.07 g, 38.5% yield).

[0366] LC-MS (ESI): m / z=607.6 [M+H] + .

[0367] Step 9: Compound 33H (0.03, 0.05 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was directly concentrated, and the resulting residue was purified by preparative HPLC. Method: 1. Equipment: Waters 2767 Preparative Liquid Chromatography Column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative Chromatography Conditions: a. Composition of Mobile Phases A and B: Mobile Phase A: acetonitrile, Mobile Phase B: water (containing 0.1% TFA); b. Gradient elution, with a mobile phase A content of 20% to 60%; c. Flow rate: 20 mL / min; d. Elution time: 20 min; Retention time: 6.94 min. Compound 33 (8 mg, yield: 31.9%) was obtained.

[0368] LC-MS (ESI): m / z=507.5 [M+H] + .

[0369] Biological Testing 1. Binding test between PRMT5 and PRMT5·MTA 1.1 PRMT5 enzyme activity test method A 1x test buffer solution (10 mM Tris, 1 mM DTT, 0.01% BSA, 0.01% Tween-20, pH adjusted to 8.0) was prepared. Test compounds were dissolved in DMSO to prepare a 10 mM stock solution and diluted to a final concentration of 100x. 100 nL of compound was added per well to the treatment group, while 100 nL of DMSO solution was added to blank and negative control wells. 5 μL of PRMT5 / MEP50 (BPS, Cat#31921) enzyme solution (final concentration: 1 nM) was added to the treatment group and negative control wells, and 5 μL of 1x test buffer was added to the blank wells. The wells were then incubated at room temperature for 15 minutes. Five microliters of a mixture of H4(1-21)S1ac (0.035 μM, GL Biochem, customized) and SAM (0.434 μM, Sigma, Cat. #A7007) was added per well and incubated at room temperature for 1 hour. 1× Epigenetics buffer (PerkinElmer, Cat. #AL008F) was prepared and used to dilute the recipient and donor microbeads. 15 μL of recipient microbeads (final concentration 10 μg / mL, PerkinElmer, Cat. #AL150C) and donor microbeads (final concentration 10 μg / mL, PerkinElmer, Cat. #AS106M) were added and incubated in the dark for 1 hour at room temperature. Detection was performed using the Alpha module on an Enspire microplate reader. The inhibition rate was calculated using Excel: inhibition rate (%) = (maximum negative control - detection signal value) / (maximum negative control - minimum blank control) x 100, and IC was calculated using XL-Fit. 50 The values were fitted.

[0370] 1.2 PRMT5·MTA enzyme activity assay method A 1x test buffer solution (10 mM Tris, 1 mM DTT, 0.01% BSA, 0.01% Tween-20, pH adjusted to 8.0) was prepared. Test compounds were dissolved in DMSO to prepare a 10 mM stock solution and diluted to a 100x final concentration. 100 nL of compound was added per well to the treatment group, while 100 nL of DMSO solution was added to blank and negative control wells. 5 μL of PRMT5 / MEP50 (BPS, Cat. #31921) (final concentration 1 nM) and MTA (final concentration 1 μM) solutions were added to the treatment group and negative control wells, and 5 μL of 1x test buffer was added to the blank wells. The plates were then incubated at room temperature for 15 minutes. Five microliters of a mixture of H4(1-21)S1ac (0.035 μM, GL Biochem, customized) and SAM (0.434 μM, Sigma, Cat. #A7007) was added per well and incubated at room temperature for 1 hour. 1× Epigenetics buffer (PerkinElmer, Cat. #AL008F) was prepared and used to dilute the recipient and donor microbeads. 15 μL of recipient microbeads (final concentration 10 μg / mL, PerkinElmer, #AL150C) and donor microbeads (final concentration 10 μg / mL, PerkinElmer, Cat. #AS106M) were added and incubated in the dark for 1 hour at room temperature. Detection was performed using the Alpha module on an Enspire microplate reader.

[0371] The inhibition rate was calculated using Excel: inhibition rate (%) = (maximum negative control - detection signal value) / (maximum negative control - minimum blank control) x 100, and IC was calculated using XL-Fit. 50 The values were fitted.

[0372] The compounds of the present invention have an IC of <100 nM against PRMT5·MTA. 50 values and IC values for some compounds 50 The values are as shown in Table 2, where AA is the IC 50 <1 nM, and A represents IC ≤ 1 nM 50<10 nM, B represents 10 nM ≤ IC 50 <50 nM, and C represents IC ≤ 50 nM 50 <100 nM.

[0373] [Table 2]

[0374] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, have significant inhibitory activity against PRMT5·MTA, and some preferred compounds, for example, compound 30, have IC 50 At the same time, in the absence of MTA, the inhibitory activity against PRMT5 was relatively weak, meaning that the compounds of the present invention were selective in inhibiting PRMT5·MTA.

