Tricyclic compound as CDK inhibitor and use thereof

Abstract

The present disclosure belongs to the field of medicinal chemistry, relates to a tricyclic compound as a CDK inhibitor and the use thereof, and specifically relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof.

Description

Tricyclic compounds as CDK inhibitors and uses thereof TECHNICAL FIELD

[0001] The present disclosure belongs to the field of medicinal chemistry, and relates to tricyclic compounds as CDK inhibitors and uses thereof, in particular to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof. BACKGROUND

[0002] Cell cycle-dependent kinases (CDKs) are a family of protein kinases that catalyze serine / threonine phosphorylation, and 21 different CDKs have been found so far. They can be divided into two categories according to their specific functions: one category is cell cycle-related CDKs, including CDK 1, 2, 4, 6 and 7, and the other category is RNA transcription-related CDKs, including CDK 7, 8, 9, 11, 12 and 13.

[0003] It is known that CDK12 has three main functions: (1) CDK12 phosphorylates RNA polymerase PoL II to promote the extension of transcription; (2) CDK12 interacts with RNA processing factors to regulate splicing; (3) mediates transcription-associated RNA polymerase II phosphorylation and mRNA 3' end processing to regulate intron polyadenylation.

[0004] Studies have shown that knocking out the CDK12 gene can cause the expression of its downstream genes to be silenced, including DNA damage repair genes that are important to cells, such as BRCA1, ATR, FANCI and FANCD2, forming a state similar to "DNA damage repair gene defects", causing cells to be more sensitive to external conditions that cause DNA damage. At the same time, CDK12 regulates exon splicing by locating on nuclear speckles and pre-mRNA splicing bodies. Overall, CDK12 mainly participates in DNA damage response or stress response by regulating genome transcription and expression. SUMMARY

[0005] The present disclosure provides a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

[0006] wherein,

[0007] Ring A is a tricyclic ring, one of the three rings in the tricyclic ring is phenyl, or 5-6 membered heteroaryl, and the remaining two rings are each independently selected from C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each of the three rings in the ring A is independently optionally substituted by one or more R A substituents;

[0008] X1 and X 2 are each independently selected from N or C;

[0009] X 3 and X 4 are each independently selected from O, S, C(R a ), N or -N(R b )-;

[0010] Y 1 and Y 2 are each independently selected from C(R a ) or N;

[0011] L 1 and L 2 are each independently selected from a single bond, -N(R b )-, -O-, -S-, -C(=O)-, -S(=O)- or -S(=O)2-;

[0012] R 1 is selected from C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-12 membered heteroaryl, said C 3-10 cycloalkyl, C 3- 10 cycloalkenyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-12 membered heteroaryl is optionally independently substituted with one or more R c ;

[0013] R 2 is selected from hydrogen, -OH, -CN, -NO2, -CHO, -COOH, halogen, -NH2, and the following groups optionally substituted with one or more R d : -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -C(O)-C 1-6 alkyl, -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 alkyl)2, -NHC(O)-C 1-6 alkyl, -N(C 1-6 alkyl)-C(O)-C 1-6 alkyl, -C(O)-O-C 1-6 alkyl, -O-C(O)-C 1-6alkyl, -S(O)-C 1-6 alkyl, -S(O)2-C 1-6 alkyl, -S(O)2-C 3-6 cycloalkyl, -S(O)2-3-6 membered heterocyclyl, -S(O)2-NH(C 1-6 alkyl), -S(O)2-N(C 1-6 alkyl)2, -C(O)-C 3-6 cycloalkyl, -C(O)-3-6 membered heterocyclyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 1-6 alkylene-OC 1-6 alkyl, -C 1-6 alkylene-SC 1-6 alkyl, -C 1-6 alkylene-NHC 1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl)2, -C 1-6 alkylene-C 3-6 cycloalkyl, -C 1-6 alkylene-3-6 membered heterocyclyl, -NH-C 3-6 cycloalkyl, -NH-3-6 membered heterocyclyl, -O-C 3- 6cycloalkyl, -O-3-6 membered heterocyclyl, -S-C 3-6 cycloalkyl, -S-3-6 membered heterocyclyl, -C 6-12 aryl, 5-12 membered heteroaryl, -C 1-6 alkylene-C 6- 12 aryl, -C 1-6 alkylene-5-12 membered heteroaryl, -NH-C 6-12 aryl, -NH-5-12 membered heteroaryl, -O-C 6-12 aryl, -O-5-12 membered heteroaryl, -S-C 6-12 aryl, or -S-5-12 membered heteroaryl;

[0014] each R 3 , R 3’ , R 4 , R 4’ is independently selected from hydrogen, deuterium, -OH, -CN, -CHO, -COOH, oxo, halogen, -NH2, or -C 1-6 alkyl optionally substituted with one or more selected from deuterium, halogen, OH, NH2, CN, 1-6 alkyl optionally substituted with one or more selected from deuterium, halogen, OH, NH2, CN, 1-6 alkyl optionally substituted with one or more selected from deuterium, halogen, OH, NH2, CN, 1- 6alkyl) optionally substituted with one or more selected from deuterium, halogen, OH, NH2, CN, 1-6 alkyl)2;

[0015] Each R a Each is independently selected from hydrogen, -OH, -CN, -NO2, -CHO, -COOH, halogen, -NH2, and optionally influenced by one or more R. e The following groups are substituted: -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1- 6-alkyl)2, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-SC 1-6 Alkyl, -C 1-6 Alkylene-NHC 1- 6-alkyl, -C 1-6 Alkylene-N(C) 1-6 Alkyl)2, -C 1-6 Alkylene-C 3-6 cycloalkyl, or -C 1-6 Alkylene-3-6-membered heterocyclic groups;

[0016] R b Selected from hydrogen, and optionally by one or more R h The following groups are substituted: -C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0017] R c and R A Each is independently selected from deuterium, -OH, -CN, -NO2, -CHO, =O, -COOH, halogen, -NH2, and optionally by one or more R f The following groups are substituted: -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-SC 1-6 Alkyl, -C 1-6 Alkylene-NHC1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl)2, -C 1-6 alkylene-C 3-6 cycloalkyl, or -C 1-6 alkylene-3-6 membered heterocyclyl;

[0018] R d , R e , and R f are each independently selected from deuterium, -OH, -CN, -NO2, -CHO, -COOH, oxo, halogen, -NH2, or -C 1-6 alkyl optionally substituted with one or more R 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2;

[0019] m is selected from 0, 1, 2, or 3;

[0020] n is selected from 0, 1, 2, or 3;

[0021] optionally, the R 3 , R 3’ , R 4 , R 4’ , R A , R a , R b , R c , R d , R e , or R f are substituted with one or more substituents.

[0022] It should be understood that the structural units of the present disclosure are fused aromatic systems.

[0023] In some embodiments of the present disclosure, R c and R A are each independently selected from deuterium, -OH, -CN, -NO2, -CHO, -COOH, halogen, -NH2, and -C f alkyl optionally substituted with one or more R 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 3-6cycloalkyl, 3-6 membered heterocyclyl, -C 1-6 alkylene-OC 1-6 alkyl, -C 1-6 alkylene-SC 1-6 alkyl, -C 1-6 alkylene-NHC 1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl)2, -C 1-6 alkylene-C 3-6 cycloalkyl, or -C 1-6 alkylene-3-6 membered heterocyclyl, ring A, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , L 1 , L 2 , R 1 , R 2 , R 3 , R 3’ , R 4 , R 4’ , R a , R b , R d , R e , R f , m and n are as defined above.

[0024] In some embodiments of the disclosure, at least two rings of the tricyclic ring described by ring A are fused rings.

[0025] In some embodiments of the disclosure, the tricyclic ring described by ring A is selected from a tri- fused ring, a bi- fused ring spiro- linked monocyclic ring, or a bridged- fused monocyclic ring.

[0026] In some embodiments of the disclosure, the tricyclic ring described by ring A is a tri- fused ring.

[0027] In some embodiments of the disclosure, ring A is a tri- fused ring, one ring of the tri- fused ring is phenyl, or 5-6 membered heteroaryl, and the remaining two rings are each independently selected from C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each of the three rings in ring A is independently optionally substituted with one or more R A substituents.

[0028] In some embodiments of the disclosure, ring A is a 5-6 membered heteroaryl and phenyl and C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is a 5-6 membered heteroaryl and 5-6 membered heteroaryl and C3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and 5-6 membered heteroaryl and C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C 3-7 cycloalkenyl and C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and 3-7 membered heterocyclyl and C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is 5-6 membered heteroaryl and C 3-7 cycloalkenyl and C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is 5-6 membered heteroaryl and 3-7 membered heterocyclyl and C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is C 3-7 cycloalkenyl and phenyl and C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is C 3-7 cycloalkenyl and 5-6 membered heteroaryl and C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is 3-7 membered heterocyclyl and phenyl and C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is 3-7 membered heterocyclyl and 5-6 membered heteroaryl and C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; each of the three rings in the above recited ring A is independently optionally substituted with 1 or more R A substituents.

[0029] In some embodiments of the disclosure, ring A is a tri-cyclic ring, two of the rings in the tri-cyclic ring are each independently selected from phenyl, or 5-6 membered heteroaryl, and the remaining ring is selected from C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; each of the three rings in the above recited ring A is independently optionally substituted with 1 or more R A substituents.

[0030] In some embodiments of the disclosure, ring A is a tri-cyclic ring, two of the rings in the tri-cyclic ring are each independently selected from phenyl, or 5-6 membered heteroaryl, and the remaining ring is selected from C 3-7 cycloalkyl, C 3-7Cycloalkenyl, 3-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl, wherein the phenyl or 5-6-membered heteroaryl group in the trifused ring is attached to the remainder of the compound of formula (I), wherein each of the three rings in ring A is independently optionally bounded by one or more R groups. A replace.

[0031] In some embodiments of this disclosure, the ring described first, ring A, is connected to the remainder of the compound of formula (I), for example, ring A is a 5-6 membered heteroarylphenyl-C 3-7 cycloalkyl, C 3-7 When the compound is cycloalkenyl, 3-7 heterocyclic, phenyl, or 5-6 heteroaryl, the 5-6 heteroaryl group described first is attached to the rest of the compound of formula (I).

[0032] In some embodiments of this disclosure, ring A is a 5-6 membered heteroarylphenyl cyclohexane. 5-6 Cycloalkenyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; or ring A is a 5-6 membered heteroaryl and 5-6 membered heteroaryl and C. 5-6 Cycloalkenyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl-5-6 membered heteroaryl-C 5-6 Cycloalkenyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl-C 5-6 cycloalkenyl-C 5-6 cycloalkyl, C 5-6 Cycloalkenyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl-5-6 membered heterocyclic and C is phenyl-5-6 membered heterocyclic. 5-6 cycloalkyl, C 5-6 Cycloalkenyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; or ring A is a 5-6 membered heteroaryl and C 5-6 cycloalkenyl-C 5-6 cycloalkyl, C 5-6 Cycloalkenyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; or ring A is a 5-6 membered heteroaryl and 5-6 membered heterocyclic and C 5-6 cycloalkyl, C 5-6 Cycloalkenyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; or ring A is C 5-6 Cycloalkenylphenyl-C 5-6 Cycloalkenyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; or ring A is C 5-6 cycloalkenyl 5-6-membered heteroaryl cycloalkenyl C 5-6 Cycloalkenyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; or ring A is a 5-6 membered heterocyclic benzophenyl benzo[C]. 5-6 Cycloalkenyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; or ring A is a 5-6 membered heterocyclic and 5-6 membered heteroaryl and C. 5-6cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and 5-6 membered heteroaryl and C A substituted.

[0033] In some embodiments of the disclosure, ring A is 5-6 membered heteroaryl and phenyl and C 5-6 cycloalkyl, C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is 5-6 membered heteroaryl and 5-6 membered heteroaryl and C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C 5-6 cycloalkenyl and phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and 5-6 membered heterocyclyl and phenyl, or 5-6 membered heteroaryl; each of the three rings of ring A described above is optionally independently substituted with 1 or more R 5-6 cycloalkyl, C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and 5-6 membered heterocyclyl and C 5-6 cycloalkyl, C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is 5-6 membered heteroaryl and 5-6 membered heteroaryl and C A substituted. In some embodiments of the disclosure, ring A is phenyl and 5-6 membered heteroaryl and C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each of the three rings of ring A described above is optionally independently substituted with 1 or more R A substituted.

[0034] In some embodiments of the disclosure, ring A is 5-6 membered heteroaryl and phenyl and C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is 5-6 membered heteroaryl and 5-6 membered heteroaryl and C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C 5-6 cycloalkenyl and phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and 5-6 membered heterocyclyl and phenyl, or 5-6 membered heteroaryl; each of the three rings of ring A described above is optionally independently substituted with 1 or more R A substituted. In some embodiments of the disclosure, ring A is phenyl and 5-6 membered heteroaryl and C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each of the three rings of ring A described above is optionally independently substituted with 1 or more R A substituted.

[0035] In some embodiments of the disclosure, ring A is 5 membered heteroaryl and phenyl and C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is 5 membered heteroaryl and 6 membered heteroaryl and C5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C A cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C A cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C

[0036] cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C A cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C

[0037] In some embodiments of the disclosure, ring A is a tri-peri-cyclic ring wherein the ring attached to the remainder of the compound of Formula (I) is selected from furanyl, pyrrolyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, or triazolyl, the middle ring is selected from phenyl, pyrrolyl, pyrazolyl, thiazolyl, thienyl, furanyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, and the terminal (i.e., distal with respect to the end attached to the remainder of the compound of Formula (I)) ring is selected from phenyl, C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C A cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C

[0038] In some embodiments of the disclosure, ring A is a tri-peri-cyclic ring wherein the ring attached to the remainder of the compound of Formula (I) is selected from furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, or triazolyl, the middle ring is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, and the terminal ring is selected from C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C A cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C

[0039] In some embodiments of the disclosure, ring A is a tri-cyclic ring wherein the ring attached to the remainder of the compound of formula (I) is selected from imidazolyl or thienyl, the intermediate ring is selected from thiazolyl, pyrrolyl or pyridyl, and the terminal ring is selected from C 5-6 cycloalkenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl, each of the three rings in ring A is independently optionally substituted with 1 or more R A substituents.

[0040] In some embodiments of the disclosure, ring A is a tri-cyclic ring wherein the ring attached to the remainder of the compound of formula (I) is selected from phenyl, the intermediate ring is selected from cyclopentenyl or cyclohexenyl, and the terminal ring is selected from 5-6 membered heteroaryl, each of the three rings in ring A is independently optionally substituted with 1 or more R A substituents.

[0041] In some embodiments of the disclosure, ring A is a tri-cyclic ring wherein the ring attached to the remainder of the compound of formula (I) is selected from phenyl, the intermediate ring is selected from imidazolyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, and the terminal ring is selected from 5-6 membered heteroaryl, each of the three rings in ring A is independently optionally substituted with 1 or more R A substituents.

[0042] In some embodiments of the disclosure, ring A is a tri-cyclic ring wherein the ring attached to the remainder of the compound of formula (I) is selected from phenyl, the intermediate ring is selected from dihydropyranyl, dihydrothiopyranyl or dihydropyridyl, and the terminal ring is selected from 5-6 membered heteroaryl, each of the three rings in ring A is independently optionally substituted with 1 or more R A substituents.

[0043] In some embodiments of the disclosure, ring A is a tri-cyclic ring wherein the ring attached to the remainder of the compound of formula (I) is selected from pyrrolyl, pyrazolyl, imidazolyl, the intermediate ring is selected from pyrimidinyl, and the terminal ring is selected from C 5-6 cycloalkenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl, each of the three rings in ring A is independently optionally substituted with 1 or more R A substituents.

[0044] In some embodiments of the disclosure, ring A is a tri-cyclic ring wherein the ring attached to the remainder of the compound of formula (I) is selected from phenyl, the intermediate ring is selected from dihydropyranyl, dihydrothiopyranyl, and the terminal ring is selected from 5-6 membered heteroaryl, each of the three rings in ring A is independently optionally substituted with 1 or more R A substituents.

[0045] In some embodiments of the disclosure, ring A is selected from the following structural units wherein,

[0046] Z 1 and Z2 each independently is selected from nothing, O, S, NH, N, CH, C, C=O, or CH2;

[0047] Ring B is selected from C 4-6 cycloalkenyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, said C 4-6 cycloalkenyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl is optionally independently substituted with one or more R A substituents;

[0048] R A is selected from deuterium, -OH, -CN, -NO2, -CHO, -COOH, halogen, -NH2, and the following groups optionally substituted with one or more R f substituents: -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 1-6 alkylene-OC 1-6 alkyl, -C 1-6 alkylene-SC 1-6 alkyl, -C 1-6 alkylene-NHC 1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl)2, -C 1-6 alkylene-C 3-6 cycloalkyl, or -C 1-6 alkylene-3-6 membered heterocyclyl;

[0049] p is selected from 0, 1, 2, or 3.

