Pyrazole substituted cyclopentyl ester derivative and application thereof

Abstract

The invention relates to a pyrazole substituted cyclopentyl ester derivative and application thereof, in particular to a compound as shown in a formula (I), and an isomer or pharmaceutically acceptable salt of the compound. # imgabs0 #

Description

[0001] This application is a divisional application of an application with an application date of April 27, 2023, an application number of 202380036025.4, and an invention title of "A Pyrazole-Substituted Cyclopentyl Ester Derivative and Its Use".

[0002] Cross-reference to Related Applications

[0003] This application claims the priority and benefits of Chinese Patent Application No. 202210469621.9 filed with the China National Intellectual Property Administration on April 28, 2022, the priority and benefits of Chinese Patent Application No. 202210836180.1 filed with the China National Intellectual Property Administration on July 15, 2022, the priority and benefits of Chinese Patent Application No. 202210999975.4 filed with the China National Intellectual Property Administration on August 19, 2022, the priority and benefits of Chinese Patent Application No. 202211603669.0 filed with the China National Intellectual Property Administration on December 13, 2022, the priority and benefits of Chinese Patent Application No. 202310250462.8 filed with the China National Intellectual Property Administration on March 15, 2023, and the priority and benefits of Chinese Patent Application No. 202310411874.5 filed with the China National Intellectual Property Administration on April 17, 2023. The disclosures of the said applications are incorporated herein by reference in their entirety. Technical Field

[0004] This application relates to a pyrazole-substituted cyclopentyl ester derivative and its use, and particularly relates to a compound represented by formula (I), its isomers or its pharmaceutically acceptable salts. Background Art

[0005] Cyclin-dependent kinases (CDKs) belong to the serine / threonine protein kinase family and are directly involved in the regulation of the cell cycle, promoting the orderly growth, proliferation, and apoptosis of cells. The cell division cycle is divided into four phases: G1 phase, S phase, G2 phase, and M phase, among which the G1-S checkpoint is the most important, and its regulation is closely related to CDKs. CDKs form a protein kinase complex by binding to cyclins. This complex can catalyze the phosphorylation of substrates, control the cell cycle process, and sequentially complete DNA replication and mitosis, causing cell division and proliferation. The cell division cycle is regulated by two factors: inhibition and promotion. Under normal circumstances, the two are in a dynamic balance. However, when the signal promoting cell proliferation is enhanced, or the signal inhibiting cell proliferation is weakened, the balance will be broken, and cell proliferation will get out of control, leading to the occurrence of tumors. Research shows that the overexpression of CDKs exists in many malignant tumors.

[0006] Studies have shown that the CDKs directly involved in cell cycle regulation mainly include CDK1, CDK2, CDK4, and CDK6, which play a key role in regulating the cell cycle. CDK2 belongs to the CDK family. It is a cell cycle-dependent kinase crucial for the completion of the G1 phase and the entry from the G1 phase to the S phase during cell mitosis. In the late G1 phase, CDK2 binds to and activates Cyclin E, promoting the continuous phosphorylation of pRb, ensuring that the cell smoothly passes through the G1 phase and enters the S phase. The inactivation of E2F is the primary condition for the completion of the S phase. At the beginning of the S phase, CDK2 binds to Cyclin A to inactivate the E2F transcription factor, thereby promoting the smooth completion of the S phase by the cell. However, the continuous activity of E2F will lead to apoptosis. Therefore, selectively inhibiting the activity of CDK2 / Cylin A, increasing the concentration of E2F, and then causing the cell cycle to arrest in the S phase or undergo apoptosis, thereby achieving the purpose of treating tumor cells. Summary of the Invention

[0007] This application provides a compound represented by formula (I), its isomers, or its pharmaceutically acceptable salts,

[0008]

[0009] wherein,

[0010] Ring A is selected from C 3-10 alkane ring, 5-10 membered heteroalkane ring, benzene ring, naphthalene ring, benzene ring fused to C 5-6 alkane ring, benzene ring fused to 5-6 membered heteroalkane ring, 5-10 membered heteroaromatic ring, 5-6 membered heteroaromatic ring fused to C 5-6 alkane ring or 5-6 membered heteroaromatic ring fused to 5-6 membered heteroalkane ring, and the C 3-10 alkane ring, 5-10 membered heteroalkane ring, benzene ring, naphthalene ring, benzene ring fused to C 5-6 alkane ring, benzene ring fused to 5-6 membered heteroalkane ring, 5-10 membered heteroaromatic ring, 5-6 membered heteroaromatic ring fused to C 5-6 alkane ring or 5-6 membered heteroaromatic ring fused to 5-6 membered heteroalkane ring is optionally independently substituted by one or more R a substituents;

[0011] L 1 and L 2 each independently selected from a single bond, -N(R b )-, -N=, -O-, -S-, -(CH2) m -, -(CD2) m -, -(CHD) m -, -C(=O)-, -S(=O)-, -S(=O)2-, -S(=O)(=N(R b ))-, -S(=O)(R c )-, -P(=O)(R c)-or -P(=O)(NR b R b )-;

[0012] R 1 is selected from H, deuterium, C 1-3 alkyl, C 1-3 alkoxy, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, C 3-6 cycloalkyl, 3-6 membered heteroalkyl, phenyl or 5-6 membered heteroaryl, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R d substituents, and the C 3-6 cycloalkyl, 3-6 membered heteroalkyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted by one or more R e substituents;

[0013] R 2 , R 3 and R 4 are each independently selected from H, deuterium, halogen, OH, CN, NH2, C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by one or more R z substituents;

[0014] or R 2 and R 3 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heteroalkyl, and R 4 is selected from H, deuterium, halogen, OH, CN, NH2, C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 3-6 membered heteroalkyl is optionally independently substituted by one or more R z substituents;

[0015] Each R a is independently selected from deuterium, halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by one or more R x substituents;

[0016] Each R bEach independently selected from H, C 1-3 alkyl, C 1-3 alkoxy, -C(=O)H, -S(=O)2C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x substituents; said C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1 or more R y substituents;

[0017] R c is selected from halogen, OH, CN or C 1-3 alkyl, said C 1-3 alkyl is optionally independently substituted by 1 or more R x substituents;

[0018] Each R d is independently selected from deuterium, halogen, OH, CN or NH2;

[0019] Each R e is independently selected from deuterium, halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, said C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1 or more R x substituents;

[0020] Each R x is independently selected from deuterium, halogen, OH, CN or NH2;

[0021] Each R y is independently selected from deuterium, halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, said C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1 or more substituents selected from deuterium, halogen, OH, CN or NH2;

[0022] Each R z is independently selected from deuterium, halogen, OH, CN or NH2;

[0023] m is selected from 1, 2 or 3;

[0024] The carbon atom with "*" is a chiral carbon atom and exists in the form of a single (R) or (S) enantiomer or an enantiomer-rich form;

[0025] Alternatively, each L 1 、L 2 、R 1 、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e 、R x 、R y or R z is independently and optionally substituted with one or more substituents.

[0026] In some embodiments of the present application, each R a 、R b 、R c 、R d 、R e 、R x 、R y or R z is independently and optionally substituted with one or more substituents.

[0027] In some embodiments of the present application, each R d 、R x 、R y or R z is independently and optionally substituted with one or more substituents.

[0028] In some other embodiments of the present application, the R 1 、R 2 、R 3 、R 4 、R a 、R d 、R e 、R x 、R y or R z is independently and optionally substituted with one or more deuteriums.

[0029] In some other embodiments of the present application, the R 1 、R 2 、R 3 、R 4 、R a 、R d 、R e 、R x 、R y or R z is independently and optionally substituted with 1, 2, 3, 4 or 5 deuteriums; or is independently and optionally substituted with 3 or 5 deuteriums.

[0030] In some embodiments of the present application, the R 1 , R 2 , R 3 , R 4 , R a , R d , R e , R x , R y and R z at least one of which is a deuterium atom-containing group.

[0031] In some embodiments of the present application, the "substituted by one or more" are each independently selected from being substituted by 1, 2, 3, 4, 5 or 6.

[0032] In some embodiments of the present application, the "substituted by one or more" are each independently selected from being substituted by 1, 2, 3, 4 or 5.

[0033] In some embodiments of the present application, the "substituted by one or more" are each independently selected from being substituted by 1, 2, 3 or 4.

[0034] In some embodiments of the present application, the "substituted by one or more" are each independently selected from being substituted by 1, 2 or 3.

[0035] In some embodiments of the present application, the "hetero" mentioned in ring A are each independently selected from heteroatoms of oxygen, sulfur and nitrogen, wherein the nitrogen atom is optionally quaternized or oxidized to N(O), the sulfur atom is optionally oxidized to S(O) or S(O)2, and other variables are as defined in the present application.

[0036] In some embodiments of the present application, the "hetero" mentioned in ring A are each independently selected from heteroatoms of oxygen, sulfur and nitrogen, wherein the sulfur heteroatom is optionally oxidized to S(O) or S(O)2, and other variables are as defined in the present application.

[0037] In some embodiments of the present application, ring A is selected from C 3-6 alkane ring, 5-6 membered heteroalkane ring, benzene ring, naphthalene ring, benzene ring-fused C 5-6 alkane ring, benzene ring-fused 5-6 membered heteroalkane ring, 5-10 membered heteroaromatic ring, 5-6 membered heteroaromatic ring-fused C 5-6 alkane ring or 5-6 membered heteroaromatic ring-fused 5-6 membered heteroalkane ring, the C 3-6 alkane ring, 5-6 membered heteroalkane ring, benzene ring, naphthalene ring, benzene ring-fused C 5-6 alkane ring, benzene ring-fused 5-6 membered heteroalkane ring, 5-10 membered heteroaromatic ring, 5-6 membered heteroaromatic ring-fused C 5-6 alkane ring or 5-6 membered heteroaromatic ring-fused 5-6 membered heteroalkane ring is optionally independently substituted by 1, 2, 3 or 4 R a substituents, and other variables are as defined in the present application.

[0038] In some embodiments of the present application, ring A is selected from a C 3-6 alkane ring, a 5- or 6-membered heteroalkane ring, a benzene ring, a naphthalene ring, a benzo-fused C 5-6 alkane ring, a benzo-fused 5- or 6-membered heteroalkane ring, a 5- or 6-membered heteroaromatic ring, a 5- or 6-membered heteroaromatic ring-fused C 5-6 alkane ring, or a 5- or 6-membered heteroaromatic ring-fused 5- or 6-membered heteroalkane ring, and the C 3-6 alkane ring, 5- or 6-membered heteroalkane ring, benzene ring, naphthalene ring, benzo-fused C 5-6 alkane ring, benzo-fused 5- or 6-membered heteroalkane ring, 5- or 6-membered heteroaromatic ring, 5- or 6-membered heteroaromatic ring-fused C 5-6 alkane ring, or 5- or 6-membered heteroaromatic ring-fused 5- or 6-membered heteroalkane ring is optionally independently substituted with 1, 2, or 3 R a groups, and other variables are as defined in the present application.

[0039] In some embodiments of the present application, ring A is selected from a 5- or 6-membered heteroalkane ring, a benzene ring, a benzo-fused 5- or 6-membered heteroalkane ring, a 5- or 6-membered heteroaromatic ring, or a 5- or 6-membered heteroaromatic ring-fused 5- or 6-membered heteroalkane ring, and the 5- or 6-membered heteroalkane ring, benzene ring, benzo-fused 5- or 6-membered heteroalkane ring, 5- or 6-membered heteroaromatic ring, or 5- or 6-membered heteroaromatic ring-fused 5- or 6-membered heteroalkane ring is optionally independently substituted with 1, 2, or 3 R a groups, and other variables are as defined in the present application.

[0040] In some embodiments of the present application, ring A is selected from a 6-membered heteroalkane ring, a benzene ring, a benzo-fused 5-membered heteroalkane ring, a 5- or 6-membered heteroaromatic ring, or a 6-membered heteroaromatic ring-fused 5- or 6-membered heteroalkane ring, and the 6-membered heteroalkane ring, benzene ring, benzo-fused 5-membered heteroalkane ring, 5- or 6-membered heteroaromatic ring, or 6-membered heteroaromatic ring-fused 5- or 6-membered heteroalkane ring is optionally independently substituted with 1, 2, or 3 R a groups, and other variables are as defined in the present application.

[0041] In some embodiments of the present application, ring A is selected from a 6-membered heteroalkane ring, a benzene ring, a benzo-fused 5-membered heteroalkane ring, a 5- to 9-membered heteroaromatic ring, or a 6-membered heteroaromatic ring-fused 5- or 6-membered heteroalkane ring, and the 6-membered heteroalkane ring, benzene ring, benzo-fused 5-membered heteroalkane ring, 5- to 9-membered heteroaromatic ring, or 6-membered heteroaromatic ring-fused 5- or 6-membered heteroalkane ring is optionally independently substituted with 1, 2, or 3 R a groups, and other variables are as defined in the present application.

[0042] In still some other embodiments of the present application, ring A is selected from a 6-membered heteroalkane ring, a benzene ring, a benzo-fused 5-membered heteroalkane ring, or a 6-membered heteroaromatic ring-fused 5- or 6-membered heteroalkane ring, and the 6-membered heteroalkane ring, benzene ring, benzo-fused 5-membered heteroalkane ring, or 6-membered heteroaromatic ring-fused 5- or 6-membered heteroalkane ring is optionally independently substituted with 1, 2, or 3 R a groups, and other variables are as defined in the present application.

[0043] In some embodiments of the present application, the 5- to 10-membered heteroaryl ring or 5- to 9-membered heteroaryl ring in the definition of ring A contains only 1 or 2 N atoms in the ring atoms, and other variables are as defined in the present application.

[0044] In some other embodiments of the present application, the 5- to 10-membered heteroaryl ring or 5- to 9-membered heteroaryl ring in the definition of ring A contains only 1 N atom in the ring atoms, and other variables are as defined in the present application.

[0045] In some embodiments of the present application, the 5- to 10-membered heteroaryl ring or 5- to 9-membered heteroaryl ring in the definition of ring A is selected from a 5-membered heteroaryl ring or a 6-membered heteroaryl ring, and other variables are as defined in the present application.

[0046] In some other embodiments of the present application, the 5-membered heteroaryl ring or 6-membered heteroaryl ring in the definition of ring A contains only 1 N atom in the ring atoms, and other variables are as defined in the present application.

[0047] In some embodiments of the present application, ring A is selected from a 6-membered heteroalkane ring, a benzene ring, a benzene ring fused to a 5-membered heteroalkane ring, a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 9-membered heteroaryl ring, a 6-membered heteroaryl ring fused to a 5-membered heteroalkane ring, or a 6-membered heteroaryl ring fused to a 6-membered heteroalkane ring. The 6-membered heteroalkane ring, benzene ring, benzene ring fused to a 5-membered heteroalkane ring, 5-membered heteroaryl ring, 6-membered heteroaryl ring, 9-membered heteroaryl ring, 6-membered heteroaryl ring fused to a 5-membered heteroalkane ring, or 6-membered heteroaryl ring fused to a 6-membered heteroalkane ring is optionally and independently substituted by 1, 2, or 3 R a substituents, and other variables are as defined in the present application.

[0048] In some embodiments of the present application, ring A is selected from a 6-membered heteroalkane ring, a benzene ring, a benzene ring fused to a 5-membered heteroalkane ring, a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 6-membered heteroaryl ring fused to a 5-membered heteroalkane ring, or a 6-membered heteroaryl ring fused to a 6-membered heteroalkane ring. The 6-membered heteroalkane ring, benzene ring, benzene ring fused to a 5-membered heteroalkane ring, 5-membered heteroaryl ring, 6-membered heteroaryl ring, 6-membered heteroaryl ring fused to a 5-membered heteroalkane ring, or 6-membered heteroaryl ring fused to a 6-membered heteroalkane ring is optionally and independently substituted by 1, 2, or 3 R a substituents, and other variables are as defined in the present application.

[0049] In some further embodiments of the present application, ring A is selected from a 6-membered heteroalkane ring, a benzene ring, a benzene ring fused to a 5-membered heteroalkane ring, a 6-membered heteroaryl ring fused to a 5-membered heteroalkane ring, or a 6-membered heteroaryl ring fused to a 6-membered heteroalkane ring. The 6-membered heteroalkane ring, benzene ring, benzene ring fused to a 5-membered heteroalkane ring, 6-membered heteroaryl ring fused to a 5-membered heteroalkane ring, or 6-membered heteroaryl ring fused to a 6-membered heteroalkane ring is optionally and independently substituted by 1, 2, or 3 R a substituents, and other variables are as defined in the present application.

[0050] In some other embodiments of the present application, ring A is selected from a benzene ring fused to a 5-membered heteroalkane ring, a 6-membered heteroaromatic ring fused to a 5-membered heteroalkane ring, or a 6-membered heteroaromatic ring fused to a 6-membered heteroalkane ring, and the benzene ring fused to a 5-membered heteroalkane ring, the 6-membered heteroaromatic ring fused to a 5-membered heteroalkane ring, or the 6-membered heteroaromatic ring fused to a 6-membered heteroalkane ring is optionally independently substituted with 1, 2, or 3 R a substituents, and the "hetero" in the 5-membered heteroalkane ring or 6-membered heteroalkane ring is independently selected from heteroatoms of oxygen, sulfur, and nitrogen, wherein the nitrogen atom is optionally quaternized or oxidized to N(O), the sulfur atom is optionally oxidized to S(O) or S(O)2, and other variables are as defined in the present application.

[0051] In some other embodiments of the present application, ring A is selected from a 6-membered heteroalkane ring containing 1-3 N atoms, a benzene ring, a benzene ring fused to a 5-membered heteroalkane ring containing 1-3 N atoms, a 5-membered heteroaromatic ring containing 1-3 N atoms, a 6-membered heteroaromatic ring having only 1 N atom, a 6-membered heteroaromatic ring containing 1-3 N atoms fused to a 5-membered heteroalkane ring containing 1-3 N atoms, or a 6-membered heteroaromatic ring containing 1-3 N atoms fused to a 6-membered heteroalkane ring containing 1-3 N atoms, and the 6-membered heteroalkane ring containing 1-3 N atoms, the benzene ring, the benzene ring fused to a 5-membered heteroalkane ring containing 1-3 N atoms, the 5-membered heteroaromatic ring containing 1-3 N atoms, the 6-membered heteroaromatic ring having only 1 N atom, the 6-membered heteroaromatic ring containing 1-3 N atoms fused to a 5-membered heteroalkane ring containing 1-3 N atoms, or the 6-membered heteroaromatic ring containing 1-3 N atoms fused to a 6-membered heteroalkane ring containing 1-3 N atoms is optionally independently substituted with 1, 2, or 3 R a substituents, and other variables are as defined in the present application.

[0052] In some embodiments of the present application, ring A is selected from a 6-membered heteroalkane ring containing 1-3 N atoms, a benzene ring, a benzene ring fused to a 5-membered heteroalkane ring containing 1-3 N atoms, a 5-membered heteroaromatic ring containing 1-3 N atoms, a 6-membered heteroaromatic ring containing 1-3 N atoms, a 9-membered heteroaromatic ring containing 1-3 N atoms, a 6-membered heteroaromatic ring containing 1-3 N atoms fused to a 5-membered heteroalkane ring containing 1-3 N atoms, or a 6-membered heteroaromatic ring containing 1-3 N atoms fused to a 6-membered heteroalkane ring containing 1-3 N atoms, and the 6-membered heteroalkane ring containing 1-3 N atoms, the benzene ring, the benzene ring fused to a 5-membered heteroalkane ring containing 1-3 N atoms, the 5-membered heteroaromatic ring containing 1-3 N atoms, the 6-membered heteroaromatic ring containing 1-3 N atoms, the 9-membered heteroaromatic ring containing 1-3 N atoms, the 6-membered heteroaromatic ring containing 1-3 N atoms fused to a 5-membered heteroalkane ring containing 1-3 N atoms, or the 6-membered heteroaromatic ring containing 1-3 N atoms fused to a 6-membered heteroalkane ring containing 1-3 N atoms is optionally independently substituted with 1, 2, or 3 R a substituents, and other variables are as defined in the present application.

[0053] In some embodiments of the present application, the ring A is selected from a 6-membered heteroalkyl ring containing 1 or 2 N atoms, a benzene ring, a 5-membered heteroalkyl ring containing 1 or 2 N atoms, a 5-membered heteroaromatic ring containing 1 or 2 N atoms, a 6-membered heteroaromatic ring containing 1 or 2 N atoms, a 5-membered heteroalkyl ring containing 1 or 2 N atoms, or a 6-membered heteroaromatic ring containing 1 or 2 N atoms and a 6-membered heteroalkyl ring containing 1 or 2 N atoms. alkyl ring, the 6-membered heteroalkyl ring containing 1 or 2 N atoms, the benzene ring, the 5-membered heteroalkyl ring containing 1 or 2 N atoms, the 5-membered heteroaromatic ring containing 1 or 2 N atoms, the 6-membered heteroaromatic ring containing 1 or 2 N atoms, the 5-membered heteroalkyl ring containing 1 or 2 N atoms, the 6-membered heteroaromatic ring containing 1 or 2 N atoms and 1 or 2 N atoms, or the 6-membered heteroaromatic ring containing 1 or 2 N atoms and 1 or 2 N atoms The 6-membered heteroalkyl ring is optionally independently substituted by 1, 2 or 3 R a Substitution, other variables are as defined in this application.

[0054] In some embodiments of the present application, the ring A is selected from a 6-membered heteroalkyl ring containing 1 N atom, a benzene ring, a 5-membered heteroalkyl ring containing 1 N atom, a 5-membered heteroaryl ring containing 1 or 2 N atoms, a 6-membered heteroaryl ring containing 1 N atom, a 5-membered heteroalkyl ring containing 1 N atom, or a 6-membered heteroaryl ring containing 1 N atom and a 6-membered heteroalkyl ring containing 1 N atom, wherein the 6-membered heteroalkyl ring containing 1 N atom, the benzene ring, the 5-membered heteroalkyl ring containing 1 N atom, the 5-membered heteroaryl ring containing 1 or 2 N atoms, the 6-membered heteroaryl ring containing 1 N atom, the 6-membered heteroalkyl ring containing 1 N atom, the 5-membered heteroaryl ring containing 1 or 2 N atoms, the 6-membered heteroaryl ring containing 1 N atom, the 5-membered heteroalkyl ring containing 1 N atom, or the 6-membered heteroaryl ring containing 1 N atom and a 6-membered heteroalkyl ring containing 1 N atom are optionally independently substituted by 1, 2 or 3 R a Substitution, other variables are as defined in this application.

[0055] In other embodiments of the present application, the ring A is selected from a 6-membered heteroalkyl ring containing 1 N atom, a benzene ring, a 5-membered heteroalkyl ring containing 1 N atom, a 5-membered heteroaryl ring containing 1 or 2 N atoms, a 6-membered heteroaryl ring with only 1 N atom, a 6-membered heteroaryl ring containing 1 N atom and a 5-membered heteroalkyl ring containing 1 N atom, or a 6-membered heteroaryl ring containing 1 N atom and a 6-membered heteroalkyl ring containing 1 N atom, wherein the 6-membered heteroalkyl ring containing 1 N atom, the benzene ring, the 5-membered heteroalkyl ring containing 1 N atom, the 5-membered heteroaryl ring containing 1 or 2 N atoms, the 6-membered heteroaryl ring with only 1 N atom, the 6-membered heteroaryl ring containing 1 N atom and a 5-membered heteroalkyl ring containing 1 N atom, or the 6-membered heteroaryl ring containing 1 N atom and a 6-membered heteroalkyl ring containing 1 N atom are optionally independently substituted by 1, 2 or 3 R a Substitution, other variables are as defined in this application.

[0056] In some embodiments of the present application, ring A is selected from a 6-membered heteroalkane ring containing 1 N atom, a benzene ring, a benzene ring fused to a 5-membered heteroalkane ring containing 1 N atom, a 5-membered heteroaromatic ring containing 1 or 2 N atoms, a 6-membered heteroaromatic ring containing 1 or 2 N atoms, a 6-membered heteroaromatic ring containing 1 N atom fused to a 5-membered heteroalkane ring containing 1 N atom, or a 6-membered heteroaromatic ring containing 1 N atom fused to a 6-membered heteroalkane ring containing 1 N atom. The 6-membered heteroalkane ring containing 1 N atom, the benzene ring, the benzene ring fused to a 5-membered heteroalkane ring containing 1 N atom, the 5-membered heteroaromatic ring containing 1 or 2 N atoms, the 6-membered heteroaromatic ring containing 1 or 2 N atoms, the 6-membered heteroaromatic ring containing 1 N atom fused to a 5-membered heteroalkane ring containing 1 N atom, or the 6-membered heteroaromatic ring containing 1 N atom fused to a 6-membered heteroalkane ring containing 1 N atom is optionally and independently substituted with 1, 2, or 3 R a substituents, and other variables are as defined in the present application.

[0057] In still other embodiments of the present application, ring A is selected from a 6-membered heteroalkane ring containing 1 N atom, a benzene ring, a benzene ring fused to a 5-membered heteroalkane ring containing 1 N atom, a 6-membered heteroaromatic ring containing 1 N atom fused to a 5-membered heteroalkane ring containing 1 N atom, or a 6-membered heteroaromatic ring containing 1 N atom fused to a 6-membered heteroalkane ring containing 1 N atom. The 6-membered heteroalkane ring containing 1 N atom, the benzene ring, the benzene ring fused to a 5-membered heteroalkane ring containing 1 N atom, the 6-membered heteroaromatic ring containing 1 N atom fused to a 5-membered heteroalkane ring containing 1 N atom, or the 6-membered heteroaromatic ring containing 1 N atom fused to a 6-membered heteroalkane ring containing 1 N atom is optionally and independently substituted with 1, 2, or 3 R a substituents, and other variables are as defined in the present application.