[0375] 2. MIAPACA-2 cell proliferation inhibition experiment MIAPACA-2 cells were cultured in DMEM medium (ATCC, Cat. #30-2002, supplemented with 10% FBS and 1% double antibody) until approximately 85% confluency was reached before cell plating. The medium was discarded, rinsed with 1x PBS, and digested with pancreatic enzymes (Gibco, Cat. #15400-054). When the cells began to round and detach, medium was added to terminate digestion. The cells were then pipetted into a sterile centrifuge tube and centrifuged at 1000 rpm for 3 minutes. After centrifugation, the cells were removed and the supernatant discarded. Medium was added to the centrifuge tube, resuspended, and counted. Based on the counting results, the cell suspension was adjusted to the appropriate concentration and placed in a sample feed chamber. The cells were then added to a first 96-well cell plate (Corning, Cat. #3903), and ten Day 0 wells were plated into a second 96-well cell plate. Compounds were dissolved in DMSO to 10 mM and stored for use. A 5-fold gradient dilution was performed against the stock compound solution. 24 hours after plating, the diluted compounds were added to the first 96-well cell plate, along with a DMSO vehicle control group, and cultured at 37°C and 5% CO2 for 5 days. After 5 days of incubation, the supernatant was carefully and slowly aspirated and discarded from the first 96-well cell plate using a multichannel pipette. TrypLE (Gibco, Cat#12604-013) was then added to each well and incubated in an incubator at 37°C for 5 minutes until the cells were completely detached. Digestion was then terminated by adding medium and pipetting thoroughly. A third 96-well cell plate (Corning, Cat#3903) was then added to each well. After digestion, the homogenous cell suspension was pipetted and mixed thoroughly using a multichannel pipette. The diluted compounds were added, and a DMSO vehicle control group was also set up, and the cells were cultured at 37°C under 5% CO2 conditions for 5 days.To the second 96-well cell plate, Cell Viability Reagent (Vazyme, Cat# DD1101-03) was added to each well 24 hours after plating. To the first 96-well cell plate, Cell Viability Reagent was added to each well 5 days after dosing. To the third 96-well plate, Cell Viability Reagent was added to each well 10 days after the initial dosing. The wells were incubated at room temperature for 10 minutes, gently shaken five times after incubation, and chemiluminescence readings were detected using a microplate reader. The cell growth inhibition rate was calculated according to the following formula: [1 - (25 × T test - T0 / 25 × T control - T0)] × 100. Furthermore, the GI of the compound's cell growth inhibition was calculated using the DoseResp function in Origin 9.2 software. 50 values were calculated.

[0376] The compounds of the present invention have GI activity against MIAPACA-2 cells. 50 is less than 1000 nM, and the GI of some compounds 50 is less than 100 nM, and the GI of some compounds 50 was less than 50 nM.

[0377] The test results for some examples are shown in Table 3, where A<50 nM, 50 nM≦B<100 nM, and 100 nM≦C<500 nM.

[0378] [Table 3]

[0379] Conclusion: The compounds of the present invention, such as the compounds of the Examples, had good inhibitory activity against MIAPACA-2 cells.

[0380] 3. HCT-116 cell proliferation inhibition experiment HCT-116 cells were cultured in RPMI 1640 medium (ATCC, Cat. #30-2001, supplemented with 10% FBS and 1% double antibody) until approximately 85% confluency was reached before cell plating. The medium was discarded, the cells were washed with 1x PBS, and then digested with pancreatic enzymes (Gibco, Cat. #15400-054). When the cells began to round and detach, medium was added to terminate digestion. The cells were then pipetted, transferred to a sterile centrifuge tube, and centrifuged at 1000 rpm for 3 minutes. After centrifugation, the cells were removed and the supernatant discarded. Medium was added to the centrifuge tube, resuspended, and counted. Based on the counting results, the cell suspension was adjusted to the appropriate concentration and placed in a sample feed chamber. The cells were then added to a first 96-well cell plate (Corning, Cat. #3903), and ten Day 0 wells were plated into a second 96-well cell plate. Compounds were dissolved in DMSO to 10 mM and stored for use. A 5-fold gradient dilution was performed against the stock compound solution. 24 hours after plating, the diluted compounds were added to the first 96-well cell plate, along with a DMSO vehicle control group, and cultured at 37°C and 5% CO2 for 5 days. After 5 days of incubation, the supernatant was carefully and slowly aspirated and discarded from the first 96-well cell plate using a multichannel pipette. TrypLE (Gibco, Cat#12604-013) was then added to each well and incubated in an incubator at 37°C for 5 minutes until the cells were completely detached. Digestion was then terminated by adding medium and pipetting thoroughly. A third 96-well cell plate (Corning, Cat#3903) was then added to each well with RPMI-1640 medium. After digestion, the homogenous cell suspension was pipetted and mixed thoroughly using a multichannel pipette. The diluted compounds were added, and a DMSO vehicle control group was also set up, and the cells were cultured at 37°C under 5% CO2 conditions for 5 days.To the second 96-well cell plate, Cell Viability Reagent (Vazyme, Cat# DD1101-03) was added to each well 24 hours after plating. To the first 96-well cell plate, Cell Viability Reagent was added to each well 5 days after dosing. To the third 96-well plate, Cell Viability Reagent was added to each well 10 days after the initial dosing. The wells were incubated at room temperature for 10 minutes, gently shaken five times after incubation, and chemiluminescence readings were detected using a microplate reader. The cell growth inhibition rate was calculated according to the following formula: [1 - (25 × T test - T0 / 25 × T control - T0)] × 100. Furthermore, the GI of the compound's cell growth inhibition was calculated using the DoseResp function in Origin 9.2 software. 50 values were calculated.

[0381] The test results for some examples are shown in Table 4, where A>500 nM, 100 nM≦B<500 nM, and C<100 nM.

[0382] [Table 4]

[0383] Conclusion: The compounds of the present invention, such as the compounds of the Examples, had weak inhibitory activity against HCT-116 cells.