[0050] In some embodiments of the disclosure, Ring A is selected from the following structural units wherein,

[0051] Q 1 is selected from NH, O, S, or CH2;

[0052] Ring B is as defined above in the structural unit of Ring B.

[0053] In some embodiments of the disclosure, Ring A is selected from the following structural units wherein,

[0054] are each independently selected from a single bond or a double bond;

[0055] Q 2 and Q 3 are each independently selected from C, CH or N;

[0056] Q 4 is selected from CH2, N, S, CH or N(R g );

[0057] Ring B is as defined above for structural unit .

[0058] In some embodiments of the disclosure, R g is selected from H or C 1-3 alkyl.

[0059] In some embodiments of the disclosure, R g is selected from H, methyl or ethyl.

[0060] In some embodiments of the disclosure, R g is selected from H or methyl.

[0061] In some embodiments of the disclosure, Ring B is selected from C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, said C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with one or more R A groups.

[0062] In some embodiments of the disclosure, Ring B is selected from said Ring B is optionally independently substituted with one or more R A groups. In some embodiments of the disclosure, Ring B is selected from said Ring B is optionally independently substituted with one or more R A groups.

[0063] In some embodiments of the disclosure, Ring B is selected from said Ring B is optionally independently substituted with one or more R A groups.

[0064] In some embodiments of the disclosure, R A is selected from deuterium, -OH, -CN, halogen, -NH2, and the following groups optionally substituted with one or more R f groups: -C 1-6 alkyl, -OC 1-6 alkyl, -NH(C 1-6 alkyl), C 3-6cycloalkyl or 3-6 membered heterocyclyl.

[0065] In some embodiments of the disclosure, R A is selected from deuterium, -OH, -CN, halogen, -NH2, and optionally substituted -C f alkyl, -OC 1-3 alkyl, -NH(C 1-3 alkyl), C 1-3 alkyl. 3-6 cycloalkyl or 3-6 membered heterocyclyl.

[0066] In some embodiments of the disclosure, R A is selected from deuterium, halogen, and optionally substituted -C f alkyl, -OC 1-3 alkyl, -NH(C 1-3 alkyl). 1-3 alkyl.

[0067] In some embodiments of the disclosure, R A is selected from halogen, -CN, and -C f alkyl. 1-3 alkyl.

[0068] In some embodiments of the disclosure, R A is selected from deuterium, halogen, and -C f alkyl. 1-3 alkyl.

[0069] In some embodiments of the disclosure, R A is selected from halogen, -CN, and -C 1-3 alkyl.

[0070] In some embodiments of the disclosure, R A is selected from halogen or -C 1-3 alkyl.

[0071] In some embodiments of the disclosure, R A is selected from F, -CN, methyl, or

[0072] In some embodiments of the disclosure, R A is selected from F or methyl.

[0073] In some embodiments of the disclosure, ring B is selected from In some embodiments of the disclosure, ring B is selected from

[0074] In some embodiments of the disclosure, ring B is selected from

[0075] In some embodiments of the disclosure, structural unit is selected from In some embodiments of the disclosure, structural unit is selected from

[0076] In some embodiments of the disclosure, structural unit is selected from In some embodiments of the disclosure, structural unit is selected from

[0077] In some embodiments of the disclosure, Z 1 and Z 2 are each independently selected from the group consisting of absent, O, S, NH, or CH2.

[0078] In some embodiments of the disclosure, Z 1 and Z 2 are each selected from CH2.

[0079] In some embodiments of the disclosure, Z 1 and Z 2 are selected from CH2, the other is absent or selected from O, S, or NH.

[0080] In some embodiments of the disclosure, Z 1 and Z 2 are selected from CH2, the other is absent or selected from O, S, or NH.

[0081] In some embodiments of the disclosure, structural unit is selected from In some embodiments of the disclosure, structural unit is selected from

[0082] In some embodiments of the disclosure, structural unit is selected from In some embodiments of the disclosure, structural unit is selected from

[0083] In some embodiments of the disclosure, the structural unit is selected from

[0084] In some embodiments of the disclosure, the structural unit is selected from

[0085] In some embodiments of the disclosure, the structural unit is selected from

[0086] In some embodiments of the disclosure, the structural unit is selected from

[0087] In some embodiments of the disclosure, the structural unit is selected from

[0088] In some embodiments of the disclosure, the structural unit is selected from

[0089] In some embodiments of the disclosure, the structural unit is selected from

[0090] In some embodiments of the disclosure, the structural unit is selected from

[0091] In some embodiments of the disclosure, ring A is selected from In some embodiments of the disclosure, ring A is selected from

[0092] In some embodiments of the disclosure, ring A is selected from In some embodiments of the disclosure, ring A is selected from

[0093] In some embodiments of the disclosure, ring A is selected from

[0094] In some embodiments of the disclosure, ring A is selected from

[0095] In some embodiments of the disclosure, p is selected from 0, 1, or 2.

[0096] In some embodiments of the disclosure, each R a , R b , R c , R d , R e , R f , or R A is each independently optionally substituted with one or more substituents.

[0097] In some embodiments of the disclosure, each R 1 , R 2 , R 3 , R 3’ , R 4 , R 4’ is each independently optionally substituted with one or more substituents.

[0098] In some embodiments of the disclosure, the "substituted with 1 or more" is each independently selected from substituted with 1, 2, 3, 4, 5, or 6.

[0099] In some embodiments of the disclosure, the "substituted with 1 or more" is each independently selected from substituted with 1, 2, 3, 4, or 5.

[0100] In some embodiments of the disclosure, the "substituted with 1 or more" is each independently selected from substituted with 1, 2, 3, or 4.

[0101] In some embodiments of the disclosure, the "substituted with 1 or more" is each independently selected from substituted with 1, 2, or 3.

[0102] In some embodiments of the disclosure, each "heterocyclyl" recited in the disclosure can be independently selected from "heterocycloalkyl" or "heterocycloalkenyl".

[0103] In some embodiments of the disclosure, each "3-12 membered heterocyclyl" recited in the disclosure can be independently selected from "3-12 membered heterocycloalkyl" or "3-12 membered heterocycloalkenyl"; each "3-7 membered heterocyclyl" recited in the disclosure can be independently selected from "3-7 membered heterocycloalkyl" or "3-7 membered heterocycloalkenyl"; and each "3-6 membered heterocyclyl" recited in the disclosure can be independently selected from "3-6 membered heterocycloalkyl" or "3-6 membered heterocycloalkenyl".

[0104] In some embodiments of the disclosure, X 1 , X 2 is selected from N and the other is C.

[0105] In some embodiments of the disclosure, X1 is selected from N, X 2 is selected from C.

[0106] In some embodiments of the disclosure, X 3 and X 4 are each independently selected from C(R a ) or N.

[0107] In some embodiments of the disclosure, X 3 and X 4 are each independently selected from N.

[0108] In some embodiments of the disclosure, X 3 is selected from C(R a ), X 4 is selected from N.

[0109] In some embodiments of the disclosure, X 3 is selected from CH, X 4 is selected from N.

[0110] In some embodiments of the disclosure, each R a is independently selected from hydrogen, -OH, -CN, halogen, -NH2, and the following groups optionally substituted with one or more R e groups: -C 1-3 alkyl or -OC 1-3 alkyl.

[0111] In some embodiments of the disclosure, each R a is independently selected from hydrogen, -OH, -CN, halogen, or -NH2.

[0112] In some embodiments of the disclosure, each R a is independently selected from hydrogen.

[0113] In some embodiments of the disclosure, Y 1 and Y 2 are each independently selected from N.

[0114] In some embodiments of the disclosure, Y 1 is selected from C(R a ), Y 2 is selected from N.

[0115] In some embodiments of the disclosure, Y 1 is selected from CH, Y 2 is selected from N.

[0116] In some embodiments of the disclosure, L 1 and L 2 are each independently selected from a single bond, -N(R b)-, -O-, or -S-.

[0117] In some embodiments of the disclosure, L 1 and L 2 are each independently selected from a single bond or -N(R b )-.

[0118] In some embodiments of the disclosure, L 1 and L 2 are each independently selected from -N(R b )-.

[0119] In some embodiments of the disclosure, L 1 and L 2 are each independently selected from -N(R b )-, and n is 1.

[0120] In some embodiments of the disclosure, R b is selected from hydrogen, and -C h alkyl optionally substituted with one or more R 1-3 alkyl.

[0121] In some embodiments of the disclosure, R b is selected from hydrogen, and -C 1-3 alkyl optionally substituted with one or more deuterium, -OH, -CN, halogen, -NH2.

[0122] In some embodiments of the disclosure, R b is selected from hydrogen.

[0123] In some embodiments of the disclosure, L 1 and L 2 are each independently selected from -NH-.

[0124] In some embodiments of the disclosure, R 1 is selected from C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally independently substituted with 1 or more R 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl optionally independently substituted with 1 or more R c In some embodiments of the disclosure, R 1 is selected from 8-10 membered heterocyclyl optionally independently substituted with 1 or more R c In some embodiments of the disclosure, R

[0125] In some embodiments of the disclosure, R1 C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, said C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, said C c optionally independently substituted with one or more R

[0126] In some embodiments of the disclosure, R 1 C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, said C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, said C c optionally independently substituted with one or more R

[0127] In some embodiments of the disclosure, R 1 is selected from cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydropyrazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 1,4-thioxinanyl, 1,4-dioxanyl, phenyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or pyrilinyl, said cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydropyrazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, 1,4-thioxinanyl, 1,4-dioxanyl, phenyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or pyrilinyl optionally independently substituted with one or more R c In some embodiments of the disclosure, R 1 is selected from said optionally independently substituted with one or more R c In some embodiments of the disclosure, R

[0128] In some embodiments of the disclosure, R 1 is selected from piperidinyl, tetrahydropyranyl, morpholinyl, or piperazinyl, said piperidinyl, tetrahydropyranyl, morpholinyl, or piperazinyl optionally independently substituted with one or more R c In some embodiments of the disclosure, R 1 is selected from pyrrolidinyl or said pyrrolidinyl or optionally independently substituted with one or more R c substituted

[0129] In some embodiments of the disclosure, R 1 is selected from piperidinyl optionally independently substituted with one or more R c substituted.

[0130] In some embodiments of the disclosure, R 1 is selected from said optionally independently substituted with one or more R c substituted.

[0131] In some embodiments of the disclosure, R c is selected from deuterium, -OH, -CN, halogen, -NH2, and the following groups optionally substituted with one or more R f substituted: -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 1-3 alkylene-OC 1-6 alkyl, -C 1-3 alkylene-SC 1-6 alkyl, -C 1-3 alkylene-NHC 1-6 alkyl, -C 1-3 alkylene-N(C 1-6 alkyl)2, -C 1-3 alkylene-C 3-6 cycloalkyl, or -C 1-3 alkylene-3-6 membered heterocyclyl. In some embodiments of the disclosure, R c is selected from =O.

[0132] In some embodiments of the disclosure, R c is selected from -OH, -CN, halogen, -NH2, and the following groups optionally substituted with one or more R f substituted: -C 1-3 alkyl, -OC 1-3 alkyl, -SC 1-3 alkyl, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl.

[0133] In some embodiments of the disclosure, R c is selected from -OH, -CN, halogen, -NH2, and the following groups optionally substituted with one or more R f substituents: -C 1-3 alkyl or -OC 1-3 alkyl.

[0134] In some embodiments of the disclosure, R c is selected from -OH, -CN, halogen, or -NH2.

[0135] In some embodiments of the disclosure, R c is selected from -OH or =O.

[0136] In some embodiments of the disclosure, R c is selected from -OH.

[0137] In some embodiments of the disclosure, R 1 is selected from

[0138] In some embodiments of the disclosure, R 1 is selected from

[0139] In some embodiments of the disclosure, R 1 is selected from

[0140] In some embodiments of the disclosure, R 1 is selected from

[0141] In some embodiments of the disclosure, R 2 is selected from hydrogen, -OH, -CN, halogen, -NH2, and the following groups optionally substituted with one or more R d substituents: -C 1-3 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -OC 1-3 alkyl, -SC 1-3 alkyl, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -C(O)-C 1-3 alkyl, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl)2, -NHC(O)-C 1-3 alkyl, -N(C 1-3 alkyl)-C(O)-C 1-3 alkyl, -C(O)-O-C 1-3Alkyl, -OC(O)-C 1-3 Alkyl, -S(O)-C 1-3 Alkyl, -S(O)2-C 1-3 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-3-6-membered heterocyclic groups, -S(O)2-NH(C 1-3 Alkyl), -S(O)2-N(C 1-3 Alkyl)2、-C(O)-C 3-6 Cycloalkyl, -C(O)-3-6 membered heterocyclic group, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, -C 1-3 Alkylene-OC 1-3 Alkyl, -C 1-3 Alkylene-SC 1-3 Alkyl, -C 1-3 Alkylene-NHC 1-3 Alkyl, -C 1-3 Alkylene-N(C) 1-3 Alkyl)2, -C 1-3 Alkylene-C 3-6 cycloalkyl, -C 1-3 Alkyl-3-6-membered heterocyclic groups, -NH-C 3-6 Cycloalkyl, -NH-3-6-membered heterocyclic group, -OC 3-6 Cycloalkyl, -O-3-6-membered heterocyclic groups, -SC 3-6 Cycloalkyl, -S-3-6 membered heterocyclic groups, -C 6-12 Aryl, 5-12 heteroaryl, -C 1-3 Alkylene-C 6-12 Aryl, -C 1-3 alkylene-5-12-membered heteroaryl, -NH-C 6-12 Aryl, -NH-5-12 heteroaryl, -OC 6-12 Aryl, -O-5-12 heteroaryl, -SC 6-12 Aryl, or -S-5-12 heteroaryl.

[0142] In some embodiments of this disclosure, R 2 Selected from -OH, -CN, halogens, -NH2, and optionally substituted by one or more R d The following groups are substituted: -C 1-3 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NH(C) 1-3 Alkyl), -C(O)-C 1-3 Alkyl, -S(O)-C 1-3 Alkyl, -S(O)2-C 1-3 Alkyl, -S(O)2-C3-6 Cycloalkyl, -S(O)2-3-6-membered heterocyclic groups, -C(O)-C 3-6 Cycloalkyl, -C(O)-3-6 membered heterocyclic group, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, -C 1-3 Alkylene-C 3-6 cycloalkyl, -C 1-3 Alkyl-3-6-membered heterocyclic groups, -NH-C 3-6 Cycloalkyl, -NH-3-6-membered heterocyclic group, -OC 3-6 Cycloalkyl, -O-3-6-membered heterocyclic groups, -SC 3-6 Cycloalkyl, -S-3-6 membered heterocyclic groups, -C 6-10 Aryl, 5-10 heteroaryl, -C 1-3 Alkylene-C 6-10 Aryl, -C 1-3 alkylene-5-10 heteroaryl, -NH-C 6-10 Aryl, -NH-5-10 heteroaryl, -OC 6-10 Aryl, -O-5-10 heteroaryl, -SC 6-10 Aryl, or -S-5-10 heteroaryl.

[0143] In some embodiments of this disclosure, R 2 Selected from -OH, -CN, halogens, -NH2, and optionally substituted by one or more R d The following groups are substituted: -C 1-3 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NH(C) 1-3 Alkyl), -C(O)-C 1-3 Alkyl, -S(O)-C 1-3 Alkyl, -S(O)2-C 1-3 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-3-6-membered heterocyclic groups, -C(O)-C 3-6 Cycloalkyl, -C(O)-3-6 membered heterocyclic group, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, -C 1-3 Alkylene-C 3-6 cycloalkyl, -C 1-3 Alkyl-3-6-membered heterocyclic groups, -NH-C 3-6 Cycloalkyl, -NH-3-6-membered heterocyclic group, -OC 3-6 Cycloalkyl, -O-3-6-membered heterocyclic groups, -SC 3-6 Cycloalkyl or -S-3-6-membered heterocyclic groups.

[0144] In some embodiments of the disclosure, R 2 is selected from the following groups optionally substituted with one or more R d -C 1-3 alkyl, -OC 1-3 alkyl, -SC 1-3 alkyl, -C(O)-C 1-3 alkyl, -S(O)-C 1-3 alkyl, -S(O)2-C 1-3 alkyl, -S(O)2-C 3-6 cycloalkyl, -S(O)2-3-6 membered heterocyclyl, -C(O)-C 3-6 cycloalkyl, -C(O)-3-6 membered heterocyclyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -O-C 3-6 cycloalkyl, -O-3-6 membered heterocyclyl, -S-C 3-6 cycloalkyl, or -S-3-6 membered heterocyclyl.