[0058] In some embodiments of the present application, ring A is selected from pyrrolidine ring, pyrazolidine ring, imidazolidine ring, tetrahydrothiophene ring, tetrahydrofuran ring, tetrahydropyran ring, thiazolidine ring, isothiazolidine ring, oxazolidine ring, isoxazolidine ring, piperidine ring, piperazine ring, morpholine ring, thiazinane ring, benzene ring, benzo[d][1,3]dioxole ring, benzo[d][1,4]dioxane ring, benzo[d][1,3]dioxolane ring, benzopyrrolidine ring, benzopyrazolidine ring, benzimidazolidine ring, benzotetrahydrothiophene ring, benzotetrahydrofuran ring, benzotetrahydropyran ring, benzothiazolidine ring, benzoisothiazolidine ring, benzoxazolidine ring, benzisoxazolidine ring, benzopiperidine ring, benzopiperazine ring, benzomorpholine ring, benzothiazinane ring, pyrrole ring, pyrazole ring, imidazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, triazole ring, furan ring, thiophene ring, pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, pyridine-fused pyrrolidine ring, pyridine-fused pyrazolidine ring, pyridine-fused imidazolidine ring, pyridine-fused tetrahydrothiophene ring, pyridine-fused tetrahydrofuran ring, pyridine-fused tetrahydropyran ring, pyridine-fused thiazolidine ring, pyridine-fused isothiazolidine ring, pyridine-fused oxazolidine ring, pyridine-fused isoxazolidine ring, pyridine-fused piperidine ring, pyridine-fused piperazine ring, pyridine-fused morpholine ring, pyridine-fused thiazinane ring, pyrazine-fused pyrrolidine ring, pyrazine-fused pyrazolidine ring, pyrazine-fused imidazolidine ring, pyrazine-fused tetrahydrothiophene ring, pyrazine-fused tetrahydrofuran ring, pyrazine-fused tetrahydropyran ring, pyrazine-fused thiazolidine ring, pyrazine-fused isothiazolidine ring, pyrazine-fused oxazolidine ring, pyrazine-fused isoxazolidine ring, pyrazine-fused piperidine ring, pyrazine-fused piperazine ring, pyrazine-fused morpholine ring, pyrazine-fused thiazinane ring, pyrimidine-fused pyrrolidine ring, pyrimidine-fused pyrazolidine ring, pyrimidine-fused imidazolidine ring, pyrimidine-fused tetrahydrothiophene ring, pyrimidine-fused tetrahydrofuran ring, pyrimidine-fused tetrahydropyran ring, pyrimidine-fused thiazolidine ring, pyrimidine-fused isothiazolidine ring, pyrimidine-fused oxazolidine ring, pyrimidine-fused isoxazolidine ring, pyrimidine-fused piperidine ring, pyrimidine-fused piperazine ring, pyrimidine-fused morpholine ring, pyrimidine-fused thiazinane ring, benzofuran ring, benzothiophene ring, indole ring, isoindole ring, benzimidazole ring, indazole ring, pyrrolo[2,3-b]pyridine ring, pyrrolo[2,3-c]pyridine ring, pyrrolo[3,2-c]pyridine ring, pyrrolo[3,2-b]pyridine ring, imidazo[4,5-b]pyridine ring, imidazo[4,5-c]pyridine ring, imidazo[1,2-a]pyridine ring, imidazo[1,5-a]pyridine ring, pyrazolo[4,3-d]pyridine ring, pyrazolo[4,3-c]pyridine ring, pyrazolo[3,4-c]pyridine ring, pyrazolo[1,5-a]pyridine ring, purine ring, indolizine ring, pyrrolo[1,2-a]pyridazine ring, imidazo[1,2-c]pyrimidine ring, pyrazolo[1,5-a]pyrazine ring or pyrrolo[1,2-a]pyrazine ring, and ring A is optionally independently substituted by 1, 2 or 3 R a substituents, and other variables are as defined in the present application.

[0059] In some embodiments of the present application, ring A is selected from a piperidine ring, a benzene ring, a benzo[d][1,3]dioxole ring, a benzo[d]pyrrolidine ring, a benzo[d]tetrahydrothiophene ring, a benzo[d]isothiazolidine ring, an imidazole ring, an oxazole ring, a thiazole ring, a pyridine ring, a pyridine-3(2H)-tetrahydrofuran ring, a pyridine-3(2H)-isothiazolidine ring, or a pyridine-3(2H)-thiazinane ring, and ring A is optionally independently substituted with 1, 2, or 3 R a substituents, with other variables as defined in the present application.

[0060] In some embodiments of the present application, ring A is selected from a piperidine ring, a benzene ring, a benzo[d]isothiazolidine ring, an imidazole ring, an oxazole ring, a thiazole ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a pyridine-3(2H)-isothiazolidine ring, a pyridine-3(2H)-thiazinane ring, a pyrrolo[3,2-c]pyridine ring, a pyrazolo[4,3-c]pyridine ring, a pyrazolo[1,5-a]pyrazine ring, or a pyrrolo[1,2-a]pyrazine ring, and ring A is optionally independently substituted with 1, 2, or 3 R a substituents, with other variables as defined in the present application.

[0061] In still some other embodiments of the present application, ring A is selected from a piperidine ring, a benzene ring, a benzo[d]isothiazolidine ring, an imidazole ring, an oxazole ring, a thiazole ring, a pyridine-3(2H)-isothiazolidine ring, or a pyridine-3(2H)-thiazinane ring, and ring A is optionally independently substituted with 1, 2, or 3 R a substituents, with other variables as defined in the present application.

[0062] In some other embodiments of the present application, ring A is selected from

[0063]

[0064] Ring A is optionally independently substituted with 1, 2, or 3 R a substituents, with other variables as defined in the present application.

[0065] In some other embodiments of the present application, ring A is selected from

[0066]

[0067] Ring A is optionally independently substituted with 1, 2, or 3 R a substituents, with other variables as defined in the present application.

[0068] In some embodiments of the present application, ring A is selected from

[0069]

[0070] Ring A is optionally and independently substituted with 1, 2 or 3 Rs a and other variables are as defined in the present application.

[0071] In some embodiments of the present application, ring A is selected from

[0072] Ring A is optionally and independently substituted with 1, 2 or 3 Rs a and other variables are as defined in the present application.

[0073] In some embodiments of the present application, ring A is selected from

[0074]

[0075] Ring A is optionally and independently substituted with 1, 2 or 3 Rs a and other variables are as defined in the present application.

[0076] In some other embodiments of the present application, ring A is selected from

[0077] Ring A is optionally and independently substituted with 1, 2, 3 or 4 Rs a and other variables are as defined in the present application.

[0078] In some further embodiments of the present application, ring A is selected from

[0079] Ring A is optionally and independently substituted with 1, 2, 3 or 4 Rs a and other variables are as defined in the present application.

[0080] In some embodiments of the present application, ring A is selected from

[0081] Ring A is optionally and independently substituted with 1, 2, 3 or 4 Rs a and other variables are as defined in the present application.

[0082] In some embodiments of the present application, ring A is selected from

[0083] Ring A is optionally and independently substituted by 1, 2 or 3 R a groups, and other variables are as defined in the present application.

[0084] In some embodiments of the present application, ring A is selected from

[0085] Ring A is optionally and independently substituted by 1, 2 or 3 R a groups, and other variables are as defined in the present application.

[0086] In some embodiments of the present application, ring A is selected from

[0087] Ring A is optionally and independently substituted by 1, 2 or 3 R a groups, and other variables are as defined in the present application.

[0088] In some other embodiments of the present application, ring A is selected from

[0089] Ring A is optionally and independently substituted by 1, 2 or 3 R a groups, and other variables are as defined in the present application.

[0090] In some other embodiments of the present application, ring A is selected from Ring A is optionally and independently substituted by 1, 2 or 3 R a groups, and other variables are as defined in the present application.

[0091] In some other embodiments of the present application, ring A is selected from Ring A is optionally and independently substituted by 1, 2 or 3 R a groups, and other variables are as defined in the present application.

[0092] In some other embodiments of the present application, ring A is selected from Ring A is optionally and independently substituted by 1, 2 or 3 R a groups, and other variables are as defined in the present application.

[0093] In some embodiments of the present application, the heteroatom sulfur in ring A is oxidized to S(O) or S(O)2, and other variables are as defined in the present application.

[0094] In some embodiments of the present application, the heteroatom sulfur in ring A is oxidized to S(O)2, and other variables are as defined in the present application.

[0095] In some embodiments of the present application, each R a is independently selected from deuterium, F, Cl, Br, I, CN, =O, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x substituents, and other variables are as defined in the present application.

[0096] In some other embodiments of the present application, each R a is independently selected from F, Cl, CN, =O, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x substituents, and other variables are as defined in the present application.

[0097] In some embodiments of the present application, each R a is independently selected from F, Cl, Br, I, =O, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x substituents, and other variables are as defined in the present application.

[0098] In some embodiments of the present application, each R a is independently selected from F, Cl, Br, I, =O or C 1-3 alkyl, and the C 1-3 alkyl is optionally independently substituted by 1, 2 or 3 R x substituents, and other variables are as defined in the present application.

[0099] In some embodiments of the present application, each R a is independently selected from F, Cl, CN, =O, methyl or methoxy, and the methyl or methoxy is optionally independently substituted by 1, 2 or 3 halogens, and other variables are as defined in the present application.

[0100] In some embodiments of the present application, each Ra Each is independently selected from F, ═O or methyl, where the methyl is optionally independently substituted with 1, 2 or 3 halogens, and other variables are as defined in the present application.

[0101] In some embodiments of the present application, each R a Each is independently selected from F, ═O, methyl or methoxy, where the methyl or methoxy is optionally independently substituted with 1, 2 or 3 halogens, and other variables are as defined in the present application.

[0102] In some embodiments of the present application, each R a Each is independently selected from F, Cl, CN, ═O, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy, and other variables are as defined in the present application.

[0103] In some embodiments of the present application, each R a Each is independently selected from F, ═O, methyl, monofluoromethyl, difluoromethyl or trifluoromethyl, and other variables are as defined in the present application.

[0104] In some other embodiments of the present application, each R a Each is independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, and other variables are as defined in the present application.

[0105] In some embodiments of the present application, each R a Each is independently selected from F, Cl, ═O, methyl, methoxy, trifluoromethyl or trifluoromethoxy, and other variables are as defined in the present application.

[0106] In some embodiments of the present application, each R a Each is independently selected from F, ═O, methyl or trifluoromethyl, and other variables are as defined in the present application.

[0107] In some embodiments of the present application, each R a Each is independently selected from F, ═O, methyl, methoxy or trifluoromethyl, and other variables are as defined in the present application.

[0108] In some other embodiments of the present application, ring A is selected from a piperidine ring, a benzene ring, a benzo - dioxolane ring, a benzo - pyrrolidine ring, a benzo - tetrahydrothiophene ring, a benzo - isothiazolidine ring, a benzo - thiazolidine ring, an imidazole ring, an oxazole ring, a thiazole ring, a pyridine ring, a pyridine - tetrahydrofuran ring, a pyridine - isothiazolidine ring or a pyridine - thiazolidine ring, and ring A is optionally independently substituted with 1, 2 or 3 R a substituents, and each R aEach independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, with other variables as defined in the present application.

[0109] In some further embodiments of the present application, ring A is selected from a piperidine ring, a benzene ring, a benzo[1,3]dioxolane ring, a benzo[1,3]pyrrolidine ring, a benzo[1,4]thiane ring, a benzo[1,2]isothiazolidine ring, a benzo[1,2]thiazinane ring, an imidazole ring, an oxazole ring, a thiazole ring, a pyridine[2,3-d]tetrahydrofuran ring, a pyridine[2,3-d]isothiazolidine ring or a pyridine[2,3-d]thiazinane ring, and ring A is optionally independently substituted by 1, 2 or 3 R a substituents, each R a Each independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, with other variables as defined in the present application.

[0110] In some embodiments of the present application, ring A is selected from a piperidine ring, a benzene ring, a benzo[1,3]dioxolane ring, a benzo[1,3]pyrrolidine ring, a benzo[1,4]thiane ring, a benzo[1,2]isothiazolidine ring, an imidazole ring, an oxazole ring, a thiazole ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a pyridine[2,3-d]tetrahydrofuran ring, a pyridine[2,3-d]isothiazolidine ring, a pyridine[2,3-d]thiazinane ring, a pyrrolo[3,2-c]pyridine ring, a pyrazolo[4,3-c]pyridine ring, a pyrazolo[1,5-a]pyrazine ring or a pyrrolo[1,2-a]pyrazine ring, and ring A is optionally independently substituted by 1, 2 or 3 R a substituents, each R a Each independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, with other variables as defined in the present application.

[0111] In some embodiments of the present application, ring A is selected from a piperidine ring, a benzene ring, a benzo[1,3]dioxolane ring, a benzo[1,3]pyrrolidine ring, a benzo[1,4]thiane ring, a benzo[1,2]isothiazolidine ring, an imidazole ring, an oxazole ring, a thiazole ring, a pyridine ring, a pyridine[2,3-d]tetrahydrofuran ring, a pyridine[2,3-d]isothiazolidine ring or a pyridine[2,3-d]thiazinane ring, and ring A is optionally independently substituted by 1, 2 or 3 R a substituents, each R a Each independently selected from F, Cl, ═O, methyl, methoxy, trifluoromethyl or trifluoromethoxy, with other variables as defined in the present application.

[0112] In some embodiments of the present application, ring A is selected from a piperidine ring, a benzene ring, a benzo[1,2]isothiazolidine ring, an imidazole ring, an oxazole ring, a thiazole ring, a pyridine ring, a pyridine[2,3-d]isothiazolidine ring or a pyridine[2,3-d]thiazinane ring, and ring A is optionally independently substituted by 1, 2 or 3 R a substituents, each R aEach is independently selected from F, ═O, methyl or trifluoromethyl, and other variables are as defined in the present application.

[0113] In some other embodiments of the present application, ring A is selected from

[0114] Ring A is optionally and independently substituted by 1, 2 or 3 R a substituents, and each R a is independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, and other variables are as defined in the present application.

[0115] In still some other embodiments of the present application, ring A is selected from

[0116] Ring A is optionally and independently substituted by 1, 2 or 3 R a substituents, and each R a is independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, and other variables are as defined in the present application.

[0117] In some embodiments of the present application, ring A is selected from

[0118] Ring A is optionally and independently substituted by 1, 2 or 3 R a substituents, and each R a is independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, and other variables are as defined in the present application.

[0119] In some embodiments of the present application, ring A is selected from

[0120] Ring A is optionally and independently substituted by 1, 2 or 3 R a substituents, and each R a is independently selected from F, Cl, ═O, methyl, methoxy, trifluoromethyl or trifluoromethoxy, and other variables are as defined in the present application.

[0121] In some embodiments of the present application, ring A is selected from

[0122] Ring A is optionally independently substituted by 1, 2 or 3 Rs a each R a is independently selected from F, ═O, methyl or trifluoromethyl, and other variables are as defined in the present application.

[0123] In some embodiments of the present application, ring A is selected from Ring A is optionally independently substituted by 1, 2 or 3 Rs a each R a is independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, and other variables are as defined in the present application.

[0124] In some embodiments of the present application, ring A is selected from Ring A is optionally independently substituted by 1, 2 or 3 Rs a each R a is independently selected from F, Cl, ═O, methyl, methoxy, trifluoromethyl or trifluoromethoxy, and other variables are as defined in the present application.

[0125] In some embodiments of the present application, ring A is selected from Ring A is optionally independently substituted by 1, 2 or 3 Rs a each R a is independently selected from F, Cl, ═O, methyl, methoxy, trifluoromethyl or trifluoromethoxy, and other variables are as defined in the present application.

[0126] In some embodiments of the present application, ring A is selected from Ring A is optionally independently substituted by 1, 2 or 3 Rs a each R a is independently selected from F, Cl, ═O, methyl, methoxy, trifluoromethyl or trifluoromethoxy, and other variables are as defined in the present application.

[0127] In some embodiments of the present application, ring A is selected from Ring A is optionally independently substituted by 1, 2 or 3 Rs a each R a is independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, and other variables are as defined in the present application.

[0128] In some embodiments of the present application, ring A is selected from Ring A is optionally and independently substituted by 1, 2 or 3 R a substituents, each R a is independently selected from F, Cl, ═O, methyl, methoxy, trifluoromethyl or trifluoromethoxy, and other variables are as defined in the present application.

[0129] In some embodiments of the present application, ring A is selected from Ring A is optionally and independently substituted by 1, 2 or 3 R a substituents, each R a is independently selected from F, Cl, ═O, methyl, methoxy, trifluoromethyl or trifluoromethoxy, and other variables are as defined in the present application.

[0130] In some other embodiments of the present application, ring A is selected from Ring A is optionally and independently substituted by 1, 2 or 3 R a substituents, and other variables are as defined in the present application.

[0131] In some other embodiments of the present application, ring A is selected from Ring A is optionally and independently substituted by 1, 2 or 3 R a substituents, each R a is independently selected from F, Cl, ═O, methyl, methoxy, trifluoromethyl or trifluoromethoxy, and other variables are as defined in the present application.

[0132] In some other embodiments of the present application, ring A is selected from Ring A is optionally and independently substituted by 1, 2 or 3 R a substituents, each R a is independently selected from F, Cl, ═O, methyl, methoxy, trifluoromethyl or trifluoromethoxy, and other variables are as defined in the present application.

[0133] In some embodiments of the present application, ring A is selected from Ring A is optionally and independently substituted by 1, 2 or 3 R a substituents, each R a is independently selected from F or trifluoromethyl, and other variables are as defined in the present application.

[0134] In some other embodiments of the present application, ring A is selected from Ring A is optionally and independently substituted by 1, 2 or 3 R a substituents, each R a is independently selected from F or trifluoromethyl, and other variables are as defined in the present application.

[0135] In some embodiments of the present application, ring A is selected from Ring A is optionally and independently substituted with 1, 2 or 3 R a substituents, each R a is independently selected from F, ═O, methyl or trifluoromethyl, and other variables are as defined in the present application.

[0136] In some embodiments of the present application, ring A is selected from Ring A is optionally and independently substituted with 1, 2 or 3 R a substituents, each R a is independently selected from F, ═O, methyl or trifluoromethyl, and other variables are as defined in the present application.

[0137] In some other embodiments of the present application, ring A is selected from

[0138] Other variables are as defined in the present application.

[0139] In some further embodiments of the present application, ring A is selected from

[0140] Other variables are as defined in the present application. In some embodiments of the present application, ring A is selected from

[0141]

[0142] Other variables are as defined in the present application. In some embodiments of the present application, ring A is selected from

[0143] Other variables are as defined in the present application.

[0144] In some embodiments of the present application, ring A is selected from

[0145] Other variables are as defined in the present application.

[0146] In some embodiments of the present application, ring A is selected from

[0147] Other variables are as defined in the present application.

[0148] In some embodiments of the present application, ring A is selected from

[0149] Other variables are as defined in the present application.

[0150] In some embodiments of the present application, ring A is selected from

[0151] Other variables are as defined in the present application.

[0152] In some embodiments of the present application, ring A is selected from

[0153] Other variables are as defined in the present application.

[0154] In some embodiments of the present application, ring A is selected from

[0155] Other variables are as defined in the present application.

[0156] In some embodiments of the present application, ring A is selected from

[0157] Other variables are as defined in the present application.

[0158] In some embodiments of the present application, ring A is selected from

[0159] Other variables are as defined in the present application.

[0160] In some embodiments of the present application, ring A is selected from Other variables are as defined in the present application.

[0161] In some embodiments of the present application, ring A is selected from

[0162] Other variables are as defined in the present application.

[0163] In some embodiments of the present application, ring A is selected from Other variables are as defined in the present application.

[0164] In some other embodiments of the present application, ring A is selected from Other variables are as defined in the present application.

[0165] In some other embodiments of the present application, ring A is selected from Other variables are as defined in the present application.

[0166] In some other embodiments of the present application, ring A is selected from Other variables are as defined in the present application.

[0167] In some embodiments of the present application, ring A is selected from Other variables are as defined in the present application.

[0168] In some embodiments of the present application, ring A is selected from Other variables are as defined in the present application.

[0169] In some other embodiments of the present application, the structural unit is selected from

[0170]

[0171] Ring A is optionally and independently substituted by 1, 2 or 3 R a substituents, and other variables are as defined in the present application. In some embodiments of the present application, each R a is independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, and other variables are as defined in the present application.

[0172] In still some other embodiments of the present application, the structural unit is selected from

[0173] Ring A is optionally and independently substituted by 1, 2 or 3 R a substituents, and other variables are as defined in the present application. In some embodiments of the present application, each Ra Each independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, with other variables as defined in the present application.

[0174] In some embodiments of the present application, the structural unit is selected from

[0175]

[0176] Ring A is optionally and independently substituted by 1, 2 or 3 R a groups, with other variables as defined in the present application. In some embodiments of the present application, each R a is independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, with other variables as defined in the present application.

[0177] In some embodiments of the present application, the structural unit is selected from

[0178] Ring A is optionally and independently substituted by 1, 2 or 3 R a groups, with other variables as defined in the present application. In some embodiments of the present application, each R a is independently selected from F, Cl, ═O, methyl, methoxy, trifluoromethyl or trifluoromethoxy, with other variables as defined in the present application.

[0179] In some embodiments of the present application, the structural unit is selected from

[0180] Ring A is optionally and independently substituted by 1, 2 or 3 R a groups, with other variables as defined in the present application. In some embodiments of the present application, each R a is independently selected from F, ═O, methyl or trifluoromethyl, with other variables as defined in the present application.

[0181] In some embodiments of the present application, the structural unit is selected from

[0182] Ring A is optionally and independently substituted by 1, 2 or 3 Ra is substituted, and other variables are as defined in the present application. In some embodiments of the present application, each R a is independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, and other variables are as defined in the present application.

[0183] In some embodiments of the present application, the structural unit is selected from

[0184] Ring A is optionally independently substituted with 1, 2 or 3 Rs a is substituted, and other variables are as defined in the present application. In some embodiments of the present application, each R a is independently selected from F, Cl, ═O, methyl, trifluoromethyl or trifluoromethoxy, and other variables are as defined in the present application.

[0185] In some embodiments of the present application, the structural unit is selected from Ring A is optionally independently substituted with 1, 2 or 3 Rs a is substituted, and other variables are as defined in the present application. In some embodiments of the present application, each R a is independently selected from F, Cl, ═O, methyl, trifluoromethyl or trifluoromethoxy, and other variables are as defined in the present application.

[0186] In some embodiments of the present application, the structural unit is selected from Ring A is optionally independently substituted with 1, 2 or 3 Rs a is substituted, and other variables are as defined in the present application. In some embodiments of the present application, each R a is independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, and other variables are as defined in the present application. In some embodiments of the present application, each R a is independently selected from F, Cl, ═O, methyl, trifluoromethyl or trifluoromethoxy, and other variables are as defined in the present application.

[0187] In some other embodiments of the present application, the structural unit is selected from Ring A is optionally independently substituted with 1, 2 or 3 Rs a is substituted, and other variables are as defined in the present application. In some embodiments of the present application, each R aEach independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, with other variables as defined in the present application.

[0188] In some other embodiments of the present application, the structural unit is selected from The ring A is optionally independently substituted by 1, 2 or 3 R a substituents, with other variables as defined in the present application. In some embodiments of the present application, each R a is independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, with other variables as defined in the present application.

[0189] In some other embodiments of the present application, the structural unit is selected from The ring A is optionally independently substituted by 1, 2 or 3 R a substituents, with other variables as defined in the present application. In some embodiments of the present application, each R a is independently selected from F, Cl, CN, ═O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, with other variables as defined in the present application.

[0190] In some embodiments of the present application, the structural unit is selected from The ring A is optionally independently substituted by 1, 2 or 3 R a substituents, with other variables as defined in the present application. In some embodiments of the present application, each R a is independently selected from F, ═O, methyl or trifluoromethyl, with other variables as defined in the present application.

[0191] In some embodiments of the present application, the structural unit is selected from The ring A is optionally independently substituted by 1, 2 or 3 R a substituents, with other variables as defined in the present application. In some embodiments of the present application, each R a is independently selected from F, ═O, methyl or trifluoromethyl, with other variables as defined in the present application.

[0192] In some other embodiments of the present application, the structural unit is selected from

[0193]

[0194] Other variables are as defined in the present application.

[0195] In some further embodiments of the present application, the structural unit is selected from

[0196]

[0197] Other variables are as defined in the present application.

[0198] In some embodiments of the present application, the structural unit is selected from

[0199]

[0200] Other variables are as defined in the present application.

[0201] In some embodiments of the present application, the structural unit is selected from

[0202]

[0203] Other variables are as defined in the present application.

[0204] In some embodiments of the present application, the structural unit is selected from

[0205] Other variables are as defined in the present application.

[0206] In some embodiments of the present application, the structural unit is selected from

[0207]

[0208] Other variables are as defined in the present application.

[0209] In some embodiments of the present application, the structural unit is selected from

[0210] Other variables are as defined in the present application.

[0211] In some embodiments of the present application, the structural unit is selected from

[0212] Other variables are as defined in the present application.

[0213] In some embodiments of the present application, the structural unit is selected from

[0214] Other variables are as defined in the present application.

[0215] In some embodiments of the present application, the structural unit is selected from

[0216] Other variables are as defined in the present application.

[0217] In some embodiments of the present application, the structural unit is selected from Other variables are as defined in the present application.

[0218] In some embodiments of the present application, the structural unit is selected from Other variables are as defined in the present application.

[0219] In some other embodiments of the present application, the structural unit is selected from Other variables are as defined in the present application.

[0220] In some other embodiments of the present application, the structural unit is selected from Other variables are as defined in the present application.

[0221] In some embodiments of the present application, the structural unit is selected from Other variables are as defined in the present application.

[0222] In some embodiments of the present application, the structural unit is selected from Other variables are as defined in the present application.

[0223] In some embodiments of the present application, L 1 is selected from a single bond, -N(R b )-, -N=, -O-, -S(=O)2-, -S-, -(CH2) m -, or -C(=O)-, with other variables as defined in the present application.

[0224] In some embodiments of the present application, L 1 is selected from a single bond, -N(R b )-, -O-, -S(=O)2-, -S-, -(CH2) m -, or -C(=O)-, with other variables as defined in the present application.

[0225] In some embodiments of the present application, L 1 is selected from a single bond, -NH-, -N=, -N(C(=O)H)-, -N(C 1-3 alkyl)-, -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -N(S(=O)2C 1-3 alkyl)-, or -C(=O)-, with other variables as defined in the present application.

[0226] In some embodiments of the present application, L 1 is selected from a single bond, -NH-, -N(C(=O)H)-, -N(C 1-3 alkyl)-, -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, or -C(=O)-, with other variables as defined in the present application.

[0227] In some embodiments of the present application, L 1 is selected from a single bond, -NH-, -N=, -N(C(=O)H)-, -N(CH3)-, -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -C(=O)-, or -N(S(=O)2CH3)-, with other variables as defined in the present application.

[0228] In some other embodiments of the present application, L 1 is selected from a single bond, -NH-, -N=, -N(C(=O)H)-, -N(CH3)-, -S(=O)2-, -CH2-, -C(=O)-, or -N(S(=O)2CH3)-, with other variables as defined in the present application.

[0229] In some embodiments of the present application, L 1Selected from a single bond, -NH-, -N(C(=O)H)-, -N(CH3)-, -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -C(=O)-, with other variables as defined in the present application.

[0230] In some embodiments of the present application, L 1 Selected from a single bond, -NH-, -N(CH3)-, -S(=O)2-, -CH2- or -C(=O)-, with other variables as defined in the present application.

[0231] In some embodiments of the present application, L 1 Selected from a single bond, -NH- or -S(=O)2-, with other variables as defined in the present application.

[0232] In some embodiments of the present application, L 1 Selected from a single bond, -N(R b )-, -O-, -S-, -(CH2) m - or -C(=O)-, with other variables as defined in the present application.

[0233] In some embodiments of the present application, L 1 Selected from a single bond, -NH-, -N(C(=O)H)-, -N(C 1-3 alkyl)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -C(=O)-, with other variables as defined in the present application.

[0234] In some embodiments of the present application, L 1 Selected from a single bond, -NH-, -N(C 1-3 alkyl)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -C(=O)-, with other variables as defined in the present application.

[0235] In some embodiments of the present application, L 1 Selected from a single bond, -NH-, -N(C(=O)H)-, -N(CH3)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -C(=O)-, with other variables as defined in the present application.

[0236] In some embodiments of the present application, L 1 Selected from a single bond, -NH-, -N(CH3)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -C(=O)-, with other variables as defined in the present application.

[0237] In some embodiments of the present application, L 1Selected from a single bond, -NH-, -N(CH3)-, -CH2-, or -C(=O)-, with other variables as defined in the present application.

[0238] In some embodiments of the present application, L 1 Selected from a single bond or -NH-, with other variables as defined in the present application.

[0239] In some embodiments of the present application, L 1 Selected from -NH-, with other variables as defined in the present application.

[0240] In some embodiments of the present application, L 2 Selected from a single bond, -NH-, -N(C 1-3 alkyl)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -C(=O)-, -S(=O)-, -S(=O)2-, -S(=O)(=NH)-, -S(=O)(C 1-3 alkyl)-, -P(=O)(C 1-3 alkyl)-, -P(=O)(NH2)-, or -P(=O)(NH(C 1-3 alkyl))-, with other variables as defined in the present application.