[0384] 4. HCT-116 MTAP- / - Cell Growth Inhibition Experiment HCT-116 MTAP - / -Cells were cultured in RPMI 1640 medium (ATCC, Cat. #30-2001, supplemented with 10% FBS and 1% double antibody) until approximately 85% confluency was reached before plating. The medium was discarded, and the cells were washed with 1x PBS. Afterwards, pancreatic enzymes (Gibco, Cat. #15400-054) were added and digested. When the cells began to round and detach, medium was added to terminate the digestion. The cells were then pipetted and transferred to a sterile centrifuge tube. The tube was centrifuged at 1000 rpm for 3 minutes. After centrifugation, the tube was removed and the supernatant discarded. Medium was added to the centrifuge tube, the cells were resuspended, and counted. Based on the counting results, the cell suspension was adjusted to the appropriate concentration and placed in a sample loading chamber. The cells were then added to a first 96-well cell plate (Corning, Cat. #3903), and ten Day 0 wells were plated into a second 96-well cell plate. Compounds were dissolved in DMSO to 10 mM and stored for use. A 5-fold gradient dilution was performed against the stock compound solution. 24 hours after plating, the diluted compounds were added to the first 96-well cell plate, along with a DMSO vehicle control group, and the plates were cultured at 37°C and 5% CO2 for 5 days. After 5 days of incubation, the supernatant was carefully and slowly aspirated and discarded from the first 96-well cell plate using a multichannel pipette. TrypLE (Gibco, Cat#12604-013) was then added to each well and the plate was placed in an incubator at 37°C for 5 minutes until the cells were completely detached. The digestion was then terminated by adding medium and pipetting thoroughly. A third 96-well cell plate (Corning, Cat#3903) was then added to each well with RPMI-1640 medium. After digestion, the homogenized original cell suspension was pipetted and mixed thoroughly using a multichannel pipette. The diluted compounds were added, and a DMSO vehicle control group was also set up, and the cells were cultured at 37°C under 5% CO2 conditions for 5 days.To the second 96-well cell plate, Cell Viability Reagent (Vazyme, Cat# DD1101-03) was added to each well 24 hours after plating. To the first 96-well cell plate, Cell Viability Reagent was added to each well 5 days after dosing. To the third 96-well plate, Cell Viability Reagent was added to each well 10 days after the initial dosing. The wells were incubated at room temperature for 10 minutes, gently shaken five times after incubation, and chemiluminescence readings were detected using a microplate reader. The cell growth inhibition rate was calculated according to the following formula: [1 - (25 × T test - T0 / 25 × T control - T0)] × 100. Furthermore, the GI of the compound's cell growth inhibition was calculated using the DoseResp function in Origin 9.2 software. 50 values were calculated.

[0385] [Table 5]

[0386] Conclusion: The compounds of the present invention, such as the compounds of the Examples, are effective against HCT-116MTAP - / - It had a strong inhibitory activity against cells.

[0387] 5. Cellular sDMA detection test 5.1. sDMA detection in MIAPACA-2 cells MIAPACA-2 cells were cultured in DMEM medium (ATCC, Cat. #30-2002, supplemented with 10% FBS and 1% double antibody) until approximately 85% confluency was reached before plating. The medium was discarded, rinsed with 1x PBS, and digested with pancreatic enzymes (Gibco, Cat. #15400-054). When the cells began to round and detach, medium was added to terminate the digestion. The cells were pipetted, transferred to a sterile centrifuge tube, and centrifuged at 1000 rpm for 3 minutes. After centrifugation, the cells were removed and the supernatant discarded. Medium was added to the centrifuge tube, resuspended, and counted. Based on the counting results, the cell suspension was adjusted to the appropriate concentration, placed in a sample tank, and 100 μL was added to each well of a 96-well plate. Compounds were dissolved in DMSO to 10 mM and stored for use. During experiments, compounds were diluted 5-fold with medium. 100 μL of diluted compound was added to the 96-well plate containing cells, along with a DMSO vehicle control group, and cultured for 3 days at 37°C and 5% CO2. After 3 days, each well was washed twice with cold PBS, and 50 μL of protease and phosphatase inhibitor cocktail (CST, Cat#5872S) and RIPA lysis solution were added to the 96-well plate at a volume appropriate for each well. The mixture was then placed on ice for 10 minutes, during which time the cells were repeatedly pipetted until complete lysis. The mixture was then centrifuged at 2500 rpm for 35 minutes at 4°C, and the supernatant protein sample was collected. Protein detection was performed using a BCA kit (Biyuntian, Cat. #P0011). Based on the measurement results, the protein concentration of the lysate was adjusted to the required concentration with PBS carbonate-bicarbonate buffer, pH 9.6 (Sigma, Cat. #C3041). 100 μL per well was added to a black high-binding 96-well plate (Nunc Maxisorp, Cat. #437111). The plate was incubated at room temperature for 2 hours. After removing the lysate, the plate was washed four times with PBST (Cell Signaling, Cat. #9809S). The plate was then blocked with 5% BSA-containing blocking solution (Solarbio, Cat. #SW3015) for 1 hour. After removing the lysate, the plate was washed four times with PBST.100 μL of sDMA antibody (CST, Cat#13222S) or SMD3 antibody (Abgent, Cat#AP12451A) was added to each well and shaken overnight at 4°C. After removing the antibody, the plate was washed four times with PBST. 100 μL of rabbit secondary antibody (Cell Signaling Technology, Cat#7074) was added to each well and incubated at room temperature for 1 hour. After removing the secondary antibody, the plate was washed four times with PBST. 100 μL of Immobilon Forte Western HRP substrate (Millipore, Cat#WBLUF0500) was added to each well and incubated with shaking for 15 minutes before detection by chemiluminescence on a BMG microplate reader. Data were normalized (SDMA reading / SMD3 reading) and plotted using Graphpad Prism 8.3.0 software, and IC was calculated. 50 values were calculated.