[0145] In some embodiments of the disclosure, R 2 is selected from the following groups optionally substituted with one or more R d C 3-6 cycloalkyl or 3-6 membered heterocyclyl. In some embodiments of the disclosure, R 2 is selected from the following groups optionally substituted with one or more R d -SC 1-3 alkyl.

[0146] In some embodiments of the disclosure, R 2 is selected from the following groups optionally substituted with one or more R d cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, or thietanyl. In some embodiments of the disclosure, R 2 is selected from the following groups optionally substituted with one or more R d -SCH3or -SCH2CH3.

[0147] In some embodiments of the disclosure, R 2 is selected from the following groups optionally substituted with one or more R d cyclopropyl.

[0148] In some embodiments of the disclosure, R 2 is selected from cyclopropyl. In some embodiments of the disclosure, R 2 is selected from -SCH3or -SCF3.

[0149] In some embodiments of the disclosure, each R 3 , R 3’ , R 4 , R4’ each independently selected from hydrogen, deuterium, -OH, oxo, halogen, -NH2, or -C 1-3 alkyl.

[0150] In some embodiments of the disclosure, each R 3 , R 3’ , R 4 , R 4’ is each independently selected from hydrogen, deuterium, -OH, oxo, or halogen.

[0151] In some embodiments of the disclosure, each R 3 , R 3’ , R 4 , R 4’ is each independently selected from hydrogen or deuterium.

[0152] In some embodiments of the disclosure, each R 3 , R 3’ , R 4 , R 4 is each selected from hydrogen.

[0153] In some embodiments of the disclosure, R d , R e , and R f is each independently selected from deuterium, -OH, -CN, halogen, -NH2, or -C 1-3 alkyl or -OC 1-3 alkyl.

[0154] In some embodiments of the disclosure, R d , R e , and R f is each independently selected from deuterium, -OH, or halogen.

[0155] In some embodiments of the disclosure, R d , R e , and R f is each independently selected from F.

[0156] In some embodiments of the disclosure, m is selected from 1.

[0157] In some embodiments of the disclosure, n is selected from 1.

[0158] In some embodiments of the disclosure, each R a , R b , R c , R A , R 1 , R2 R 3 R 3’ R 4 R 4’ R d R e R f each independently optionally substituted with one or more of deuterium, oxo, halogen, -OH, -NH2, -CN, thiol, nitro, nitroso, azido, sulfoxide group, sulfone group, sulfonamide group, carboxyl, aldehyde group, imine group, C 1-12 alkyl, halo-C 1-12 alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3-12 membered cycloalkenyl, halo-3-12 membered cycloalkenyl, C 2-12 alkynyl, halo-C 2-12 alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C 1-12 heteroalkyl, halo-C 1-12 heteroalkyl, C 1-12 alkoxy, C 1-12 alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered aryl C 1-12 alkylene, 6-10 membered aryl C 1-12 alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered heterocyclyl C 1-12 alkoxy, 3-12 membered heterocyclyl C 1-12 alkylthio, C 1-12 acyl, C 1-12 acyloxy, carbamate group, C 1-12 amido, ureido, epoxy group, C 2-12 ester group, oxo, and thio, optionally substituted with one or more substituents selected from deuterium atom, oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, halo-C 1-12 alkoxy, C 1-12 alkylamino, di-C 1-12 alkylamino, halo-C1-12 alkylamino, halo-d 1-12 alkylamino, carboxy, -C(O)O-C 1-12 alkyl, -OC(O)-C 1-12 alkyl, -C(O)NH2, -C(O)NH-C 1-12 alkyl, -C(O)N(C 1-12 alkyl)2, -NHC(O)-C 1-12 alkyl, -C(O)-C 1-12 alkyl, -S(O)-C 1-12 alkyl, -S(O)2-C 1-12 alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 alkyl, -S(O)2N(C 1-12 alkyl)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl C 1-12 alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryl C 1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered aryl C 1-12 alkylene, or 6-10 membered aryloxy.

[0159] In some embodiments, each R a , R b , R c , R A , R 1 , R 2 , R 3 , R 3’ , R 4 , R 4’ , R d , R e or R f is optionally substituted with one or more substituents selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkyl, or halo-C 1-3 alkoxy.

[0160] In some embodiments, the 3-12 membered or 3-10 membered or 4-9 membered or 4-7 membered or 4-6 membered heterocyclyl of the present disclosure is selected from 3-12 membered or 3-10 membered or 4-9 membered or 4-7 membered or 4-6 membered heterocycloalkyl. In some embodiments, the 3-12 membered or 3-10 membered or 4-9 membered or 4-7 membered or 4-6 membered heterocyclyl of the present disclosure is selected from 3-12 membered or 3-10 membered or 4-9 membered or 4-7 membered or 4-6 membered heterocycloalkenyl.

[0161] In some embodiments, the C of the present disclosure is selected from C 1-12 selected from C 1-10 , C 3-10 , C 1-8 , C 3-8 , C 1-6 , C 3-6 , C 5-6 , C 1-4 , C 1-3 , or C 1- 2.

[0162] In some embodiments, the C of the present disclosure is selected from C 1-6 alkyl is selected from C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl.

[0163] In some embodiments, the C of the present disclosure is selected from C 1-4 alkylene is selected from C 1-3 alkylene, or C 1-2 alkylene.

[0164] In some embodiments, the halogen of the present disclosure is selected from F, Cl, Br, or I.

[0165] In some embodiments, the halo of the present disclosure is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo of the present disclosure is fluoro.

[0166] In some embodiments, the "one or more" of the present disclosure can refer to an integer of one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" refers to one, two, three, four, five, or six; or, "one or more" refers to one, two, three, or four.

[0167] In some embodiments, the 3-12 membered of the present disclosure is selected from 3-10 membered, 3-8 membered, 3-6 membered, 4-9 membered, 4-7 membered, 4-6 membered, 5-8 membered, 5-7 membered, or 5-6 membered.

[0168] In some embodiments, the heterocycloalkyl or heterocycloalkenyl of the present disclosure contains one or two heteroatoms selected from N or O.

[0169] In some embodiments, the heterocycloalkyl or heterocycloalkenyl of the present disclosure contains one N atom.

[0170] In some embodiments, the heterocycloalkyl or heterocycloalkenyl of the present disclosure contains one O atom.

[0171] In some embodiments, the heterocycloalkyl or heterocycloalkenyl of the present disclosure contains one N atom and one O atom.

[0172] In some embodiments, the heterocyclyl or heteroaryl of the present disclosure contains one or two heteroatoms selected from N, O or S.

[0173] In some embodiments, the heterocyclyl or heteroaryl of the present disclosure contains one or two N atoms.

[0174] In some embodiments, the heterocyclyl or heteroaryl of the present disclosure contains one N atom and one O atom.

[0175] In some embodiments, the heterocyclyl or heteroaryl of the present disclosure contains one N atom and one S atom.

[0176] In some embodiments, the heterocyclyl or heterocycloalkyl of the present disclosure comprises a monocyclic, spiro, fused or bridged ring.

[0177] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, of the present disclosure, all hydrogen atoms can be optionally substituted with one or more deuterium.

[0178] In some embodiments of the present disclosure, the compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from a compound of Formula (II-a), an isomer thereof, or a pharmaceutically acceptable salt thereof,

[0179] wherein R 1 , R 2 , R 3 , R 3’ , R 4 , R 4’ , L 1 , L 2 , m, n and ring A are defined as described in the present disclosure.

[0180] In some embodiments of the present disclosure, the compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from a compound of Formula (II-b), an isomer thereof, or a pharmaceutically acceptable salt thereof,

[0181] wherein R 1 , R 2 , L 1 , L 2 and ring A are as described in the disclosure.

[0182] In some embodiments of the disclosure, the compound represented by formula (I), isomers thereof, or pharmaceutically acceptable salts thereof are selected from compounds of formula (II-b1), isomers thereof, or pharmaceutically acceptable salts thereof,

[0183] wherein R 1 , R 2 , m, L 2 and ring A are as described in the disclosure.

[0184] In some embodiments of the disclosure, the compound represented by formula (I), isomers thereof, or pharmaceutically acceptable salts thereof are selected from compounds of formula (II-c), isomers thereof, or pharmaceutically acceptable salts thereof,

[0185] wherein R 1 , R 2 and ring A are as described in the disclosure.

[0186] In some embodiments of the disclosure, the compound represented by formula (I), isomers thereof, or pharmaceutically acceptable salts thereof are selected from compounds of formula (II-c1), compounds of formula (II-c2), isomers thereof, or pharmaceutically acceptable salts thereof,

[0187] wherein R 1 , R 2 , ring B, R A , Z 1 , Z 2 and p are as described in the disclosure.

[0188] In some embodiments of the disclosure, the compound represented by formula (I), isomers thereof, or pharmaceutically acceptable salts thereof are selected from compounds of formula (II-c1-a), compounds of formula (II-c1-b), compounds of formula (II-c2-a), compounds of formula (II-c2-b), isomers thereof, or pharmaceutically acceptable salts thereof,

[0189] wherein R 2 , ring B, R A , Z 1 , Z 2 and p are as described in the disclosure.

[0190] In some embodiments of this disclosure, the compound represented by formula (I), its isomers, or pharmaceutically acceptable salts thereof are selected from compounds of formula (II-c1-a1), (II-c1-b1), (II-c2-a1), (II-c1-b1), their isomers, or pharmaceutically acceptable salts thereof.

[0191] Among them, R 2 Ring B, R A Z 1 Z 2 The definitions of p and p are as described in this disclosure.

[0192] In some embodiments of this disclosure, this disclosure includes the variables defined above and their implementations, as well as any combination thereof.

[0193] In some embodiments of this disclosure, this disclosure relates to compounds of formula (II-b1), isomers thereof, or pharmaceutically acceptable salts thereof.

[0194] Among them, ring A is

[0195] L 2 It can be -NH-, -O-, or -S-;

[0196] m is 0 or 1;

[0197] R 1 for

[0198] R 2 C 3-5 Cycloalkyl (e.g., cyclopropyl), -SCH3, -SCH2CH3, or -SCF3.

[0199] In some embodiments of this disclosure, this disclosure relates to compounds of formula (II-d), isomers thereof, or pharmaceutically acceptable salts thereof.

[0200] Among them, ring A is

[0201] In some embodiments of this disclosure, this disclosure relates to compounds of formula (II-e), their isomers, or pharmaceutically acceptable salts thereof.

[0202] Among them, ring A is

[0203] R 1For

[0204] R 2 C 3-5 cycloalkyl (e.g., cyclopropyl), -SCH3, -SCH2CH3, or -SCF3.

[0205] In some embodiments of the present disclosure, the compound of the present disclosure, stereoisomer thereof, or pharmaceutically acceptable salt thereof is selected from the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0206] In some embodiments of the present disclosure, the compound of the present disclosure, stereoisomer thereof, or pharmaceutically acceptable salt thereof is selected from the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0207] In another aspect, the present disclosure also provides a pharmaceutical composition containing a therapeutically or prophylactically effective amount of the compound of the present disclosure, isomer thereof, or pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0208] In another aspect, the present disclosure also provides the use of the compound of the present disclosure, isomer thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing a disease. Alternatively, the present disclosure also provides the use of the compound of the present disclosure, isomer thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a CDK inhibitor.

[0209] In another aspect, the present disclosure also provides a method for treating or preventing a disease, comprising administering to a mammal (preferably a human) in need of such treatment or prevention a therapeutically or prophylactically effective amount of the compound of the present disclosure, isomer thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Alternatively, the present disclosure also provides a method for inhibiting CDK activity in a subject (e.g., a mammal, preferably a human) in need thereof, comprising administering to the subject a therapeutically or prophylactically effective amount of the compound of the present disclosure, isomer thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0210] In another aspect, the present disclosure also provides the use of the compound of the present disclosure, isomer thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment or prevention of a disease. Alternatively, the present disclosure also provides the use of the compound of the present disclosure, isomer thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the inhibition of CDK activity

[0211] In another aspect, the present disclosure also provides a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof described herein for use in treating or preventing a disease. Alternatively, the present disclosure also provides a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof described herein for use as a CDK inhibitor.

[0212] In some embodiments of the present disclosure, the disease described herein is selected from a CDK12-mediated disease.

[0213] In some embodiments of the present disclosure, the disease described herein is selected from a tumor or a cancer (e.g., rhabdomyosarcoma).

[0214] In some embodiments of the present disclosure, the CDK12-mediated disease is selected from a tumor or a cancer (e.g., rhabdomyosarcoma).

[0215] In the present disclosure, the “isomer” includes, but is not limited to, a stereoisomer or a tautomer.

[0216] In some embodiments of the present disclosure, the “isomer” is selected from a stereoisomer.

[0217] Technical effects

[0218] The compounds in the present disclosure are CDK12 inhibitors with novel structures, which have good inhibitory effect on CDK12-induced signaling, good inhibitory activity on CDK12 and cells expressing the kinase (e.g., A-673 cells), and good properties in one or more aspects of in vivo and in vitro inhibitory activity, safety (e.g., low toxicity), etc. The compounds in the present disclosure have good pharmacokinetic properties and can be developed into new CDK12 inhibitor drugs.

[0219] Related definitions

[0220] The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase should not be construed as indefinite or unclear in the absence of a specific definition, but should be understood according to the ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0221] The term “pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0222] The term "pharmaceutically acceptable salt" means a salt of a compound of the present disclosure that is prepared from a compound of the present disclosure having a particular substituent with a relatively non-toxic acid or base. Alkali addition salts can be prepared from the free acid form of the compounds of the present disclosure by contacting the compound in pure solution or in a suitable inert solvent with a sufficient amount of a base to produce the salt. Acid addition salts can be prepared by contacting the free base form of the compounds of the present disclosure with a sufficient amount of an acid to produce the salt in pure solution or in a suitable inert solvent. Certain specific compounds of the present disclosure contain both a basic and an acidic moiety, and accordingly can be converted into either base or acid addition salts.

[0223] The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in a water-immiscible organic solvent or in a mixture of the two.

[0224] The compounds of the present disclosure can exist in particular stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans- isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as the racemic mixtures and other mixtures thereof, such as for example, mixtures of enantiomers or diastereomers. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure.

[0225] Unless otherwise stated, a wedged line and a dashed-wedged line indicate the absolute configuration at a stereocenter, a straight line and a dashed-straight line indicate the relative configuration at a stereocenter.

[0226] The compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are embraced within the scope of the present disclosure. The term "tautomers" or "tautomeric forms" refers to different energy structures that can interconvert via a low energy barrier. For example, prototropic tautomers (also known as proton-shift tautomers) include interconversions via the migration of a proton, such as keto-enol and imine-enamine isomerization. A specific example of a prototropic tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0227] The compounds of the present disclosure can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For example, hydrogen can be substituted by deuterium to form deuterated drugs, which have advantages of reducing side effects, increasing drug stability, enhancing efficacy, prolonging the biological half-life of drugs, etc. compared with non-deuterated drugs. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. For example, it should be understood that a compound of the present disclosure in which one or more hydrogen atoms are replaced by deuterium atoms is still within the scope of the present disclosure.

[0228] The term "optionally" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the described event or circumstance occurs and instances where it does not.

[0229] The term "substituted" means that any one or more hydrogen atoms on the specified atom are replaced with a substituent, which can include variations of deuterium and hydrogen, provided that the valency of the specified atom is normal and that the substituted compound is stable. When the substituent is oxygen (i.e., =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it can or can not be substituted, and unless otherwise specified, the types and number of substituents can be any that are chemically possible.

[0230] The term "one or more substitutions" means that any one or more hydrogen atoms on the specified atom are replaced with a substituent, which can include variations of deuterium and hydrogen, and the number of substituents includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, on the basis of what is chemically possible.

[0231] "substituents" include, but are not limited to, the terms "alkyl," "alkoxy," "cycloalkyl," "cycloalkenyl," "heterocyclyl," "heterocycloalkyl," "heterocycloalkenyl," "heteroaryl," "alkylcyclo," "heteroalkylcyclo," "heteroarylcyclo," and the like, and corresponding non-limiting or exemplary groups, where some non-limiting examples of the "substituents" include deuterium, tritium, -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azido, sulfoxide, sulfone, sulfonamide, carboxy, carboxaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, aralkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroaralkoxy, heteroaralkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate, amide, urea, epoxy, and ester, and the like, optionally substituted with one or more substituents selected from oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl, or aryloxy.