[0241] In some embodiments of the present application, L 2 Selected from a single bond, -NH-, -N(CH3)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -C(=O)-, -S(=O)-, -S(=O)2-, -S(=O)(=NH)-, -S(=O)(CH3)-, -P(=O)(CH3)-, -P(=O)(NH2)-, or -P(=O)(NHCH3)-, with other variables as defined in the present application.

[0242] In some embodiments of the present application, L 2 Selected from a single bond, -NH-, -N(CH3)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -C(=O)-, -S(=O)-, -S(=O)2-, -S(=O)(=NH)-, -P(=O)(CH3)-, -P(=O)(NH2)-, or -P(=O)(NHCH3)-, with other variables as defined in the present application.

[0243] In some other embodiments of the present application, L 2Selected from a single bond, -NH-, -N(CH3)-, -CH2-CH2-, -C(=O)-, -S(=O)2-, -S(=O)(=NH)-, -S(=O)(CH3)-, -P(=O)(CH3) or -P(=O)(NHCH3)-, with other variables as defined in the present application.

[0244] In some embodiments of the present application, L 2 Selected from a single bond, -NH-, -N(CH3)-, -CH2-CH2-, -C(=O)-, -S(=O)2-, -S(=O)(=NH)-, -P(=O)(CH3) or -P(=O)(NHCH3)-, with other variables as defined in the present application.

[0245] In some embodiments of the present application, L 2 Selected from a single bond, -NH- or -S(=O)2-, with other variables as defined in the present application.

[0246] In some embodiments of the present application, L 2 Selected from a single bond or -S(=O)2-, with other variables as defined in the present application.

[0247] In some embodiments of the present application, L 2 Selected from -S(=O)2-, with other variables as defined in the present application.

[0248] In some embodiments of the present application, -L 2 -L 1-selected from a single bond, -NH-, -N(CH3)-, -C(=O)-, -CH2-, -CH2-CH2-, -S(=O)2-, -CH2-NH-, -NH-CH2-, -CH2-N(CH3)-, -CH2-N(C(=O)H)-, -N(CH3)-CH2-, -N(C(=O)H)-CH2-, -C(=O)-CH2-, -CH2-C(=O)-, -C(=O)-NH-, -NH-C(=O)-, -NH-S(=O)2-, -S(=O)2-NH-, -N(CH3)-S(=O)2-, -N(S(=O)2CH3)-S(=O)2-, -S(=O)2-N(S(=O)2CH3)-, -S(=O)(CH3)=N-, -S(=O)2-N(CH3)-, -N(CH3)-C(=O)-, -C(=O)-N(CH3)-, -NH-S(=O)(=NH)-, -S(=O)(=NH)-NH-, -S(=O)(=NH)-, -P(=O)(CH3)-, -CH2-S(=O)(=NH)-, -S(=O)(=NH)-CH2-, -CH2-P(=O)(CH3)-, -P(=O)(CH3)-CH2-, -NH-P(=O)(CH3)-, -P(=O)(CH3)-NH-, -NH-P(=O)(NHCH3)-, -P(=O)(NHCH3)-NH-, -NH-P(=O)(NH2)-, -P(=O)(NH2)-NH-, -CH2-P(=O)(NHCH3)-, -P(=O)(NHCH3)-CH2-, -N(CH3)-CH2-CH2-, -N(C(=O)H)-CH2-CH2-, -CH2-CH2-N(CH3)-, -CH2-CH2-N(C(=O)H)-, -NH-CH2-CH2- or -CH2-CH2-NH-, with other variables as defined in the present application.

[0249] In some embodiments of the present application, -L 2 -L 1- selected from a single bond, -NH-, -N(CH3)-, -C(=O)-, -CH2-, -CH2-CH2-, -S(=O)2-, -CH2-NH-, -NH-CH2-, -CH2-N(CH3)-, -CH2-N(C(=O)H)-, -N(CH3)-CH2-, -N(C(=O)H)-CH2-, -C(=O)-CH2-, -CH2-C(=O)-, -C(=O)-NH-, -NH-C(=O)-, -NH-S(=O)2-, -S(=O)2-NH-, -N(CH3)-S(=O)2-, -S(=O)2-N(CH3)-, -N(CH3)-C(=O)-, -C(=O)-N(CH3)-, -NH-S(=O)(=NH)-, -S(=O)(=NH)-NH-, -S(=O)(=NH)-, -P(=O)(CH3)-, -CH2-S(=O)(=NH)-, -S(=O)(=NH)-CH2-, -CH2-P(=O)(CH3)-, -P(=O)(CH3)-CH2-, -NH-P(=O)(CH3)-, -P(=O)(CH3)-NH-, -NH-P(=O)(NHCH3)-, -P(=O)(NHCH3)-NH-, -NH-P(=O)(NH2)-, -P(=O)(NH2)-NH-, -CH2-P(=O)(NHCH3)-, -P(=O)(NHCH3)-CH2-, -N(CH3)-CH2-CH2-, -N(C(=O)H)-CH2-CH2-, -CH2-CH2-N(CH3)-, -CH2-CH2-N(C(=O)H)-, -NH-CH2-CH2- or -CH2-CH2-NH-, with other variables as defined in the present application.

[0250] In some embodiments of the present application, -L 2 -L 1- selected from a single bond, -NH-, -N(CH3)-, -C(=O)-, -CH2-, -CH2-CH2-, -S(=O)2-, -CH2-NH-, -NH-CH2-, -CH2-N(CH3)-, -N(CH3)-CH2-, -C(=O)-CH2-, -CH2-C(=O)-, -C(=O)-NH-, -NH-C(=O)-, -NH-S(=O)2-, -S(=O)2-NH-, -N(CH3)-S(=O)2-, -S(=O)2-N(CH3)-, -N(CH3)-C(=O)-, -C(=O)-N(CH3)-, -NH-S(=O)(=NH)-, -S(=O)(=NH)-NH-, -S(=O)(=NH)-, -P(=O)(CH3)-, -CH2-P(=O)(CH3)-, -P(=O)(CH3)-CH2-, -NH-P(=O)(CH3)-, -P(=O)(CH3)-NH-, -NH-P(=O)(NHCH3)-, -P(=O)(NHCH3)-NH-, -NH-P(=O)(NH2)-, -P(=O)(NH2)-NH-, -CH2-P(=O)(NHCH3)-, -P(=O)(NHCH3)-CH2-, -N(CH3)-CH2-CH2-, -CH2-CH2-N(CH3)-, -NH-CH2-CH2- or -CH2-CH2-NH-, with other variables as defined in the present application.

[0251] In some other embodiments of the present application, -L 2 -L 1 - selected from a single bond, -NH-, -CH2-, -S(=O)2-, -N(CH3)-CH2-, -NH-C(=O)-, -N(CH3)-C(=O)-, -S(=O)2-NH-, -NH-S(=O)2-, -S(=O)(CH3)=N-, -S(=O)2-N(CH3)-, -C(=O)-NH-, -C(=O)-N(CH3)-, -S(=O)(=NH)-NH-, -S(=O)(=NH)-, -P(=O)(CH3)-, -S(=O)(=NH)-CH2-, -P(=O)(CH3)-CH2-, -P(=O)(CH3)-NH-, -P(=O)(NHCH3)-NH-, -CH2-CH2-N(CH3)-, -CH2-CH2-N(C(=O)H)-, -CH2-CH2-NH- or -S(=O)2-N(S(=O)2CH3)-, with other variables as defined in the present application.

[0252] In some embodiments of the present application, -L 2 -L1 - selected from a single bond, -NH-, -CH2-, -S(=O)2-, -N(CH3)-CH2-, -NH-C(=O)-, -S(=O)2-NH-, -NH-S(=O)2-, -S(=O)(CH3)=N-, -S(=O)2-N(CH3)-, -C(=O)-NH-, -C(=O)-N(CH3)-, -S(=O)(=NH)-NH-, -S(=O)(=NH)-, -P(=O)(CH3)-, -CH2-S(=O)(=NH)-, -P(=O)(CH3)-CH2-, -P(=O)(CH3)-NH-, -P(=O)(NHCH3)-NH-, -CH2-CH2-N(CH3)-, -CH2-CH2-N(C(=O)H)-, -CH2-CH2-NH- or -S(=O)2-N(S(=O)2CH3)-, with other variables as defined in the present application.

[0253] In some embodiments of the present application, -L 2 -L 1 - selected from a single bond, -NH-, -CH2-, -S(=O)2-, -N(CH3)-CH2-, -NH-C(=O)-, -C(=O)-NH-, -S(=O)2-NH-, -S(=O)2-N(CH3)-, -C(=O)-NH-, -C(=O)-N(CH3)-, -S(=O)(=NH)-NH-, -S(=O)(=NH)-, -P(=O)(CH3)-, -CH2-S(=O)(=NH)-, -P(=O)(CH3)-CH2-, -P(=O)(CH3)-NH-, -P(=O)(NHCH3)-NH-, -CH2-CH2-N(CH3)-, -CH2-CH2-N(C(=O)H)- or -CH2-CH2-NH-, with other variables as defined in the present application.

[0254] In some embodiments of the present application, -L 2 -L 1-Selected from a single bond, -NH-, -CH2-, -S(=O)2-, -N(CH3)-CH2-, -NH-C(=O)-, -C(=O)-NH-, -S(=O)2-NH-, -S(=O)2-N(CH3)-, -C(=O)-NH-, -C(=O)-N(CH3)-, -S(=O)(=NH)-NH-, -S(=O)(=NH)-, -P(=O)(CH3)-, -P(=O)(CH3)-CH2-, -P(=O)(CH3)-NH-, -P(=O)(NHCH3)-NH-, -CH2-CH2-N(CH3)- or -CH2-CH2-NH-, with other variables as defined in the present application.

[0255] In some embodiments of the present application, -L 2 -L 1 -Selected from a single bond, -NH-, -CH2-, -NH-S(=O)2- or -S(=O)2-NH-, with other variables as defined in the present application.

[0256] In some embodiments of the present application, -L 2 -L 1 -Selected from a single bond, -NH-, -CH2- or -S(=O)2-NH-, with other variables as defined in the present application.

[0257] In some embodiments of the present application, -L 2 -L 1 -Selected from a single bond or -S(=O)2-NH-, with other variables as defined in the present application.

[0258] In some embodiments of the present application, -L 2 -L 1 -Selected from -S(=O)2-NH-, with other variables as defined in the present application.

[0259] In some embodiments of the present application, -L 2 -L 1 -Selected from -NH-S(=O)2-, with other variables as defined in the present application.

[0260] In some embodiments of the present application, -L 2 -L 1 -Selected from a single bond, with other variables as defined in the present application.

[0261] In some embodiments of the present application, R 1 Selected from H, C 1-3 alkyl, C 1-3 alkoxy, -NH2, -NH(C 1-3(alkyl), cyclopropyl, cyclobutyl, cyclopentyl, a 4-6 membered heterocycloalkyl containing 1 or 2 atoms selected from N, O, S atoms or a 5-6 membered heteroaryl containing 1 or 2 N atoms, said C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R d substituents; said 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R e substituents, and other variables are as defined in the present application.

[0262] In some embodiments of the present application, R 1 is selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, cyclopentyl, a 4-6 membered heterocycloalkyl containing 1 or 2 atoms selected from N, O, S atoms or a 5-6 membered heteroaryl containing 1 or 2 N atoms, said methyl, ethyl or methoxy is optionally independently substituted by 1, 2 or 3 R d substituents, said 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R e substituents, and other variables are as defined in the present application.

[0263] In some embodiments of the present application, R 1 is selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, said methyl, ethyl or methoxy is optionally independently substituted by 1, 2 or 3 R d substituents; said cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl is optionally independently substituted by 1, 2 or 3 R e substituents, and other variables are as defined in the present application.

[0264] In some embodiments of the present application, R 1Selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, pyrazolyl, oxazolyl or pyrimidinyl, wherein the methyl, ethyl or methoxy is optionally independently substituted by 1, 2 or 3 R d ; the cyclopropyl, oxetanyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, oxazolyl or pyrimidinyl is optionally independently substituted by 1, 2 or 3 R e , and other variables are as defined in the present application.

[0265] In some embodiments of the present application, R 1 is selected from H, methyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, oxetanyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, oxazolyl or pyrimidinyl, wherein the methyl, ethyl or methoxy is optionally independently substituted by 1, 2 or 3 R d ; the cyclopropyl, oxetanyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, oxazolyl or pyrimidinyl is optionally independently substituted by 1, 2 or 3 R e , and other variables are as defined in the present application.

[0266] In some embodiments of the present application, R 1 is selected from H or methyl, and other variables are as defined in the present application.

[0267] In some embodiments of the present application, each R d is independently selected from F, Cl, Br, I or OH, and other variables are as defined in the present application.

[0268] In some embodiments of the present application, each R d is independently selected from F or OH, and other variables are as defined in the present application.

[0269] In some embodiments of the present application, each R e is independently selected from F, Cl, Br, I, =O or C 1-3 alkyl, and the C 1-3 alkyl is optionally independently substituted by 1, 2 or 3 R x , and other variables are as defined in the present application.

[0270] In some embodiments of the present application, each R x is independently selected from halogen, and other variables are as defined in the present application.

[0271] In some embodiments of the present application, each R e is independently selected from F, Cl, Br, I, =O or C1-3 Alkyl, with other variables as defined in the present application.

[0272] In some other embodiments of the present application, each R e is independently selected from =O or methyl, with other variables as defined in the present application.

[0273] In some other embodiments of the present application, each R y is independently selected from halogen, with other variables as defined in the present application.

[0274] In some embodiments of the present application, R 1 is selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, pyrazolyl, imidazolyl, oxazolyl or pyrimidinyl, wherein the methyl, ethyl or methoxy is optionally independently substituted by 1, 2 or 3 R d and the cyclopropyl, oxetanyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, oxazolyl or pyrimidinyl is optionally independently substituted by 1, 2 or 3 R e , with other variables as defined in the present application. In some embodiments of the present application, each R d is independently selected from F, Cl, Br, I and OH, and the R e is selected from F, Cl, Br, I, =O or C 1-3 alkyl; with other variables as defined in the present application.

[0275] In some embodiments of the present application, R 1 is selected from H, methyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, oxetanyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, pyrazolyl, oxazolyl or pyrimidinyl, wherein the methyl, ethyl or methoxy is optionally independently substituted by 1, 2 or 3 R d and the cyclopropyl, oxetanyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, oxazolyl or pyrimidinyl is optionally independently substituted by 1, 2 or 3 R e , with other variables as defined in the present application. In some embodiments of the present application, each R d is independently selected from F, Cl, Br, I and OH, and the R e is selected from F, Cl, Br, I, =O or C 1-3 alkyl; with other variables as defined in the present application.

[0276] In some embodiments of the present application, R 1Selected from H, methyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, oxetanyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, oxazolyl or pyrimidinyl, wherein the methyl, ethyl or methoxy is optionally independently substituted by 1, 2 or 3 R d substituents, and the cyclopropyl, oxetanyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, oxazolyl or pyrimidinyl is optionally independently substituted by 1, 2 or 3 R e substituents, and other variables are as defined in the present application. In some embodiments of the present application, each R d is independently selected from F or OH, and the R e is selected from ═O or methyl; other variables are as defined in the present application.

[0277] In some embodiments of the present application, R 1 is selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3),

[0278] wherein the methyl, ethyl or methoxy is optionally independently substituted by 1, 2 or 3 R d substituents, and the

[0279] is optionally independently substituted by 1, 2 or 3 R e substituents; other variables are as defined in the present application. In some embodiments of the present application, each R d is independently selected from F or OH, and each R e is independently selected from ═O or methyl, and other variables are as defined in the present application.

[0280] In other embodiments of the present application, R 1 is selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3),

[0281]

[0282] wherein the methyl, ethyl or methoxy is optionally independently substituted by 1, 2 or 3 R d substituents, and the is optionally independently substituted by 1, 2 or 3 R e substituents; other variables are as defined in the present application. In some embodiments of the present application, each R d is independently selected from F or OH, and each R eEach is independently selected from ═O or methyl, and other variables are as defined in the present application.

[0283] In some embodiments of the present application, R 1 is selected from H, methyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3),

[0284] the methyl or methoxy is optionally independently substituted by 1, 2 or 3 R d substituents, and the

[0285] is optionally independently substituted by 1, 2 or 3 R e substituents; other variables are as defined in the present application. In some embodiments of the present application, each R d is independently selected from F or OH, and each R e is independently selected from ═O or methyl, and other variables are as defined in the present application.

[0286] In other embodiments of the present application, R 1 is selected from H, methyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), the methyl, ethyl or methoxy is optionally independently substituted by 1, 2 or 3 R d substituents, and the is optionally independently substituted by 1, 2 or 3 R e substituents; other variables are as defined in the present application. In some embodiments of the present application, each R d is independently selected from F or OH, and each R e is independently selected from ═O or methyl, and other variables are as defined in the present application.

[0287] In some embodiments of the present application, R 1 is selected from H, methyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), the methyl, ethyl or methoxy is optionally independently substituted by 1, 2 or 3 R d substituents, and the is optionally independently substituted by 1, 2 or 3 R e substituents; other variables are as defined in the present application. In some embodiments of the present application, each R d is independently selected from F or OH, and each R eEach is independently selected from ═O or methyl, and other variables are as defined in the present application.

[0288] In some other embodiments of the present application, R 1 is selected from H, methyl, -CH2CH2OH, methoxy, -OCF3, -CH2OH, -NH2, -NH(CH3), -NH(CH2CH2OH), and other variables are as defined in the present application.

[0289] In some embodiments of the present application, R 1 is selected from H, methyl, -CH2CH2OH, methoxy, -OCF3, -CH2OH, -NH2, -NH(CH3), -NH(CH2CH2OH), and other variables are as defined in the present application.

[0290] In some embodiments of the present application, R 1 is selected from H, methyl, methoxy, -OCF3, -CH2OH, -NH2, -NH(CH3), -NH(CH2CH2OH), and other variables are as defined in the present application.

[0291] In some embodiments of the present application, R 1 is selected from H, methyl or methoxy, and other variables are as defined in the present application.

[0292] In some embodiments of the present application, R 1 is selected from methyl, and other variables are as defined in the present application.

[0293] In some embodiments of the present application, R 1 is selected from H, and other variables are as defined in the present application.

[0294] In some embodiments of the present application, each R b is independently selected from H, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x ; the C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R y and other variables are as defined in the present application.

[0295] In some other embodiments of the present application, each Rb Each is independently selected from H, -C(=O)H, -S(=O)2CH3 or methyl, and the methyl is optionally independently substituted with 1, 2 or 3 Rs x and other variables are as defined in the present application.

[0296] In some embodiments of the present application, each R b is independently selected from H or C 1-3 alkyl, and the C 1-3 alkyl is optionally independently substituted with 1, 2 or 3 Rs x and other variables are as defined in the present application.

[0297] In some embodiments of the present application, each R b is independently selected from H or methyl, and the methyl is optionally independently substituted with 1, 2 or 3 Rs x and other variables are as defined in the present application.

[0298] In some other embodiments of the present application, each R b is independently selected from H, -C(=O)H, -S(=O)2CH3 or methyl, and other variables are as defined in the present application.

[0299] In some embodiments of the present application, each R b is independently selected from H or methyl, and other variables are as defined in the present application.

[0300] In some embodiments of the present application, R c is selected from C 1-3 alkyl, and the C 1-3 alkyl is optionally independently substituted with 1, 2 or 3 Rs x and other variables are as defined in the present application.

[0301] In some embodiments of the present application, R c is selected from methyl, and the methyl is optionally independently substituted with 1, 2 or 3 Rs x and other variables are as defined in the present application.

[0302] In some embodiments of the present application, R c is selected from methyl, and other variables are as defined in the present application.

[0303] In some embodiments of the present application, m is selected from 1 or 2, and other variables are as defined in the present application.

[0304] In some embodiments of the present application, R 2 , R 3 and R 4 are each independently selected from H, deuterium or C 1-3 alkyl, and the C1-3 The alkyl group is optionally independently substituted by 1, 2 or 3 Rs z and other variables are as defined in the present application.

[0305] In some embodiments of the present application, R 2 , R 3 and R 4 are each independently selected from H or C 1-3 alkyl, and the C 1-3 alkyl is optionally independently substituted by 1, 2 or 3 Rs z and other variables are as defined in the present application.

[0306] In some embodiments of the present application, R 2 , R 3 and R 4 are each independently selected from H, deuterium, methyl, -CD3, difluoromethyl, trifluoromethyl or ethyl, and other variables are as defined in the present application.

[0307] In some other embodiments of the present application, R 2 , R 3 and R 4 are each independently selected from H, deuterium, methyl, -CD3, or trifluoromethyl, and other variables are as defined in the present application.

[0308] In some embodiments of the present application, R 2 , R 3 and R 4 are each independently selected from H, methyl or ethyl, and other variables are as defined in the present application. In some embodiments of the present application, R 2 , R 3 and R 4 are each independently selected from H or methyl, and other variables are as defined in the present application.

[0309] In some embodiments of the present application, at least one of R 2 , R 3 and R 4 is selected from H, and other variables are as defined in the present application.

[0310] In some other embodiments of the present application, R 2 is selected from H or deuterium, R 3 and R 4 are each independently selected from H, methyl, -CD3 or trifluoromethyl, and other variables are as defined in the present application.

[0311] In some embodiments of the present application, R 2 is selected from H or deuterium, R 3 and R 4Each independently selected from methyl, -CD3 or trifluoromethyl, and other variables are as defined in the present application.

[0312] In some embodiments of the present application, R 2 is selected from deuterium, R 3 and R 4 are each independently selected from -CD3, and other variables are as defined in the present application.

[0313] In some embodiments of the present application, R 2 is selected from H, R 3 and R 4 are each independently selected from methyl, and other variables are as defined in the present application.

[0314] In some other embodiments of the present application, R 2 is selected from H, R 3 and R 4 are each independently selected from methyl and CF3, and other variables are as defined in the present application.

[0315] In some embodiments of the present application, R 2 is selected from methyl, R 3 and R 4 are each independently selected from H, and other variables are as defined in the present application.

[0316] In some embodiments of the present application, R 2 , R 3 and R 4 are all H, and other variables are as defined in the present application.

[0317] In some embodiments of the present application, R 2 and R 3 together with the jointly connected carbon atom form a cycloalkyl or 3- to 4-membered heterocycloalkyl, R 3-4 is selected from H or C 4 alkyl, and the C 1-3 alkyl, C 1-3 cycloalkyl or 3- to 4-membered heterocycloalkyl is optionally independently substituted with 1, 2 or 3 R 3-4 s, and other variables are as defined in the present application. z

[0318] In some embodiments of the present application, R 2 and R 3 together with the jointly connected carbon atom form a cyclopropyl, oxiranyl or aziridinyl, R 4 is selected from H, methyl or ethyl, and the methyl, ethyl, cyclopropyl, oxiranyl or aziridinyl is optionally independently substituted with 1, 2 or 3 R z s, and other variables are as defined in the present application.

[0319] In some embodiments of the present application, R 2 and R 3 together with the jointly connected carbon atom form a cyclopropyl group, and R 4 is selected from H or methyl, and the methyl or cyclopropyl group is optionally independently substituted by 1, 2 or 3 R z groups, and other variables are as defined in the present application.

[0320] In some embodiments of the present application, R 2 and R 3 together with the jointly connected carbon atom form a cyclopropyl group, and R 4 is selected from methyl, and other variables are as defined in the present application.

[0321] In some embodiments of the present application, R 2 and R 3 together with the jointly connected carbon atom form a cyclopropyl group, and R 4 is selected from H, and other variables are as defined in the present application.

[0322] In some embodiments of the present application, each R z is independently selected from deuterium, halogen or OH, and other variables are as defined in the present application.

[0323] In some embodiments of the present application, each R z is independently selected from halogen or OH, and other variables are as defined in the present application.

[0324] In some embodiments of the present application, each R z is independently selected from F, and other variables are as defined in the present application.

[0325] In some embodiments of the present application, the compound represented by formula (I), its isomers or its pharmaceutically acceptable salts, wherein,

[0326] ring A is selected from C 3-10 alkane ring, 5- to 10-membered heteroalkane ring, benzene ring, naphthalene ring, benzene ring-fused C 5-6 alkane ring, benzene ring-fused 5- to 6-membered heteroalkane ring, 5- to 6-membered heteroaromatic ring, 5- to 6-membered heteroaromatic ring-fused C 5-6 alkane ring or 5- to 6-membered heteroaromatic ring-fused 5- to 6-membered heteroalkane ring, and the C 3-10 alkane ring, 5- to 10-membered heteroalkane ring, benzene ring, naphthalene ring, benzene ring-fused C 5-6 alkane ring, benzene ring-fused 5- to 6-membered heteroalkane ring, 5- to 6-membered heteroaromatic ring, 5- to 6-membered heteroaromatic ring-fused C 5-6 alkane ring or 5- to 6-membered heteroaromatic ring-fused 5- to 6-membered heteroalkane ring is optionally independently substituted by 1, 2 or 3 R a groups;

[0327] L 1and L 2 each independently selected from a single bond, -N(R b )-, -N=, -O-, -S-, -(CH2) m -, -C(=O)-, -S(=O)-, -S(=O)2-, -S(=O)(=N(R b ))-, -S(=O)(R c )-, -P(=O)(R c )- or -P(=O)(NR b R b )-;

[0328] R 1 is selected from H, C 1-3 alkyl, C 1-3 alkoxy, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl, the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R d substituents, and the C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl is optionally independently substituted by 1, 2 or 3 R e substituents;

[0329] R 2 , R 3 and R 4 each independently selected from H, halogen, OH, CN, NH2, C 1-3 alkyl or C 1-3 alkoxy, the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R z substituents;

[0330] or R 2 and R 3 together with the carbon atom to which they are commonly attached form a C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, and R 4 is selected from H, halogen, OH, CN, NH2, C 1-3 alkyl or C 1-3 alkoxy, the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R z substituents;

[0331] Each Ra Each independently selected from halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, said C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x substituents;

[0332] Each R b is independently selected from H, C 1-3 alkyl, C 1-3 alkoxy, -C(=O)H, -S(=O)2C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heteroalkyl, said C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x substituents; said C 3-6 cycloalkyl or 3-6 membered heteroalkyl is optionally independently substituted by 1, 2 or 3 R y substituents;

[0333] R c is selected from halogen, OH, CN or C 1-3 alkyl, said C 1-3 alkyl is optionally independently substituted by 1, 2 or 3 R x substituents;

[0334] Each R d is independently selected from halogen, OH, CN or NH2;

[0335] Each R e is independently selected from halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, said C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x substituents;

[0336] Each R x is independently selected from halogen, OH, CN or NH2;

[0337] Each R y is independently selected from halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, said C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 substituents selected from halogen, OH, CN or NH2;

[0338] Each R z is independently selected from halogen, OH, CN or NH2;

[0339] m is selected from 1, 2 or 3;

[0340] The carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched with one enantiomer form.