[0388] 5.2. SDMA detection in HCT-116 cells HCT-116 cells were cultured in RPMI 1640 medium (ATCC, Cat. #30-2001, supplemented with 10% FBS and 1% double antibody) until approximately 85% confluency was reached before plating. The medium was discarded, rinsed with 1x PBS, and digested with pancreatic enzymes (Gibco, Cat. #15400-054). When the cells began to round and detach, medium was added to terminate digestion. The cells were pipetted, transferred to a sterile centrifuge tube, and centrifuged at 1000 rpm for 3 minutes. After centrifugation, the cells were removed and the supernatant discarded. Medium was added to the centrifuge tube, resuspended, and counted. Based on the counting results, the cell suspension was adjusted to the appropriate concentration, placed in a sample tank, and 100 μL was added to each well of a 96-well plate. Compounds were dissolved in DMSO to 10 mM and stored for use. During experiments, compounds were diluted 5-fold with medium. 100 μL of diluted compound was added to the 96-well plate containing cells, along with a DMSO vehicle control group, and cultured for 3 days at 37°C and 5% CO2. After 3 days, each well was washed twice with cold PBS, and 50 μL of protease and phosphatase inhibitor cocktail (CST, Cat#5872S) and RIPA lysis solution were added to the 96-well plate at a volume appropriate for each well. The mixture was then placed on ice for 10 minutes, during which time the cells were repeatedly pipetted until complete lysis. The mixture was then centrifuged at 2500 rpm for 35 minutes at 4°C, and the supernatant protein sample was collected. Protein detection was performed using a BCA kit (Biyuntian, Cat. #P0011). Based on the measurement results, the protein concentration of the lysate was adjusted to the required concentration with PBS carbonate-bicarbonate buffer, pH 9.6 (Sigma, Cat. #C3041). 100 μL per well was added to a black high-binding 96-well plate (Nunc Maxisorp, Cat. #437111). The plate was incubated at room temperature for 2 hours. After removing the lysate, the plate was washed four times with PBST (Cell Signaling, Cat. #9809S). The plate was then blocked with 5% BSA-containing blocking solution (Solarbio, Cat. #SW3015) for 1 hour. After removing the lysate, the plate was washed four times with PBST.100 μL of sDMA antibody (CST, Cat#13222S) or SMD3 antibody (Abgent, Cat#AP12451A) was added to each well and shaken overnight at 4°C. After removing the antibody, the plate was washed four times with PBST. 100 μL of rabbit secondary antibody (Cell Signaling Technology, Cat#7074) was added to each well and incubated at room temperature for 1 hour. After removing the secondary antibody, the plate was washed four times with PBST. 100 μL of Immobilon Forte Western HRP substrate (Millipore, Cat#WBLUF0500) was added to each well and incubated with shaking for 15 minutes before detection by chemiluminescence on a BMG microplate reader. Data were normalized (SDMA reading / SMD3 reading) and plotted using Graphpad Prism 8.3.0 software, and IC was calculated. 50 values were calculated.

[0389] [Table 6]

[0390] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, had weak inhibitory activity against the production of SDMA by HCT-116 cells.

[0391] HCT-116 MTAP - / - SDMA detection in cells HCT-116 MTAP- / - cells were cultured in RPMI 1640 medium (ATCC, #30-2001, supplemented with 10% FBS and 1% double antibody) until approximately 85% confluency was reached before plating. The medium was discarded, rinsed with 1x PBS, and digested with pancreatic enzymes (Gibco, Cat#15400-054). When the cells began to round and detach, medium was added to terminate digestion. The cells were pipetted, transferred to a sterile centrifuge tube, and centrifuged at 1000 rpm for 3 minutes. After centrifugation, the cells were removed and the supernatant discarded. Medium was added to the centrifuge tube, resuspended, and counted. Based on the counting results, the cell suspension was adjusted to the appropriate concentration, placed in a sample tank, and 100 μL was added to each well of a 96-well plate. Compounds were dissolved in DMSO to 10 mM and stored for use. During experiments, compounds were diluted 5-fold with medium. 100 μL of diluted compound was added to the 96-well plate containing cells, along with a DMSO vehicle control group, and cultured for 3 days at 37°C and 5% CO2. After 3 days, each well was washed twice with cold PBS, and 50 μL of protease and phosphatase inhibitor cocktail (CST, Cat#5872S) and RIPA lysis solution were added to the 96-well plate at a volume appropriate for each well. The mixture was then placed on ice for 10 minutes, during which time the cells were repeatedly pipetted until complete lysis. The mixture was then centrifuged at 2500 rpm for 35 minutes at 4°C, and the supernatant protein sample was collected. Protein detection was performed using a BCA kit (Biyuntian, Cat. #P0011). Based on the measurement results, the protein concentration of the lysate was adjusted to the required concentration with PBS carbonate-bicarbonate buffer, pH 9.6 (Sigma, Cat. #C3041). 100 μL per well was added to a black high-binding 96-well plate (Nunc Maxisorp, Cat. #437111). The plate was incubated at room temperature for 2 hours. After removing the lysate, the plate was washed four times with PBST (Cell Signaling, Cat. #9809S). The plate was then blocked with 5% BSA-containing blocking solution (Solarbio, Cat. #SW3015) for 1 hour. After removing the lysate, the plate was washed four times with PBST.100 μL of sDMA antibody (CST, Cat#13222S) or SMD3 antibody (Abgent, Cat#AP12451A) was added to each well and shaken overnight at 4°C. After removing the antibody, the plate was washed four times with PBST. 100 μL of rabbit secondary antibody (Cell Signaling Technology, Cat#7074) was added to each well and incubated at room temperature for 1 hour. After removing the secondary antibody, the plate was washed four times with PBST. 100 μL of Immobilon Forte Western HRP substrate (Millipore, Cat#WBLUF0500) was added to each well and incubated with shaking for 15 minutes before detection by chemiluminescence on a BMG microplate reader. Data were normalized (SDMA reading / SMD3 reading) and plotted using Graphpad Prism 8.3.0 software, and IC was calculated. 50 values were calculated.

[0392] [Table 7]

[0393] Conclusion: The compounds of the present invention, such as the compounds of the Examples, have the following properties: - / - It had a strong inhibitory activity against the production of SDMA by cells.