[0232] In some embodiments herein, the "substituents" are selected from deuterium, tritium, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide, carboxy, aldehyde, imine, C 1-12 alkyl, halo-C 1-12 alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3-12 membered cycloalkenyl, halo-3-12 membered cycloalkenyl, C 2-12 alkynyl, halo-C 2-12 alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C 1-12 heteroalkyl, halo-C1-12 heteroalkyl, C 1-12 alkoxy, C 1-12 alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered aryl C 1-12 alkylene, 6-10 membered aryl C 1-12 alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered heterocyclyl C 1-12 alkoxy, 3-12 membered heterocyclyl C 1-12 alkylthio, C 1-12 acyl, C 1-12 acyloxy, carbamate, C 1-12 amide, ureido, epoxy, C 2-12 ester and oxo, said substituent is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, halo C 1-12 alkyl, C 1-12 alkylamino, di C 1-12 alkylamino, halo C 1-12 alkylamino, halo di C 1-12 alkylamino, carboxy, -C(O)O-C 1-12 alkyl, -OC(O)-C 1-12 alkyl, -C(O)NH2, -C(O)NH-C 1-12 alkyl, -C(O)N(C 1-12 alkyl)2, -NHC(O)-C 1-12 alkyl, -C(O)-C 1-12 alkyl, -S(O)-C 1-12 alkyl, -S(O)2-C 1-12 alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 alkyl, -S(O)2N(C 1-12 alkyl)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyl C 1-12alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 alkylene or 6-10 membered aryloxy.

[0233] C in the present document m-n means that the moiety has an integer number of carbon atoms in the given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. For example, C 1-3 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms.

[0234] When any variable (e.g., R) occurs more than one time in a compound, each definition is independent. Thus, for example, if a group is substituted with 0-2 R, then the group is optionally substituted with up to two R, and at each occurrence R is selected independently. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0235] When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected, such as L represents a single bond in A-L-Z means that the structure is actually A-Z.

[0236] When a linking group is listed without specifying its direction of connection, its direction of connection is arbitrary, for example, where the linking group L is -M-W-, then -M-W- can either connect ring A and ring B to form or ring A and ring B to form combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0237] Unless otherwise specified, when a group has one or more attachable sites, any one or more of the sites of the group can be attached to other groups by a chemical bond. When the attachment of the chemical bond is not defined and there is an H atom at the attachable site, then upon attachment of the chemical bond, the number of H atoms at the site is reduced by the number of chemical bonds attached, to the corresponding valence group. The chemical bond by which the site is attached to other groups can be represented by a straight solid line bond a straight dashed line bond or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the text indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0238] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-4 and C 1-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1- Examples of 6-alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0239] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C2 and C1 alkoxy groups, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0240] Unless otherwise specified, the term "C" 1-6 "alkylene" itself or as part of another substituent represents a straight-chain or branched divalent hydrocarbon group consisting of 1 to 6 carbon atoms, C 1-6 Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), and propylene (-CH2CH2CH2- or -CH2CH(CH3)-).

[0241] Unless otherwise specified, C n-n+m Or C n -C n+mAny one of the specific cases including n to n+m carbons, for example C 1-12 including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 Any one of the ranges n to n+m, for example C 1-12 including C 1- 3, C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n-member to n+m-member means the number of atoms on the ring is n to n+m, for example 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, also includes any one of the ranges n to n+m, for example 3-12 membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.

[0242] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon and hydrogen atoms. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 1 -butenyl, isobutenyl, 1,3- butadienyl, and the like.

[0243] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group having at least one triple bond, consisting of carbon and hydrogen atoms. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-CºCH), 1 -propynyl (-CºC-CH3), 2-propynyl (-CH2-CºCH), 1,3-butadiynyl (-CºC-CºCH), and the like.

[0244] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably comprising 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups; preferred are cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0245] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl ring, and non-limiting examples include indenyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl ring may be optionally substituted or unsubstituted.

[0246] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms (e.g., 1-4, 1-3, 1 or 2) are selected from nitrogen, oxygen, S or S(O). m (where m is an integer from 0 to 2) heteroatoms, excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon; wherein the ring atoms may further be boron or P(O). p (Where p is an integer from 0 to 2). Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably tetrahydrofuranyl, pyrazolyl, morpholinyl, piperazinyl, and pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring. Non-limiting examples of heterocyclic groups include:

[0247] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m The ring atoms are (where m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of shared spiroatoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0248] The term "fused heterocyclyl" refers to a polycyclic heterocyclic radical of 5 to 20 members, each ring in the system sharing a pair of adjacent atoms with another ring in the system, one or more rings can contain one or more double bonds, but no ring has a completely conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O)m m wherein m is an integer from 0 to 2, the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings comprising the ring system, it can be a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic, more preferably 5 / 5 or 5 / 6 bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl groups include:

[0249] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic radical of 5 to 14 members, any two rings sharing two non-adjacent atoms, which can contain one or more double bonds, but no ring has a completely conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O)m m wherein m is an integer from 0 to 2, the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings comprising the ring system, it can be a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0250] The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring that is connected together with the parent structure is the heterocyclyl ring, it is understood that the fused system formed after the fusion belongs to the category of "heterocyclyl" as defined in the present disclosure, non-limiting examples of "heterocyclyl" also include: etc.

[0251] The term "aryl" refers to a radical of a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings which share a pair of adjacent carbon atoms) aromatic ring having a conjugated pi-electron system, preferably 6 to 10 members, the aromatic ring can be a phenyl ring and a naphthyl ring, more preferably a phenyl ring, the aromatic ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring that is connected together with the parent structure is the aromatic ring, it is understood that the fused system formed after the fusion belongs to the category of "aryl" as defined in the present disclosure, non-limiting examples of "aryl" include: phenyl, naphthyl,

[0252] The term "heteroaryl" refers to a heteroaromatic system comprising from 1 to 4 (e.g., 1-3, 1, or 2) heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaromatic ring in a heteroaryl group is preferably from 5 to 10 membered, more preferably 5 or 6 membered, and can be, for example, an imidazolyl ring, a furanyl ring, a thienyl ring, a thiazolyl ring, a pyrazolyl ring, an oxazolyl ring, a pyrrolyl ring, a triazolyl ring, a tetrazolyl ring, a pyridyl ring, a pyrimidinyl ring, a thiadiazole ring, a pyrazinyl ring, and the like, preferably a triazolyl ring, a thienyl ring, an imidazolyl ring, a pyrazolyl ring, a pyrimidinyl ring, or a thiazolyl ring; more preferably a triazolyl ring, a pyrrolyl ring, a thienyl ring, a thiazolyl ring, or a pyrimidinyl ring. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaromatic ring, and it is understood that the fused system that results after fusion is within the scope of "heteroaryl" as defined by the present disclosure, non-limiting examples of which include: imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl,

[0253] Unless otherwise specified, the term "hetero" includes heteroatoms of sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron.

[0254] The term "treatment" means the administration of a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0255] (i) inhibiting the disease or condition, i.e., arresting its development;

[0256] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0257] The term "prevention" means the administration of a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the onset of a disease or condition in a mammal, particularly when such mammal is predisposed to the condition, but has not yet been diagnosed as having it.

[0258] The term "therapeutically or prophylactically effective amount" means the amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, or (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of a particular disease, condition, or disorder recited herein. The amount of a compound of the present disclosure that constitutes a "therapeutically or prophylactically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be routinely determined by the artisan without undue experimentation, based on the knowledge in the art and the teachings of the present disclosure.

[0259] The therapeutic or prophylactic dosage of a compound of the present disclosure can be determined by, for example, the particular use for which the treatment or prevention is made, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition can vary depending upon a number of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, a composition of the present disclosure can be provided in an aqueous physiological buffer solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosages are in the range of about 0.001 mg / kg to about 1000 mg / kg body weight per day. The dosage will likely depend on such variables as the kind and degree of disease or condition, the general health and age of the patient, the relative biological efficacy of the compound selected, the excipient formulation employed, and the route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0260] The words "comprise" or "comprising" and variations such as "comprises" or "comprising", when used in this disclosure and claims, are to be interpreted as a non- exclusive inclusion. The use of these terms in the detailed description are not meant to exclude additional, unrecited elements or limitations.

[0261] A "pharmaceutical composition" refers to a composition comprising one or more compounds of the present disclosure, isomers thereof, or pharmaceutically acceptable salts thereof, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of an active ingredient to a subject to thereby effectuate its biological activity.

[0262] The pharmaceutical composition of the present disclosure can be prepared by combining a compound of the present disclosure with suitable pharmaceutically acceptable excipients.

[0263] In some embodiments of the present disclosure, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art.

[0264] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the embodiments set forth below with other chemical synthetic methods well known in the art, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

[0265] The chemical reactions of the specific embodiments of the present disclosure are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical changes being effected. In the synthetic schemes and examples of the present disclosure, all substituents unless otherwise indicated, are as previously defined. Further, the skilled worker will appreciate that certain variables can be modified or selected on the basis of the existing embodiments by one skilled in the art.

[0266] The starting materials or intermediates used in the embodiments of the present disclosure can be obtained commercially or prepared by methods known in the art.

[0267] One important consideration in the synthetic route planning in the art is the selection of a suitable protecting group for a reactive functional group, such as an amino group in the present disclosure. For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0268] In some embodiments of the present disclosure, some of the compounds of the present disclosure can be prepared by one skilled in the art of organic synthesis with reference to the following routes:

[0269] wherein, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , R 1 , R 2 , R 3 , R 3’ , R 4 , R 4’ , m, n and ring A are as described in the present disclosure.

[0270] wherein, Z 1 and Z 2 are selected from halogen, -OH, -SH, -NH2, OTf, ONf or tin reagents.

[0271] In some embodiments of the present disclosure, Z 1 and Z 2 are selected from halogen.

[0272] In some embodiments of the present disclosure, Z 1 and Z 2 are selected from Cl.

[0273] The compounds of the present disclosure can be confirmed in structure by conventional methods well known to those skilled in the art, and if the present application relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional means in the art. For example, single crystal X-ray diffraction method (S XRD) and microcrystal electron diffraction method.

[0274] For the sake of clarity, the present disclosure is further illustrated by examples, but the examples are not intended to limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and used without further purification. DETAILED DESCRIPTION

[0275] The present disclosure is described in detail below with examples, but is not meant to be limited by any of the details of the examples. The present disclosure has been described in detail by specific embodiments, and specific embodiments ways thereof are disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the present disclosure.

[0276] Example 1: Preparation of compound I-1

[0277] Step A: Preparation of compound 1a

[0278] Into a reaction flask was added 1,3-dichloroacetone (2.1 g), ethanol (50 mL) and 6,7-dihydro-5H-cyclopenta[b]pyridin-2-amine (2.1 g) successively. After addition, the reaction was stirred at reflux. TLC monitoring until the reaction was complete, the reaction was concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give compound 1a. MS (ESI, [M+H] + )m / z: 206.9.

[0279] Step B: Preparation of compound 1b

[0280] Into a reaction flask was added compound 1a (3 g), acetonitrile (5 mL) and ammonia water (40 mL) successively, and after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was complete, the reaction was concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 1b.

[0281] MS (ESI, [M+H] + )m / z: 188.0.

[0282] Step C: Preparation of compound 1c

[0283] Into a reaction flask was added compound 1b (1.2 g), N,N-diisopropylethylamine (3.4 g), N,N-dimethylformamide (20 mL) and 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (1.0 g) successively. After addition, the reaction was stirred at 75°C. TLC monitoring until the reaction was complete, the reaction was concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 1c. MS (ESI, [M+H] + )m / z: 379.1.

[0284] Step D: Preparation of compound 1d

[0285] To a reaction flask was added compound 1c (1.0 g), tetrahydrofuran (40 mL), di-tert-butyl dicarbonate (0.86 g), and 4-dimethylaminopyridine (0.16 g) successively, and after the addition, the reaction was carried out at room temperature, and TLC monitoring was performed until the reaction was completed. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to obtain compound 1d. MS (ESI, [M+H] + )m / z: 479.1.

[0286] Step E: Preparation of compound 1e

[0287] To a reaction flask was added compound 1d (0.20 g), (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.096 g), bis(dibenzylideneacetone)palladium (0.04 g), 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (0.052 g), cesium carbonate (0.28 g), and toluene (30 mL) successively, and after the addition, the reaction was stirred at 100°C, and TLC monitoring was performed until the reaction was completed. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 1e. MS (ESI, [M+H] + )m / z: 673.3.

[0288] Step F: Preparation of compound I-1

[0289] To a reaction flask was added compound 1e (0.24 g), dichloromethane (5 mL), and trifluoroacetic acid (5 mL) successively, and after the addition, the reaction was carried out at room temperature, and TLC monitoring was performed until the reaction was completed. To the reaction solution was added saturated aqueous sodium bicarbonate solution to adjust to alkaline (pH about 8), and extraction was performed with dichloromethane and water. After drying, filtration, and concentration, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to obtain compound I-1. HRMS (ESI, [M+H] + )m / z: 473.2761. 1H NMR (500 MHz, DMSO-d6) δ 7.55 (d, J = 2.3 Hz, 2H), 7.51 (s, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 9.1 Hz, 1H), 6.73 (s, 1H), 5.30 (s, 2H), 4.56 (d, J = 5.9 Hz, 2H), 3.52 (s, 1H), 3.21 (dd, J = 10.9, 6.9 Hz, 1H), 3.05 (q, J = 5.8 Hz, 3H), 2.93 (t, J = 7.2 Hz, 3H), 2.78 (d, J = 11.8 Hz, 1H), 2.30 (dd, J = 13.3, 10.6 Hz, 1H), 2.25 - 2.12 (m, 3H), 1.71 (tt, J = 8.4, 5.2 Hz, 1H), 1.56 (dd, J = 12.9, 3.4 Hz, 1H), 1.37 - 1.29 (m, 1H), 1.19 - 1.09 (m, 1H), 0.76 (dq, J = 8.2, 1.7 Hz, 2H), 0.65 (ddt, J = 12.3, 5.1, 2.5 Hz, 2H).

[0290] Example 2: Preparation of compound I-2

[0291] Step A: Preparation of compound 2a

[0292] To a reaction flask was added 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide (0.30 g), 2-bromonicotinic acid methyl ester (0.26 g), chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl- 1, 1 '-biphenyl)[2-(2'-amino- 1, 1 '-biphenyl)]palladium(II) (0.09 g), potassium phosphate tribasic (0.48 g), 1,4-dioxane (6 mL) and water (1 mL) successively, after addition, the reaction was stirred at 100 °C under nitrogen protection. TLC monitoring until the reaction was completed, the reaction liquid was filtered and concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 2a.

[0293] MS (ESI, [M+H] + )m / z: 275.0.

[0294] Step B: Preparation of compound 2b

[0295] To a reaction flask was added compound 2a (0.33 g) and tetrahydrofuran (30 mL) under ice-bath condition, after addition, a solution of lithium aluminum hydride (0.08 g) in tetrahydrofuran (10 mL) was added dropwise slowly under nitrogen protection, the reaction was stirred at room temperature. TLC was used to monitor the reaction until it was completed. The reaction was quenched by adding 15% potassium hydroxide aqueous solution (0.15 mL) dropwise slowly under ice-bath condition. The reaction was filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (dichloromethane / methanol = 40 / 1) to give compound 2b. MS (ESI, [M+H] + )m / z: 247.0.

[0296] Step C: Preparation of compound 2c

[0297] To a reaction flask was added compound 2b (0.21 g), tetrahydrofuran (30 mL) and sodium hydride (0.05 g) under ice-bath condition, after addition, the reaction was stirred at room temperature. TLC was used to monitor the reaction until it was completed. The reaction was quenched by adding saturated ammonium chloride aqueous solution dropwise slowly under ice-bath condition, extracted with ethyl acetate and water, dried, filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (dichloromethane / methanol = 40 / 1) to give compound 2c. MS (ESI, [M+H] + )m / z: 227.0.

[0298] Step D: Preparation of compound 2d

[0299] To a reaction flask was added compound 2c (0.13 g), tetrahydrofuran (5 mL) and borane dimethyl sulfide (0.13 g), after addition, the reaction was stirred at 60 °C. TLC was used to monitor the reaction until it was completed. The reaction was quenched by adding methanol (5 mL) dropwise slowly under ice-bath condition, after addition, the reaction was stirred at 60 °C for 3 hours. The reaction was concentrated to give a residue, which was purified by column chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound 2d. MS (ESI, [M+H] + )m / z: 213.1.

[0300] Step E: Preparation of compound 2e

[0301] To a reaction flask was added compound 5,7-dichloro-3-cyclopropylpyrazolo[l,5-a]pyrimidine (0.10 g), compound 2d (0.10 g), N,N-diisopropylethylamine (0.05 g) and N,N-dimethylformamide (5 mL), after addition, the reaction was heated and stirred at 75 °C. TLC was used to monitor the reaction until it was completed. The reaction was concentrated to give a residue, which was purified by column chromatography on silica gel (dichloromethane / methanol = 30 / 1) to give compound 2e. MS (ESI, [M+H] + )m / z: 404.0.