[0341] This application provides the compound shown in formula (II), its isomers or its pharmaceutically acceptable salts,

[0342]

[0343] wherein,

[0344] Ring A is selected from C 3-10 alkane ring, 5-10 membered heteroalkane ring, benzene ring, naphthalene ring, benzene ring fused to C 5-6 alkane ring, benzene ring fused to 5-6 membered heteroalkane ring, 5-6 membered heteroaryl ring, 5-6 membered heteroaryl ring fused to C 5-6 alkane ring or 5-6 membered heteroaryl ring fused to 5-6 membered heteroalkane ring, and the C 3-10 alkane ring, 5-10 membered heteroalkane ring, benzene ring, naphthalene ring, benzene ring fused to C 5-6 alkane ring, benzene ring fused to 5-6 membered heteroalkane ring, 5-6 membered heteroaryl ring, 5-6 membered heteroaryl ring fused to C 5-6 alkane ring or 5-6 membered heteroaryl ring fused to 5-6 membered heteroalkane ring is optionally independently substituted by 1, 2 or 3 R a substituents;

[0345] L 1 and L 2 are independently selected from single bond, -N(R b )-, -O-, -S-, -(CH2) m -, -C(=O)-, -S(=O)-, -S(=O)2-, -S(=O)(=N(R b ))-, -P(=O)(R c )- or -P(=O)(NR b R b )-;

[0346] R 1 is selected from H, C 1-3 alkyl, C 1-3 alkoxy, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 Rd is substituted, and the C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl is optionally independently substituted by 1, 2 or 3 R e substituents;

[0347] Each R a is independently selected from halogen, OH, CN, NH2, ═O, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x substituents;

[0348] Each R b is independently selected from H, C 1-3 alkyl, C 1-3 alkoxy, -C(═O)H, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x substituents; the C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R y substituents;

[0349] R c is selected from halogen, OH, CN or C 1-3 alkyl, and the C 1-3 alkyl is optionally independently substituted by 1, 2 or 3 R x substituents;

[0350] Each R d is independently selected from halogen, OH, CN or NH2;

[0351] Each R e is independently selected from halogen, OH, CN, NH2, ═O, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x substituents;

[0352] Each R x is independently selected from halogen, OH, CN or NH2;

[0353] Each R y is independently selected from halogen, OH, CN, NH2, ═O, C 1-3 alkyl or C 1-3 alkoxy, and the C1-3 Alkyl or C 1-3 Alkoxy is optionally substituted independently with 1, 2 or 3 substituents selected from halogen, OH, CN or NH2;

[0354] m is selected from 1, 2 or 3;

[0355] The carbon atom with "*" is a chiral carbon atom, which exists in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer.

[0356] In some embodiments of the present application, the compound represented by formula (II), its isomer or pharmaceutically acceptable salt thereof, wherein ring A, R 1 , L 1 and L 2 It may also be defined as in the compound represented by formula (I) above.

[0357] In some embodiments of the present application, the compound represented by formula (II), its isomer or pharmaceutically acceptable salt thereof is selected from the compound represented by formula (II-1),

[0358]

[0359] Among them, ring A, R 1 , L 1 and L 2 The compound is defined as represented by formula (II).

[0360] In some embodiments of the present application, the compound of formula (II), its isomer or pharmaceutically acceptable salt thereof is selected from the compound of formula (II-2):

[0361]

[0362] in,

[0363] X is selected from CH or N;

[0364] R 1 , R a , L 1 and L 2 As defined by the compound represented by formula (II);

[0365] The carbon atom with "*" is a chiral carbon atom, which exists in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer.

[0366] In some embodiments of the present application, the X is selected from N, and other variables are as defined herein.

[0367] In some embodiments of the present application, the compound of formula (II), its isomer or its pharmaceutically acceptable salt is selected from the compounds represented by formula (II-2a)

[0368]

[0369] Wherein,

[0370] X is selected from CH or N;

[0371] R 1 、R a 、L 1 and L 2 are as defined for the compound of formula (II).

[0372] In some embodiments of the present application, X is selected from N, and other variables are as defined in the present application.

[0373] In some embodiments of the present application, the compound of formula (II), its isomer or its pharmaceutically acceptable salt is selected from the compounds represented by formula (II-3)

[0374]

[0375] Wherein,

[0376] X is selected from CH or N;

[0377] R 1 and R a are as defined for the compound of formula (II);

[0378] The carbon atom with "*" is a chiral carbon atom and exists in the form of a single (R) or (S) enantiomer or an enantiomer-rich form.

[0379] In some embodiments of the present application, X is selected from N, and other variables are as defined in the present application.

[0380] In some embodiments of the present application, the compound of formula (II), its isomer or its pharmaceutically acceptable salt is selected from the compounds represented by formula (II-3a)

[0381]

[0382] Wherein,

[0383] X is selected from CH or N;

[0384] R 1 and R a are as defined for the compound of formula (II).

[0385] In some embodiments of the present application, X is selected from N, and other variables are as defined in the present application.

[0386] In some embodiments of the present application, the compound represented by formula (I), its isomers or its pharmaceutically acceptable salts are selected from the compounds represented by formula (I-4),

[0387]

[0388] wherein ring A, R 1 , L 1 and L 2 are as defined for the compound represented by formula (I).

[0389] In some embodiments of the present application, the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2) or formula (II-2a) do not include the following structures:

[0390]

[0391]

[0392]

[0393] Some embodiments of the present application are formed by any combination of the various variables.

[0394] On the other hand, the present application also provides a compound of the following formula, its isomers or its pharmaceutically acceptable salts,

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403] On the other hand, the present application also provides a compound of the following formula, its isomers or its pharmaceutically acceptable salts,

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418] On the other hand, the present application also provides a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of the compound, its isomers or its pharmaceutically acceptable salts described in the present application. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0419] On the other hand, the present application also provides the use of the compound, its isomers or its pharmaceutically acceptable salts or its pharmaceutical composition described in the present application in the preparation of a medicament for treating or preventing CDK2-mediated diseases.

[0420] On the other hand, the present application also provides a method for treating or preventing CDK2-mediated diseases, comprising administering to a mammal (preferably human) in need of such treatment or prevention a therapeutically or prophylactically effective amount of the compound, its isomers or its pharmaceutically acceptable salts or its pharmaceutical composition described in the present application.

[0421] On the other hand, the present application also provides the use of the compound, its isomers or its pharmaceutically acceptable salts or its pharmaceutical composition described in the present application in treating or preventing CDK2-mediated diseases.

[0422] On the other hand, the present application also provides the compound, its isomers or its pharmaceutically acceptable salts or its pharmaceutical composition described in the present application for treating or preventing CDK2-mediated diseases.

[0423] On the other hand, in some embodiments of the present application, the CDK2-mediated diseases are selected from tumors or cancers.

[0424] In the present application, the "isomers" include, but are not limited to, stereoisomers or tautomers.

[0425] Technical effects

[0426] As a CDK2 inhibitor with a novel structure, the compounds in the present application have good inhibitory effects on CDK2-induced signal transduction, and have good inhibitory activities against both CDK2 CycA2 and CDK2 CycE1 kinases, and have good properties in at least one or more aspects such as in vitro and in vivo inhibitory activities, safety (such as low toxicity), and CDK2 selectivity. The compounds of the present application have good pharmacokinetic properties and can be developed into novel CDK2 inhibitor drugs.

[0427] Related definitions

[0428] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without a specific definition, but should be understood in its ordinary meaning. When a trade name appears in this application, it is intended to refer to the corresponding product or its active ingredient.

[0429] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0430] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present application, prepared from compounds having specific substituents found in the present application with relatively non-toxic acids or bases. When a compound of the present application contains a relatively acidic functional group, the base addition salt can be obtained by contacting such a compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. When a compound of the present application contains a relatively basic functional group, the acid addition salt can be obtained by contacting such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Certain specific compounds of the present application contain both basic and acidic functional groups and can thus be converted into either base or acid addition salts.

[0431] The pharmaceutically acceptable salts of the present application can be synthesized by conventional chemical methods from parent compounds containing acid radicals or basic groups. Generally, the preparation method of such salts is to react these compounds in the form of free acids or bases with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of both.

[0432] The compounds of the present application may exist in specific stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present application.

[0433] Unless otherwise specified, a solid wedge bond and a dashed wedge bond are used to represent the absolute configuration of a stereocenter, and a solid straight bond and a dashed straight bond are used to represent the relative configuration of a stereocenter.

[0434] The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The terms "tautomer" or "tautomeric form" refer to structural isomers of different energies that can interconvert via a low energy barrier. For example, prototropic tautomers (also known as proton-transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Specific examples of prototropic tautomers are imidazole moieties, where the proton can migrate between two ring nitrogens. Valence tautomers include interconversions through the reorganization of some bonding electrons.

[0435] The compounds of the present application may contain non-natural proportions of atomic isotopes on one or more atoms that make up the compound. For example, the compound can be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). Alternatively, deuterium can replace hydrogen to form deuterated drugs, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has advantages such as reducing toxic and side effects, increasing drug stability, enhancing efficacy, and prolonging the biological half-life of the drug. All isotopic compositions of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

[0436] The term "optionally" or "optionally" means that the subsequent described event or condition may but does not necessarily occur, and the description includes the case where the described event or condition occurs and the case where the described event or condition does not occur.

[0437] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on an aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary based on what is chemically achievable.

[0438] The term "one or more substitutions" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and variants of hydrogen, and the number of substituents includes 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, based on what is chemically achievable.

[0439] As used herein, "substituent" includes, but is not limited to, the terms "alkyl", "alkoxy", "cycloalkyl", "heterocycloalkyl", "heteroaryl", "alkacyclic", "heteroalkacyclic", "heteroarylcyclic", etc. mentioned in the context, and corresponding non-limiting or exemplary groups, where some non-limiting examples of said "substituent" include protium, deuterium, tritium, -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine group, 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, aralkyloxy, aralkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroaralkyloxy, heteroaralkylthio, heterocyclic group, heterocyclic group oxy, heterocyclic group thio, heterocyclic group alkyl, heterocyclic group alkoxy, heterocyclic group alkthio, acyl group, acyloxy group, carbamate group, amide group, urea group, epoxy group and ester group, etc., and said groups are optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -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, heterocyclic group, heterocyclic group alkyl, heterocyclic group oxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl or aryloxy.

[0440] In some embodiments of the present disclosure, the "substituent" is selected from deuterium, tritium, hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl, aldehyde, imine, C 1-12 alkyl, halo-C 1-12 alkyl, 3- to 12-membered cycloalkyl, halo-3- to 12-membered cycloalkyl, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3- to 12-membered cycloalkenyl, halo-3- to 12-membered cycloalkenyl, C 2-12 alkynyl, halo-C 2-12 alkynyl, 8- to 12-membered cycloalkynyl, halo-8- to 12-membered cycloalkynyl, C 1-12 heteroalkyl, halo-C 1-12 heteroalkyl, C 1-12 alkoxy, C 1-12 alkylthio, 6- to 10-membered aryl, 6- to 10-membered aryloxy, 6- to 10-membered arylthio, 6- to 10-membered arylC 1-12 alkylene, 6- to 10-membered arylC 1-12 alkoxy, 6- to 10-membered arylC 1-12 alkylthio, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, 5- to 10-membered heteroarylthio, 5- to 10-membered heteroarylene, 5- to 10-membered heteroarylalkoxy, 5- to 10-membered heteroarylalkylthio, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic oxy, 3- to 12-membered heterocyclic thio, 3- to 12-membered heterocyclicC 1-12 alkylene, 3- to 12-membered heterocyclicC 1-12 alkoxy, 3- to 12-membered heterocyclicC 1-12 alkylthio, C 1-12 acyl, C 1-12 acyloxy, carbamate group, C 1-12 amide group, urea group, epoxy group, C 2-12 ester group and oxo, and the substituent is optionally substituted by one or more substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, haloC 1-12 alkoxy, C 1-12 alkylamino, diC 1-12 alkylamino, haloC 1-12 alkylamino, halodiC 1-12 alkylamino, carboxyl, -C(O)O-C 1-12 alkyl, -OC(O)-C 1-12Alkyl, -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- to 12-membered cycloalkyl, 3- to 12-membered cycloalkylC 1-12 alkylene, 3- to 12-membered cycloalkyloxy, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic groupC 1-12 alkylene, 3- to 12-membered heterocyclyloxy, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkylC 1-12 alkylene, 3- to 12-membered heterocycloalkyloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylC 1-12 alkylene, 5- to 10-membered heteroaryloxy, 6- to 10-membered aryl, 6- to 10-membered arylC 1-12 alkylene or 6- to 10-membered aryloxy.

[0441] C in this text m-n , means that this part has an integer number of carbon atoms within a given range. For example, "C 1-6 " means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms. For example, C 1-3 means that the group can have 1, 2, or 3 carbon atoms.

[0442] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0 - 2 R's, the group can optionally be substituted by at most two R's, and R in each case has independent options. In addition, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0443] When one of the variables is selected from a single bond, it means that the two groups it connects are directly linked. For example, when L in A-L-Z represents a single bond, it means the structure is actually A-Z.

[0444] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary. For example, in which the linking group L is -M-W-, in this case, -M-W- can link ring A and ring B in the same direction as the reading order from left to right to form The rings A and B can also be connected in a direction opposite to the left-to-right reading order to form The combination of the linking group, substituents and / or their variants is only permitted if such a combination results in a stable compound.

[0445] Unless otherwise specified, when a group has one or more connectable sites, any one or more of these sites of the group can be connected to other groups by chemical bonds. When the connection mode of the chemical bond is non-specific and there are H atoms at the connectable sites, then when connecting the chemical bonds, the number of H atoms at this site will correspondingly decrease according to the number of connected chemical bonds to form a group with the corresponding valence. The chemical bond connecting the site to other groups can be represented by a straight solid line bond a straight dashed line bond or a wavy line For example, the straight solid line bond in -OCH3 represents connection to other groups through the oxygen atom in this group; the straight dashed line bond in represents connection to other groups through both ends of the nitrogen atom in this group; the wavy line in represents connection to other groups through the 1- and 2-carbon atoms in this phenyl group; represents that any connectable site on this piperidyl group can be connected to other groups by 1 chemical bond, including at least these 4 connection modes. Even if an H atom is drawn on -N-, however it still includes groups with this connection mode. It's just that when connecting 1 chemical bond, the H at this site will correspondingly decrease by 1 to become the corresponding monovalent piperidyl group.

[0446] Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight-chain or branched-chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl includes C 1-2 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C 1-3 alkyl include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0447] Unless otherwise specified, the term "C 1-3 alkoxy" denotes those alkyl groups containing 1 to 3 carbon atoms that are connected to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy includes C 1-2 , C 2-3 , C3 and C2 alkoxy, etc. C 1-3Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0448] Unless otherwise specified, the term "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom.

[0449] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including from n to n + m carbon atoms, such as C 1-12 including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 , also includes any range from n to n + m, such as 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-membered to n + m-membered means that the number of atoms in the ring is from n to n + m, for example, a 3- to 12-membered ring includes a 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, and also includes any range from n to n + m, such as a 3- to 12-membered ring includes a 3- to 6-membered ring, 3- to 9-membered ring, 5- to 6-membered ring, 5- to 7-membered ring, 6- to 7-membered ring, 6- to 8-membered ring, and 6- to 10-membered ring, etc.

[0450] Unless otherwise specified, the term "C 3-6 cycloalkyl" refers to a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 , and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent, or polyvalent. Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0451] Unless otherwise specified, the term "3- to 6-membered heterocycloalkyl" by itself or in combination with other terms separately refers to a saturated cyclic group composed of 3 to 6 ring atoms, where 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remaining are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p, where p is 1 or 2). It is a monocyclic system. In addition, for the "3- to 6-membered heterocycloalkyl", the heteroatom can occupy the position where the heterocycloalkyl is connected to the rest of the molecule. The 3- to 6-membered heterocycloalkyl includes 3-membered, 4-membered, 5-membered, and 6-membered heterocycloalkyls, etc. Examples of the 3- to 6-membered heterocycloalkyl include, but are not limited to, oxiranyl, thiiranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrothiophene 1,1,-dioxide-3-yl, tetrahydrothiophene 1,1,-dioxide-2-yl, tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxolanyl, dithiolanyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl, etc.

[0452] Unless otherwise specified, the term "5- to 6-membered heteroaryl" refers to a cyclic group composed of 5 to 6 ring atoms with a conjugated π-electron system, where 1, 2, or 3 of the ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, where the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms can be optionally oxidized (i.e., C=O, NO, and S(O) p , where p is 1 or 2)). The 5- to 6-membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl includes 5-membered and 6-membered heteroaryls. Examples of the 5- to 6-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thiophenyl (including 2-thiophenyl and 3-thiophenyl, etc.), pyridinyl (including 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), etc.

[0453] Unless otherwise specified, the term "C 3-10"C alicyclic ring" means a saturated carbocyclic ring composed of 3 to 10 carbon atoms, including monocyclic and bicyclic systems, where the bicyclic system includes spiro, fused, and bridged rings. The C 3-10 alicyclic ring includes C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 alicyclic rings; it can be monovalent, divalent, or polyvalent. Examples of C 3-10 alicyclic rings include, but are not limited to, cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, norbornane ring, [2.2.2] bicyclooctane ring, etc.

[0454] Unless otherwise specified, the term "5-10 membered heteroalicyclic ring" means a saturated cyclic group composed of 5 to 10 ring atoms, where 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, where the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms can be optionally oxidized (i.e., C=O, NO, and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic systems, where the bicyclic system includes spiro, fused, and bridged rings. In addition, for this "5-10 membered heteroalicyclic ring", the heteroatoms can occupy the connection positions of the heteroalicyclic ring to the rest of the molecule. The 5-10 membered heteroalicyclic ring includes 5-6 membered heteroalicyclic rings, etc. Examples of 5-10 membered heteroalicyclic rings include, but are not limited to, azetidine ring, oxetane ring, thiolane ring, pyrrolidine ring, pyrazolidine ring, imidazolidine ring, tetrahydrothiophene ring (including tetrahydrothiophene-2-ring and tetrahydrothiophene-3-ring, etc.), tetrahydrofuran ring (including tetrahydrofuran-2-ring, etc.), tetrahydropyran ring, piperidine ring (including 1-piperidine ring, 2-piperidine ring, and 3-piperidine ring, etc.), piperazine ring (including 1-piperazine ring and 2-piperazine ring, etc.), morpholine ring (including 3-morpholine ring and 4-morpholine ring, etc.), dioxane ring, dithiane ring, isoxazolidine ring, isothiazolidine ring, 1,2-oxazine ring, 1,2-thiazine ring, hexahydropyridazine ring, homopiperazine ring, homopiperidine ring, or dioxepane ring, etc. It should be understood that the term "5-10 membered heteroalicyclic ring" includes the cases where the ring heteroatoms are oxidized. For example, when a substituent is represented as selected from , it at least contains of the specific structure.

[0455] Unless otherwise specified, the terms "benzene ring-fused C 5-6 alicyclic ring" or "benzene ring-fused 5-6 membered heteroalicyclic ring" respectively mean a fused bicyclic ring formed by a benzene ring and a C 5-6 alicyclic ring, or a 5-6 membered heteroalicyclic ring, for example: etc.

[0456] Unless otherwise specified, the term "5- or 6-membered heteroaryl-fused C 5-6 alkane ring" or "5- or 6-membered heteroaryl-fused 5- or 6-membered heteroalkane ring" respectively refers to a fused bicyclic ring formed by a 5- or 6-membered heteroaryl ring and a C 5-6 alkane ring, or a 5- or 6-membered heteroalkane ring, such as: etc.

[0457] Unless otherwise specified, the term "5- to 10-membered heteroaryl ring" refers to a cyclic group having a conjugated π-electron system composed of 5 to 10 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms are optionally oxidized (i.e., C=O, NO, and S(O) p , p is 1 or 2)). It can be a monocyclic, fused bicyclic, or fused tricyclic system, wherein each ring is aromatic. The 5- to 10-membered heteroaryl ring can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5- to 10-membered heteroaryl ring includes 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 5-membered, and 6-membered heteroaryl rings, etc. Examples of the 5- to 10-membered heteroaryl ring include, but are not limited to, pyrrole rings (including N-pyrrole rings, 2-pyrrole rings, 3-pyrrole rings, etc.), pyrazole rings (including 2-pyrazole rings, 3-pyrazole rings, etc.), imidazole rings (including N-imidazole rings, 2-imidazole rings, 4-imidazole rings, 5-imidazole rings, etc.), oxazole rings (including 2-oxazole rings, 4-oxazole rings, 5-oxazole rings, etc.), triazole rings (1H-1,2,3-triazole rings, 2H-1,2,3-triazole rings, 1H-1,2,4-triazole rings, 4H-1,2,4-triazole rings, etc.), tetrazole rings, isoxazole rings (3-isoxazole rings, 4-isoxazole rings, 5-isoxazole rings, etc.), thiazole rings (including 2-thiazole rings, 4-thiazole rings, 5-thiazole rings, etc.), furan rings (including 2-furan rings, 3-furan rings, etc.), thiophene rings (including 2-thiophene rings, 3-thiophene rings, etc.), pyridine rings (including 2-pyridine rings, 3-pyridine rings, 4-pyridine rings, etc.), pyrazine rings, pyrimidine rings (including 2-pyrimidine rings, 4-pyrimidine rings, etc.), benzothiazole rings (including 5-benzothiazole rings, etc.), purine rings, benzimidazole rings (including 2-benzimidazole rings, etc.), benzoxazole rings, indole rings (including 5-indole rings, etc.), isoquinoline rings (including 1-isoquinoline rings, 5-isoquinoline rings, etc.), quinoxaline rings (including 2-quinoxaline rings, 5-quinoxaline rings, etc.), quinoline rings (including 3-quinoline rings, 6-quinoline rings, etc.), etc.

[0458] Unless otherwise specified, the term "fused" refers to a non-aromatic, saturated or partially unsaturated ring system formed by two or more cyclic structures sharing two adjacent atoms with each other, including fused carbocyclic rings and fused heterocyclic rings, wherein the ring atoms of the fused heterocyclic rings include one or more heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0459] The term "treatment" means administering the compounds or formulations described in the present application to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0460] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0461] (ii) alleviating a disease or disease state, i.e., causing the disease or disease state to regress.

[0462] The term "prevention" means administering the compounds or formulations described in the present application to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, particularly when such a mammal is susceptible to the disease state but has not been diagnosed as having the disease state.

[0463] The term "therapeutically or prophylactically effective amount" means (i) an amount of a compound of the present application that 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 described herein. The amount of the compound of the present application that constitutes a "therapeutically or prophylactically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0464] The therapeutic or prophylactic dose of the compound of the present application can depend on, for example: the specific use for treatment or prevention, the manner of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present application in a pharmaceutical composition is not fixed and depends on various factors, including the dose, chemical properties (such as hydrophobicity), and route of administration. For example, the compound of the present application can be provided in a physiologically buffered aqueous solution containing about 0.1 - 10% w / v of the compound for parenteral administration. Some typical dose ranges are from about 0.001 mg / kg to about 1000 mg / kg body weight per day. The dose will likely depend on such variables as the type and progression of the disease or disorder, the general health status of the particular patient, the relative biological potency of the compound selected, the excipient formulation, and the route of administration. The effective dose can be extrapolated from a dose - response curve derived from in vitro or animal model test systems.

[0465] The words "comprise" or "comprising" and their English variants such as "comprises" or "comprising" should be understood in an open, non - exclusive sense, i.e., "including but not limited to".

[0466] "Pharmaceutical composition" means a composition containing one or more compounds, isomers or pharmaceutically acceptable salts thereof described in the present application, as well as other components such as physiological / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and thus exert biological activity.

[0467] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with a suitable pharmaceutically acceptable adjuvant.

[0468] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable adjuvants well known in the art.

[0469] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of the same with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present application.

[0470] The chemical reactions of the specific embodiments of the present application are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, sometimes those skilled in the art need to modify or select the synthesis steps or reaction processes on the basis of the existing embodiments.

[0471] The raw materials or intermediates used in the embodiments of the present application can be obtained commercially or prepared by methods of the prior art.

[0472] An important consideration in the synthesis route planning in the art is to select a suitable protecting group for reactive functional groups (such as amino groups in the present application). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0473] In some embodiments, some compounds of the present application can be prepared by those skilled in the art of organic synthesis with reference to the following routes:

[0474] Route 1:

[0475]

[0476] Wherein,

[0477] R 1 、L 2 and Ring A are defined as described above;

[0478] Y is selected from a halogen (such as bromine).

[0479] Route 2:

[0480]

[0481] Wherein,

[0482] R 1 and the definition of ring A are as described above;

[0483] Y is selected from a halogen (such as bromine).

[0484] For clarity, the present application is further illustrated by examples, but the examples do not limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification. Detailed Description of the Invention

[0485] The present application will be described in detail below by way of examples, but this does not mean any adverse limitation to the present application. The present application has been described in detail herein, and its specific embodiments have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0486] Example 1: Preparation of Compound 1

[0487]

[0488] 6-Bromopyridin-3-amine (0.50 g), diisopropylethylamine (0.49 g), methanesulfonic anhydride (1.01 g) were stirred at room temperature in dichloromethane (5 mL). After the reaction was complete, the solvent was removed under reduced pressure, and the intermediate 1A (0.43 g) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 329.0 [M+H] + .

[0489] Intermediate 1A (200 mg), intermediate K (256 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (25 mg), potassium phosphate (203 mg) were reacted in dioxane (10 mL) under nitrogen protection by microwave at 120 °C. After the reaction was complete, it was filtered and concentrated to obtain intermediate 1B (365 mg). MS (ESI): m / z 557.3 [M+H] + .

[0490] Intermediate 1B (365 mg), potassium carbonate (100 mg) were stirred and reacted in 1,4-dioxane (5 mL) and water (1 mL) at 100 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution, and Intermediate 1C (95 mg) was obtained by column chromatography (eluent: dichloromethane / methanol). MS (ESI): m / z 479.3 [M+H] + .

[0491] Intermediate 1C (95 mg) was stirred and reacted in formic acid (5 mL) at 70 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution, sodium bicarbonate aqueous solution was added to the residue to adjust the pH to alkaline, a solid precipitated, filtered, and the filter cake was slurried with methanol to obtain Compound 1 of Example 1 (47 mg). MS (ESI): m / z 423.2 [M+H] + .

[0492] 1 H NMR (500 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.21 (s, 1H), 9.14 (s, 1H), 7.98 (d, J = 2.7 Hz, 1H), 7.42 (dd, J = 8.9, 2.7 Hz, 1H), 7.27 (s, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.08 (s, 1H), 5.11–4.93 (m, 1H), 3.61 - 3.54 (m, 1H), 3.07 - 3.00 (m, 1H), 2.90 (s, 3H), 2.48 - 2.43 (m, 1H), 2.04 - 1.97 (m, 1H), 1.94–1.85 (m, 1H), 1.76 - 1.68 (m, 2H), 1.64 - 1.57 (m, 1H), 1.03 (d, J = 6.7 Hz, 6H).

[0493] Example 2: Preparation of Compound 2

[0494]

[0495] Referring to the preparation method of the compound in Reference Example 1, 6-bromopyridin-3-amine was replaced with 6-bromo-N-methylpyridin-3-amine to obtain a crude product of Compound 2.

[0496] The crude product of Compound 2 was purified by medium and low pressure preparative liquid phase (silica gel column, dichloromethane / methanol (30 / 1)) to obtain Compound 2 (13 mg). MS (ESI): m / z 437.2 [M+H] + .

[0497] 11H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.28 (s, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.59 (dd, J = 9.0, 2.8 Hz, 1H), 7.28 (s, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.12 (s, 1H), 4.99 (s, 1H), 3.61 - 3.54 (m, 1H), 3.19 (s, 3H), 3.07 - 3.00 (m, 1H), 2.95 (s, 3H), 2.48 - 2.45 (m, 1H), 2.05–1.97 (m, 1H), 1.95–1.84 (m, 1H), 1.76 - 1.67 (m, 2H), 1.64 - 1.56 (m, 1H), 1.03 (d, J = 6.2 Hz, 6H).