[0394] 6. hERG potassium ion channel activity test Experimental platform: electrophysiological manual patch clamp system Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium ion channel Experimental Method: hERG potassium channel currents were recorded at room temperature using the whole-cell patch clamp technique in CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel. Glass microelectrodes were prepared by pulling glass electrode blanks with a BF150-86-10 Sutter puller. After filling the electrode with the internal solution, the tip resistance was approximately 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe and connected to a patch clamp amplifier. The clamping voltage and data recording were computer-controlled using pClamp 10 software. The sampling frequency was 10 kHz and the filter frequency was 2 kHz. After obtaining whole-cell recordings, the cells were clamped to -80 mV, and the hERG potassium current (I hERG The voltage step eliciting the hERG current was applied from -80 mV to +20 mV for 2 s, followed by a repolarization to -50 mV, which lasted for 1 s, and then back to -80 mV. This voltage was applied every 10 s, and the hERG potassium current was stabilized (for at least 1 min) before the administration process began. Each compound was tested for at least 1 min, and at least two cells were tested for each concentration (n ≥ 2).

[0395] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The inhibition of hERG potassium current (peak hERG tail current evoked at -50 mV) by different compound concentrations was calculated using the following formula:

[0396] Inhibition%=[1-(I / Io)]×100% Here, Inhibition% represents the percentage of inhibition of the hERG potassium current by the compound, and I and Io represent the amplitude of the hERG potassium current after administration and before administration, respectively.

[0397] Compound IC 50 was calculated by fitting the following equation using GraphPad Prism 5 software:

[0398] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)×HillSlope)) where X is the Log value of the sample detection concentration, Y is the percentage inhibition at the corresponding concentration, and Bottom and Top are the minimum and maximum percentage inhibition, respectively.

[0399] 7. CYP3A4 enzyme inhibition test The purpose of this study was to evaluate the effects of test substances on the activity of CYP3A4 enzymes, a cytochrome P450 (CYP) enzyme, in human liver microsomes using an in vitro test system. A specific probe substrate for CYP3A4 enzymes was incubated with human liver microsomes and different concentrations of test substances, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction was completed, the metabolites generated by the specific substrate were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after sample processing. The changes in CYP enzyme activity were measured and the IC was calculated. 50 The values were calculated to evaluate the potential inhibitory ability of the test substance against each CYP3A4 enzyme. Under the test conditions, the incubation concentration was 0 to 30 μM.

[0400] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, had weak inhibitory activity against the CYP3A4 enzyme.

[0401] 8. Pharmacokinetic studies in mice 8.1. Test animals: male C57 mice, 22-25g, 6 mice / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0402] 8.2. Experimental Design: On the day of the experiment, C57 mice (6 × number of test compounds, n) were randomly divided into groups according to weight. One day before administration, they were fasted for 12-14 hours without water restriction, and fed 4 hours after administration.

[0403] Before and after administration, 0.06 mL of blood was collected from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected at 0, 5, 15, 30 minutes, 1, 2, 4, 7, and 24 hours for both the intravenous and intragastric administration groups. All samples were stored at -80°C before analytical detection, and quantitative analysis of the samples was performed by LC-MS / MS.

[0404] Conclusion: The compounds of the present invention, such as the compounds of the Examples, had good pharmacokinetic characteristics in mice.

[0405] 9. Pharmacokinetic study in rats 9.1. Test animals: Male SD rats, approximately 220 g, 6-8 weeks old, 6 rats per compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0406] 9.2. Experimental Design On the day of the experiment, SD rats (6 × number of test compounds, n) were randomly divided into groups based on their body weight. One day before administration, they were fasted for 12 to 14 hours without water prohibition, and fed 4 hours after administration.

[0407] Before and after administration, 0.15 mL of blood was collected from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm for 10 minutes at 4°C to collect plasma. Blood was collected at 0, 5, 15, and 30 minutes, and 1, 2, 4, 6, 8, and 24 hours for both the intravenous and intragastric administration groups. All samples were stored at -80°C before analytical detection, and quantitative analysis of the samples was performed by LC-MS / MS.

[0408] Conclusion: The compounds of the present invention, such as the compounds of the Examples, had good pharmacokinetic characteristics in rats.

[0409] 10. Pharmacokinetic study in beagle dogs 10.1. Test animals: Male beagle dogs, approximately 8-11 kg, 6 dogs per compound, purchased from Beijing Masu Biotechnology Co., Ltd.

[0410] 10.2. Test Method: On the day of the test, (6 x number of test compounds, n) beagle dogs were randomly divided into groups based on weight. One day before administration, they were fasted for 12-14 hours without water prohibition, and fed 4 hours after administration. Administration was performed according to Table 8.

[0411] [Table 8]

[0412] Before and after administration, 1 mL of blood was collected from the jugular or limb vein and placed in an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 minutes. Blood was collected at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, 10, 12, and 24 hours for both the intravenous and intragastric administration groups. All samples were stored at -80°C before analytical detection, and quantitative analysis of the samples was performed by LC-MS / MS.

[0413] [Table 9]

[0414] Conclusion: The compounds of the present invention, such as the compounds of the Examples, had good pharmacokinetic characteristics in beagle dogs.

[0415] 11. Pharmacokinetic studies in monkeys 11.1. Test animals: male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 animals per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0416] 11.2. Test method: On the day of the test, monkeys (4 × number of test compounds, n) were randomly divided into groups based on their weight. One day before administration, they were fasted for 14 to 18 hours without water prohibition, and fed 4 hours after administration.

[0417] Before and after administration, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 minutes. Blood was collected at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 hours for both the intravenous and intragastric administration groups. All samples were stored at -80°C before analytical detection and quantitative analysis of the samples was performed by LC-MS / MS.

[0418] Conclusion: The compounds of the present invention, for example the compounds of the Examples, had good pharmacokinetic characteristics in monkeys.