[0302] Step F: Preparation of compound 2f

[0303] To a reaction flask was added compound 2e (0.12 g), 4-dimethylaminopyridine (0.05 g), dichloromethane (5 mL) and di-tert-butyl dicarbonate (0.10 g) successively, after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed, the reaction liquid was concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 2f. MS (ESI, [M+H] + )m / z: 504.0.

[0304] Step G: Preparation of compound 2g

[0305] To a reaction flask was added compound 2f (0.15 g), (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.09 g), tris(dibenzylideneacetone)dipalladium (0.03 g), 1,1'-binaphthalene-2,2'-diphenylphosphine (0.04 g), cesium carbonate (0.19 g) and toluene (5 mL) successively, after addition, the reaction was stirred at 100 °C under nitrogen protection. TLC monitoring until the reaction was completed, the reaction liquid was filtered, concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 2g. MS (ESI, [M+H] + )m / z: 698.2.

[0306] Step E: Preparation of compound I-2

[0307] To a reaction flask was added compound 2g (0.16 g), dichloromethane (5 mL) and trifluoroacetic acid (0.50 g) successively, after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed, saturated aqueous sodium bicarbonate solution was added to the reaction liquid to adjust to alkaline (pH about 8), extracted with dichloromethane and water, dried, filtered, concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-2. HRMS (ESI, [M+H] + )m / z: 498.2612. 1H NMR (500 MHz, DMSO-d6) δ 8.54 (dd, J = 5.0, 1.7 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 7.90 (t, J = 6.6 Hz, 1H), 7.66 (dd, J = 7.6, 1.6 Hz, 1H), 7.53 (s, 1H), 7.31 (dd, J = 7.6, 4.8 Hz, 1H), 7.09 (dd, J = 8.0, 1.6 Hz, 1H), 6.95 (d, J = 1.6 Hz, 1H), 6.74 (t, J = 6.0 Hz, 1H), 5.39 (s, 1H), 5.26 (s, 2H), 5.18 (s, 1H), 4.44 (d, J = 6.5 Hz, 2H), 3.50 (s, 1H), 3.21 (dt, J = 13.4, 4.4 Hz, 1H), 3.11 - 3.01 (m, 1H), 2.94 (dd, J = 11.7, 4.5 Hz, 1H), 2.82 (d, J = 12.2 Hz, 1H), 2.35 (td, J = 11.3, 3.8 Hz, 1H), 2.21 (dd, J = 11.7, 9.9 Hz, 1H), 1.71 (tt, J = 8.4, 5.2 Hz, 1H), 1.58 (dd, J = 13.2, 3.3 Hz, 1H), 1.41 - 1.29 (m, 1H), 1.17 (tt, J = 12.3, 6.1 Hz, 1H), 0.76 (dq, J = 8.3, 1.6 Hz, 2H), 0.71 - 0.60 (m, 2H).

[0308] Example 3: Preparation of compound I-3

[0309] Step A: Preparation of compound 3a

[0310] To a reaction flask was added 2-iodo-3-hydroxypyridine (0.47 g), 4- (bromomethyl)benzamide (0.45 g), potassium carbonate (0.59 g), potassium iodide (0.02 g) and N,N-dimethylformamide (10 mL) successively, and the reaction was stirred at 80 °C after addition. TLC monitoring was performed until the reaction was complete, and the reaction solution was filtered and concentrated to give a residue which was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to give compound 3a. MS (ESI, [M+H] + )m / z: 355.0.

[0311] Step B: Preparation of compound 3b

[0312] To a microwave tube was added compound 3a (0.70 g), o-phenanthroline (0.04 g), potassium tert-butoxide (0.44 g), and pyridine (14 mL) sequentially. After addition, the reaction was stirred at 160 °C for 0.5 h in the microwave tube under nitrogen. The reaction was monitored by TLC until completion. The reaction was concentrated to give a residue which was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to give compound 3b. MS (ESI, [M+H] + )m / z: 227.1.

[0313] Step C: Preparation of compound 3c

[0314] To a reaction flask was added compound 3b (0.15 g), tetrahydrofuran (5 mL), and borane dimethyl sulfide (0.18 g) sequentially. After addition, the reaction was stirred at 60 °C. The reaction was monitored by TLC until completion. To the reaction was added methanol (5 mL) dropwise slowly under ice bath condition. After addition, the reaction was stirred at 60 °C for 3 h. The reaction was concentrated to give a residue which was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 3c. MS (ESI, [M+H] + )m / z: 213.1.

[0315] Step D: Preparation of compound 3d

[0316] To a reaction flask was added compound 5,7-dichloro-3-cyclopropylpyrazolo[l,5- a]pyrimidine (0.17 g), compound 3c (0.12 g), N,N-diisopropylethylamine (0.07 g), and N,N-dimethylformamide (5 mL) sequentially. After addition, the reaction was stirred at 80 °C. The reaction was monitored by TLC until completion. The reaction was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 3d. MS (ESI, [M+H] + )m / z: 404.2.

[0317] Step E: Preparation of compound 3e

[0318] To a reaction flask was added compound 3d (0.11 g), 4-dimethylaminopyridine (0.03 g), dichloromethane (5 mL), and di-tert-butyl dicarbonate (0.07 g) sequentially. After addition, the reaction was stirred at room temperature. The reaction was monitored by TLC until completion. The reaction was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 3e. MS (ESI, [M+H] + )m / z: 504.2.

[0319] Step F: Preparation of compound 3f

[0320] To a reaction flask was added compound 3e (0.13 g), (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.08 g), tris(dibenzylideneacetone)dipalladium (0.02 g), 1,1'-binaphthalene-2,2'-diphenylphosphine (0.03 g), cesium carbonate (0.16 g) and toluene (5 mL) successively, after addition, the reaction was stirred at 110 °C under nitrogen protection. TLC monitoring until the reaction was completed, the reaction liquid was filtered, concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 25 / 1) to obtain compound 3f. MS (ESI, [M+H] + )m / z: 698.5.

[0321] Step G: Preparation of compound I-3

[0322] To a reaction flask was added compound 3f (0.13 g), dichloromethane (5 mL) and trifluoroacetic acid (0.43 g) successively, after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed, saturated aqueous sodium bicarbonate solution was added to the reaction liquid to adjust to alkaline (pH about 8), extracted with dichloromethane and water, dried, filtered, concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound I-3. HRMS (ESI, [M+H] + )m / z: 498.2593. 1 H NMR (500 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.68 (s, 1H), 8.26 (dd, J = 4.6, 1.5 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.97 (s, 1H), 7.55 (s, 1H), 7.45 - 7.40 (m, 1H), 7.36 (dd, J = 8.2, 1.5 Hz, 1H), 7.29 - 7.25 (m, 2H), 6.90 (s, 1H), 6.06 (s, 1H), 5.26 (s, 2H), 5.15 (s, 1H), 4.50 (d, J = 6.5 Hz, 2H), 3.51 (s, 1H), 3.43 (s, 1H), 3.23 - 3.12 (m, 2H), 2.76 (s, 1H), 2.61 (d, J = 9.2 Hz, 1H), 1.80 (dd, J = 14.3, 3.6 Hz, 1H), 1.72 (tt, J = 8.3, 5.1 Hz, 1H), 1.59 (s, 1H), 1.49 - 1.39 (m, 1H), 0.77 (dd, J = 8.4, 2.8 Hz, 2H), 0.71 - 0.62 (m, 2H).

[0323] Example 4: Preparation of compound I-4

[0324] Step A: Preparation of compound 4a

[0325] To a reaction vial was added compound 3e (0.13 g), (S)-l-Boc-3-aminopiperidine (0.07 g), tris(dibenzylideneacetone)dipalladium (0.02 g), 1,1'-binaphthalene-2,2'-diphenylphosphine (0.03 g), cesium carbonate (0.16 g) and toluene (5 mL) successively. After addition, the reaction was stirred at 110 °C under nitrogen protection. TLC was used to monitor the reaction until completion. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 25 / 1) to give compound 4a. MS (ESI, [M+H] + )m / z: 668.5.

[0326] Step B: Preparation of compound I-4

[0327] To a reaction vial was added compound 4a (0.14 g), dichloromethane (5 mL) and trifluoroacetic acid (0.47 g) successively. After addition, the reaction was stirred at room temperature. TLC was used to monitor the reaction until completion. The reaction mixture was adjusted to basic (pH about 8) by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane and water. The organic layer was dried, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-4.

[0328] HRMS (ESI, [M+H] + )m / z: 468.2506. 1H NMR (500 MHz, DMSO-d6) δ 8.25 (dd, J = 4.6, 1.4 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.85 (t, J = 6.4 Hz, 1H), 7.55 (s, 1H), 7.42 (dd, J = 8.0, 1.8 Hz, 1H), 7.35 (dd, J = 8.2, 1.5 Hz, 1H), 7.28 - 7.23 (m, 2H), 6.52 (d, J = 7.4 Hz, 1H), 5.25 (s, 2H), 5.11 (s, 1H), 4.49 (d, J = 6.4 Hz, 2H), 3.84 (s, 1H), 3.12 (dd, J = 12.0, 3.9 Hz, 1H), 2.85 (dt, J = 12.2, 4.2 Hz, 1H), 2.58 - 2.52 (m, 1H), 2.40 (dd, J = 11.8, 8.7 Hz, 1H), 1.84 (td, J = 8.4, 4.3 Hz, 1H), 1.77 (tt, J = 8.1, 5.4 Hz, 1H), 1.66 (dt, J = 13.4, 4.3 Hz, 1H), 1.46 (dddt, J = 13.7, 10.1, 7.5, 3.7 Hz, 1H), 1.34 (dtt, J = 12.8, 6.0, 3.0 Hz, 1H), 0.79 - 0.69 (m, 4H).

[0329] Example 5: Preparation of compound I-5

[0330] Step A: Preparation of compound 5a

[0331] Into a reaction flask was added 5-bromoindanone (2.1 g), tetrakis triphenylphosphine palladium (1.1 g), zinc cyanide (1.2 g) and N,N-dimethylformamide (30 mL) successively. After addition, the reaction was stirred at 100 °C under nitrogen protection. TLC monitoring until the reaction was completed. The reaction solution was concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give compound 5a. MS (ESI, [M+H] + )m / z: 158.3.

[0332] Step B: Preparation of compound 5b

[0333] Into a reaction flask was added compound 5a (1.4 g), copper 1,3,5-benzenetricarboxylate (0.7 g), propargylamine (1.76 g) and ethanol (20 mL) successively. After addition, the reaction was stirred at 85 °C under nitrogen protection. TLC monitoring until the reaction was completed. The reaction solution was concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 5b. MS (ESI, [M+H] + )m / z: 193.2.

[0334] Step C: Preparation of compound 5c

[0335] To a reaction flask was added compound 5b (0.4 g), tetrahydrofuran (10 mL), borane (10 mL, 2 M tetrahydrofuran solution) successively. After addition, the reaction was stirred at 66 °C under nitrogen protection. TLC monitoring until the reaction was completed. The reaction solution was concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to give compound 5c. MS (ESI, [M+H] + )m / z: 197.3.

[0336] Step D: Preparation of compound 5d

[0337] To a reaction flask was added compound 5c (0.2 g), 5,7-dichloro-3- cyclopropylpyrazolo[l,5-a]pyrimidine (0.25 g), N,N-diisopropylethylamine (0.3 g), N,N-dimethylformamide (20 mL) successively. After addition, the reaction was heated and stirred at 75 °C. TLC monitoring until the reaction was completed. The reaction solution was concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 5d. MS (ESI, [M+H] + )m / z: 388.2.

[0338] Step E: Preparation of compound 5e

[0339] To a reaction flask was added compound 5d (0.3 g), tetrahydrofuran (10 mL), di-tert-butyl dicarbonate (0.3 g) and 4-dimethylaminopyridine (0.05 g) successively. After addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed. The reaction solution was concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give compound 5e. MS (ESI, [M+H] + )m / z: 488.1.

[0340] Step F: Preparation of compound 5f

[0341] To a reaction flask was added compound 5e (0.4 g), (S)-l-Boc-3-aminopiperidine (0.2 g), bis(dibenzylideneacetone)palladium (0.08 g), 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (0.1 g), cesium carbonate (0.5 g) and toluene (10 mL) successively. After addition, the reaction was stirred at 100 °C under nitrogen protection. TLC monitoring until the reaction was completed. The reaction solution was concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 5f.

[0342] MS (ESI, [M+H] + )m / z: 652.4.

[0343] Step G: Preparation of compound I-5

[0344] Into a reaction vial was added compound 5f (0.2 g), dichloromethane (5 mL) and trifluoroacetic acid (1 mL) successively, after addition, the reaction was carried out at room temperature, TLC monitoring until the reaction was completed, saturated aqueous sodium bicarbonate solution was added to adjust to alkaline (pH about 8), extracted with dichloromethane and water, dried, filtered, concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-5. HRMS (ESI, [M+H] + )m / z: 452.2559. 1 H NMR (500 MHz, DMSO-d6) δ 8.52 (dd, J = 4.9, 1.5 Hz, 1H), 7.97 - 7.91 (m, 2H), 7.85 (t, J = 6.5 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.34 - 7.25 (m, 1H), 6.44 (d, J = 7.6 Hz, 1H), 5.16 (s, 1H), 4.55 (d, J = 6.5 Hz, 2H), 3.93 (s, 2H), 3.77 (s, 1H), 3.04 (dd, J = 12.0, 3.8 Hz, 1H), 2.77 (dt, J = 12.0, 4.2 Hz, 1H), 2.48 - 2.40 (m, 1H), 2.30 (dd, J = 11.7, 8.7 Hz, 1H), 1.87 - 1.79 (m, 1H), 1.76 (tt, J = 8.0, 5.5 Hz, 1H), 1.59 (dt, J = 13.0, 4.2 Hz, 1H), 1.35 - 1.26 (m, 1H), 1.23 (s, 2H), 0.81 - 0.71 (m, 4H).

[0345] Example 6: Preparation of compound I-6

[0346] Step A: Preparation of compound 6a

[0347] To a reaction flask was added sodium tert-butoxide (1.25 g), 1,1'- binaphthalene-2,2'-diphenylphosphine (0.21 g), bis(diphenylphosphino) palladium (0.30 g), benzophenone imine (1.42 g), 5-chlorofuran[3,2- b]pyridine (1.0 g), and toluene (20 mL) successively. After addition, the reaction was stirred at 80 °C under nitrogen. TLC monitoring was performed until the reaction was complete. The reaction was concentrated, and the resulting residue was added to dichloromethane (10 mL) and hydrochloric acid 1,4-dioxane solution (20 mL, 4 M). After addition, the reaction was stirred at room temperature. TLC monitoring was performed until the reaction was complete. The reaction was concentrated, and the resulting residue was adjusted to basic (pH about 10) with saturated sodium bicarbonate solution. Extraction was performed with dichloromethane and water, and the resulting residue was dried, filtered, and concentrated. Purification of the resulting residue by silica gel column chromatography (dichloromethane / methanol = 20 / 1) provided compound 6a. MS (ESI, [M+H] + )m / z: 135.0.

[0348] Step B: Preparation of compound 6b

[0349] To a reaction flask was added compound 6a (0.5 g), 1,3-dichloroacetone (0.71 g), and ethanol (20 mL) successively. After addition, the reaction was stirred at 85 °C. TLC monitoring was performed until the reaction was complete. The reaction was concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to provide compound 6b. MS (ESI, [M+H] + )m / z: 207.0.

[0350] Step C: Preparation of compound 6c

[0351] To a reaction flask was added compound 6b (0.33 g), ammonia water (30 mL), and acetonitrile (30 mL) successively. After addition, the reaction was stirred at room temperature. TLC monitoring was performed until the reaction was complete. The reaction was concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to provide compound 6c.

[0352] MS (ESI, [M+H] + )m / z: 188.0.

[0353] Step D: Preparation of compound 6d

[0354] To a reaction flask was added 5,7-dichloro-3-cyclopropylpyrazolo[l,5- a]pyrimidine (0.34 g), compound 6c (0.28 g), N,N-diisopropylethylamine (0.41 g) and N,N-dimethylformamide (18 mL) successively, and the reaction was stirred at 80 °C after addition. TLC monitoring until the reaction was completed, and the reaction solution was concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 6d. MS (ESI, [M+H] + )m / z: 379.2.

[0355] Step E: Preparation of compound 6e

[0356] To a reaction flask was added compound 6d (0.33 g), 4-dimethylaminopyridine (5.46 mg), dichloromethane (15 mL) and di-tert-butyl dicarbonate (0.30 g) successively, and the reaction was stirred at room temperature after addition. TLC monitoring until the reaction was completed, and the reaction solution was concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 6e. MS (ESI, [M+H] + )m / z: 479.3.