[0498] Example 3: Preparation of Compound 3

[0499]

[0500] Referring to the preparation method of the compound in Reference Example 1, 6-bromopyridin-3-amine was replaced with 4-bromo-3-fluoroaniline therein to obtain the crude product of Compound 3.

[0501] The crude product of Compound 3 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), the eluent contained one-thousandth ammonia water) to obtain Compound 3 (10 mg). MS (ESI): m / z 440.2 [M + H] + .

[0502] 1 1H NMR (500 MHz, DMSO-d6) δ 11.73 (s, 1H), 9.37 (s, 1H), 8.00 (brs, 1H), 7.96 (s, 1H), 6.99 (d, J = 13.0,, 1H), 6.94 - 6.90 (m, 2H), 5.71 (s, 1H), 4.99 (s, 1H), 3.67–3.49 (m, 1H), 3.06 - 2.99 (m, 1H), 2.91 (s, 3H), 2.48 - 2.42 (m, 1H), 2.03 - 1.96 (m, 1H), 1.93 - 1.85 (m, 1H), 1.76 - 1.65 (m, 2H), 1.62 - 1.54 (m, 1H), 1.03 (d, J = 5.35 Hz, 6H).

[0503] Example 4: Preparation of Compound 4

[0504]

[0505] 6-Bromo-N-methylpyridin-3-amine (500 mg), triethylamine (580 mg), and acetic anhydride (468 mg) were stirred at room temperature in dichloromethane (5 mL). After the reaction was complete, the solvent was removed by distillation under reduced pressure, and the residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 4A (396 mg). MS (ESI): m / z 229.0 [M+H] + 。

[0506] Referring to the preparation method of the compound of Reference Example 2, intermediate 2A was replaced with intermediate 4A to obtain the crude product of compound 4.

[0507] The crude product of compound 4 was purified by medium and low pressure preparative liquid chromatography (silica gel column, dichloromethane / methanol (30 / 1)) to obtain compound 4 (28 mg). MS (ESI): m / z 401.2 [M+H] + 。

[0508] 1 H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.29 (s, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.52 (dd, J = 9.1, 2.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.15 (s, 1H), 5.13–4.92 (m, 1H), 3.58 (h, J = 6.7 Hz, 1H), 3.09 (s, 3H), 3.08 - 3.03 (m, 1H), 2.49 - 2.44 (m, 1H), 2.06 - 1.98 (m, 1H), 1.94 - 1.88 (m, 1H), 1.76 (s, 3H), 1.75–1.67 (m, 2H), 1.64 - 1.56 (m, 1H), 1.03 (dd, J = 6.7, 2.6 Hz, 6H).

[0509] Example 5: Preparation of Compound 5

[0510]

[0511] Under nitrogen protection at 0 °C, methylsulfonamide (20.00 g) and tert-butyldimethylchlorosilane (41.20 g) were placed in chloroform (350 mL), and triethylamine (42.60 g) was added. The mixture was stirred at room temperature. After the reaction was complete, the solvent was removed by distillation under reduced pressure. Water and ethyl acetate were added to the residue, and the layers were separated. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 5A (43.00 g), which was used directly in the next step without further purification.

[0512] Under nitrogen protection, triphenylphosphine (18.19 g) and hexachloroethane (16.42 g) were placed in chloroform (90 ml), and the mixture was stirred at 73 °C for 6 h. After cooling to room temperature, triethylamine (10.50 g) was added, and the mixture was stirred at room temperature for 15 minutes. Then it was cooled to 0 °C, and a chloroform (10 ml) solution of intermediate 5A (12.10 g) was added, and the mixture was stirred at 0 °C for 0.5 h. A solution of 6-bromopyridin-3-amine (2.00 g) and triethylamine (11.70 g) in tetrahydrofuran (10 ml) was added, and the mixture was stirred at 0 °C for reaction. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution. Water and dichloromethane were added to the residue, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 5B (1.60 g).

[0513] Referring to the preparation method of intermediate 1B in Reference Example 1, intermediate 1A was replaced with intermediate 5B to obtain intermediate 5C (0.07 g). MS (ESI): m / z 592.4 [M+H] + 。

[0514] Intermediate 5C (0.07 g) and a 1,4-dioxane solution of hydrochloric acid (0.6 mL, 4 mol / L) were placed in dichloromethane (10 mL), and the mixture was stirred at room temperature for reaction. After the reaction was complete, saturated aqueous sodium bicarbonate was added to adjust the pH to 9-10, and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain intermediate 5D (0.05 g), which was directly used in the next step without further purification.

[0515] Intermediate 5D (0.05 g) was placed in formic acid (20 mL), and the mixture was stirred at 70 °C for reaction. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution, and the product was separated by medium and low pressure preparative liquid chromatography (C18 chromatographic column, acetonitrile / water (25 / 75), and the eluent contained one-thousandth ammonia water) to obtain compound 5 (6 mg). MS (ESI): m / z 373.2 [M+H] + 。

[0516] 11H NMR (500 MHz, DMSO) δ 11.77 (s, 1H), 10.03 (9.85) (s, 1H), 8.99 (8.56) (s, 1H), 8.32 (8.48) (s, 1H), 8.21 (7.98) (s, 1H), 7.74 - 7.72 (7.43 - 7.42) (m, 1H), 7.29 (s, 1H), 6.94 (s, 1H), 6.03 (s, 1H), 4.99 (s, 1H), 3.62 - 3.51 (m, 1H), 3.09 - 2.98 (m, 1H), 2.48 - 2.40 (m, 1H), 2.05 - 1.95 (m, 1H), 1.94 - 1.84 (m, 1H), 1.79 - 1.66 (m, 2H), 1.65 - 1.55 (m, 1H), 1.03 (d, 6H).

[0517] Example 6: Preparation of Compound 6

[0518]

[0519] 6 - Bromopyridin - 3 - amine (500 mg), triethylamine (731 mg) and acetic anhydride (590 mg) were stirred at room temperature in dichloromethane (5 mL). After the reaction was complete, the solvent was removed by distillation under reduced pressure, and the residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain Compound 6A (0.528 g). MS (ESI): m / z 214.85 [M + H] + .

[0520] Referring to the preparation method of Compound 2 in Reference Example 2, Intermediate 2A was replaced with Intermediate 6A to obtain the crude product of Compound 6.

[0521] The crude product of Compound 6 was slurried with methanol to obtain Compound 6 (46 mg). MS (ESI): m / z 387.2144 [M + H] + .

[0522] 11H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 9.76 (s, 1H), 8.93 (s, 1H), 8.27 (s, 1H), 7.70 (d, J = 8.20 Hz, 1H), 7.26 (s, 1H), 6.95 (d, J = 7.10 Hz, 1H), 6.03 (s, 1H), 5.13 - 4.90 (m, 1H), 3.56 - 3.60 (m, 1H), 3.01 - 3.04 (m, 1H), 2.44 - 2.47 (m, 1H), 2.01 (s, 3H), 1.99 - 1.96 (m, 1H), 1.92 - 1.84 (m, 1H), 1.76 - 1.68 (m, 2H), 1.64 - 1.56 (m, 1H), 1.03 (d, J = 6.40 Hz, 6H).

[0523] Example 7: Preparation of Compound 7

[0524]

[0525] 4-Bromoaniline (1.00 g), diisopropylethylamine (3.00 g), and methanesulfonic anhydride (4.10 g) were stirred at room temperature in dichloromethane (15 mL). After the reaction was complete, the solvent was removed under reduced pressure, and the intermediate 7A (0.66 g) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 325.0 [M-H] - .

[0526] Intermediate 7A (200 mg), intermediate K (125 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (95 mg), potassium phosphate (283 mg), and diatomaceous earth (480 mg) were reacted in toluene / tert-butanol (10 mL, 5:1 (v / v)) under nitrogen protection at 120 °C in an oil bath. After the reaction was complete, the mixture was filtered, concentrated, and the intermediate 7B (208 mg) was obtained by column chromatography (eluent: dichloromethane / methanol). MS (ESI): m / z 556.3 [M+H] + .

[0527] Intermediate 7B (208 mg) and potassium carbonate (100 mg) were stirred at 100 °C in 1,4-dioxane (5 mL) and water (5 mL). After the reaction was complete, the solvent was removed under reduced pressure, and the intermediate 7C (130 mg) was obtained by column chromatography (eluent: dichloromethane / methanol). MS (ESI): m / z 478.3 [M+H] + .

[0528] Referring to the preparation method of Compound 1 in Reference Example 1, replace Intermediate 1C with Intermediate 7C therein to obtain the crude product of Compound 7.

[0529] The crude product of Compound 7 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 7 (40 mg). MS (ESI): m / z 442.2 [M+H] + 。

[0530] 1 1H NMR (500 MHz, DMSO-d6) δ 11.67 (s, 1H), 9.10 (s, 1H), 8.27 (s, 1H), 7.28 (d, J = 8.30 Hz, 2H), 7.11 - 6.99 (m, 2H), 6.95 (d, J = 7.8 Hz, 1H), 5.60 (s, 1H), 4.99 (m, 1H), 3.59 - 2.55 (m, 1H), 3.05 - 2.98 (m, 1H), 2.85 (s, 3H), 2.47 - 2.42 (m, 1H), 2.02 - 1.98 (m, 1H), 1.95 - 1.83 (m, 1H), 1.74 - 1.67 (m, 2H), 1.63 - 1.56 (m, 1H), 1.03 (d, J = 6.60 Hz, 6H).

[0531] Example 8: Preparation of Compound 8

[0532]

[0533] 3-Amino-6-bromopyridine (500 mg), pyridine (700 mg), and cyclopropanesulfonyl chloride (800 mg) were stirred and reacted at 50 °C in dichloromethane (20 mL). After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution, and the residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain Intermediate 8A (758 mg). MS (ESI): m / z 276.9 [M+H] + 。

[0534] 1 1H NMR (500 MHz, DMSO-d6): δ 10.17 (s, 1H), 8.25 - 8.24 (m, 1H), 7.62 - 7.61 (m, 2H), 2.77 - 2.72 (m, 1H), 1.00 - 0.92 (m, 4H).

[0535] Intermediate 8A (216 mg), Intermediate K (120 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (65 mg), (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) chloride (100 mg), and potassium phosphate (330 mg) were placed in 1,4-dioxane (50 mL). Under nitrogen protection, the reaction was carried out in an oil bath at 110 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure. The resulting residue 8B was used directly in the next reaction without further purification.

[0536] Referring to the preparation method of Compound 1 in Reference Example 1, Intermediate 1C was replaced with Intermediate 8B to obtain the crude product of Compound 8.

[0537] The crude product of Compound 8 was first preliminarily purified by column chromatography (eluent: dichloromethane / methanol), and then purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (40 / 60), and the eluent contained one-thousandth ammonia water) to obtain Compound 8 (10 mg). MS(ESI): m / z 449.1965 [M+H] + 。

[0538] 1 1H NMR (500 MHz, DMSO-d6): δ 11.81 (s, 1H), 9.13 (brs, 1H), 9.13 (s, 1H), 7.99 (s, 1H), 7.43 (d, J = 7.60 Hz, 1H), 7.26 (s, 1H), 6.94 (d, J = 7.05 Hz, 1H), 6.08 (s, 1H), 4.99 (s, 1H), 3.61 - 3.52 (m, 1H), 3.10 - 2.98 (m, 1H), 2.48 - 2.41 (m, 1H), 2.06 - 1.95 (m, 1H), 1.94 - 1.85 (m, 1H), 1.80 - 1.66 (m, 2H), 1.64 - 1.55 (m, 1H), 1.03 (d, J = 6.25 Hz, 6H), 0.96 - 1.80 (m, 5H).

[0539] Example 9: Preparation of Compound 9

[0540]

[0541] Referring to the preparation method of Compound 1 in Reference Example 1, Intermediate 1A was replaced with 2-bromo-5-methoxypyridine to obtain the crude product of Compound 9.

[0542] The crude product of Compound 9 was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 9 (18 mg). MS(ESI): m / z 360.2031[M+H] + 。

[0543] 1 1H NMR(500 MHz, DMSO-d6) δ 11.68(s, 1H), 8.76(s, 1H), 7.84(s, 1H), 7.27(d, J = 12.5 Hz, 2H), 6.95(d, J = 7.0 Hz, 1H), 6.03(s, 1H), 4.99(s, 1H), 3.73(s, 3H), 3.58(dd, J = 13.3, 6.4 Hz, 1H), 3.02(s, 1H), 2.47 - 2.44(m, 1H), 2.02 - 1.97(m, 1H), 1.93 - 1.85(m, 1H), 1.74 - 1.67(m, 2H), 1.62 - 1.56(m, 1H), 1.03(d, J = 6.4 Hz, 6H).

[0544] Example 10: Preparation of Compound 10

[0545]

[0546] Under nitrogen protection at 0 °C, 4-bromo-3-fluorobenzyl alcohol (2.0 g), triethylamine (2.0 g), and methanesulfonic anhydride (2.7 g) were placed in dichloromethane (20 mL) and stirred at 0 °C for reaction. After the reaction was complete, dimethylamine (1.3 g) was added and stirring was continued. After the reaction was complete, the solvent was removed by distillation under reduced pressure, and the intermediate 10A (1.9 g) was obtained by column chromatography (eluent: dichloromethane / methanol).

[0547] Referring to the preparation method of Compound 1 in Reference Example 1, replacing intermediate 1A with intermediate 10A therein, the crude product of Compound 10 was obtained.

[0548] The crude product of Compound 10 was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (25 / 75), and the eluent contained one-thousandth ammonia water) to obtain Compound 10 (60 mg). MS(ESI): m / z 404.2458[M+H] + 。

[0549] 11H NMR (500 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.96 - 7.91 (m, 2H), 6.99 (dd, J = 12.8, 1.2 Hz, 1H), 6.95 - 6.91 (m, 2H), 5.73 (s, 1H), 4.99 (s, 1H), 3.60 - 3.54 (m, 1H), 3.27 (s, 2H), 3.06 - 3.01 (m, 1H), 2.49 - 2.41 (m, 1H), 2.11 (s, 6H), 2.04 - 1.97 (m, 1H), 1.94 - 1.85 (m, 1H), 1.74 - 1.64 (m, 2H), 1.61 - 1.56 (m, 1H), 1.03 (d, J = 6.3 Hz, 6H).

[0550] Example 11: Preparation of Compound 11

[0551]

[0552] Referring to the preparation method of Compound 1 in Reference Example 1, replace 6-bromopyridin-3-amine with 6-chloro-2-(trifluoromethyl)pyridin-3-amine to obtain the crude product of Compound 11.

[0553] The crude product of Compound 11 was purified by column chromatography (eluent: dichloromethane / methanol (96 / 4)) to obtain Compound 11 (40 mg). MS (ESI): m / z 491.1687 [M + H] + .

[0554] 1 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 9.75 (s, 1H), 9.26 (s, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 9.1 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.22 (s, 1H), 5.00 (s, 1H), 3.60 - 3.53 (m, 1H), 3.11 - 3.04 (m, 1H), 3.02 (s, 3H), 2.48 - 2.44 (m, 1H), 2.05 - 1.88 (m, 2H), 1.76 - 1.56 (m, 3H), 1.03 (d, J = 5.7 Hz, 6H).

[0555] Example 12: Preparation of Compound 12

[0556]

[0557] 6-Bromopyridin-3-amine (1000 mg), sodium tert-butoxide (1666 mg), and 1-bromo-2-methoxyethane (1606 mg) were stirred and reacted in acetonitrile (10 mL) at 80 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure, and the intermediate 12A (486 mg) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 231.0 [M+H] + 。

[0558] Intermediate 12A (486 mg), N,N-dimethylaminopyridine (52 mg), and di-tert-butyl carbonate (660 mg) were stirred and reacted in dichloromethane (5 mL) at room temperature. After the reaction was complete, the solvent was removed by distillation under reduced pressure, and the intermediate 12B (0.36 g) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 331.0 [M+H] + 。

[0559] Intermediate K1 (200 mg), intermediate 12B (240 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (120 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (160 mg), cesium carbonate (2400 mg), and diatomaceous earth (800 mg) were placed in toluene / tert-butanol (35 mL, 5:1 (v / v)). After addition, the mixture was stirred and reacted at 120 °C. After the reaction was complete, it was filtered, the filtrate was concentrated under reduced pressure, and the intermediate 12C (224 mg) was obtained by column chromatography (eluent: dichloromethane / methanol). MS (ESI): m / z 559.58 [M+H] + 。

[0560] Intermediate 12C (224 mg) was stirred and reacted in formic acid (10 mL) at 70 °C. After the reaction was complete, it was concentrated, the pH of the residue was adjusted to basic with saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the compound 12 (105 mg) was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), the eluent contained one-thousandth ammonia). MS (ESI): m / z 434.2403 [M+H] + 。

[0561] 11H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.27 (s, 1H), 8.22 (s, 1H), 8.04 - 8.03 (m, 1H), 7.57 - 7.55 (m, 1H), 7.29 (s, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.12 (s, 1H), 5.00 - 4.99 (m, 1H), 3.81 - 3.76 (m, 2H), 3.61 - 3.54 (m, 1H), 3.41 - 3.39 (m, 2H), 3.19 (s, 3H), 3.08 - 3.00 (m, 1H), 2.48 - 2.44 (m, 1H), 2.03 - 1.99 (m, 1H), 1.93 - 1.85 (m, 1H), 1.76 - 1.68 (m, 2H), 1.63 - 1.57 (m, 1H), 1.03 (d, J = 6.5 Hz, 6H).

[0562] Example 13: Preparation of Compound 13

[0563]

[0564] Referring to the preparation method of Compound 12 in Reference Example 12, replace Intermediate 12B with 2-bromopyridine and Intermediate K1 with Intermediate K to obtain the crude product of Compound 13.

[0565] The crude product of Compound 13 was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (28 / 72), and the eluent contained one-thousandth ammonia water) to obtain Compound 13 (50 mg). MS (ESI): m / z 330.1927 [M + H] + .

[0566] 1 1H NMR (500 MHz, DMSO-d6): δ 11.79 (s, 1H), 9.04 (s, 1H), 8.09 (d, J = 3.95 Hz, 1H), 7.51 (t, J = 7.50 Hz, 1H), 7.24 (s, 1H), 6.95 (d, J = 7.25 Hz, 1H), 6.66 (t, J = 5.40 Hz, 1H), 6.10 (s, 1H), 5.00 (s, 1H), 3.60 - 3.56 (m, 1H), 3.05 - 3.02 (m, 1H), 2.47 - 2.43 (m, 1H), 2.01 - 1.98 (m, 1H), 1.93 - 1.85 (m, 1H), 1.76 - 1.66 (m, 2H), 1.64 - 1.58 (m, 1H), 1.03 (d, J = 6.30 Hz, 6H).

[0567] Example 14: Preparation of Compound 14

[0568]

[0569] 6-Bromo-N-methylpyridin-3-amine (500 mg), 4-chlorobutyryl chloride (530 mg), and N,N-diisopropylethylamine (1121 mg) were placed in dichloromethane (10 mL). After addition, the reaction was stirred at room temperature. After the reaction was complete, the solvent was removed by distillation under reduced pressure, and the intermediate 14A (800 mg) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 276.9 [M+H] + 。

[0570] Intermediate 14A (800 mg) and potassium tert-butoxide (485 mg) were placed in acetonitrile (10 mL), and the reaction was stirred at 80 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure, and the intermediate 14B (572 mg) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 241.0 [M+H] + 。

[0571] Referring to the preparation method of compound 12 in Reference Example 12, intermediate 12B was replaced with intermediate 14B and intermediate K1 was replaced with intermediate K to obtain the crude product of compound 14.

[0572] The crude product of compound 14 was purified by column chromatography (eluent: dichloromethane / methanol = 5 / 1) to obtain compound 14 (30 mg). MS (ESI): m / z 413.2303 [M+H] + 。

[0573] 1 H NMR (500 MHz, DMSO-d6) δ 11.79 (s, 1H), 9.08 (s, 1H), 8.30 (d, J = 2.7 Hz, 1H), 7.86 - 7.85 (m, 1H), 7.30 (s, 1H), 6.95 (d, J = 7.7 Hz, 1H), 6.06 (s, 1H), 4.99 (m, 1H), 3.78 (t, J = 7.0 Hz, 2H), 3.61 - 3.54 (m, 1H), 3.08 - 2.97 (m, 1H), 2.47 (d, J = 7.2 Hz, 1H), 2.46 - 2.43 (m, 2H), 2.09 - 2.03 (m, 2H), 2.02 - 1.98 (m, 1H), 1.93 - 1.85 (m, 1H), 1.75 - 1.68 (m, 2H), 1.63 - 1.56 (m, 1H), 1.03 (d, J = 6.4 Hz, 6H).

[0574] Example 15: Preparation of Compound 15

[0575]

[0576] Referring to the preparation method of Compound 1 in Reference Example 1, replace 6-bromopyridin-3-amine therein with 2-amino-5-bromopyridine to obtain the crude product of Compound 15.

[0577] The crude product of Compound 15 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (22 / 78), and the eluent contained one-thousandth ammonia water) to obtain Compound 15 (13 mg). MS (ESI): m / z 423.1810 [M+H] + 。

[0578] 1 1H NMR (500 MHz, DMSO-d6) δ 8.05 (d, J = 2.9 Hz, 1H), 7.83 (s, 1H), 7.49 - 7.37 (m, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 5.50 (s, 1H), 4.98 - 4.97 (m, 1H), 3.59 - 3.55 (m, 1H), 3.02 - 2.96 (m, 1H), 2.83 (s, 3H), 2.46 - 2.40 (m, 1H), 2.02 - 1.96 (m, 1H), 1.92 - 1.83 (m, 1H), 1.75 - 1.66 (m, 2H), 1.59 - 1.55 (m, 1H), 1.03 (d, J = 6.5 Hz, 6H).

[0579] Example 16: Preparation of Compound 16

[0580]

[0581] Methylamine hydrochloride (1000 mg), sodium hydroxide (285 mg), and 4-bromo-3-fluorobenzenesulfonyl chloride (1000 mg) were stirred at room temperature in acetonitrile (20 mL). After the reaction was complete, the solvent was removed by distillation under reduced pressure, and the intermediate 16A (800 mg) was separated by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 268.04 [M-H] - 。

[0582] Referring to the preparation method of Compound 1 in Reference Example 1, replace Intermediate 1A therein with Intermediate 16A and Intermediate K with Intermediate K1 to obtain the crude product of Compound 16.

[0583] The crude product of Compound 16 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 16 (60 mg). MS (ESI): m / z 440.5 [M+H] + 。

[0584] 1 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.70 (s, 1H), 8.20 (m, 1H), 7.46 - 7.44 (m, 2H), 7.23 - 7.20 (m, 1H), 6.95 (d, J = 7.8 Hz, 1H), 5.83 (s, 1H), 5.00 (m, 1H), 3.59 - 3.55 (m, 1H), 3.09 - 3.03 (m, 1H), 2.48 - 2.44 (s, 1H), 2.39 (d, J = 4.1 Hz, 3H), 2.04 - 2.00 (m, 1H), 1.96 - 1.86 (m, 1H), 1.76 - 1.67 (m, 2H), 1.64 - 1.56 (m, 1H), 1.03 (d, J = 6.6 Hz, 6H).

[0585] Example 17: Preparation of Compound 17

[0586]

[0587] 2-Bromo-4-aminopyridine (500 mg), methanesulfonic anhydride (503 mg), and N,N-diisopropylethylamine (747 mg) were stirred at room temperature in dichloromethane (30 mL). After the reaction was complete, the reaction solution was evaporated under reduced pressure, and the intermediate 17A (200 mg) was obtained by column chromatography (eluent: dichloromethane / methanol). MS (ESI): m / z 251.02 [M + H] + .

[0588] Referring to the preparation method of Compound 12 in Reference Example 12, intermediate 12B was replaced with intermediate 17A to obtain the crude product of Compound 17.

[0589] The crude product of Compound 17 was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (40 / 60), and the eluent contained one-thousandth ammonia water) to obtain Compound 17 (30 mg). MS (ESI): m / z 423.1813 [M + H] + .

[0590] 11H NMR (500 MHz, DMSO-d6): δ 8.78 (s, 1H), 7.66 (d, J = 8.85 Hz, 1H), 6.95 (d, J = 7.40 Hz, 1H), 6.58 (s, 1H), 6.24 (dd, J = 1.50, 5.80 Hz, 1H), 5.81 (s, 1H), 4.99 (s, 1H), 3.61 - 3.54 (m, 1H), 3.00 - 2.95 (m, 1H), 2.73 (s, 3H), 2.45 - 2.40 (m, 1H), 1.99 - 1.95 (m, 1H), 1.91 - 1.85 (m, 1H), 1.71 - 1.68 (m, 2H), 1.64 - 1.59 (m, 1H), 1.03 (d, J = 6.50 Hz, 6H).

[0591] Example 18: Preparation of Compound 18

[0592]

[0593] At 0 °C under nitrogen protection, sodium hydride (1.3 g) and 6-bromo-3-pyridinemethanol (2.0 g) were stirred in N,N-dimethylformamide (20 mL) at 0 °C for half an hour. Methyl iodide (2.3 g) was added, and the reaction was stirred at 0 °C. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 18A (1.6 g). MS (ESI): m / z 202.0 [M+H] + 。

[0594] Referring to the preparation method of Compound 1 in Reference Example 1, intermediate 1A was replaced with intermediate 18A, and intermediate K was replaced with intermediate K1 to obtain the crude product of Compound 18.

[0595] The crude product of Compound 18 was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (35 / 65), and the eluent contained one-thousandth ammonia water) to obtain Compound 18 (19 mg). MS (ESI): m / z 374.2188 [M+H] + 。

[0596] 11H NMR (500 MHz, DMSO-d6) δ 11.79 (s, 1H), 9.09 (s, 1H), 8.04 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 6.95 (d, J = 6.9 Hz, 1H), 6.10 (s, 1H), 5.00 (s, 1H), 4.26 (s, 2H), 3.58 (dd, J = 13.3, 6.7 Hz, 1H), 3.23 (s, 3H), 3.05 - 3.04 (m, 1H), 2.47 - 2.45 (m, 1H), 2.08 - 1.99 (m, 1H), 1.93 - 1.85 (m, 1H), 1.72 - 1.68 (m, 2H), 1.63 - 1.57 (m, 1H), 1.03 (d, J = 6.4 Hz, 6H).

[0597] Example 19: Preparation of Compound 19

[0598]

[0599] Referring to the preparation method of Compound 17 in Reference Example 17, replace 2-bromo-4-aminopyridine therein with 5-amino-2-bromopyrimidine to obtain the crude product of Compound 19.

[0600] The crude product of Compound 19 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (40 / 60), and the eluent contained one-thousandth ammonia water) to obtain Compound 19 (32 mg). MS (ESI): m / z 424.1760 [M + H] + .

[0601] 1 1H NMR (500 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.17 (s, 2H), 6.95 (d, J = 7.45 Hz, 1H), 6.20 (s, 1H), 4.99 (s, 1H), 3.61 - 3.53 (m, 1H), 3.04 - 3.00 (m, 1H), 2.79 (s, 3H), 2.48 - 2.42 (m, 1H), 2.02 - 1.97 (m, 1H), 1.92 - 1.84 (m, 1H), 1.75 - 1.69 (m, 2H), 1.65 - 1.60 (m, 1H), 1.03 (d, J = 6.50 Hz, 6H).