[0419] 12. In vivo drug efficacy experiments HCT-116 MTAP- / - cells were cultured in RPMI-1640 medium at 37°C in a 5% CO2 incubator. They were passaged every 2–3 days. When the required number of cells was reached, they were harvested, counted, and the cell concentration adjusted with PBS. They were then diluted 1:1 with Matrigel to a cell concentration of 2.5 × 107 cells / mL. Mice (Balb / c nude, female, purchased from Weitong Lihua Laboratory Animal Technology Co., Ltd.) were inoculated at 5 × 106 cells / 200 μL into the right forelimb flank. When tumors grew to 80–100 mm3 (days 5–7 after inoculation), they were sorted according to tumor size and then grouped for treatment (the day of grouping and treatment was designated Day 0). Tumor and animal weights were measured three times weekly during the treatment period. At the end of the experiment, tumor samples were collected at multiple time points, and tumor weights were recorded and photographed. The in vivo efficacy results of Compound 30 are shown in Figure 1 (tumor volume (a in the figure) and mouse body weight (b in the figure)), and the in vivo efficacy results of Compound 30 (tumor weight) are shown in Figure 2.

[0420] The experimental data are expressed as mean ± standard error (mean ± SEM). The data were statistically analyzed using one-way ANOVA and Dunnett's multiple comparison test with Graphpad Prism, and differences were considered significant when P < 0.05. [ka]

[0421] Conclusion: The compounds of the present invention, such as the compounds of the Examples, inhibit the activity of mouse CDX (HCT-116 MTAP - / - In a cell model, it had a good tumor-inhibiting effect.

Claims

1. A compound represented by formula (I-a) or (I-b), a stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof, 【Chemical 1】 where: D is 【Chemistry 2】 is selected from D1 is, 【Chemistry 3】 is selected from Ld is C １－４ Alkyl group, C ２－４ Alkenyl group, C ２－４ alkynyl groups, Rd1 is selected from 5-membered heteroaryl groups, said heteroaryl groups optionally containing halogen, D, CN, OH, C １－４ Alkyl group, C １－４ Alkoxy groups and NH ２ and is substituted with 1 to 3 groups selected from X is CR １ or N, Y, Z, and V are independently CR ５ , C(R ５ ) ２ , N.R. ６ , N, O or S, and the total number of O and S is 1 or less; Ring A is a phenyl group, a 5- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S; Ring B is C ３－１２ a carbocycle or a 4- to 12-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S; Ring C is C ３－１２ a carbocycle or a 4- to 12-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S; R １ H, D, C １－４ Alkyl group, C １－４ Alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl groups, halogens, CN, OH, NH ２ or COOH, wherein the alkyl, alkoxy, alkenyl, and alkynyl groups are optionally selected from the group consisting of halogen, D, CN, OH, and NH. ２ and is substituted with 1 to 3 groups selected from R ２ OH, NH ２ , -CH ２ NH ２ or —NH—OH, R ３ , R ４ are independently H, D, halogen, C １－４ Alkyl groups, CN, OH, NH ２ , C １－４ Alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group or C ３－６ and cycloalkyl groups, wherein the alkyl, alkoxy, alkenyl, alkynyl or cycloalkyl groups are optionally selected from the group consisting of halogen, D, CN, OH and NH. ２ and is substituted with 1 to 3 groups selected from One option is R ３ , R ４ together form =NH, Each R ５ are independently H, D, ═O, OH, C １－４ Alkyl group, CN, halogen, C １－４ Alkoxy group, C ２－４ Alkenyl group, C ２－４ an alkynyl group, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C ３－６ and a cycloalkyl group, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, heteroaryl group, or cycloalkyl group is optionally selected from the group consisting of halogen, D, CN, OH, C １－４ Alkyl group, C １－４ Alkoxy groups and NH ２ and is substituted with 1 to 3 groups selected from R ６ H, D, C １－４ Alkyl group or C ３－６ and cycloalkyl groups, wherein the alkyl or cycloalkyl groups are optionally selected from the group consisting of halogen, D, CN, OH, and NH. ２ and is substituted with 1 to 3 groups selected from Each R ７ are independently H, ═O, D, OH, CN, halogen, C １－４ Alkyl group, C １－４ Alkoxy group, N(R ７ ') ２ , C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－６ A cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, or heterocycloalkyl group optionally contains halogen, D, OH, NH ２ , C.N., C. １－４ Alkyl group, —C(O)C １－４ Alkyl group, —C(O)NHC １－４ Alkyl group, —C(O)NH ２ , -NHC(O)C １－４ Alkyl group and C １－４ substituted with 1 to 3 groups selected from alkoxy groups; Each R ８ are independently H, D, a nitro group, an amino group, C １－６ Alkoxy group, ═O, OH, CN, halogen, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -SF ５ , N ３ , C １－６ Alkyl group, -COC １－４ alkyl group, —N(R ７ ') ２ , -C(=O)N(R ７ ') ２ , -NR ７ 'C(=O)-R ７ ', -C(=O)-R ７ ', - (CH ２ ) ｒ -O-(CH ２ ) ｒ -R ８ ', -S-C １－６ Alkyl group, —S(O)—C １－６ Alkyl group, —S(O) ２ -C １－６ Alkyl group, -S-(CH ２ ) ｒ -R ８ ', -NR ７ '-(CH ２ ) ｒ -R ８ ' or - (CH ２ ) ｒ -R ８ ', wherein the alkyl, alkenyl, or alkynyl group is optionally selected from the group consisting of R ８’’ and is substituted with 1 to 5 members selected from Each R ７ ' are independently H, D, an amino group, a hydroxy group, C １－６ Alkyl group, halo C １－６ Alkyl groups, deuterated C １－６ Alkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－１２ Heterocycloalkyl group, —NHC １－６ Alkyl group, —N(C １－６ alkyl) ２ , or deuterated C １－６ The cycloalkyl group and heterocycloalkyl group may optionally contain deuterium, halogen, cyano, amino, hydroxy, C １－６ Alkyl group, halo C １－６ Alkyl groups, deuterated C １－６ Alkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group or deuterated C １－６ substituted with 1 to 3 groups selected from alkoxy groups; Each R ８ ' is independently H, D, C １－６ Alkyl group, C １－４ Alkoxy group, C ３－１２ A 4- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from a carbocycle, N, O, and S, wherein the alkyl and alkoxy groups are optionally halogen, ═O, D, OH, NH ２ , C.N., C. １－６ Alkyl group, halo C １－６ Alkyl groups, deuterated C １－６ Alkyl group, —C(O)C １－４ Alkyl group, —C(O)NHC １－４ Alkyl group, —C(O)NH ２ , -NHC(O)C １－４ Alkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy groups and deuterated C １－６ alkoxy groups, and the carbocyclic or heterocyclic ring is optionally substituted with 1 to 3 groups selected from R ８’’ and is substituted with 1 to 5 members selected from R ８’’ is a halogen, D, OH, NH ２ , C.N., C. １－６ Alkyl group and C １－６ alkoxy groups, wherein the alkyl or alkoxy groups are optionally selected from halogen, deuterium, cyano, amino, hydroxy, C １－６ Alkyl group or C １－６ is further substituted with 1 to 5 groups selected from alkoxy groups; each r is independently 0, 1, 2, or 3; p is 0, 1 or 2; n and m are independently integers from 0 to 5; As a condition, 1. base 【Chemistry 4】 teeth, 【Chemistry 5】 Instead, ２． 【Chemistry 6】 but 【Chemistry 7】 If R ３ is H, C １－４ Alkyl group, C １－４ is a haloalkyl group, and R ５ is H, halogen, C １－４ Alkyl group, C １－４ Alkoxy group, C １－４ is a haloalkyl group, and R ３ and R ５ is not simultaneously H, the group 【Chemistry 8】 teeth, 【Chemistry 9】 A compound represented by formula (Ia) or (Ib), a stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof, wherein:

2. A structure of formula (I): 【Chemistry 10】 2. The compound of formula (Ia) according to claim 1, or a stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof, having the formula:

3. D is 【Chemistry 11】 2. The compound of claim 1, a stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof, selected from:

4. X is CR １ or N, Y, Z, and V are independently CR ５ , N, O or S, and the total number of O and S is 1 or less; Ring A is a phenyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S; Ring B is a phenyl group, C ３－６ a cycloalkyl group represented by the formula (I), a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S; Ring C is a phenyl group, C ３－６ a cycloalkyl group represented by the formula (I), a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S; R １ H, D, C １－４ alkyl groups, halogen, CN, said alkyl groups being optionally substituted with 1 to 3 groups selected from halogen, D, CN and OH; R ２ OH, NH ２ , -CH ２ NH ２ or —NH—OH, R ３ , R ４ are independently H, D, halogen, C １－４ Alkyl group, CN, OH or NH ２ wherein the alkyl group is optionally selected from halogen, D, CN, OH and NH ２ and is substituted with 1 to 3 groups selected from Each R ５ are independently H, D, OH, C １－４ Alkyl group, CN, halogen, C １－４ Alkoxy group, C ２－４ Alkenyl group, C ２－４ an alkynyl group, a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C ３－４ and cycloalkyl groups, wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, heteroaryl group, heterocycloalkyl group, and cycloalkyl group are optionally selected from the group consisting of halogen, D, CN, OH, C １－４ Alkyl group, C １－４ Alkoxy groups, and NH ２ is substituted with 1 to 3 groups selected from Each R ７ are independently H, ═O, D, OH, CN, halogen, C １－４ Alkyl group, C １－４ Alkoxy group, N(R ７ ') ２ , C ２－４ Alkenyl group, or C ２－４ and an alkynyl group, wherein said alkyl, alkoxy, alkenyl, or alkynyl group optionally includes halogen, D, OH, NH. ２ , C.N., C. １－４ Alkyl group, —C(O)C １－４ Alkyl group, —C(O)NHC １－４ Alkyl group, —C(O)NH ２ , -NHC(O)C １－４ Alkyl group and C １－４ substituted with 1 to 3 groups selected from alkoxy groups; Each R ８ are independently H, D, ═O, OH, CN, halogen, C ２－４ Alkenyl group, C ２－４ Alkynyl group, N ３ , C １－４ Alkyl group, -COC １－４ alkyl group, -CONR ７ 'C １－４ alkyl group, -NR ７ 'COC １－４ alkyl group, N(R ７ ') ２ , —O—(CH ２ ) r-R ８ ', or -(CH ２ ) r-R ８ ', wherein the alkyl, alkenyl, and alkynyl groups are optionally selected from the group consisting of halogen, D, OH, NH ２ , C.N., C. １－４ Alkyl group and C １－４ substituted with 1 to 3 groups selected from alkoxy groups; Each R ７ ' are independently H, C １－４ Alkyl group or halo C １－４ is an alkyl group, Each R ８ ' are independently H, C １－４ Alkoxy group, C ３－６ a cycloalkyl group, a phenyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenyl group, heterocycloalkyl group, or heteroaryl group optionally contains halogen, ═O, D, OH, NH ２ , C.N., C. １－４ Alkyl group, halo C １－４ Alkyl groups, and C １－４ substituted with 1 to 3 groups selected from alkoxy groups; each r is independently 0, 1, or 2; p is 0 or 1; The compound according to any one of claims 1 to 3, wherein n and m are independently 0, 1, 2, 3 or 4, or a stereoisomer, deuterated product, solvate or pharmaceutically acceptable salt thereof.