[0357] Step F: Preparation of compound 6f

[0358] To a reaction flask was added compound 6e (0.11 g), (S)-l-Boc-3-aminopiperidine (0.06 g), tris(dibenzylideneacetone)dipalladium (0.03 g), 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (0.03 g), cesium carbonate (0.22 g) and toluene (4 mL) successively, and the reaction was stirred at 100 °C under nitrogen protection after addition. TLC monitoring until the reaction was completed, and the reaction solution was filtered and concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 6f. MS (ESI, [M+H] + )m / z: 643.5.

[0359] Step G: Preparation of compound I-6

[0360] To a reaction flask was added compound 6f (0.13 g), dichloromethane (5 mL) and trifluoroacetic acid (1.00 g) successively, and the reaction was stirred at room temperature after addition. TLC monitoring until the reaction was completed, and saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust to alkaline (pH about 8), and extraction was performed with dichloromethane and water. After drying, filtration and concentration, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-6. HRMS (ESI, [M+H] + )m / z: 443.2304. 1H NMR (500 MHz, DMSO-d6) δ 8.12 (d, J = 2.2 Hz, 1H), 8.07 (s, 1H), 7.69 (d, J = 9.7 Hz, 1H), 7.61 (t, J = 6.1 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.41 (d, J = 9.7 Hz, 1H), 6.49 (d, J = 7.6 Hz, 1H), 5.24 (s, 1H), 4.61 (d, J = 6.0 Hz, 2H), 3.79 (s, 1H), 3.08 (dd, J = 11.8, 3.8 Hz, 1H), 2.79 (dt, J = 12.6, 4.0 Hz, 1H), 2.50 - 2.41 (m, 1H), 2.32 (dd, J = 11.8, 8.7 Hz, 1H), 1.90 - 1.72 (m, 2H), 1.65 - 1.57 (m, 1H), 1.47 - 1.28 (m, 2H), 0.81 - 0.71 (m, 4H).

[0361] Example 7: Preparation of compound I-7

[0362] Step A: Preparation of compound 7a

[0363] To a reaction flask was added compound Id (0.16 g), (S)-l-Boc-3-aminopiperidine (0.087 g), bis(dibenzylideneacetone)palladium (0.031 g), 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (0.042 g), cesium carbonate (0.22 g) and toluene (10 mL) successively, after addition, the reaction was stirred at 100 °C, TLC was used to monitor the reaction until it was completed, the reaction solution was concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 7a.

[0364] MS (ESI, [M+H] + )m / z: 643.5.

[0365] Step B: Preparation of compound I-7

[0366] To a reaction flask was added compound 7a (0.15 g), dichloromethane (5 mL) and trifluoroacetic acid (5 mL) successively, after addition, the reaction was carried out at room temperature, TLC was used to monitor the reaction until it was completed, saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust to alkaline (pH about 8), extraction was carried out with dichloromethane and water, after drying, filtration, concentration, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-7. HRMS (ESI, [M+H] + )m / z: 443.2652. 1H NMR (500 MHz, DMSO-d6) δ 7.56 - 7.47 (m, 3H), 7.36 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 9.1 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 5.26 (s, 1H), 4.56 (d, J = 6.0 Hz, 2H), 3.82 (s, 1H), 3.08 (dt, J = 26.0, 7.9 Hz, 3H), 2.93 (t, J = 7.4 Hz, 2H), 2.83 (dt, J = 12.6, 4.3 Hz, 1H), 2.38 (dd, J = 11.7, 8.9 Hz, 1H), 2.21 (p, J = 7.6 Hz, 2H), 1.86 (dq, J = 9.4, 5.8 Hz, 1H), 1.76 (tt, J = 8.1, 5.4 Hz, 1H), 1.65 (dt, J = 13.2, 4.3 Hz, 1H), 1.49 - 1.30 (m, 2H), 0.75 (ddt, J = 8.6, 6.7, 2.2 Hz, 4H).

[0367] Example 8: Preparation of compound I-8

[0368] Step A: Preparation of compound 8a

[0369] To a reaction flask were added compound 2f (0.10 g), (S)-l-Boc-3-aminopiperidine (0.05 g), tris(dibenzylideneacetone)dipalladium (0.02 g), 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (0.03 g), cesium carbonate (0.13 g) and toluene (5 mL) successively, and the mixture was stirred at 100 °C under nitrogen protection. TLC monitoring until the reaction was completed. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 2 / 3) to give compound 8a. MS (ESI, [M+H] + )m / z: 668.4.

[0370] Step B: Preparation of compound I-8

[0371] To a reaction flask were added compound 8a (0.08 g), dichloromethane (5 mL) and trifluoroacetic acid (0.29 g) successively, and the mixture was stirred at room temperature. TLC monitoring until the reaction was completed. The reaction mixture was adjusted to alkaline (pH about 8) by adding saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane and water. After drying, filtering and concentrating, the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound I-8. HRMS (ESI, [M+H] + )m / z: 468.2522. 1H NMR (500 MHz, DMSO-d6) δ 8.54 (dd, J = 5.0, 1.7 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.97 (t, J = 6.5 Hz, 1H), 7.66 (dd, J = 7.6, 1.7 Hz, 1H), 7.59 (s, 1H), 7.31 (dd, J = 7.6, 4.9 Hz, 1H), 7.08 (dd, J = 8.0, 1.7 Hz, 1H), 6.93 (d, J = 1.6 Hz, 1H), 6.71 (d, J = 6.6 Hz, 1H), 5.25 (s, 2H), 5.12 (s, 1H), 4.45 (d, J = 6.5 Hz, 2H), 4.13 - 4.01 (m, 1H), 3.39 (dd, J = 12.1, 4.0 Hz, 2H), 3.12 (dt, J = 12.5, 4.3 Hz, 1H), 2.84 (ddd, J = 13.7, 11.4, 3.4 Hz, 1H), 2.75 (dd, J = 12.0, 9.4 Hz, 1H), 1.96 - 1.88 (m, 1H), 1.88 - 1.76 (m, 2H), 1.71 - 1.61 (m, 1H), 1.53 - 1.40 (m, 1H), 0.83 - 0.66 (m, 4H).

[0372] Example 9: Preparation of compound I-9

[0373] Step A: Preparation of compound 9a

[0374] Into a reaction bottle was added 4-bromo-2-(tetrahydro pyrrolyl)aniline (1.2 g), hydrogen peroxide (0.2 g), ethyl acetate (20 mL) successively, after addition, 80 °C stirring under the condition of nitrogen protection. TLC monitoring until the reaction was complete, the reaction liquid was concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 9a. MS (ESI, [M+H] + )m / z: 237.0.

[0375] Step B: Preparation of compound 9b

[0376] Into a reaction bottle was added compound 9a (0.5 g), tetrakis triphenyl phosphine palladium (2.2 g), zinc cyanide (0.3 g) and N,N-dimethylacetamide (20 mL) successively, after addition, 120 °C stirring under the condition of nitrogen protection. TLC monitoring until the reaction was complete, the reaction liquid was concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 9b. MS (ESI, [M+H] + )m / z: 184.2.

[0377] Step C: Preparation of compound 9c

[0378] To the reaction flask was added compound 9b (0.38 g) and tetrahydrofuran (10 mL) successively, after addition, 1 M borane in tetrahydrofuran (10 mL) was added slowly at 0 °C, after addition, the reaction was stirred at 70 °C. TLC monitoring until the reaction was completed, the reaction was concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to give compound 9c. MS (ESI, [M+H] + )m / z: 188.2.

[0379] Step D: Preparation of compound 9d

[0380] To the reaction flask was added 5,7-dichloro-3-cyclopropylpyrazolo[l,5-a]pyrimidine (0.4 g), compound 9c (0.3 g), N,N-diisopropylethylamine (0.5 g) and N,N-dimethylformamide (10 mL) successively, after addition, the reaction was stirred at 80 °C. TLC monitoring until the reaction was completed, the reaction was concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 9d. MS (ESI, [M+H] + )m / z: 379.3.

[0381] Step E: Preparation of compound 9e

[0382] To the reaction flask was added compound 9d (0.3 g), 4-dimethylaminopyridine (5 mg), dichloromethane (10 mL) and di-tert-butyl dicarbonate (0.25 g) successively, after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed, the reaction was concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 9e. MS (ESI, [M+H] + )m / z: 479.4.

[0383] Step F: Preparation of compound 9f

[0384] To the reaction flask was added compound 9e (0.3 g), (S)-l-Boc-3-aminopiperidine (0.15 g), tris(dibenzylideneacetone)dipalladium (0.09 g), 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (0.09 g), cesium carbonate (0.6 g) and toluene (12 mL) successively, after addition, the reaction was stirred at 100 °C under nitrogen protection. TLC monitoring until the reaction was completed, the reaction was filtered, concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 9f. MS (ESI, [M+H] + )m / z: 643.4.

[0385] Step G: Preparation of compound I-9

[0386] To a reaction flask was added compound 9f (0.13 g), dichloromethane (5 mL) and trifluoroacetic acid (1.00 g) sequentially, after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed, to the reaction liquid was added saturated aqueous sodium bicarbonate solution to adjust to alkaline (pH about 10), extracted with dichloromethane and water, dried, filtered, concentrated, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound I-9. HRMS (ESI, [M+H] + )m / z: 443.2669. 1 H NMR (500 MHz, DMSO-d6) δ 7.72 (t, J = 6.5 Hz, 1H), 7.52 (d, J = 6.9 Hz, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 7.8 Hz, 1H), 5.16 (s, 1H), 4.50 (d, J = 6.4 Hz, 2H), 4.06 (t, J = 7.0 Hz, 2H), 3.74 (s, 1H), 3.00 (dd, J = 11.5, 3.8 Hz, 1H), 2.92 (t, J = 7.6 Hz, 2H), 2.74 (dt, J = 12.3, 4.2 Hz, 1H), 2.60 (p, J = 7.4 Hz, 2H), 2.45 - 2.37 (m, 1H), 2.25 (dd, J = 11.7, 8.7 Hz, 1H), 1.86 - 1.78 (m, 1H), 1.78 - 1.71 (m, 1H), 1.57 (dt, J = 12.7, 4.2 Hz, 1H), 1.41 - 1.34 (m, 1H), 1.27 (dt, J = 18.5, 9.1 Hz, 1H), 0.74 (t, J = 7.1 Hz, 4H).

[0387] Example 10: Preparation of compound I-10

[0388] Step A: Preparation of compound 10a

[0389] To a reaction flask was added 2-(dimethylaminomethyl)-3-hydroxypyridine (6.00 g), acetone (18 mL) and iodomethane (6.44 g) sequentially at 0 °C, after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed, the reaction liquid was filtered, the filter cake was washed with acetone three times, and dried to obtain compound 10a. MS (ESI, [M+H] + )m / z: 295.0.

[0390] Step B: Preparation of compound 10b

[0391] To a reaction flask was added trimethylsulfoxonium iodide (8.60 g), dimethylsulfoxide (20 mL) and sodium hydride (1.95 g) sequentially under nitrogen. After the addition, the reaction was stirred for 1.5 h. Compound 10a (9.58 g) was then added and the reaction was stirred at room temperature. The reaction was monitored by TLC until completion. The reaction mixture was poured into ice water and extracted with ethyl acetate and water. The organic layer was dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound 10b. HRMS (ESI, [M+H] + m / z: 122.0.

[0392] Step C: Preparation of compound 10c

[0393] To a reaction flask was added compound 10b (2.83 g), sulfuric acid (25 mL) and nitric acid (2 mL) sequentially at 0 °C. After the addition, the reaction was stirred at 0 °C. The reaction was monitored by TLC until completion. The reaction mixture was poured into ice water and extracted with ethyl acetate and water. The organic layer was dried, filtered and concentrated to give compound 10c. MS (ESI, [M+H] + m / z: 166.9.

[0394] Step D: Preparation of compound 10d

[0395] To a reaction flask was added compound 10c (3.30 g), 10% palladium on carbon (1.00 g) and methanol (50 mL) sequentially. After the addition, the reaction was stirred at room temperature under hydrogen. The reaction was monitored by TLC until completion. The reaction mixture was filtered and concentrated to give compound 10d. MS (ESI, [M+H] + m / z: 137.0.

[0396] Step E: Preparation of compound 10e

[0397] To a reaction flask was added 1,3-dichloroacetone (2.7 g), ethanol (30 mL) and compound 10d (2.6 g) sequentially. After the addition, the reaction was stirred at reflux. The reaction was monitored by TLC until completion. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 50 / 1) to give compound 10e. MS (ESI, [M+H] + m / z: 209.1.

[0398] Step F: Preparation of compound 10f

[0399] To a reaction flask was added compound 10e (1.00 g), acetonitrile (4 mL) and aqueous ammonia (40 mL) sequentially. After the addition, the reaction was stirred at room temperature. The reaction was monitored by TLC until completion. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound 10f.

[0400] MS (ESI, [M+H] + m / z: 190.0.

[0401] Step G: Preparation of compound 10g

[0402] To a reaction flask was added compound 10f (0.30 g), N,N-diisopropylethylamine (0.41 g), N,N-dimethylformamide (20 mL) and 5,7-dichloro-3- cyclopropylpyrazolo[l,5-a]pyrimidine (0.4 g) successively, after addition, the reaction was heated and stirred at 80 °C. TLC monitoring until the reaction was completed, the reaction was concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 10g. MS (ESI, [M+H] + m / z: 381.2.

[0403] Step H: Preparation of compound 10h

[0404] To a reaction flask was added compound 10g (0.28 g), dichloromethane (15 mL), triethylamine (0.22 g), di-tert-butyl dicarbonate (0.24 g) and 4-dimethylaminopyridine (0.005 g) successively, after addition, the reaction was carried out at room temperature, TLC monitoring until the reaction was completed, the reaction was concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give compound 10h. MS (ESI, [M+H] + m / z: 481.3.

[0405] Step I: Preparation of compound 10i

[0406] To a reaction flask was added compound 10h (0.23 g), (S)-l-Boc-3-aminopiperidine (0.12 g), tris(dibenzylideneacetone)dipalladium (0.04 g), 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (0.06 g), cesium carbonate (0.48 g) and toluene (12 mL) successively, after addition, the reaction was stirred at 110 °C under nitrogen protection. TLC monitoring until the reaction was completed, the reaction was filtered and concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 25 / 1) to give compound 10i. MS (ESI, [M+H] + m / z: 645.4.

[0407] Step J: Preparation of compound I-10

[0408] To a reaction vial was added compound 10i (0.21 g), dichloromethane (5 mL) and trifluoroacetic acid (1.53 g) successively, after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed, to the reaction liquid was added saturated aqueous sodium bicarbonate solution to adjust to alkaline (pH about 8), extracted with dichloromethane and water, dried, filtered, concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-10. HRMS (ESI, [M+H] + )m / z: 445.2456. 1 H NMR (500 MHz, DMSO-d6) δ 7.56 (s, 1H), 7.50 (d, J = 12.9 Hz, 2H), 7.37 (d, J = 9.5 Hz, 1H), 7.05 (d, J = 9.5 Hz, 1H), 6.46 (d, J = 7.7 Hz, 1H), 5.25 (s, 1H), 4.70 (t, J = 9.0 Hz, 2H), 4.55 (d, J = 5.9 Hz, 2H), 3.76 (s, 1H), 3.43 (t, J = 9.0 Hz, 2H), 3.04 (d, J = 11.8 Hz, 1H), 2.76 (d, J = 12.0 Hz, 1H), 2.43 (d, J = 10.9 Hz, 1H), 2.29 (d, J = 10.0 Hz, 1H), 1.84 (d, J = 12.2 Hz, 1H), 1.76 (q, J = 4.9 Hz, 1H), 1.59 (d, J = 12.4 Hz, 1H), 1.35 (dd, J = 40.7, 11.1 Hz, 2H), 0.75 (t, J = 7.5 Hz, 4H).

[0409] Example 11: Preparation of compound I-11

[0410] Step A: Preparation of compound 11a

[0411] To a reaction vial was added compound 2f (0.10 g), (S)-1-Boc-3-hydroxypiperidine (0.10 g), tris(dibenzylideneacetone)dipalladium (0.02 g), (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyl ditert-butylphosphine (0.03 g), cesium carbonate (0.19 g) and toluene (15 mL) successively, after addition, the reaction was stirred at 140 °C under nitrogen protection. TLC monitoring until the reaction was completed, the reaction liquid was filtered and concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 11a. MS (ESI, [M+H] + )m / z: 669.4.