[0602] Example 20: Preparation of Compound 20

[0603]

[0604] In Example 12, compound 12 (80 mg) was stirred and reacted in dilute hydrochloric acid (1 M, 5 mL) at 50 °C. After the reaction was complete, the solvent was removed by evaporation under reduced pressure from the reaction solution. The residue was adjusted to alkaline pH with saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation under reduced pressure from the filtrate. It was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain compound 20 (25 mg). MS (ESI): m / z 403.2455 [M+H] + 。

[0605] 1 1H NMR (500 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.43 (s, 1H), 7.57 (d, J = 2.9 Hz, 1H), 7.11 (s, 1H), 6.98 - 6.94 (m, 2H), 5.90 (s, 1H), 5.11 - 4.84 (m, 2H), 3.59 - 3.56 (m, 1H), 3.48 (t, J = 5.6 Hz, 2H), 3.28 (s, 3H), 3.13 (m, 2H), 3.04 - 2.95 (m, 1H), 2.46 - 2.39 (m, 1H), 2.00 - 1.96 (m, 1H), 1.94 - 1.83 (m, 1H), 1.73 - 1.67 (m, 2H), 1.63 - 1.56 (s, 1H), 1.03 (d, J = 6.6 Hz, 6H).

[0606] Example 21: Preparation of Compound 21

[0607]

[0608] Intermediate K1 (200 mg), 6-chloro-2,3-dihydrofuro[2,3-b]pyridine (120 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (120 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (160 mg), cesium carbonate (2400 mg), and diatomaceous earth (800 mg) were stirred and reacted in toluene / tert-butanol (35 mL, 5:1 (v / v)) under nitrogen protection at 120 °C. After the reaction was complete, it was filtered, and the solvent was removed by evaporation under reduced pressure from the reaction solution. It was separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 21A (108 mg). MS (ESI): m / z 428.51 [M+H] + 。

[0609] Intermediate 21A (108 mg) was stirred and reacted in formic acid (5 mL) at 70 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution. The residue was adjusted to alkaline pH with saturated aqueous sodium bicarbonate, and a solid precipitated. It was filtered, and the filter cake was slurried with methanol to obtain Compound 21 (49 mg). MS (ESI): m / z 372.2036 [M+H] + 。

[0610] 1 H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.89 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.01 (s, 1H), 5.00 (s, 1H), 4.49 (t, J = 8.4 Hz, 2H), 3.58 - 3.57 (m, 1H), 3.08 - 3.02 (m, 3H), 2.48 - 2.40 (m, 1H), 2.07 - 1.95 (m, 1H), 1.92 - 1.84 (m, 1H), 1.77 - 1.65 (m, 2H), 1.63 - 1.54 (m, 1H), 1.03 (d, J = 6.6 Hz, 6H).

[0611] Example 22: Preparation of Compound 22

[0612]

[0613] 1-N-Methanesulfonyl-4-piperidone (264 mg), Intermediate K1 (200 mg), and acetic acid (42.8 mg) were stirred and reacted in 1,2-dichloroethane (15 mL) under nitrogen protection at room temperature. After the reaction was complete, sodium triacetoxyborohydride (550 mg) was added, and the reaction was stirred at room temperature. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution, and it was separated by column chromatography (eluent: dichloromethane / methanol) to obtain Intermediate 22A (300 mg). MS (ESI): m / z 470.6 [M+H] + 。

[0614] Intermediate 22A (200 mg) was stirred and reacted in formic acid (10 mL) at 110 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution. Triethylamine was added to the residue to adjust the pH to alkaline, and the solvent was removed by distillation under reduced pressure from the reaction solution. The crude product of Compound 22 was purified by medium and low pressure preparative liquid chromatography (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 22 (37 mg). MS (ESI): m / z 414.5 [M+H] + 。

[0615] 11H NMR (500 MHz, DMSO-d6) δ 11.17 (s, 1H), 6.94 (d, J = 7.8 Hz, 1H), 5.25 (s, 1H), 5.04 - 4.84 (m, 2H), 3.60 - 3.54 (m, 1H), 3.48 - 3.44 (m, 2H), 3.26 (s, 1H), 2.98 - 2.89 (m, 1H), 2.89 - 2.77 (m, 5H), 2.41 - 2.35 (m, 1H), 2.03 - 1.91 (m, 3H), 1.88 - 1.84 (m, 1H), 1.71 - 1.62 (m, 2H), 1.57 - 1.52 (m, 1H), 1.46 - 1.39 (m, 2H), 1.03 (d, J = 6.5 Hz, 6H).

[0616] Example 23: Preparation of Compound 23

[0617]

[0618] 4-Bromo-2-fluoroaniline (3.00 g), N,N-diisopropylethylamine (10.20 g), and methanesulfonic anhydride (8.25 g) were placed in dichloromethane (85 mL). The reaction was stirred at room temperature under nitrogen protection. After the reaction was complete, the solvent was removed by distillation under reduced pressure. Dichloromethane and saturated ammonium chloride aqueous solution were added to the residue. The organic phase was separated, dried, filtered, and the solvent was removed by distillation under reduced pressure to obtain intermediate 23A (3.80 g).

[0619] Intermediate K (0.60 g), intermediate 23A (1.00 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.46 g), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.28 g), tripotassium phosphate (1.40 g), and diatomaceous earth (2.4 g) were placed in toluene / tert-butanol (30 mL, 5:1 (v / v)). The reaction was stirred at 120 °C under nitrogen protection. After the reaction was complete, it was filtered, the solvent was removed by distillation under reduced pressure, and the residue was separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 23B (1.00 g).

[0620] Intermediate 23B (0.12 g) was placed in formic acid (20 mL). The reaction was stirred at 70 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure. The residue was intermediate 23C, which was not further purified and was directly used in the next step of the reaction.

[0621] Intermediate 23C, sodium carbonate (0.74 g) was stirred and reacted in methanol (25 mL) and water (5 mL) at 70 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution. Dichloromethane and water were added to the residue, and the organic phase was separated. The solvent was removed by distillation under reduced pressure from the organic phase, and the compound 23 (0.30 g) was obtained by purification through column chromatography (eluent: dichloromethane / methanol (40 / 1)). HRMS (ESI, [M+H] + ) m / z: 440.1841.

[0622] 1 1H NMR (500 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.06 (s, 1H), 8.67 (s, 1H), 7.43 (d, J = 12.4 Hz, 1H), 7.11 (t, J = 8.9 Hz, 1H), 6.96 - 6.95 (m, 2H), 5.62 (s, 1H), 4.99 (s, 1H), 3.62 - 3.54 (m, 1H), 3.09 - 3.00 (m, 1H), 2.91 (s, 3H), 2.49 - 2.43 (m, 1H), 2.03 - 1.99 (m, 1H), 1.94 - 1.85 (m, 1H), 1.74 - 1.66 (m, 2H), 1.62 - 1.56 (m, 1H), 1.03 (d, J = 6.3 Hz, 6H).

[0623] Example 24: Preparation of Compound 24

[0624]

[0625] Referring to the preparation method of Compound 1 in Reference Example 1, 2-bromo-4-aminopyridine was replaced with 2-fluoro-6-bromo-3-aminopyridine therein to obtain the crude product of Compound 24.

[0626] The crude product of Compound 24 was purified through column chromatography (eluent: dichloromethane / methanol (96 / 4)) to obtain Compound 24 (106 mg). MS (ESI): m / z 441.1722 [M+H] + .

[0627] 11H NMR (500 MHz, DMSO-d6) δ 11.95 (s, 1H), 9.52 (s, 1H), 9.19 (s, 1H), 7.58 (dd, J = 10.3, 8.5 Hz, 1H), 7.21 - 7.08 (m, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.06 (s, 1H), 5.04 - 4.96 (m, 1H), 3.61 - 3.54 (m, 1H), 3.08 - 3.03 (m, 1H), 2.95 (s, 3H), 2.48 - 2.44 (m, 1H), 2.05 - 1.99 (m, 1H), 1.94 - 1.85 (m, 1H), 1.76 - 1.67 (m, 2H), 1.64 - 1.54 (m, 1H), 1.03 (dd, J = 6.6, 2.4 Hz, 6H).

[0628] Example 25: Preparation of Compound 25

[0629]

[0630] Referring to the preparation method of Compound 16A in Reference Example 16, replace methylamine hydrochloride with ammonia water therein to obtain Compound 25A.

[0631] Referring to the preparation method of Compound 16 in Reference Example 16, replace Intermediate 16A with Intermediate 25A and Intermediate K1 with Intermediate K therein to obtain the crude product of Compound 25.

[0632] The crude product of Compound 25 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), the eluent contains one-thousandth ammonia water) to obtain Compound 25 (50 mg). MS (ESI): m / z 426.5 [M + H] + .

[0633] 1 1H NMR (500 MHz, DMSO-d6) δ 11.96 (s, 1H), 8.62 (s, 1H), 8.19 (t, J = 8.5 Hz, 1H), 7.50 (d, J = 9.9 Hz, 2H), 7.17 (s, 2H), 6.94 (d, J = 7.8 Hz, 1H), 5.82 (s, 1H), 5.00 (s, 1H), 3.68 - 3.48 (m, 1H), 3.09 - 3.02 (m, 1H), 2.48 - 2.44 (m, 1H), 2.04 - 2.00 (m, 1H), 1.95 - 1.89 (m, 1H), 1.75 - 1.67 (m, 2H), 1.62 - 1.56 (m, 1H), 1.03 (d, J = 6.5 Hz, 6H).

[0634] Example 26: Preparation of Compound 26

[0635]

[0636] Intermediate K (450 mg), 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide (241 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (230 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (139 mg), potassium phosphate (960 mg) in N,N-dimethylformamide (20 ml). After addition, stir and react at 110 °C. After the reaction is complete, filter, distill off the solvent under reduced pressure from the filtrate, and separate by column chromatography (developing solvent: dichloromethane / methanol) to obtain Intermediate 26A (655 mg). MS (ESI): m / z 475.33 [M+H] + 。

[0637] Intermediate 26A (108 mg) in formic acid (10 ml), stir and react at 70 °C. After the reaction is complete, distill off the solvent under reduced pressure from the reaction solution, adjust the pH of the residue to alkaline with saturated aqueous sodium bicarbonate solution, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, distill off the solvent under reduced pressure from the filtrate, and purify by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), the eluent contains one-thousandth ammonia water) to obtain Compound 26 (140 mg). MS (ESI): m / z 419.1753 [M+H] + 。

[0638] 1H NMR (500 MHz, DMSO-d6) δ 11.73 (s, 1H), 8.48 (s, 1H), 7.41 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 5.63 (s, 1H), 4.99 (m, 1H), 4.41 (s, 2H), 4.32 (s, 2H), 3.60 - 3.56 (m, 1H), 3.08 - 3.00 (m, 1H), 2.48 - 2.42 (m, 1H), 2.03 - 1.98 (m, 1H), 1.93 - 1.85 (m, 1H), 1.73 - 1.68 (m, 2H), 1.62 - 1.56 (m, 1H), 1.04 - 1.02 (m, 6H).

[0639] Example 27: Preparation of Compound 27

[0640]

[0641] Referring to the preparation method of compound 1A in Reference Example 1, replace 6-bromopyridin-3-amine therein with 2-amino-5-bromobenzotrifluoride to obtain compound 27A.

[0642] Referring to the preparation method of compound 1 in Reference Example 1, replace compound 1A with compound 27A to obtain the crude product of compound 27.

[0643] The crude product of compound 27 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain compound 27 (60 mg). MS (ESI): m / z 490.3 [M+H] + 。

[0644] 1 1H NMR (500 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.04 (s, 1H), 8.80 (s, 1H), 7.90 (s, 1H), 7.46 - 7.45 (m, 1H), 7.34 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 5.62 (s, 1H), 5.01 - 4.97 (m, 1H), 3.61 - 3.54 (m, 1H), 3.05 - 2.98 (m, 1H), 2.99 (s, 3H), 2.48 - 2.40 (m, 1H), 2.04 - 1.98 (m, 1H), 1.95 - 1.84 (m, 1H), 1.75 - 1.67 (m, 2H), 1.62 - 1.59 (m, 1H), 1.03 (d, J = 6.1 Hz, 6H).

[0645] Example 28: Preparation of Compound 28

[0646]

[0647] Referring to the preparation method of compound 14A in Reference Example 14, replace 4-chlorobutyryl chloride therein with 3-chloropropanesulfonyl chloride to obtain compound 28A.

[0648] Referring to the preparation method of compound 14B in Reference Example 14, replace intermediate 14A therein with compound 28A to obtain compound 28B.

[0649] Referring to the preparation method of compound 14 in Reference Example 14, replace intermediate 14B therein with compound 28B to obtain the crude product of compound 28.

[0650] The crude product of compound 28 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (25 / 75), and the eluent contained one-thousandth ammonia water) to obtain compound 28 (25 mg). MS (ESI): m / z 449.1964 [M+H] +。

[0651] 1 H NMR(500 MHz, DMSO-d6) δ 11.81 (s, 1H), 9.17 (s, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.33 (s, 1H), 6.93 (d, J = 6.8 Hz, 1H), 6.08 (s, 1H), 5.00 (s, 1H), 3.66 (t, J = 6.6 Hz, 2H), 3.62 - 3.54 (m, 1H), 3.43 (t, J = 7.6 Hz, 2H), 3.07 - 3.00 (m, 1H), 2.48 - 2.42 (m, 1H), 2.41 - 2.35 (m, 2H), 2.03 - 1.99 (m, 1H), 1.93 - 1.84 (m, 1H), 1.76 - 1.68 (m, 2H), 1.63 - 1.56 (s, 1H), 1.03 (d, J = 6.4 Hz, 6H).

[0652] Example 29: Preparation of Compound 29

[0653]

[0654] 2-Bromo-5-nitropyridine (5.00 g), hydrazine hydrate (1.48 g), and rhodium on carbon (485 mg) were stirred at room temperature in tetrahydrofuran (150 ml). The reaction was complete, and the mixture was filtered. The filtrate was concentrated under reduced pressure to remove the solvent, giving Intermediate 29A (4.20 g). MS (ESI): m / z 189.0 [M + H] + 。

[0655] Intermediate 29A (4.20 g), sodium bicarbonate (2.10 g), and benzyl chloroformate (4.17 g) were stirred at room temperature in 1,4-dioxane (200 ml). The reaction was complete, and the mixture was filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluent: dichloromethane / methanol) to give Intermediate 29B (3.63 g). MS (ESI): m / z 323.16 [M + H] + 。

[0656] Intermediate 29B (3.63 g) and 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxol-3(1H)-one (4.17 g) were stirred at room temperature in dichloromethane (100 ml). The reaction was complete, and the reaction mixture was concentrated under reduced pressure to remove the solvent, giving Intermediate 29C (4.00 g). MS (ESI): m / z 391.25 [M + H] + 。

[0657] Intermediate 29C (4.00 g) was stirred and reacted in nitromethane (50 ml) at 120 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution, and Intermediate 29D (930 mg) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 391.25 [M+H] + .

[0658] Intermediate K (200 mg), Intermediate 29D (300 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (120 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (160 mg), cesium carbonate (2400 mg), and diatomaceous earth (800 mg) were stirred and reacted in toluene / tert-butanol (35 mL, 5:1 (v / v)) under nitrogen protection at 120 °C. After the reaction was complete, the mixture was filtered, and the solvent was removed by distillation under reduced pressure from the filtrate. Intermediate 29E (120 mg) was obtained by column chromatography (eluent: dichloromethane / methanol). MS (ESI): m / z 619.49 [M+H] + .

[0659] Intermediate 29E (120 mg) and palladium on carbon (30 mg, 50% (w / w)) were stirred and reacted in tetrahydrofuran (5 ml) at room temperature under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the solvent was removed by distillation under reduced pressure from the filtrate to obtain Intermediate 29F (70 mg). MS (ESI): m / z 485.31 [M+H] + .

[0660] Intermediate 29F (70 mg), methanesulfonic anhydride (83 mg), and N,N-diisopropylethylamine (42 mg) were stirred and reacted in dichloromethane (5 ml) at room temperature. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution to obtain Compound 29G (90 mg). MS (ESI): m / z 641.31 [M+H] + .

[0661] Intermediate 29G (90 mg) was stirred and reacted in formic acid (5 ml) at 90 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution, and the residue was adjusted to alkaline pH with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure from the filtrate to obtain Intermediate 29H (70 mg). MS (ESI): m / z 585.18 [M+H] + .

[0662] Intermediate 29H (70 mg), sodium carbonate (70 mg) were stirred and reacted in methanol (5 ml) and water (1 ml) at 70 °C. After the reaction was complete, methanol was removed by distillation under reduced pressure. The residue was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was removed by distillation under reduced pressure. It was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 29 (20 mg). MS (ESI): m / z 507.1638 [M+H] + 。

[0663] 1 1H NMR (500 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.62 (s, 1H), 9.26 (s, 1H), 7.58 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 6.31 (s, 1H), 4.99 (s, 1H), 3.62 - 3.55 (m, 1H), 3.07 - 3.01 (m, 1H), 2.92 (s, 3H), 2.48 - 2.44 (m, 1H), 2.05 - 1.99 (m, 1H), 1.96 - 1.85 (m, 1H), 1.75 - 1.65 (m, 2H), 1.61 - 1.55 (m, 1H), 1.03 (d, J = 6.7 Hz, 6H).

[0664] Example 30: Preparation of Compound 30

[0665]

[0666] Referring to the preparation method of Compound 1A in Reference Example 1, 2-bromo-4-aminopyridine was replaced with 2-chloro-3-amino-6-bromopyridine therein to obtain Compound 30A.

[0667] Referring to the preparation method of Compound 1 in Reference Example 1, Intermediate 1A was replaced with Intermediate 30A therein to obtain the crude product of Compound 30.

[0668] The crude product of Compound 30 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (18 / 82), and the eluent contained one-thousandth ammonia water) to obtain Compound 30 (30 mg). MS (ESI): m / z 457.1422 [M+H] + 。

[0669] 11H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 9.59 (s, 1H), 9.26 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.30 (s, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.04 (s, 1H), 5.00 (s, 1H), 3.62 - 3.53 (m, 1H), 3.12 - 3.02 (m, 1H), 2.99 (s, 3H), 2.48 - 2.44 (m, 1H), 2.05 - 1.99 (m, 1H), 1.94 - 1.85 (m, 1H), 1.76 - 1.67 (m, 2H), 1.64 - 1.54 (m, 1H), 1.03 (d, J = 4.8 Hz, 6H).

[0670] Example 31: Preparation of Compound 31

[0671]

[0672] Referring to the preparation method of Compound 29D in Reference Example 29, after reacting Intermediate 29C in nitromethane, Intermediate 31A was obtained by column chromatography.

[0673] Referring to the preparation method of Compound 29 in Reference Example 29, Intermediate 29D was replaced with Intermediate 31A to obtain the crude product of Compound 31.

[0674] The crude product of Compound 31 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 31 (13 mg). MS (ESI): m / z 507.1638 [M + H] + 。

[0675] 1 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 9.60 (s, 1H), 9.28 (s, 1H), 8.12 (s, 1H), 7.64 (s, 1H), 6.93 (d, J = 7.2 Hz, 1H), 5.99 (s, 1H), 4.99 (s, 1H), 3.64 - 3.54 (m, 1H), 3.06 - 3.01 (m, 1H), 2.98 (s, 3H), 2.49 - 2.43 (m, 1H), 2.07 - 1.97 (m, 1H), 1.96 - 1.84 (m, 1H), 1.75 - 1.67 (m, 2H), 1.62 - 1.56 (m, 1H), 1.03 (d, J = 6.3 Hz, 6H).

[0676] Example 32: Preparation of Compound 32

[0677]

[0678] Referring to the preparation method of Compound 23A in Reference Example 23, replace 4-bromo-2-fluoroaniline with 4-bromo-2,5-difluoroaniline to obtain Compound 32A.

[0679] Referring to the preparation method of Compound 23 in Reference Example 23, replace Intermediate 23A with Compound 32A to obtain the crude product of Compound 32.

[0680] The crude product of Compound 32 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (24 / 76), and the eluent contained one-thousandth ammonia water) to obtain Compound 32 (25 mg). MS(ESI): m / z 458.1670 [M+H] + 。

[0681] 1 H NMR(500 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.29 (s, 1H), 8.47 (s, 1H), 8.13 - 8.09 (m, 1H), 7.14 - 7.10 (m, 1H), 6.93 (d, J = 7.1 Hz, 1H), 5.77 (s, 1H), 5.00 (s, 1H), 3.61 - 3.55 (m, 1H), 3.08 - 3.01 (m, 1H), 2.96 (s, 3H), 2.47 - 2.43 (m, 1H), 2.05 - 1.99 (m, 1H), 1.94 - 1.87 (m, 1H), 1.75 - 1.65 (m, 2H), 1.61 - 1.55 (m, 1H), 1.03 (d, J = 6.3 Hz, 6H).

[0682] Example 33: Preparation of Compound 33

[0683]

[0684] Referring to the preparation method of Compound 16A in Reference Example 16, replace methylamine hydrochloride with ammonia water and 4-bromo-3-fluorobenzenesulfonyl chloride with 4-bromo-2-fluorobenzenesulfonyl chloride to prepare Compound 33A.

[0685] Referring to the preparation method of Compound 16 in Reference Example 16, replace Intermediate K1 with Intermediate K to obtain the crude product of Compound 33.

[0686] The crude product of Compound 33 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 33 (40 mg). MS(ESI): m / z 426.3 [M+H] + 。

[0687] 11H NMR (500 MHz, DMSO-d6) δ 11.96 (s, 1H), 9.15 (s, 1H), 7.54 (t, J = 8.7 Hz, 1H), 7.43 (dd, J = 13.9, 2.1 Hz, 1H), 7.27 (s, 2H), 7.03 (dd, J = 8.8, 2.1 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 5.69 (d, J = 2.2 Hz, 1H), 5.00 (s, 1H), 3.66 - 3.54 (m, 1H), 3.10 - 3.02 (m, 1H), 2.48 - 2.44 (m, 1H), 2.07 - 1.97 (m, 1H), 1.95 - 1.83 (m, 1H), 1.75 - 1.66 (m, 2H), 1.63 - 1.56 (s, 1H), 1.03 (d, J = 6.8 Hz, 6H).

[0688] Example 34: Preparation of Compound 34

[0689]

[0690] Referring to the preparation method of Compound 16A in Reference Example 16, replace methylamine hydrochloride with ammonia water therein, and replace 4-bromo-3-fluorobenzenesulfonyl chloride with 4-bromo-2-fluorobenzenesulfonyl chloride to prepare Compound 34A.

[0691] Referring to the preparation method of Compound 16 in Reference Example 16, replace Intermediate K1 with Intermediate K2 therein to obtain the crude product of Compound 34.

[0692] The crude product of Compound 34 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), the eluent contains one-thousandth ammonia water) to obtain Compound 34 (25 mg). MS (ESI): m / z 426.3 [M + H] + 。

[0693] 1 1H NMR (500 MHz, DMSO-d6) δ 11.96 (s, 1H), 8.61 (s, 1H), 8.18 (t, J = 8.4 Hz, 1H), 7.57–7.45 (m, 2H), 7.16 (s, 2H), 6.93 (d, J = 7.9 Hz, 1H), 5.82 (s, 1H), 5.00 (s, 1H), 3.65 - 3.50 (m, 1H), 3.16 - 2.97 (m, 1H), 2.50 - 2.42 (m, 1H), 2.08 - 1.97 (m, 1H), 1.96 - 1.85 (m, 1H), 1.79 - 1.61 (m, 2H), 1.63 - 1.54 (m, 1H), 1.03 (d, J = 6.9, 6H).

[0694] Example 35: Preparation of Compound 35

[0695]

[0696] Referring to the preparation method of Compound 14 in Reference Example 14, replace 6-bromo-N-methylpyridin-3-amine therein with 4-bromo-2-fluoroaniline to obtain the crude product of Compound 35.

[0697] The crude product of Compound 35 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 35 (30 mg). MS (ESI): m / z 430.2246 [M+H] + 。

[0698] 1 1H NMR (500 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.66 (s, 1H), 7.41 (d, J = 13.9 Hz, 1H), 7.13 (t, J = 8.8 Hz, 1H), 7.03–6.88 (m, 2H), 5.62 (s, 1H), 4.99 (s, 1H), 3.65 (t, J = 7.0 Hz, 2H), 3.60 - 3.56 (m, 1H), 3.07 - 3.00 (m, 1H), 2.49–2.426 (m, 1H), 2.38 (t, J = 8.0 Hz, 2H), 2.11–2.06 (m, 2H), 2.04–1.97 (m, 1H), 1.94–1.84 (m, 1H), 1.74 - 1.68 (m, 2H), 1.62 - 1.56 (m, 1H), 1.03 (d, J = 6.5 Hz, 6H).

[0699] Example 36: Preparation of Compound 36

[0700]

[0701] 1-(6-Bromopyridin-3-yl)ethan-1-one (3.00 g) and liquid bromine (0.90 mL) were placed in hydrobromic acid (45 mL), and the reaction was stirred at 70 °C under nitrogen protection. After the reaction was complete, ether was added, stirred for 30 min, filtered, and the filter cake was dried to obtain Intermediate 36A (4.00 g). MS (ESI): m / z 277.88 [M+H] + 。

[0702] Intermediate 36A (3.00 g) was subjected to microwave reaction at 150 °C in formamide (20 mL). After the reaction was complete, it was poured into water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography (eluent: dichloromethane / methanol) to obtain Intermediate 36B (0.45 g). MS (ESI): m / z 225.0 [M+H] + 。

[0703] Referring to the preparation method of Compound 12 in Reference Example 12, Intermediate 12B was replaced with Intermediate 36B to obtain the crude product of Compound 36.

[0704] The crude product of Compound 36 was purified by slurrying with methanol to obtain Compound 36 (28 mg). MS (ESI): m / z 397.1988 [M+H] + 。

[0705] 1 H NMR (500 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.27 (s, 1H), 8.55 (s, 1H), 8.48 (s, 1H), 8.43 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 6.94 (d, J = 6.8 Hz, 1H), 6.12 (s, 1H), 5.00 (s, 1H), 3.60 - 3.56 (m, 1H), 3.08 - 3.02 (m, 1H), 2.53 - 2.50 (m, 1H), 2.05 - 1.98 (m, 1H), 1.94 - 1.86 (m, 1H), 1.78 - 1.68 (m, 2H), 1.66 - 1.57 (m, 1H), 1.03 (d, J = 5.9 Hz, 6H).

[0706] Example 37: Preparation of Compound 37

[0707]

[0708] Referring to the preparation method of Compound 23 in Reference Example 23, 4-bromo-2-fluoroaniline was replaced with 4-bromo-2,3-difluoroaniline to obtain the crude product of Compound 37.

[0709] The crude product of Compound 37 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (28 / 72), the eluent contained one-thousandth ammonia water) to obtain Compound 37 (156 mg). MS (ESI): m / z 458.1674 [M+H] + 。

[0710] 11H NMR (500 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.31 (s, 1H), 8.31 (s, 1H), 7.80 - 7.76 (m, 1H), 7.02 - 6.98 (m, 1H), 6.93 (d, J = 7.1 Hz, 1H), 5.75 (s, 1H), 5.00 (s, 1H), 3.60 - 3.56 (m, 1H), 3.08 - 3.02 (m, 1H), 2.96 (s, 3H), 2.47 - 2.43 (m, 1H), 2.05 - 1.99 (m, 1H), 1.94 - 1.86 (m, 1H), 1.75 - 1.65 (m, 2H), 1.61 - 1.55 (m, 1H), 1.03 (d, J = 6.4 Hz, 6H).