5. The B ring is 【Chemistry 12】 2. The compound of claim 1, a stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof, selected from:

6. The compound has the structure of formula (II-a), (II): 【Chemistry 13】 10. The compound of claim 1, a stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof, having the formula:

7. X is CR １ or N, Y, Z, and V are independently CR ５ , N, O or S, and the total number of O and S is 1 or less; Ring A is a phenyl group, a thienyl group, a thiazolyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, or a pyridazinyl group; D is 【Chemistry 14】 is selected from R １ H, D, C １－４ an alkyl group, F, Cl, Br, I, or CN, said alkyl group being optionally substituted with 1 to 3 groups selected from F, Cl, Br, I, D, CN, and OH; R ２ OH, NH ２ , -CH ２ NH ２ or —NH—OH, R ３ , R ４ are independently H, D, F, Cl, Br, I, C １－４ alkyl group or CN, said alkyl group optionally being selected from F, Cl, Br, I, D, CN, OH and NH ２ is substituted with 1 to 3 groups selected from Each R ５ are independently H, D, OH, C １－４ Alkyl groups, CN, F, Cl, Br, I, C １－４ Alkoxy group, C ２－４ Alkenyl group, C ２－４ an alkynyl group, a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, a 4- to 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or C ３－４ and cycloalkyl groups, wherein the alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, heteroaryl groups, heterocycloalkyl groups, and cycloalkyl groups are optionally selected from the group consisting of F, Cl, Br, I, D, CN, OH, methoxy groups, and NH ２ and is substituted with 1 to 3 groups selected from Each R ７ are independently H, D, OH, CN, halogen, C １－４ Alkyl group, C １－４ Alkoxy group, N(R ７ ') ２ , C ２－４ Alkenyl group, or C ２－４ and an alkynyl group, wherein said alkyl, alkoxy, alkenyl, or alkynyl group optionally includes halogen, D, OH, NH. ２ , C.N., C. １－４ Alkyl group and C １－４ substituted with 1 to 3 groups selected from alkoxy groups; Each R ８ are independently H, D, OH, CN, F, Cl, Br, I, C ２－４ Alkenyl group, C ２－４ Alkynyl group, N ３ , C １－４ Alkyl group, -COC １－４ alkyl group, -CONR ７ 'C １－４ alkyl group, -NR ７ 'COC １－４ alkyl group, N(R ７ ') ２ , —O—(CH ２ ) r-R ８ ', or -(CH ２ ) r-R ８ ', wherein the alkyl, alkenyl, and alkynyl groups are optionally selected from the group consisting of halogen, D, OH, NH ２ , C.N., C. １－４ Alkyl group and C １－４ substituted with 1 to 3 groups selected from alkoxy groups; Each R ７ ' are independently H, C １－４ Alkyl group or halo C １－４ is an alkyl group, Each R ８ ' are independently H, C １－４ Alkoxy group, C ３－６ a cycloalkyl group, a phenyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenyl group, heterocycloalkyl group, or heteroaryl group optionally contains halogen, ═O, D, OH, NH ２ , C.N., C. １－４ Alkyl group, halo C １－４ Alkyl groups, and C １－４ substituted with 1 to 3 groups selected from alkoxy groups; each r is independently 0, 1, or 2; p is 0 or 1; n is 0, 1, 2 or 3; 7. The compound of claim 6, or a stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4.

8. Each R ８ are independently D, CN, F, Cl, Br, C ２－４ Alkenyl group, C ２－４ Alkynyl group, N ３ , C １－４ Alkyl group, —O—(CH ２ ) r-R ８ ', or -(CH ２ ) r-R ８ ', wherein the alkyl, alkenyl, and alkynyl groups are optionally selected from the group consisting of halogen, D, OH, NH ２ , C.N., C. １－２ Alkyl group and C １－２ 8. The compound of claim 7, or a stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof, substituted with 1 to 3 groups selected from alkoxy groups.

9. R ８ ' is independently １－４ an alkoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a phenyl group, a tetrahydropyrrolyl group, an azetidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, 【Chemistry 15】 thienyl, thiazolyl, pyrrolyl, imidazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl group, optionally F, Cl, Br, I, ═O, D, OH, NH ２ , C.N., C. １－４ Alkyl group, halo C １－２ Alkyl groups, and C １－２ 7. The compound of claim 6, or a stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof, substituted with 1 to 3 groups selected from alkoxy groups.

10. D1 is, 【Chemistry 16】 is selected from Ld is C ２－４ alkenyl groups, preferably 【Chemistry 17】 and Rd1 is selected from a 5-membered heteroaryl group, said heteroaryl group optionally being selected from the group consisting of NH ２ Rd1 is preferably substituted with 1 to 2 groups selected from 【Chemistry 18】 2. The compound of claim 1, a stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof, wherein:

11. 2. The compound of claim 1, wherein the compound is selected from the structures in Table 1, a stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound of any one of claims 1 to 11, its stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

13. Use of a compound according to any one of claims 1 to 11, a stereoisomer, deuterated product, solvate or pharmaceutically acceptable salt thereof, or a composition according to claim 12 in the manufacture of a medicament for treating / preventing a PRMT5 / MTA-mediated disease.

14. The use according to claim 13, wherein the PRMT5 / MTA mediated disease is selected from liver cancer, breast cancer, skin cancer, bladder cancer, pancreatic cancer or head and neck cancer.

15. 12. A pharmaceutical composition or formulation comprising 1 to 1500 mg of a compound according to any one of claims 1 to 11, a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, and a pharmaceutical excipient.

16. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 11, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably liver cancer, breast cancer, skin cancer, bladder cancer, pancreatic cancer, or head and neck cancer.

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