[0412] Step B: Preparation of compound I-11

[0413] To a reaction flask was added compound 11a (0.08 g), dichloromethane (5 mL) and trifluoroacetic acid (0.29 g) successively. After addition, the reaction was stirred at room temperature. TLC monitoring was performed until the reaction was completed. The reaction solution was adjusted to basicity (pH about 8) by adding saturated aqueous sodium bicarbonate solution. Extraction was performed with dichloromethane and water. After drying, filtration and concentration, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-11. HRMS (ESI, [M+H] + )m / z: 469.2347. 1 H NMR (500 MHz, DMSO-d6) δ 8.54 (dd, J = 4.8, 1.6 Hz, 1H), 8.46 (t, J = 6.6 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 7.81 (s, 1H), 7.66 (dd, J = 7.6, 1.6 Hz, 1H), 7.32 (dd, J = 7.6, 4.9 Hz, 1H), 7.10 (dd, J = 7.9, 1.6 Hz, 1H), 6.97 (d, J = 1.6 Hz, 1H), 5.35 (s, 1H), 5.26 (s, 3H), 4.61 - 4.50 (m, 2H), 3.17 (dd, J = 12.7, 6.0 Hz, 1H), 3.03 - 2.95 (m, 2H), 2.57 - 2.51 (m, 1H), 1.94 (tt, J = 9.0, 4.2 Hz, 1H), 1.84 (tdd, J = 13.2, 9.5, 5.8 Hz, 3H), 1.71 - 1.59 (m, 1H), 1.25 (d, J = 7.3 Hz, 1H), 0.84 (dt, J = 8.2, 2.3 Hz, 2H), 0.81 (dt, J = 4.9, 2.4 Hz, 2H).

[0414] Example 12: Preparation of compound I-12

[0415] Step A: Preparation of compound 12a

[0416] To a reaction flask was added compound 1b (1.2 g), N,N-diisopropylethylamine (3.4 g), N,N-dimethylformamide (20 mL) and 5,7-dichloro-3-cyclopropylpyrazolo[l,5-a]pyrimidine (1.2 g) successively. After addition, the reaction was stirred at 75 °C. TLC monitoring was performed until the reaction was completed. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 12a. MS (ESI, [M+H] + )m / z: 417.1.

[0417] Step B: Preparation of compound 12b

[0418] To a reaction flask was added compound 12a (1.0 g), tetrahydrofuran (40 mL), di-tert-butyl dicarbonate (0.86 g), and 4-dimethylaminopyridine (0.16 g) sequentially. After addition, the reaction was stirred at room temperature until completion by TLC monitoring. The reaction was concentrated to give a residue, which was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give compound 12b. MS (ESI, [M+H] + )m / z: 517.1.

[0419] Step C: Preparation of compound 12c

[0420] To a reaction flask was added compound 12b (1.0 g), N,N-diisopropylethylamine (3.4 g), N,N-dimethylformamide (20 mL), and (S)-1-Boc-3-aminopiperidine (0.58 g) sequentially. After addition, the reaction was stirred at 100 °C until completion by TLC monitoring. The reaction was concentrated to give a residue, which was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 12c. MS (ESI, [M+H] + )m / z: 681.4.

[0421] Step D: Preparation of compound 12d

[0422] To a reaction flask was added compound 12c (0.1 g), dichloromethane (2 mL), acetic acid (4 mL), and potassium thiocyanate (0.43 g) sequentially at 0 °C. After addition, the reaction was stirred at room temperature until completion by TLC monitoring. The reaction was adjusted to basic (pH about 8) by adding saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane and water. After drying, filtration, and concentration, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 12d. MS (ESI, [M+H] + )m / z: 660.3.

[0423] Step E: Preparation of compound 12e

[0424] To a reaction flask was added compound 12d (0.23 g), N,N-dimethylformamide (5 mL), (trifluoromethyl)trimethylsilane (0.15 g), and cesium fluoride (0.16 g) sequentially. After addition, the reaction was stirred at room temperature until completion by TLC monitoring. The reaction was concentrated to give a residue, which was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 12e. MS (ESI, [M+H] + )m / z: 703.3.

[0425] Step F: Preparation of compound I-12

[0426] To a reaction vial was added compound 12e (0.12 g), dichloromethane (5 mL) and trifluoroacetic acid (0.29 g) successively, after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed, the reaction solution was adjusted to basic (pH about 8) with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane and water, dried, filtered, concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-12. HRMS (ESI, [M+H] + )m / z: 503.1958. 1 H NMR (500 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.36 (d, J = 9.1 Hz, 1H), 7.22 (d, J = 9.1 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 5.46 (s, 1H), 4.59 (d, J = 6.0 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H), 3.01 (d, J = 11.8 Hz, 1H), 2.93 (t, J = 7.4 Hz, 2H), 2.74 (d, J = 12.1 Hz, 1H), 2.42 (d, J = 10.8 Hz, 1H), 2.28 (t, J = 10.1 Hz, 1H), 2.21 (p, J = 7.5 Hz, 2H), 1.83 (s, 1H), 1.69 (s, 4H), 1.57 (s, 1H).

[0427] Example 13: Preparation of compound I-13

[0428] Step A: Preparation of compound 13a

[0429] To a reaction vial was added compound 2f (0.10 g), 2-amino-7-Boc-7-azaspiro[3.5]nonane (0.07 g), tris(dibenzylideneacetone)dipalladium (0.02 g), 1,1'-binaphthalene-2,2'-diphenylphosphine (0.03 g), cesium carbonate (0.13 g) and toluene (5 mL) successively, after addition, the reaction was stirred at 100 °C under nitrogen protection. TLC monitoring until the reaction was completed, the reaction solution was filtered, concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 13a. MS (ESI, [M+H] + )m / z: 708.1.

[0430] Step B: Preparation of compound I-13

[0431] To a reaction vial was added compound 13a (0.11 g), dichloromethane (5 mL) and trifluoroacetic acid (0.34 g) successively, after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed, saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust to alkaline (pH about 8), extracted with dichloromethane and water, dried, filtered, concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-13. HRMS (ESI, [M+H] + )m / z:508.2814. 1 H NMR (500 MHz, DMSO-d6) δ 8.54 (dd, J = 5.0, 1.6 Hz, 1H), 8.39 (s, 2H), 8.08 (d, J = 7.9 Hz, 1H), 7.65 (dd, J = 7.7, 1.6 Hz, 1H), 7.56 (s, 1H), 7.34 - 7.29 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 5.26 (s, 2H), 5.07 (s, 1H), 4.46 (d, J = 6.3 Hz, 2H), 4.24 (s, 1H), 3.02 (s, 2H), 2.92 (s, 2H), 2.31 - 2.23 (m, 2H), 1.75 (q, J = 8.3 Hz, 3H), 1.70 - 1.61 (m, 4H), 0.81 - 0.69 (m, 4H).

[0432] Example 14: Preparation of compound I-14

[0433] Step A: Preparation of compound 14a

[0434] To a reaction vial was added 2-amino-6-bromobenzothiazole (4 g), chloroacetaldehyde (35), ethanol (60 mL) successively, after addition, the reaction was stirred at 80 °C under nitrogen protection. TLC monitoring until the reaction was completed, the reaction solution was concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 14a. MS (ESI, [M+H] + )m / z:253.0.

[0435] Step B: Preparation of compound 14b

[0436] To a reaction vial was added compound 14a (1 g), tetrakis(triphenylphosphine)palladium (0.4 g), zinc cyanide (0.6 g) and N,N-dimethylacetamide (20 mL) successively, after addition, the reaction was stirred at 120 °C under nitrogen protection. TLC monitoring until the reaction was completed, the reaction solution was concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 14b. MS (ESI, [M+H] +m / z: 200.3.

[0437] Step C: Preparation of compound 14c

[0438] To the reaction flask were added compound 14b (0.6 g) and tetrahydrofuran (20 mL) successively, after addition, 1 M borane tetrahydrofuran solution (20 mL) was added slowly at 0 °C, the reaction was stirred at 70 °C. TLC monitoring until the reaction was completed, the reaction was concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to give compound 14c. MS (ESI, [M+H] + m / z: 204.3.

[0439] Step D: Preparation of compound 14d

[0440] To the reaction flask were added 5,7-dichloro-3-cyclopropylpyrazolo[l,5-a]pyrimidine (0.4 g), compound 14c (0.3 g), N,N-diisopropylethylamine (0.6 g) and N,N-dimethylformamide (15 mL) successively, after addition, the reaction was stirred at 80 °C. TLC monitoring until the reaction was completed, the reaction was concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 14d. MS (ESI, [M+H] + m / z: 395.2.

[0441] Step E: Preparation of compound 14e

[0442] To the reaction flask were added compound 14d (0.28 g), 4-dimethylaminopyridine (6 mg), dichloromethane (10 mL) and di-tert-butyl dicarbonate (0.2 g) successively, after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed, the reaction was concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 14e. MS (ESI, [M+H] + m / z: 495.3.

[0443] Step F: Preparation of compound 14f

[0444] To the reaction flask were added compound 14e (0.3 g), (S)-l-Boc-3-aminopiperidine (0.15 g), tris(dibenzylideneacetone)dipalladium (0.09 g), 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (0.09 g), cesium carbonate (0.6 g) and toluene (12 mL) successively, after addition, the reaction was stirred at 100 °C under nitrogen protection. TLC monitoring until the reaction was completed, the reaction was filtered, concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 14f. MS (ESI, [M+H] +m / z: 659.3.

[0445] Step G: Preparation of compound I-14

[0446] To a reaction vial was added compound 14f (0.13 g), dichloromethane (5 mL) and trifluoroacetic acid (1.00 g) successively, after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed, to the reaction liquid, saturated sodium bicarbonate aqueous solution was added to adjust to alkaline (pH about 10), extracted with dichloromethane and water, dried, filtered, concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-9. HRMS (ESI, [M+H] + m / z: 459.2079. 1 H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 2H), 8.25 (d, J = 1.5 Hz, 1H), 8.01 - 7.92 (m, 3H), 7.59 (s, 1H), 7.51 (dd, J = 8.4, 1.6 Hz, 1H), 7.33 (d, J = 1.5 Hz, 1H), 6.71 (d, J = 6.7 Hz, 1H), 5.14 (s, 1H), 4.57 (d, J = 6.4 Hz, 2H), 4.11 - 4.05 (m, 1H), 3.39 (dd, J = 12.1, 4.1 Hz, 1H), 3.17 - 3.11 (m, 1H), 2.89 - 2.83 (m, 1H), 2.75 (dd, J = 12.0, 9.5 Hz, 1H), 2.02 - 1.75 (m, 2H), 1.69 (td, J = 10.8, 5.3 Hz, 1H), 1.49 - 1.43 (m, 1H), 0.82 - 0.71 (m, 4H).

[0447] Example 15: Preparation of compound I-15

[0448] Step A: Preparation of compound 15a

[0449] To a reaction vial was added compound 2f (0.15 g), (S)-1-Boc-3-aminopyrrolidine (0.11 g), tris(dibenzylideneacetone)dipalladium (0.03 g), 1,1'-binaphthalene-2,2'-diphenylphosphine (0.04 g), cesium carbonate (0.19 g) and toluene (5 mL) successively, after addition, the reaction was stirred at 100 °C under nitrogen protection. TLC monitoring until the reaction was completed, the reaction liquid was filtered and concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 15a. MS (ESI, [M+H] + m / z: 654.4.

[0450] Step B: Preparation of compound 1-15

[0451] To a reaction vial was added compound 15a (0.14 g), dichloromethane (5 mL) and trifluoroacetic acid (0.50 g) successively, after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed, the reaction solution was adjusted to basicity (pH about 8) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane and water, dried, filtered, concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 1-15. HRMS (ESI, [M+H] + )m / z: 454.2339. 1 H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 2H), 8.54 (dd, J = 5.0, 1.6 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.00 (t, J = 6.5 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.31 (dd, J = 7.6, 4.9 Hz, 1H), 7.08 (dd, J = 8.0, 1.6 Hz, 1H), 6.94 (d, J = 3.8 Hz, 2H), 5.25 (s, 2H), 5.09 (s, 1H), 4.46 (d, J = 6.5 Hz, 2H), 4.38 (q, J = 5.9 Hz, 1H), 3.44 (dd, J = 11.8, 6.4 Hz, 1H), 3.25 - 3.18 (m, 1H), 3.08 (dd, J = 11.8, 4.7 Hz, 1H), 2.19 (dd, J = 13.6, 7.0 Hz, 1H), 1.87 (dt, J = 13.2, 6.5 Hz, 1H), 1.78 (td, J = 8.1, 4.1 Hz, 1H), 0.78 (dq, J = 11.4, 3.7 Hz, 4H).

[0452] Example 16: Preparation of compound 1-16

[0453] Step A: Preparation of compound 16a

[0454] To a reaction vial was added compound 2f (0.15 g), (S)-3-aminopiperidin-2-one hydrochloride (0.20 g), tris(dibenzylideneacetone)dipalladium (0.03 g), 1,1'-binaphthalene-2,2'-diphenylphosphine (0.04 g), cesium carbonate (0.25 g) and toluene (5 mL) successively, after addition, the reaction was stirred at 100 °C under nitrogen protection. TLC monitoring until the reaction was completed, the reaction solution was filtered and concentrated, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 16a. MS (ESI, [M+H] +m / z: 582.4.

[0455] Step B: Preparation of compound 1-16

[0456] Into a reaction vial was added compound 16a (0.12 g), dichloromethane (5 mL) and trifluoroacetic acid (0.50 g) successively. After addition, the reaction was stirred at room temperature. TLC monitoring was used to ensure the completion of the reaction. The reaction mixture was adjusted to basic (pH about 8) by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane and water. The organic layer was dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound 1-16. HRMS (ESI, [M+H] + m / z: 482.2329. 1 H NMR (500 MHz, DMSO-d6) δ 8.54 (dd, J = 5.0, 1.6 Hz, 1H), 8.45 (t, J = 6.5 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.87 (s, 1H), 7.65 (dd, J = 7.6, 1.6 Hz, 1H), 7.31 (dd, J = 7.6, 4.8 Hz, 1H), 7.10 (dd, J = 8.0, 1.6 Hz, 1H), 6.96 (d, J = 1.6 Hz, 1H), 6.65 (s, 1H), 5.25 (s, 2H), 4.55 (t, J = 4.9 Hz, 2H), 4.23 - 4.07 (m, 1H), 3.70 (dt, J = 12.3, 5.8 Hz, 1H), 3.43 (dd, J = 11.0, 6.6 Hz, 1H), 2.08 (dq, J = 12.2, 5.9 Hz, 1H), 2.04 - 1.75 (m, 5H), 1.54 (ddt, J = 12.7, 10.8, 7.7 Hz, 1H), 0.90 - 0.78 (m, 4H).

[0457] Example 17: Preparation of compound 1-17

[0458] Step A: Preparation of compound 17a

[0459] Into a reaction vial was added compound 12d (0.70 g), methanol (20 mL) and triphenylphosphine (0.28 g) successively. After addition, the reaction was heated to reflux under nitrogen protection. TLC monitoring was used to ensure the completion of the reaction. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 30 / 1) to give compound 17a. MS (ESI, [M+H] + m / z: 649.4.

[0460] Step B: Preparation of compound 1-17

[0461] To the reaction bottle was added compound 17a (0.10 g), dichloromethane (5 mL) and trifluoroacetic acid (0.29 g) successively, after addition, the reaction was stirred at room temperature. TLC monitoring until the reaction was completed, saturated aqueous sodium bicarbonate solution was added to the reaction liquid to adjust to alkaline (pH about 8), extracted with dichloromethane and water, dried, filtered, concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound I-17. HRMS (ESI, [M+H] + )m / z: 449.2223. 1 H NMR (500 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.64 (t, J = 6.1 Hz, 1H), 7.56 (s, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 9.1 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 5.36 (s, 1H), 4.58 (d, J = 6.0 Hz, 2H), 3.07 (t, J = 7.7 Hz, 2H), 3.04 - 2.99 (m, 1H), 2.93 (t, J = 7.3 Hz, 2H), 2.75 (d, J = 12.0 Hz, 1H), 2.41 (t, J = 10.7 Hz, 1H), 2.33 - 2.25 (m, 1H), 2.23 (d, J = 15.1 Hz, 5H), 1.88 - 1.80 (m, 1H), 1.65 - 1.55 (m, 1H), 1.46 - 1.28 (m, 3H), 1.24 (q, J = 4.0 Hz, 1H).

[0462] Experimental Example 1 In vitro CDK12 kinase inhibitory activity and antiproliferative activity

[0463] 1.1 A-673 cell proliferation inhibitory activity assay

[0464] Take well-grown A-673 cells, collect into centrifuge tubes, adjust the cell density to 1 × 10 5 6 / mL, inoculate on 96-well plates (100 μL / well), at the same time use nanoliter injectors for compound addition, so that the final concentration of the compound is 200 nM-0.091 nM (3-fold gradient dilution), 2 replicate wells for each concentration, and set controls. After continuing to culture in the cell incubator for 72 hours, add detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well), incubate in the cell incubator for 2 hours, then detect the absorbance at 450 nm by PerkinElmer Envision microplate reader, four-parameter analysis, fit the dose-effect curve, and calculate the IC 50 . The test results are shown in Table 1.