[0711] Example 38: Preparation of Compound 38

[0712]

[0713] 2-Bromo-5-fluoropyridine (2.00 g), 1H-imidazole (0.90 g), and potassium carbonate (3.10 g) were stirred in N,N-dimethylformamide (20 mL) at 100 °C. After the reaction was complete, the reaction mixture was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 38A (0.50 g).

[0714] Referring to the preparation method of Compound 12 in Reference Example 12, intermediate 12B was replaced with intermediate 38A to obtain the crude product of Compound 38.

[0715] The crude product of Compound 38 was purified by slurrying with acetonitrile to obtain Compound 38 (100 mg). MS (ESI): m / z 396.2147 [M + H] + 。

[0716] 11H NMR (500 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.42 (s, 1H), 8.38 (d, J = 2.6 Hz, 1H), 8.09 (s, 1H), 7.81 (dd, J = 9.0, 2.8 Hz, 1H), 7.61 (s, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.09 (s, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.13 (s, 1H), 5.01 (s, 1H), 3.62 - 3.55 (m, 1H), 3.09 – 3.02 (m, 1H), 2.49 – 2.45 (m, 1H), 2.06 - 2.00 (m, 1H), 1.94 - 1.86 (m, 1H), 1.79 - 1.67 (m, 2H), 1.64 - 1.58 (m, 1H), 1.03 (d, J = 6.4 Hz, 6H).

[0717] Example 39: Preparation of Compound 39

[0718]

[0719] Referring to the preparation method of Compound 26 in Reference Example 26, replace 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide therein with 4-bromo-1,2-methylenedioxybenzene to obtain the crude product of Compound 39.

[0720] The crude product of Compound 39 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 39 (28 mg). MS (ESI): m / z 373.1869 [M + H] + .

[0721] 1 1H NMR (500 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.09 (s, 1H), 7.09 (s, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.72 – 6.69 (m, 2H), 5.87 (s, 2H), 5.54 (s, 1H), 4.99 (s, 1H), 3.61 - 3.54 (m, 1H), 3.04 - 2.98 (m, 1H), 2.47 - 2.41 (m, 1H), 2.03 - 1.97 (m, 1H), 1.93 – 1.85 (m, 1H), 1.75 - 1.65 (m, 2H), 1.61 - 1.55 (m, 1H), 1.03 (d, J = 6.4 Hz, 6H).

[0722] Example 40: Preparation of Compound 40

[0723]

[0724] Referring to the preparation method of Compound 23 in Reference Example 23, replace 4-bromo-2-fluoroaniline with 4-bromo-2-chloroaniline to obtain the crude product of Compound 40.

[0725] The crude product of Compound 40 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 40 (70 mg). MS (ESI): m / z 456.1470 [M+H] + 。

[0726] 1 H NMR (500 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.08 (s, 1H), 8.64 (s, 1H), 7.68 (s, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 5.61 (s, 1H), 4.99 (s, 1H), 3.61 - 3.54 (m, 1H), 3.07 - 3.00 (m, 1H), 2.93 (s, 3H), 2.48 - 2.42 (m, 1H), 2.04 - 1.99 (m, 1H), 1.94 - 1.86 (m, 1H), 1.75 - 1.67 (m, 2H), 1.62 - 1.56 (m, 1H), 1.03 (d, J = 6.4 Hz, 6H).

[0727] Example 41: Preparation of Compound 41

[0728]

[0729] Referring to the preparation method of Compound 26 in Reference Example 26, replace 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide with 4-bromophenyl dimethylphosphine oxide to obtain the crude product of Compound 41.

[0730] The crude product of Compound 41 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 41 (120 mg). MS (ESI): m / z 405.2055 [M+H] + 。

[0731] 11H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.68 (s, 1H), 7.53 - 7.49 (m, 2H), 7.39 - 7.37 (m, 2H), 6.94 (d, J = 7.9 Hz, 1H), 5.67 (s, 1H), 5.04 - 4.95 (m, 1H), 3.61 - 3.55 (m, 1H), 3.08 - 3.01 (m, 1H), 2.47 - 2.43 (m, 1H), 2.04 - 1.99 (m, 1H), 1.96 - 1.86 (m, 1H), 1.76 - 1.69 (m, 2H), 1.63 - 1.54 (m, 1H), 1.58 (s, 3H), 1.55 (s, 3H), 1.03 (d, J = 6.7 Hz, 6H).

[0732] Example 42: Preparation of Compound 42

[0733]

[0734] 4-Bromoindolin-2-one (4.60 g), sodium carbonate (18.39 g), and di-tert-butyl dicarbonate (9.47 g) were stirred and reacted in tetrahydrofuran (150 mL) at 65 °C. After the reaction was complete, the reaction solution was filtered, concentrated, and separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 42A (3.25 g). MS (ESI): m / z: 412.21 [M+H] + .

[0735] Referring to the preparation method of Compound 1 in Reference Example 11, intermediate 1A was replaced with intermediate 42A to obtain the crude product of Compound 42.

[0736] The crude product of Compound 42 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 42 (10 mg). MS (ESI): m / z 384.20 [M+H] + 。

[0737] 11H NMR (500 MHz, DMSO-d6) δ 11.51 (s, 1H), 10.04 (s, 1H), 7.97 (s, 1H), 7.26 (s, 1H), 7.10 - 7.08 (m, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 5.55 (s, 1H), 4.99 (s, 1H), 3.60 - 3.55 (m, 1H), 3.39 (s, 2H), 3.05 - 2.98 (m, 1H), 2.47 - 2.41 (m, 1H), 2.03 - 1.97 (m, 1H), 1.95 - 1.84 (m, 1H), 1.76 - 1.65 (m, 2H), 1.61 - 1.55 (m,

[0738] 1H), 1.03 - 1.02 (m, 6H).

[0739] Example 43: Preparation of Compound 43

[0740]

[0741] 2-Nitrobenzyl bromide (10.00 g), anhydrous sodium sulfite (7.58 g), and tetrabutylammonium iodide (171 mg) were stirred in water (80 mL) at 90 °C for reaction. After the reaction was complete, the solvent was removed by distillation under reduced pressure to obtain intermediate 43A (10.00 g).

[0742] Intermediate 43A (10.00 g) and palladium on carbon (palladium content 5%, water content 50% (w / w), 1.90 g) were stirred in methanol (50 mL). After purging with hydrogen, the reaction was stirred at room temperature. After the reaction was complete, it was filtered and concentrated to obtain intermediate 43B (5.00 g).

[0743] Intermediate 43B (5.00 g) was stirred in phosphorus oxychloride (100 mL) under nitrogen protection at 115 °C for reaction. After the reaction was complete, the solvent was removed by distillation under reduced pressure, and then the pH was adjusted to alkaline with aqueous sodium hydroxide solution (1 Mol / L). It was extracted with ethyl acetate, and then the pH of the organic phase was adjusted to acidic with dilute hydrochloric acid (2N). It was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 43C (670 mg). MS (ESI): m / z 168.1 [M - H] - .

[0744] Intermediate 43C (0.63 g) and bromine (0.46 g) were stirred in acetic acid (8 mL) at room temperature for reaction. After the reaction was complete, the solvent was removed by distillation under reduced pressure, and separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 43D (0.75 g). MS (ESI): m / z 246.0 [M - H] - .

[0745] Intermediate 43D (0.75 g), potassium carbonate (0.83 g), and benzyl bromide (0.54 g) were stirred at room temperature in DMF (10 mL). After the reaction was complete, the solvent was removed by distillation under reduced pressure, and the residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain Intermediate 43E (800 mg). MS (ESI): m / z 335.95 [M-H] - .

[0746] Intermediate K (425 mg), Intermediate 43E (680 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (217 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (131 mg), and potassium phosphate (877 mg) were stirred at 110 °C under nitrogen protection in N,N-dimethylformamide (20 mL). After the reaction was complete, the mixture was filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to obtain Intermediate 43F (223 mg). MS (ESI): m / z 566.41 [M+H] + 。

[0747] Intermediate 43F (223 mg) and palladium on carbon (5% palladium content, 50% water content (w / w), 83 mg) were stirred at room temperature in methanol (20 mL) after purging with hydrogen. After the reaction was complete, the mixture was filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to obtain Intermediate 43G (127 mg). MS (ESI): m / z 476.32 [M+H] + 。

[0748] Intermediate 43G (127 mg) was reacted in ethanol (1 mL) and dilute hydrochloric acid (1 N, 20 mL) by microwave at 100 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction mixture. The residue was adjusted to alkaline pH with saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by distillation under reduced pressure. The product was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing one-thousandth ammonia) to obtain Compound 43 (9 mg). MS (ESI): m / z 420.1701 [M+H] + .

[0749] 11H NMR (500 MHz, DMSO-d6) δ 11.61 (s, 1H), 9.74 (s, 1H), 8.18 (s, 1H), 7.37 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.71 (d, J = 8.6 Hz, 1H), 5.57 (s, 1H), 4.99 (s, 1H), 4.43 (s, 2H), 3.61 - 3.55 (m, 1H), 3.03 (q, J = 8.7 Hz, 1H), 2.44 (dt, J = 14.3, 7.4 Hz, 1H), 2.04 - 1.97 (m, 1H), 1.94 - 1.85 (m, 1H), 1.76 - 1.67 (m, 2H), 1.63 - 1.55 (m, 1H), 1.03 (dd, J = 6.7, 2.3 Hz, 6H).

[0750] Example 44: Preparation of Compound 44

[0751]

[0752] Referring to the preparation method of Compound 1B in Reference Example 1, replace 6-bromopyridin-3-amine therein with 3-amino-2-methoxy-6-bromopyridine to obtain the crude product of Intermediate 44B.

[0753] Referring to the preparation method of Compound 1 in Reference Example 1, replace Intermediate 1C therein with Intermediate 44B to obtain the crude product of Compound 44.

[0754] The crude product of Compound 44 was purified by column chromatography (eluent: dichloromethane / methanol (90 / 10)) to obtain Compound 44 (39 mg). MS (ESI): m / z 531.27 [M + H] + .

[0755] 1 1H NMR (500 MHz, DMSO-d6) δ 12.17 (s, 1H), 9.12 (s, 1H), 9.00 (s, 1H), 7.78 (s, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.54 (s, 1H), 5.00 (d, J = 8.6 Hz, 1H), 4.01 (s, 3H), 3.64 - 3.48 (m, 1H), 3.26 (s, 3H), 3.11 (q, J = 8.7 Hz, 1H), 2.97 (s, 3H), 2.49 - 2.42 (m, 1H), 2.09 - 1.99 (m, 1H), 1.98 - 1.85 (m, 1H), 1.79 - 1.67 (m, 2H), 1.64 - 1.60 (m, 1H), 1.02 (d, J = 6.2 Hz, 6H).

[0756] Example 45: Preparation of Compound 45

[0757]

[0758] Referring to the preparation method of Compound 1 in Reference Example 1, replace Intermediate 1A with Intermediate 44A therein to obtain the crude product of Compound 45.

[0759] The crude product of Compound 45 was purified by column chromatography (eluent: dichloromethane / methanol (90 / 10)) to obtain Compound 45 (55 mg). MS (ESI): m / z 453.29 [M+H] + .

[0760] 1 H NMR (500 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.18 (s, 1H), 8.72 (s, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 6.79 - 6.62 (m, 1H), 6.23 (s, 1H), 5.00 (d, J = 7.8 Hz, 1H), 3.90 (s, 3H), 3.58 (dt, J = 13.8, 7.0 Hz, 1H), 3.08 - 3.02 (m, 1H), 2.88 (s, 3H), 2.48 - 2.40 (m, 1H), 2.05 - 1.96 (m, 1H), 1.95 - 1.84 (m, 1H), 1.80 - 1.66 (m, 2H), 1.64 - 1.60 (m, 1H), 1.02 (d, J = 6.6 Hz, 6H).

[0761] Example 46: Preparation of Compound 46

[0762]

[0763] p-Bromobenzamide (1.00 g), 4-dimethylaminopyridine (0.06 g), N,N-diisopropylethylamine (2.58 g) and di-tert-butyl dicarbonate (3.27 g) were stirred at room temperature in dichloromethane (50 mL). After the reaction was complete, the solvent was removed under reduced pressure and the residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain Intermediate 46A (0.37 g). MS (ESI): m / z: 422.1 [M+Na] + .

[0764] 1 H NMR (500 MHz, DMSO-d6) δ 7.81 - 7.83 (m, 2H), 7.71 - 7.68 (m, 2H), 1.36 (s, 18H).

[0765] For the preparation method of Compound 23 in Reference Example 23, replace 23A with 46A and formic acid with ethanol / 1N dilute hydrochloric acid (1 / 5) to obtain the crude product of Compound 46.

[0766] The crude product of Compound 46 was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), the eluent containing one-thousandth ammonia water) to obtain Compound 46 (13 mg). MS (ESI): m / z 372.2035 [M+H] + .

[0767] 1 1H NMR (500 MHz, DMSO-d6) δ 11.51 (s, 1H), 10.04 (s, 1H), 7.97 (s, 1H), 7.26 (s, 1H), 7.10 - 7.08 (m, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 5.55 (s, 1H), 4.99 (s, 1H), 3.60 - 3.55 (m, 1H), 3.39 (s, 2H), 3.05 - 2.98 (m, 1H), 2.47 - 2.41 (m, 1H), 2.03 - 1.97 (m, 1H), 1.95 - 1.84 (m, 1H), 1.76 - 1.65 (m, 2H), 1.61 - 1.55 (m, 1H), 1.03 - 1.02 (m, 6H).

[0768] Example 47: Preparation of Compound 47

[0769]

[0770] For the preparation method of Compound 7 in Reference Example 7, replace 4-bromoaniline with 4-bromo-2-trifluoromethoxyaniline to obtain Intermediate 47C (146 mg). MS (ESI): m / z 562.14 [M+H] + .

[0771] Intermediate 47C (145 mg) was reacted in ethanol (2 mL) and dilute hydrochloric acid (1N, 20 mL) by microwave at 100 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure. The residue was adjusted to alkaline pH with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), the eluent containing one-thousandth ammonia water) to obtain Compound 47 (30 mg). MS (ESI): m / z 506.1693 [M+H] + .

[0772] 11H NMR (500 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.12 (s, 1H), 8.75 (s, 1H), 7.70 (s, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.14 - 7.12 (m, 1H), 6.93 (d, J = 7.8 Hz, 1H), 5.60 (d, J = 2.2 Hz, 1H), 4.99 (s, 1H), 3.60 - 3.55 (m, 1H), 3.09 - 2.98 (m, 1H), 2.93 (s, 3H), 2.49 - 2.42 (m, 1H), 2.03 - 1.98 (m, 1H), 1.92 - 1.87 (m, 1H), 1.77 - 1.66 (m, 2H), 1.63 - 1.55 (m, 1H), 1.03 (d, J = 6.5 Hz, 6H).

[0773] Example 48: Preparation of Compound 48

[0774]

[0775] Benzyl (1-(tert-butyl)-3-((1S,3R)-3-(4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (0.50 g), N,N-diisopropylethylamine (0.50 g) and 1-methylcyclopropan-1-amine hydrochloride (0.15 g) were stirred and reacted in tetrahydrofuran (20 mL) at 60 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure. The residue was added with ethyl acetate, washed with aqueous sodium hydroxide solution (1 N) and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 48A (0.40 g). MS (ESI): m / z 455.35 [M + H] + .

[0776] Intermediate 48A (0.40 g) and palladium on carbon (palladium content 5%, water content 50% (w / w), 0.30 g) were stirred and reacted at room temperature in a hydrogen atmosphere in tetrahydrofuran (5 mL) and ethyl acetate (5 mL). After the reaction was complete, it was filtered and concentrated to obtain Intermediate 48B (0.25 g). MS (ESI): m / z 321.30 [M + H] + .

[0777] Intermediate 48B (0.23 g), 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide (0.27 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.11 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.10 g), and potassium phosphate (0.46 g) were placed in N,N-dimethylformamide (10 mL). After addition, the reaction was stirred at 110 °C under nitrogen protection. After the reaction was complete, it was filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to obtain Intermediate 48C (0.20 g). MS (ESI): m / z 487.29 [M+H] + .

[0778] Intermediate 48C (0.20 g) was placed in ethanol (2 mL) and dilute hydrochloric acid (1 N, 20 mL), and the reaction was stirred by microwave at 100 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution. The residue was adjusted to alkaline pH with saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (20 / 80), and the eluent contained one-thousandth ammonia water) to obtain Compound 48 (15 mg). MS (ESI): m / z 431.1745 [M+H] + 。

[0779] 1 H NMR (500 MHz, DMSO) δ 11.69 (s, 1H), 8.46 (s, 1H), 7.36 (d, J = 22.0 Hz, 2H), 7.20 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 5.62 (s, 1H), 4.98 (s, 1H), 4.40 (s, 2H), 4.32 (s, 2H), 3.03 (s, 1H), 2.48 - 2.41 (m, 1H), 2.05 - 1.84 (m, 2H), 1.75 - 1.52 (m, 3H), 1.23 (s, 3H), 0.63 - 0.44 (m, 4H).

[0780] Example 49: Preparation of Compound 49

[0781]

[0782] Referring to the preparation method of Intermediate 26A in Reference Example 26, Intermediate K was replaced with Intermediate K2 to obtain Intermediate 49A (120 mg). MS (ESI): m / z 475.50 [M+H] + 。

[0783] Preparation method of reference example 47, compound 47. Replace intermediate 47C with intermediate 49A to obtain compound 49 (40 mg). MS (ESI): m / z 419.1756 [M+H] + .

[0784] 1 H NMR (500 MHz, DMSO-d6) δ 11.73 (s, 1H), 8.46 (s, 1H), 7.41 (s, 1H), 7.22 - 7.21 (m, 1H), 7.14 - 7.13 (m, 1H), 6.94 (d, J = 7.05 Hz, 1H), 5.63 (s, 1H), 4.99 (s, 1H), 4.40 (s, 2H), 4.32 (s, 2H), 3.60 - 3.56 (m, 1H), 3.05 - 3.02 (m, 1H), 2.48 - 2.42 (m, 1H), 2.03 - 1.99 (m, 1H), 1.92 - 1.88 (m, 1H), 1.75 - 1.68 (m, 2H), 1.62 - 1.56 (m, 1H), 1.03 (d, J = 6.35 Hz, 6H).

[0785] Example 50: Preparation of compound 50

[0786]

[0787] Reference the preparation method of compound 47 in reference example 47. Replace 4-bromo-2-trifluoromethoxyaniline with 4-bromo-2-trifluoromethylaniline, and intermediate K with intermediate K2 to obtain the crude product of compound 50.

[0788] The crude product of compound 50 was purified by medium and low pressure preparative liquid chromatography (C18 chromatographic column, acetonitrile / water (30 / 70), the eluent contained one-thousandth ammonia water) to obtain compound 50 (20 mg). MS (ESI): m / z 490.1742 [M+H] + .

[0789] 11H NMR (500 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.04 (s, 1H), 8.77 (s, 1H), 7.89 (s, 1H), 7.46 - 7.45 (m, 1H), 7.34 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 5.62 (s, 1H), 5.01 - 4.97 (m, 1H), 3.58 - 3.56 (m, 1H), 3.05 - 2.98 (m, 1H), 2.98 (s, 3H), 2.48 - 2.40 (m, 1H), 2.04 - 1.98 (m, 1H), 1.95 - 1.84 (m, 1H), 1.75 - 1.67 (m, 2H), 1.62 - 1.59 (m, 1H), 1.03 (d, J = 6.1 Hz, 6H).

[0790] Example 51: Preparation of Compound 51

[0791]

[0792] 5-Bromoindoline (1.00 g), triethylamine (1.02 g), and methanesulfonic anhydride (1.05 g) were stirred in dichloromethane (30 mL) at room temperature overnight. After the reaction was complete, the reaction solution was evaporated under reduced pressure and separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 51A (1.05 g).

[0793] 1 1H NMR (500 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.38 - 7.36 (m, 1H), 7.18 (d, J = 8.55 Hz, 1H), 3.94 (t, J = 8.40 Hz, 2H), 3.12 (t, J = 8.45 Hz, 2H), 3.01 (s, 3H).

[0794] Referring to the preparation method of Compound 47 in Reference Example 47, intermediate 47A was replaced with intermediate 51A to obtain Compound 51 (72 mg). MS (ESI): m / z 448.2015 [M + H] + .

[0795] 11H NMR (500 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.21 (s, 1H), 7.34 (s, 1H), 7.11 - 7.06 (m, 2H), 6.95 (d, J = 7.35 Hz, 1H), 5.58 (s, 1H), 4.99 (s, 1H), 3.86 (t, J = 8.35 Hz, 1H), 3.60 - 3.54 (m, 1H), 3.06 - 3.00 (s, 3H), 2.86 (s, 3H), 2.47 - 2.42 (m, 1H), 2.03 - 1.98 (m, 1H), 1.93 - 1.85 (m, 1H), 1.75 - 1.67 (m, 2H), 1.62 - 1.55 (m, 1H), 1.03 (d, J = 6.40 Hz, 6H).

[0796] Example 52: Preparation of Compound 52

[0797]

[0798] Referring to the preparation method of Compound 16 in Reference Example 16, replace methylamine hydrochloride with ammonia water and Intermediate K1 with Intermediate K to obtain Intermediate 52B (210 mg). MS (ESI): m / z 499.48 [M + H] + .

[0799] Referring to the preparation method of Compound 47 in Reference Example 47, replace Intermediate 47C with Intermediate 52B to obtain Compound 52 (60 mg). MS (ESI): m / z 443.42 [M + H] + .

[0800] 1 1H NMR (500 MHz, DMSO-d6) δ 12.10 (s, 1H), 10.10 (s, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.43 (s, 2H), 7.34 (s, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.08 (s, 1H), 5.08 - 4.93 (m, 1H), 3.65 - 3.52 (m, 1H), 3.14 - 2.98 (m, 1H), 2.49 - 2.42 (m, 1H), 2.09 - 1.98 (m, 1H), 1.97 - 1.85 (m, 1H), 1.79 - 1.66 (m, 2H), 1.65 - 1.54 (m, 1H), 1.03 (d, J = 6.8 Hz, 6H).

[0801] Example 53: Preparation of Compound 53

[0802]

[0803] Referring to the preparation method of Compound 48 in Example 48, replace 1-methylcyclopropane-1-amine hydrochloride therein with methylamine hydrochloride to obtain the crude product of Compound 53.

[0804] The crude product of Compound 53 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 53 (55 mg). MS (ESI): m / z 391.46 [M+H] + .

[0805] 1 H NMR (500 MHz, DMSO-d6) δ 11.73 (s, 1H), 8.48 (s, 1H), 7.41 (s, 1H), 7.22 - 7.21 (m, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 5.3 Hz, 1H), 5.62 (d, J = 2.2 Hz, 1H), 5.08 - 4.88 (m, 1H), 4.40 (s, 2H), 4.32 (s, 2H), 3.07 - 3.00 (m, 1H), 2.55 (d, J = 4.6 Hz, 3H), 2.47 - 2.41 (m, 1H), 2.06 - 1.96 (m, 1H), 1.95 - 1.85 (m, 1H), 1.79 - 1.64 (m, 2H), 1.65 - 1.52 (m, 1H).

[0806] Example 54: Preparation of Compound 54

[0807]

[0808] Referring to the preparation method of Compound 26 in Example 26, replace 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide therein with 1-bromo-4-methylsulfonylbenzene to obtain the crude product of Compound 54.

[0809] The crude product of Compound 54 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 54 (20 mg). MS (ESI, [M+H] + ) m / z: 407.1748.

[0810] 11H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.73 - 7.64 (m, 2H), 7.50 - 7.39 (m, 2H), 6.94 (d, J = 7.2 Hz, 1H), 5.75 (s, 1H), 5.13 - 4.97 (m, 1H), 4.11 (s, 3H), 3.63 - 3.53 (m, 1H), 2.46 (m, 1H), 2.02 (m, 1H), 1.91 (m, 1H), 1.72 (m, 2H), 1.61 (m, 1H), 1.03 (m, 6H).

[0811] Example 55: Preparation of Compound 55

[0812]

[0813] Referring to the preparation method of Compound 47 in Reference Example 47, replace 4-bromo-2-trifluoromethoxyaniline therein with 4-bromo-2-methoxyaniline to obtain the crude product of Compound 55.

[0814] The crude product of Compound 55 was purified by column chromatography (eluent: dichloromethane / methanol (90 / 10)) to obtain Compound 55 (44 mg). MS (ESI): m / z 452.28 [M + H] + .

[0815] 1 1H NMR (500 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.72 - 8.44 (m, 1H), 8.38 (s, 1H), 7.19 (s, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 5.62 (s, 1H), 4.99 (s, 1H), 3.76 (s, 3H), 3.64 - 3.51 (m, 1H), 3.04 - 2.99 (m, 1H), 2.82 (s, 3H), 2.50 - 2.39 (m, 1H), 2.06 - 1.95 (m, 1H), 1.95 - 1.81 (m, 1H), 1.76 - 1.69 (m, 2H), 1.62 - 1.57 (m, 1H), 1.03 (d, J = 6.3 Hz, 6H).

[0816] Example 56: Preparation of Compound 56

[0817]

[0818] 4-Bromo-2-methylbenzene-1-sulfonyl chloride (5.0 g) and ammonia water (115.0 g) were reacted with stirring in dioxane (70 mL) in an ice bath. After the reaction was complete, the solvent was removed by distillation under reduced pressure to obtain intermediate 56A (4.6 g).

[0819] Intermediate 56A (4.60 g), sodium hydroxide (3.34 g), and potassium permanganate (14.7 g) were reacted with stirring in water (50 mL) at 40 °C. After the reaction was complete, the reaction was quenched with a saturated aqueous solution of sodium sulfite, filtered, and the pH of the filtrate was adjusted to 2, followed by concentration to obtain intermediate 56B (2.58 g).

[0820] Intermediate 56B (2.58 g) was dissolved in polyphosphoric acid (50 mL), and the mixture was reacted with stirring at 140 °C. After the reaction was complete, the mixture was cooled to room temperature, quenched with ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 56C (2.00 g). MS (ESI): m / z 260.0 [M-H] - 。

[0821] Intermediate 56C (2.00 g) and sodium borohydride (2.89 g) were dissolved in tetrahydrofuran (50 mL), and boron trifluoride diethyl etherate (12.00 g) was added at -10 °C. The mixture was reacted with stirring at 80 °C. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 56D (1.72 g). MS (ESI): m / z 246.0 [M-H] - 。

[0822] Referring to the preparation method of compound 47 in Reference Example 47, intermediate 47A was replaced with intermediate 56D to obtain intermediate 56E (200 mg). MS (ESI): m / z 476.16 [M+H] + .

[0823] Referring to the preparation method of compound 47 in Reference Example 47, intermediate 47C was replaced with intermediate 56E to obtain a crude product of compound 56.

[0824] The crude product of compound 56 was purified by medium and low pressure preparative liquid chromatography (C18 chromatographic column, acetonitrile / water (33 / 67), and the eluent contained one-thousandth ammonia water) to obtain compound 56 (40 mg). MS (ESI): m / z 420.1693 [M+H] + 。

[0825] 11H NMR (500 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.99 (s, 1H), 7.58 - 7.38 (m, 3H), 7.30 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 5.71 (s, 1H), 4.99 (q, J = 7.2, 6.1 Hz, 1H), 4.29 (s, 2H), 3.58 (h, J = 7.0 Hz, 1H), 3.07 (q, J = 8.7 Hz, 1H), 2.48 - 2.42 (m, 1H), 2.02 (m, 1H), 1.90 (m, 1H), 1.73 (m, 2H), 1.66 - 1.55 (m, 1H), 1.06 - 1.01 (m, 6H).