[0465] Table 1 A-673 cell proliferation inhibitory activity

[0466] 1.2 In vitro CDK12 kinase inhibition activity assay

[0467] CDK12 / CycK kinase solution (10 ng / μL) was added into the assay well at 5 μL per well, and different compounds dissolved in DMSO were added into the assay well by nanoliter injector to make the final concentration of the compounds 1000 nM-0.24 nM (2-fold gradient dilution), 2 replicates for each concentration, and controls were set. After incubation for 30 min, ATP (40 μM) and ULight-Myelin Basic Protein Peptide substrate (manufacturer: PerkinElmer, 0.2 μM) were mixed at 1:1, and 5 μL was added into the assay well; after reaction for 4 h at room temperature, 5 μL EDTA (40 mM) was added to terminate the reaction, and 5 μL Europium-anti-phospho-Myelin Basic Protein (manufacturer: PerkinElmer, 8 nM) was added, and incubation was performed for more than 1 h at room temperature; PerkinElmer Envision multifunctional microplate reader was used to detect the plate (excitation 320 nm, emission 665 nm / 620 nm), and four-parameter fitting was used to calculate IC50. 50 The test results are shown in Table 2.

[0468] Table 2 In vitro CDK12 kinase inhibition activity .

[0469] For purposes of description and disclosure, all patents, patent applications, and other publications identified herein are expressly incorporated herein by reference. Such publications are provided solely for their disclosure prior to the filing date of the present application. All statements as to the date or

[0470] Those skilled in the art will recognize that the scope of the present application is not limited to the various specific embodiments and examples described above, but that various modifications, substitutions, combinations or re-combinations of the various specific embodiments and examples can be made without departing from the spirit and scope of the present application, which is defined by the appended claims.

Claims

1. A compound represented by Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is a tricyclic ring, one ring of said tricyclic ring is phenyl, or 5-6 membered heteroaryl, and the remaining two rings are each independently selected from C 3-7 Cycloalkyl, C 3-7 Cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each ring of said ring A is independently optionally substituted with one or more R A substituents; X 1 and X 2 are each independently selected from N or C; X 3 and X 4 are each independently selected from O, S, C(R a ), N or -N(R b )-; Y 1 and Y 2 each independently is selected from C(R a ) or N; L 1 and L 2 each independently is selected from a single bond, -N(R b )-, -O-, -S-, -C(=O)-, -S(=O)-, or -S(=O)2-; R 1 selected from C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-12 membered heteroaryl, said C 3-10 cycloalkyl, C 3- 10 cycloalkenyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-12 membered heteroaryl are optionally independently substituted with one or more R c substituents; R 2 Selected from hydrogen, -OH, -CN, -NO2, -CHO, -COOH, halogens, -NH2, and optionally substituted with one or more R d The following groups are substituted: -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-C(O)-C 1-6 Alkyl, -C(O)NH(C) 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2、-NHC(O)-C 1-6 Alkyl, -N(C) 1-6 alkyl)-C(O)-C 1-6 Alkyl, -C(O)-OC 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-3-6-membered heterocyclic groups, -S(O)2-NH(C 1-6 Alkyl), -S(O)2-N(C 1-6 Alkyl)2、-C(O)-C 3-6 Cycloalkyl, -C(O)-3-6 membered heterocyclic group, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-SC 1-6 Alkyl, -C 1-6 Alkylene-NHC 1-6 Alkyl, -C 1-6 Alkylene-N(C) 1-6 Alkyl)2, -C 1-6 Alkylene-C 3-6 cycloalkyl, -C 1-6 Alkyl-3-6-membered heterocyclic groups, -NH-C 3-6 Cycloalkyl, -NH-3-6-membered heterocyclic group, -OC 3- 6-cycloalkyl, -O-3-6-membered heterocyclic group, -SC 3-6 Cycloalkyl, -S-3-6 membered heterocyclic groups, -C 6-12 Aryl, 5-12 heteroaryl, -C 1-6 Alkylene-C 6- 12 aryl, -C 1-6 alkylene-5-12 membered heteroaryl, -NH-C 6-12 aryl, -NH-5-12 membered heteroaryl, -O-C 6-12 aryl, -O-5-12 membered heteroaryl, -S-C 6-12 aryl, or -S-5-12 membered heteroaryl; Each R 3 R 3’ R 4 R 4’ Each is independently selected from hydrogen, deuterium, -OH, -CN, -CHO, -COOH, oxo, halogen, -NH2, or optionally substituted with one or more of deuterium, halogen, OH, NH2, CN. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2; Each R a Each is independently selected from hydrogen, -OH, -CN, -NO2, -CHO, -COOH, halogen, -NH2, and optionally influenced by one or more R. e The following groups are substituted: -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-SC 1-6 Alkyl, -C 1-6 Alkylene-NHC 1-6 Alkyl, -C 1-6 Alkylene-N(C) 1-6 Alkyl)2, -C 1-6 Alkylene-C 3-6 cycloalkyl, or -C 1-6 alkylene-3-6-membered heterocyclic groups; R b Selected from hydrogen, and optionally by one or more R h The following groups are substituted: -C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; R c and R A are each independently selected from deuterium, -OH, -CN, -NO2, -CHO, =0, -COOH, halogen, -NH2, and optionally substituted with one or more R f substituents: -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 1-6 alkylene-OC 1-6 alkyl, -C 1-6 alkylene-SC 1-6 alkyl, -C 1-6 alkylene-NHC 1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl)2, -C 1-6 alkylene-C 3-6 cycloalkyl, or -C 1-6 alkylene-3-6 membered heterocyclyl; R d , R e , and R f are each independently selected from deuterium, -OH, -CN, -NO2, -CHO, -COOH, oxo, halogen, -NH2, or -C 1-6 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2, CN; -OC 1-6 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2, CN; -SC 1-6 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2, CN; -NH(C 1-6 alkyl) optionally substituted with one or more of deuterium, halogen, OH, NH2, CN; -N(C 1-6 alkyl)2 optionally substituted with one or more of deuterium, halogen, OH, NH2, CN; m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, or 3; Optionally, said R 3 , R 3’ , R 4 , R 4’ , R A , R a , R b , R c , R d , R e or R f is substituted by one or more substituents.

2. The compound of formula (I), isomers thereof, or pharmaceutically acceptable salts thereof according to claim 1, wherein, Ring A is a tri-cyclic ring, one ring of said tri-cyclic ring is phenyl, or 5-6 membered heteroaryl, and the remaining two rings are each independently selected from C 3-7 Cycloalkyl, C 3-7 Cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each ring of said ring A is independently optionally substituted with one or more R A substituents; or, ring A is a tri-cyclic ring, two rings of said tri-cyclic ring are each independently selected from phenyl, or 5-6 membered heteroaryl, and the remaining ring is selected from C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each ring of said ring A is independently optionally substituted with 1 or more R A substituents; or, ring A is 5-6 membered heteroaryl and phenyl and C 5-6 cycloalkyl, C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and C 5-6 cycloalkenyl and C 5-6 cycloalkyl, C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and 5-6 membered heterocyclyl and C 5-6 cycloalkyl, C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or ring A is phenyl and 5-6 membered heteroaryl and C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; each of the three rings in the above described ring A is independently optionally substituted with 1 or more R A substituents; Alternatively, ring A is a tri-cyclic ring wherein the ring attached to the remainder of the compound of formula (I) is selected from furanyl, pyrrolyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, or triazolyl, the intermediate ring is selected from phenyl, pyrrolyl, pyrazolyl, thiazolyl, thienyl, furanyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, and the terminal ring is selected from phenyl, C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, or 5-6 membered heteroaryl, each of the three rings in ring A being independently optionally substituted with 1 or more R A substituents; Alternatively, ring A is a tri-cyclic ring wherein the ring attached to the remainder of the compound of Formula (I) is selected from phenyl, the middle ring is selected from dihydropyranyl, dihydrothiopyranyl, and the terminal ring is selected from 5-6 membered heteroaryl, each of the three rings in ring A is independently optionally substituted with 1 or more R A substituents; Alternatively, ring A is a tri-cyclic ring wherein the ring attached to the remainder of the compound of Formula (I) is selected from phenyl, the middle ring is selected from imidazolyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, and the terminal ring is selected from 5-6 membered heteroaryl, each of the three rings in said ring A being independently optionally substituted with 1 or more R A substituents; Alternatively, ring A is a tri-cyclic ring wherein the ring attached to the remainder of the compound of Formula (I) is selected from phenyl, the middle ring is selected from cyclopentenyl or cyclohexenyl, and the terminal ring is selected from 5-6 membered heteroaryl, each of the three rings in said ring A being independently optionally substituted with 1 or more R A substituents; Alternatively, ring A is a tri-cyclic ring wherein the ring attached to the remainder of the compound of Formula (I) is selected from pyrrolyl, pyrazolyl, imidazolyl, the intermediate ring is selected from pyrimidinyl, and the terminal ring is selected from C 5-6 Cycloalkenyl, 5-6 membered heterocyclyl, or 5-6 membered heteroaryl, each of the three rings in ring A is independently optionally substituted with 1 or more R A substituents.

3. The compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, Ring A is selected from the following structural elements wherein, Z 1 and Z 2 each independently is selected from absent, O, S, NH, N, CH, C, C=0, or CH2; Ring B is selected from C 4-6 cycloalkenyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, said C 4-6 cycloalkenyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, said C A substituted; R A selected from deuterium, -OH, -CN, -NO2, -CHO, -COOH, halogen, -NH2, and optionally substituted with one or more R f substituents selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 3- 6cycloalkyl, 3-6 membered heterocyclyl, -C 1-6 alkylene-OC 1-6 alkyl, -C 1-6 alkylene-SC 1-6 alkyl, -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- alkylene-N(C 1-6 alkyl)2, -C 1-6 alkylene-C 3-6 cycloalkyl, or -C 1-6 alkylene-3-6 membered heterocyclyl; p is selected from 0, 1, 2, or 3; Alternatively, ring A is selected from the following structural elements wherein, Q 1 is selected from NH, O, S or CH2; Ring B is a structural unit as above as defined in Alternatively, ring A is selected from the following structural elements wherein, are each independently selected from a single bond or a double bond; Q 2 and Q 3 are each independently selected from C, CH or N; Q 4 selected from CH2, N, S, CH or N(R g ); Ring B is a structural unit as above as defined in Preferably, ring B is selected from C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, said C 5-6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, said C A substituted; Alternatively, ring B is selected from said ring B is optionally independently substituted with one or more R A substituents; Alternatively, ring B is selected from said ring B is optionally independently substituted with one or more R A substituents; Alternatively, ring B is selected from 4. The compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein, R A selected from deuterium, -OH, -CN, halogen, -NH2, and optionally substituted with one or more R f substituted -C 1-6 alkyl, -OC 1-6 alkyl, -NH(C 1-6 alkyl), C 3-6 cycloalkyl or 3-6 membered heterocyclyl; or R is selected from the group consisting of deuterium, halogen, and optionally substituted -C A alkyl, -OC f alkyl, -OC 1-3 alkyl, -OC 1-3 alkyl, -OC 1-3 alkyl, -OC or R A is selected from halogen, -CN, and -C f substituted -C 1-3 alkyl; Or, R A Selected from halogens, -CN, and -C optionally substituted with one or more -OH groups. 1-3 alkyl; or R is selected from halo, or -C A selected from halo, or -C 1-3 alkyl.

5. The compound of formula (I) according to claim 3, an isomer thereof, or a pharmaceutically acceptable salt thereof, the structural unit selected from or the structural unit selected from Structural unit selected from the group consisting of or a structural unit selected from the group consisting of Structural unit selected from the group consisting of or structural units selected from the group consisting of Structural unit selected from the group consisting of or structural units selected from the group consisting of Structural unit selected from the group consisting of or structural units selected from the group consisting of Structural unit selected from the group consisting of or structural units selected from the group consisting of 6. The compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-5, wherein ring A is selected from Alternatively, ring A is selected from Alternatively, ring A is selected from 7. The compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-6, wherein, X 1 , X 2 one of X 3 and X 4 are each independently selected from C(R a ) or N; Y 1 and Y 2 one of Y or X 1 selected from N, X 2 selected from C; X 3 selected from C(R a ), X 4 selected from N; Y 1 selected from C(R a ), Y 2 selected from N; or X is selected from N, CH, and CR 1 Y is selected from N, CH, and CR 2 X is selected from C; and R 3 Y is selected from CH, and CR 4 Y is selected from N; and R 1 X is selected from C(R a ), and Y 2 Y is selected from N.

8. The compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein, L 1 and L 2 are each independently selected from a single bond, -N(R b )-, -O- or -S-; or L 1 and L 2 each independently is selected from a single bond or -N(R b )-; or L 1 and L 2 each independently is selected from -N(R b )-, and n is 1.

9. The compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-8, wherein, R 1 selected from C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, 8-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl, 8-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl are optionally independently substituted with 1 or more R c substituents; or R 1 selected from C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, said C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, optionally independently substituted with one or more R c substituents; or R is selected from the group consisting of piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, pyrrolidinyl or 1 or R is selected from the group consisting of piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, pyrrolidinyl or said piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, pyrrolidinyl or optionally independently substituted by one or more R c substituents; or R 1 selected from The optionally independently substituted by one or more R c substituted.

10. The compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-9, wherein, R 2 selected from the following groups: -C d alkyl, -OC 1-3 alkyl, -SC 1-3 alkyl, -C(O)-C 1-3 alkyl, -S(O)-C 1-3 alkyl, -S(O)2-C 1-3 alkyl, -S(O)2-C 1-3 alkyl, -S(O)2-C 3-6 cycloalkyl, -S(O)2-3-6 membered heterocyclyl, -C(O)-C 3-6 cycloalkyl, -C(O)-3-6 membered heterocyclyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -O-C 3-6 cycloalkyl, -O-3-6 membered heterocyclyl, -S-C 3-6 cycloalkyl, or -S-3-6 membered heterocyclyl; Or, R 2 Selected from one or more R d The following groups are substituted: cyclopropyl, cyclobutyl, aziridine, oxadiazine, thioheterobutyl, -SCH3 or -SCH2CH3; or R 2 is selected from cyclopropyl.

11. The compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-10, wherein, each R is independently selected from hydrogen, deuterium, -OH, oxo, halogen, -NH2, or -C 3 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2, CN; 3’ alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2, CN; 4 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2, CN; 4’ alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2, CN; 1-3 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2, CN; or each R is independently selected from hydrogen or deuterium; 3 , R is independently selected from hydrogen or deuterium; 3’ , R is independently selected from hydrogen or deuterium; 4 , R is independently selected from hydrogen or deuterium; 4’ each R is independently selected from hydrogen or deuterium; and / or R d , R e , and R f are each independently selected from deuterium, -OH, -CN, halogen, -NH2, or -C 1-3 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2, CN; or -OC 1-3 alkyl; or R d , R e , and R f are each independently selected from deuterium, -OH, or halogen.

12. The compound of Formula (I), isomers thereof, or pharmaceutically acceptable salts thereof, according to any one of claims 1-11, selected from a compound of Formula (II-a), isomers thereof, or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 3’ , R 4 , R 4’ , L 1 , L 2 , m, n and ring A are as defined in any one of claims 1-11; or a compound selected from the group consisting of a compound of Formula (II-b), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , L 1 , L 2 and ring A are as defined in any one of claims 1 to 11 ; or a compound selected from the group consisting of a compound of Formula (II-c), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and ring A are as defined in any one of claims 1 to 11 ; or a compound selected from the group consisting of a compound of Formula (II-c1), a compound of Formula (II-c2), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , ring B, R A , Z 1 , Z 2 and p are as defined in any one of claims 1-11; or a compound selected from a compound of Formula (II-c1-a), a compound of Formula (II-c1-b), a compound of Formula (II-c2-a), a compound of Formula (II-c2-b), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 , ring B, R A , Z 1 , Z 2 and p are as defined in any one of claims 1-11; or a compound selected from the group consisting of a compound of Formula (II-c1-a1), a compound of Formula (II-c1-b1), a compound of Formula (II-c2-a1), a compound of Formula (II-c1-b1), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 , ring B, R A , Z 1 , Z 2 and p are as defined in any one of claims 1-11.

13. The following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof: or a stereoisomer or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound of any one of claims 1-13, an isomer thereof, or a pharmaceutically acceptable salt thereof.

15. The compound, isomer, or pharmaceutically acceptable salt thereof of any one of claims 1-13, or the pharmaceutical composition of claim 14, for use in the treatment or prevention of a disease, wherein, The disease is selected from a CDK12-mediated disease.

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