[0826] Example 57: Preparation of Compound 57

[0827]

[0828] Referring to the preparation method of Compound 14 in Reference Example 14, replace the intermediate 6-bromo-N-methylpyridin-3-amine therein with 3-amino-6-bromo-2-chloropyridine to obtain the crude product of Compound 57.

[0829] The crude product of Compound 57 was purified by medium and low pressure preparative liquid chromatography (C18 chromatographic column, acetonitrile / water (32 / 68), and the eluent contained one-thousandth ammonia water) to obtain Compound 57 (9 mg). MS (ESI): m / z 447.1904 [M + H] + 。

[0830] 1 1H NMR (500 MHz, DMSO-d6): δ 11.89 (s, 1H), 9.64 (s, 1H), 9.44 (s, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 6.03 (s, 1H), 5.08 - 4.91 (m, 1H), 3.58 (h, J = 6.8 Hz, 1H), 3.05 (p, J = 8.7, 8.3 Hz, 1H), 2.46 (q, J = 7.2 Hz, 1H), 2.02 (m, 1H), 1.89 (m, 2H), 1.78 - 1.55 (m, 3H), 1.03 (d, J = 6.8 Hz, 6H), 0.78 (d, J = 6.1 Hz, 4H).

[0831] Example 58: Preparation of Compound 58

[0832]

[0833] For the preparation method of Compound 16 in Reference Example 16, replace methylamine hydrochloride therein with 2-benzyl-1-ethylamine, 4-bromo-3-fluorobenzenesulfonyl chloride with 4-bromo-2-fluorobenzenesulfonyl chloride, and Intermediate K1 with K to obtain the crude product of Intermediate 58C.

[0834] The crude product of Intermediate 58C was separated by column chromatography (eluent: dichloromethane / methanol) to obtain Product 58C (150 mg). MS (ESI): m / z 560.29 [M+H] + 。

[0835] Under hydrogen gas, palladium-carbon (palladium content 5%, water content 50% (w / w), 70 mg) and Intermediate 58C (150 mg) were placed in methanol (10 mL), and stirred at room temperature for reaction. After the reaction was complete, it was filtered, concentrated, and purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), the eluent contained one-thousandth ammonia water) to obtain Compound 58 (23 mg). MS (ESI): m / z 470.29 [M+H] + 。

[0836] 1 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.67 (s, 1H), 8.17 (s, 1H), 7.59 - 7.38 (m, 2H), 7.35 (s, 1H), 6.93 (d, J = 7.8 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.66 (s, 1H), 3.58 (q, J = 8.5, 7.7 Hz, 1H), 3.36 (t, J = 6.4 Hz, 2H), 3.13 - 2.99 (m, 1H), 2.76 (t, J = 6.3 Hz, 2H), 2.50 - 2.40 (m, 1H), 2.10 - 1.98 (m, 1H), 1.96 - 1.83 (m, 1H), 1.79 - 1.65 (m, 2H), 1.65 - 1.55 (m, 1H), 1.03 (d, J = 6.6 Hz, 6H).

[0837] Example 59: Preparation of Compound 59

[0838]

[0839] For the preparation method of Compound 26 in Reference Example 26, replace 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide therein with ((4-bromophenyl)imino)dimethyl-λ 6 -cyclosulfone to obtain the crude product of Compound 59.

[0840] The crude product of Compound 59 was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (34 / 66), and the eluent contained one-thousandth ammonia water) to obtain Compound 59 (8 mg). MS (ESI, [M+H] + ) m / z: 420.2058.

[0841] 1 H NMR (500 MHz, DMSO-d6) δ 11.56 (s, 1H), 7.92 (s, 1H), 7.14 - 7.13 (m, 2H), 6.95 - 6.94 (m, 1H), 6.77 - 6.75 (s, 2H), 5.56 (s, 1H), 4.99 (m, 1H), 3.61 - 3.53 (m, 1H), 3.11 (s, 6H), 3.04 - 2.97 (m, 1H),

[0842] 2.47 - 2.41 (s, 1H), 2.02 - 1.96 (m, 1H), 1.91 - 1.85 (m, 1H), 1.76 - 1.65 (m, 2H), 1.61 - 1.55 (m, 1H), 1.03 (d, J = 6.85 Hz, 6H).

[0843] Example 60: Preparation of Compound 60

[0844]

[0845] Referring to the preparation method of Compound 22 in Reference Example 22, replacing 1-N-methylsulfonyl-4-piperidone therein with tert-butyl 4-oxopiperidine-1-carboxylate gave Intermediate 60A (203 mg). MS (ESI): m / z 492.39 [M+H] + .

[0846] Intermediate 60A (200 mg) and dioxane hydrochloride solution (4 M, 5 mL) were stirred at room temperature in dichloromethane (20 mL). After the reaction was complete, the solvent was removed by distillation under reduced pressure to obtain Intermediate 60B (150 mg). MS (ESI): m / z 392.38 [M+H] + .

[0847] Intermediate 60B (32 mg), Intermediate 60C (22 mg), and N,N-diisopropylethylamine (53 mg) were stirred at room temperature in dichloromethane (10 mL). After the reaction was complete, the solvent was removed by distillation under reduced pressure to obtain Intermediate 60D (40 mg). MS (ESI): m / z 536.37 [M+H] + .

[0848] Referring to the preparation method of Compound 47 in Reference Example 47, replacing Intermediate 47C therein with Intermediate 60D gave the crude product of Compound 60.

[0849] The crude product of compound 60 was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (32 / 68), and the eluent contained one-thousandth ammonia water) to obtain compound 60 (8 mg). MS (ESI, [M+H] + ) m / z: 480.2387.

[0850] 1 H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.31 (s, 1H), 7.76 (s, 1H), 6.91 (d, J = 7.6 Hz, 1H), 5.22 (s, 1H), 4.94 (m, 2H), 3.91 (s, 3H), 3.60 - 3.53 (m, 1H), 3.38 - 3.35 (m, 2H), 3.15 - 3.069 (m, 1H), 2.93 - 2.86 (m, 1H), 2.45 - 2.41 (m, 2H), 2.39 - 2.33 (m, 1H), 1.98 - 1.80 (m, 4H), 1.72 - 1.44 (m, 5H), 1.03 - 1.01 (m, 6H).

[0851] Example 61: Preparation of Compound 61

[0852]

[0853] 4-Bromoanisole (1.0 g), diethyl iodobenzene-1,2-dicarboxylate (1.7 g), and cyanamide (0.4 g) were stirred at room temperature in dichloromethane (30 mL). After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and the residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 61A (1.1 g). MS (ESI): m / z 243.03 [M+H] + .

[0854] Potassium permanganate (1.6 g) was added to a solution of 61A (1.1 g) in acetone (30 mL), and the mixture was stirred at room temperature. After the reaction was complete, the mixture was filtered, concentrated, and the residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 61B (1.2 g). MS (ESI): m / z 258.91 [M+H] + .

[0855] Trifluoroacetic anhydride (3.3 mL) was added to a solution of 61B (1.2 g) in dichloromethane (50 mL). After addition, the mixture was stirred at room temperature. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and the residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 61C (1.5 g). MS (ESI): m / z 329.99 [M-H] - .

[0856] Intermediate 61C (241 mg), Intermediate K (150 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (114 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (70 mg), and potassium phosphate (475 mg) were placed in dioxane (40 ml). Under nitrogen protection, the mixture was stirred at 100 °C for reaction. After the reaction was complete, it was filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to obtain Intermediate 61D (200 mg). MS (ESI): m / z 462.32 [M+H] + .

[0857] Intermediate 61D (200 mg) was placed in 1.0 M hydrochloric acid aqueous solution (10 ml). The mixture was stirred at 100 °C for reaction. After the reaction was complete, the pH was adjusted to alkaline with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure from the filtrate. It was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia) to obtain Compound 61 (100 mg). MS (ESI): m / z 406.25 [M+H] + 。

[0858] 1 H NMR (500 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.92 (s, 1H), 7.74–7.63 (m, 2H), 7.42 (d, J = 7.8 Hz, 2H), 6.94 (d, J = 7.8 Hz, 1H), 5.70 (s, 1H), 5.00 (s, 1H), 3.81 (s, 1H), 3.65–3.50 (m, 1H), 3.12–3.01 (m, 1H), 2.97 (d, J = 1.1 Hz, 3H), 2.48–2.43 (m, 1H), 2.05–1.99 (m, 1H), 1.96–1.84 (m, 1H), 1.75–1.69 (m, 2H), 1.64–1.60 (m, 1H), 1.03 (d, J = 6.8 Hz, 6H).

[0859] Example 62: Preparation of Compound 62

[0860]

[0861] Referring to the preparation method of Compound 61 in Reference Example 61, 4-bromoanisole was replaced with 1-bromo-4-(cyclopropylthio)benzene therein to obtain a crude product of Compound 62.

[0862] The crude compound 62 was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain compound 62 (40 mg). MS (ESI): m / z 432.24 [M+H] + .

[0863] 1 1H NMR (500 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.91 (s, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 7.8 Hz, 1H), 5.70 (s, 1H), 5.00 (s, 1H), 3.76 (s, 1H), 3.60–3.56 (m, 1H), 3.36–3.33 (m, 1H), 3.13–2.99 (m, 1H), 2.59–2.50 (m, 1H), 2.48–2.41 (m, 1H), 2.08–1.97 (m, 1H), 1.95–1.83 (m, 1H), 1.79–1.66 (m, 2H), 1.64–1.56 (m, 1H), 1.03 (d, J = 6.4 Hz, 6H), 0.94–0.88 (m, 1H), 0.88–0.77 (m, 2H).

[0864] Examples 63 and 64: Preparation of Compounds 63 and 64

[0865]

[0866] (1-(tert-Butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (2.00 g), triethylamine (1.70 g), and bis(2,5-dioxopyrrolidin-1-yl) carbonate (4.30 g) were stirred and reacted in acetonitrile (20 mL) at 40 °C. After the reaction was complete, the reaction solution was evaporated under reduced pressure and separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 63A (1.73 g). MS (ESI): m / z 499.32 [M+H] + 。

[0867] N,N-Diisopropylethylamine (1.02 g), 1,1,1-trifluoropropan-2-amine (0.36 g), and intermediate 63A (1.00 g) were stirred and reacted in dichloromethane (20 mL) at 35 °C. After the reaction was complete, the reaction solution was washed successively with saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 63B (0.80 g). MS (ESI): m / z 497.34 [M+H] + 。

[0868] Intermediate 63B (0.80 g), palladium on carbon (palladium content 5%, water content 50% (w / w), 0.34 g) were placed in tetrahydrofuran (8 mL) and ethyl acetate (8 mL), and stirred at room temperature under a hydrogen atmosphere for reaction. After the reaction was complete, it was filtered and concentrated to obtain Intermediate 63C (0.45 g). MS (ESI): m / z 363.27 [M+H] + 。

[0869] Intermediate 63C (0.25 g), 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide (0.26 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.11 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.10 g), potassium phosphate (0.44 g) were placed in N,N-dimethylformamide (10 mL). After addition, it was stirred at 110 °C under nitrogen protection for reaction. After the reaction was complete, it was filtered, concentrated and separated by column chromatography (eluent: dichloromethane / methanol) to obtain Intermediate 63D (0.23 g). MS (ESI): m / z 529.28 [M+H] + 。

[0870] Intermediate 63D (0.23 g) was placed in ethanol (2 mL) and dilute hydrochloric acid (1 N, 20 mL), and stirred at 100 °C by microwave for reaction. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution. The residue was adjusted to alkaline pH with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography (eluent: dichloromethane / methanol) to obtain Intermediate 63E (70 mg). MS (ESI): m / z 473.14 [M+H] + 。

[0871] Intermediate 63E (70 mg) was prepared by SFC chiral separation (CHIRALART Amylose-SA column (30*250 mm, 5 μm), mobile phase: ethanol / n-hexane (0-60%)) to obtain Compound 63 (35 mg). MS (ESI): m / z 473.1491 [M+H] + 。

[0872] 11H NMR (500 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.47 (s, 1H), 7.82 (d, J = 8.95 Hz, 1H), 7.40 (m, 1H), 7.22 - 7.20 (m, 1H), 7.14 - 7.13 (m, 1H), 5.64 (s, 1H), 5.18 - 4.94 (m, 1H), 4.40 (s, 2H), 4.32 (s, 2H), 4.30 - 4.23 (m, 1H), 3.08 - 3.02 (m, 1H), 2.05 - 2.00 (m, 1H), 1.97 - 1.90 (m, 1H), 1.77 - 1.69 (m, 2H), 1.68 - 1.54 (m, 1H), 1.23 - 1.22 (m, 3H).

[0873] Compound 64 (35 mg). MS (ESI): m / z 473.1485 [M + H] + .

[0874] 1 1H NMR (500 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.47 (s, 1H), 7.82 (d, J = 8.95 Hz, 1H), 7.40 (m, 1H), 7.22 - 7.20 (m, 1H), 7.14 - 7.13 (m, 1H), 5.64 (s, 1H), 5.18 - 4.94 (m, 1H), 4.40 (s, 2H), 4.32 (s, 2H), 4.30 - 4.23 (m, 1H), 3.08 - 3.02 (m, 1H), 2.05 - 2.00 (m, 1H), 1.97 - 1.90 (m, 1H), 1.77 - 1.69 (m, 2H), 1.68 - 1.54 (m, 1H), 1.23 - 1.22 (m, 3H).

[0875] Example 65: Preparation of Compound 65

[0876]

[0877] Referring to the preparation method of Compound 33 in Reference Example 33, replace 4-bromo-2-fluorobenzenesulfonyl chloride therein with 4-bromobenzenesulfonyl chloride to prepare Compound 65 (35 mg). MS (ESI): m / z 408.1709 [M + H] + .

[0878] 11H NMR (500 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.85 (s, 1H), 7.61 - 7.59 (m, 2H), 7.39 (d, J = 8.40 Hz, 2H), 7.00 (s, 2H), 6.95 - 6.93 (m, 1H), 5.68 (s, 1H), 5.09 - 4.92 (m, 1H), 3.61 - 3.55 (m, 1H), 3.09 - 3.02 (m, 1H), 2.49 - 2.42 (m, 1H), 2.04 - 2.00 (m, 1H), 1.94 - 1.86 (m, 1H), 1.75 - 1.69 (m, 2H), 1.63 - 1.57 (m, 1H), 1.03 (d, J = 6.40 Hz, 6H).

[0879] Example 66: Preparation of Compound 66

[0880]

[0881] Referring to the preparation method of Compound 33 in Reference Example 33, replacing 4-bromo-2-fluorobenzenesulfonyl chloride therein with 4-bromo-2-(trifluoromethyl)benzenesulfonyl chloride, Compound 66 (35 mg) was prepared. MS (ESI): m / z 476.1585 [M + H] + .

[0882] 1 1H NMR (500 MHz, DMSO-d6) δ 12.03 (s, 1H), 9.28 (s, 1H), 8.00 (s, 1H), 7.93 (d, J = 8.90 Hz, 1H), 7.58 - 7.57 (m, 1H), 7.30 (s, 2H), 6.93 (d, J = 7.15 Hz, 1H), 5.69 (s, 1H), 4.99 (s, 1H), 3.60 - 3.56 (m, 1H), 3.08 - 3.03 (m, 1H), 2.49 - 2.42 (m, 1H), 2.05 - 2.00 (m, 1H), 1.94 - 1.88 (m, 1H), 1.75 - 1.69 (m, 2H), 1.64 - 1.54 (m, 1H), 1.03 (d, J = 6.45 Hz, 6H).

[0883] Example 67: Preparation of Compound 67

[0884]

[0885] Referring to the preparation method of Compound 48 in Reference Example 48, replacing 1-methylcyclopropan-1-amine hydrochloride therein with cyclopropylamine, the crude product of Compound 67 was obtained.

[0886] The crude product of compound 67 was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain compound 67 (20 mg). MS (ESI): m / z 417.1596 [M+H] + .

[0887] 1 1H NMR (500 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.46 (s, 1H), 7.40 (s, 1H), 7.21 (d, J = 9.8 Hz, 2H), 7.13 (d, J = 8.4 Hz, 1H), 5.63 (s, 1H), 5.00 (s, 1H), 4.40 (s, 2H), 4.32 (s, 2H), 3.05 (m, 1H), 2.45 (m, 2H), 2.03 - 1.98 (m, 1H), 1.94 - 1.86 (m, 1H), 1.78 - 1.67 (m, 2H), 1.63 - 1.56 (s, 1H), 0.55 - 0.53 (m, 2H), 0.39 - 0.35 (m, 2H).

[0888] Example 68: Preparation of compound 68

[0889]

[0890] Referring to the preparation method of compound 1 in Reference Example 1, replace 1A therein with 6-chloro-N-cyclopropylpyridine-3-sulfonamide to obtain the crude product of compound 68 in Example 68.

[0891] The crude product of compound 68 was purified by column chromatography (developing agent: dichloromethane / methanol (90 / 10)) to obtain compound 68 (70 mg). MS (ESI): m / z 449.1967 [M+H] + 。

[0892] 11H NMR (500 MHz, DMSO-d6) δ 12.02 (s, 1H), 9.85 (s, 1H), 8.46 (d, J = 2.5 Hz, 1H), 7.83 (dd, J = 8.9, 2.5 Hz, 1H), 7.70 (s, 1H), 7.34 (s, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.18 (s, 1H), 5.00 (s, 1H), 3.60 - 3.54 (m, 1H), 3.17 - 2.98 (m, 1H), 2.49 - 2.44 (m, 1H), 2.15 - 2.12 (m, 1H), 2.05 - 2.00 (m, 1H), 1.95 - 1.83 (m, 1H), 1.80 - 1.67 (m, 2H), 1.64 - 1.58 (m, 1H), 1.03 (dd, J = 6.9, 2.8 Hz, 6H), 0.57–0.42 (m, 2H), 0.38–0.35 (m, 2H).

[0893] Example 69: Preparation of Compound 69

[0894]

[0895] Referring to the preparation method of Compound 33 in Reference Example 33, replace 4-bromo-2-fluorobenzenesulfonyl chloride with 2-chloropyridine-5-sulfonyl chloride and ammonia water with dimethylamine to prepare Compound 69 (10 mg). MS (ESI): m / z 437.1966 [M+H] + 。

[0896] 1 1H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 9.93 (s, 1H), 8.41 (d, J = 1.30 Hz, 1H), 7.82 (dd, J = 2.15, 8.90 Hz, 1H), 7.35 (s, 1H), 6.93 (d, J = 6.85 Hz, 1H), 6.22 (s, 1H), 5.11 - 4.90 (m, 1H), 3.61 - 3.54 (m, 1H), 3.14 - 3.02 (m, 1H), 2.60 (s, 6H), 2.49 - 2.35 (m, 1H), 2.06 - 2.00 (m, 1H), 1.94 - 1.86 (m, 1H), 1.78 - 1.67 (m, 2H), 1.65 - 1.58 (m, 1H), 1.03 (m, 6H).

[0897] Example 70: Preparation of Compound 70

[0898]

[0899] For the preparation method of Reference Example 61, Compound 61, 4-bromoanisole therein was replaced with 4-bromo-2-fluoro-1-(methylthio)benzene to obtain the crude product of Compound 70 in Example 70.

[0900] The crude product of Compound 70 was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 70 (80 mg) in Example 70. MS (ESI): m / z 424.23 [M+H] + 。

[0901] 1 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.20 (s, 1H), 7.61 (t, J = 8.7 Hz, 1H), 7.44 (d, J = 13.7 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 5.70 (s, 1H), 4.99 (s, 1H), 4.27 (s, 1H), 3.68 - 3.49 (m, 1H), 3.10 - 3.04 (m, 4H), 2.49 - 2.41 (m, 1H), 2.09 - 1.97 (m, 1H), 1.96 - 1.85 (m, 1H), 1.75 - 1.68 (m, 2H), 1.63 - 1.59 (m, 1H), 1.15 - 0.94 (m, 6H).

[0902] Example 71: Preparation of Compound 71

[0903]

[0904] N-Bromosuccinimide (2.46 g) and 2-(difluoromethoxy)aniline (2.00 g) were stirred and reacted in dichloromethane (20 mL) in an ice bath. After the reaction was complete, it was concentrated to obtain Intermediate 71A (1.90 g).

[0905] Intermediate 71A (1.80 g), N,N-diisopropylethylamine (2.93 g), and methanesulfonic anhydride (3.95 g) were stirred and reacted in dichloromethane (20 mL) at room temperature. After the reaction was complete, it was concentrated and separated by column chromatography (developing agent: petroleum ether / ethyl acetate) to obtain Intermediate 71B (2.0 g). MS (ESI): m / z 315.97 [M-H] - .

[0906] Intermediate 71B (0.46 g), Intermediate K (0.3 g), [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2'-amino-1,1'-biphenyl]palladium(II) dichloromethane adduct (0.18 g), and cesium carbonate (0.95 g) were placed in dioxane (20 mL), and the mixture was stirred at 110 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to obtain Intermediate 71C (350 mg). MS (ESI): m / z 544.46 [M+H] + .

[0907] Intermediate 71C (0.35 g) and saturated aqueous sodium carbonate solution (10 mL) were placed in dioxane (20 mL). After addition, the mixture was stirred at 50 °C. After the reaction was complete, the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 71D (300 mg).

[0908] Intermediate 71D (300 mg) was placed in ethanol (1 mL) and dilute hydrochloric acid (1 N, 15 mL), and the mixture was stirred at 100 °C under microwave irradiation. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution. The residue was adjusted to alkaline pH with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to obtain Intermediate 71 (100 mg). MS (ESI): m / z 488.1787 [M+H] + 。

[0909] 1 H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 7.44 (s, 1H), 7.23 - 7.02 (m, 3H), 6.95 - 6.90 (m, 1H), 5.61 (s, 1H), 4.99 (s, 1H), 3.61 - 3.54 (m, 1H), 3.06 - 2.98 (m, 1H), 2.91 (s, 3H), 2.48 - 2.42 (m, 1H), 2.03 - 1.98 (m, 1H), 1.93 - 1.86 (m, 1H), 1.76 - 1.65 (m, 2H), 1.62 - 1.55 (m, 1H), 1.03 (d, J = 7.10 Hz, 6H).

[0910] Example 72: Preparation of Compound 72

[0911]

[0912] Referring to the preparation method of Compound 1 in Example 1, replace 1A with 4-bromobenzonitrile to obtain Compound 72 (60 mg). MS (ESI): m / z 354.1923 [M+H] + 。

[0913] 1 H NMR (500 MHz, DMSO-d6) δ 11.96 (s, 1H), 9.07 (s, 1H), 7.57 - 7.55 (m, 2H), 7.42 - 7.40 (m, 2H), 7.70 (s, 1H), 6.94 - 6.93 (m, 1H), 5.71 (s, 1H), 5.00 (s, 1H), 3.60 - 3.56 (m, 1H), 3.08 - 3.04 (m, 1H), 2.48 - 2.44 (m, 1H), 2.05 - 2.00 (m, 1H), 1.94 - 1.86 (m, 1H), 1.76 - 1.67 (m, 2H), 1.64 - 1.58 (m, 1H), 1.04 - 1.02 (m, 6H).

[0914] Example 73: Preparation of Compound 73

[0915]

[0916] Referring to the preparation method of Compound 61 in Example 61, replace 4-bromoanisole with 1-bromo-3-chloro-4-(methylthio)benzene to obtain the crude product of Compound 73.

[0917] The crude product of Compound 73 was purified by medium and low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 73 (50 mg) of Example 73. MS (ESI): m / z 440.15 [M+H] + 。

[0918] 11H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.15 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.31 - 7.22 (m, 1H), 6.94 (d, J = 7.8 Hz, 1H), 5.68 (s, 1H), 5.00 (s, 1H), 4.20 (s, 1H), 3.62 - 3.55 (m, 1H), 3.13 (d, J = 1.2 Hz, 3H), 3.10 - 3.03 (m, 1H), 2.49 - 2.40 (m, 1H), 2.05 - 1.97 (m, 1H), 1.96 - 1.83 (m, 1H), 1.79 - 1.65 (m, 2H), 1.63 - 1.57 (m, 1H), 1.03 (dd, J = 6.6, 2.2 Hz, 6H).

[0919] Example 74: Preparation of Compound 74

[0920]

[0921] 5-Bromo-2-nitrobenzaldehyde (3.00 g) and diethylaminosulfur trifluoride (3.15 g) were placed in dichloromethane (20 mL), and the reaction was stirred in an ice bath. After the reaction was complete, it was concentrated to obtain intermediate 74A (3.00 g).

[0922] Intermediate 74A (3.00 g), zinc powder (3.89 g), and ammonium chloride (3.82 g) were placed in methanol (30 mL). After addition, the reaction was stirred at room temperature. After the reaction was complete, it was filtered, concentrated, and separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 74B (1.37 g).

[0923] Intermediate 74B (1.37 g), N,N-diisopropylethylamine (2.39 g), and methanesulfonic anhydride (3.22 g) were placed in dichloromethane (20 mL). After addition, the reaction was stirred at room temperature. After the reaction was complete, it was concentrated and separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain intermediate 74C (0.90 g).

[0924] Intermediate 74C (0.36 g), intermediate K (0.20 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.10 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.06 g), and potassium phosphate (0.34 g) were placed in dioxane (20 mL). After addition, the reaction was stirred at 100 °C under nitrogen protection. After the reaction was complete, it was filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 74D (0.30 g).

[0925] Intermediate 74D (0.3 g), saturated aqueous sodium carbonate solution (10 mL) were stirred and reacted in dioxane (20 mL) at 50 °C. After the reaction was complete, it was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 74E (230 mg). MS (ESI): m / z 528.29 [M+H] + 。

[0926] Intermediate 74E (100 mg) was stirred and reacted in ethanol (1 mL) and dilute hydrochloric acid (1 N, 15 mL) by microwave at 100 °C. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution. The residue was adjusted to alkaline pH with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 74 (25 mg). MS (ESI): m / z 472.1821 [M+H] + 。

[0927] 1 H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.07 (s, 1H), 8.69 (s, 1H), 7.81 (s, 1H), 7.47 - 7.34 (m, 1H), 7.26 - 6.89 (m, 3H), 5.62 (s, 1H), 5.00 (s, 1H), 3.60 - 3.56 (m, 1H), 3.08 - 3.01 (m, 1H), 2.94 (s, 3H), 2.46 - 2.43 (m, 1H), 2.03 - 2.00 (m, 1H), 1.95 - 1.85 (m, 1H), 1.76 - 1.68 (m, 2H), 1.63 - 1.57 (m, 1H), 1.03 (d, J = 6.25 Hz, 6H).

[0928] Example 75: Preparation of Compound 75

[0929]

[0930] Referring to the preparation method of Compound 26 in Reference Example 26, 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide was replaced with 6-bromo-2,3-dihydrobenzo[b]thiophene-1,1-dioxide to obtain a crude product of Compound 75.

[0931] The crude product of Compound 75 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), the eluent contained one-thousandth ammonia water) to obtain Example 75 Compound 75 (60 mg). MS (ESI): m / z 419.23 [M+H] + 。

[0932] 1 1H NMR (500 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.82 (s, 1H), 7.93 (s, 1H), 7.38 (dd, J = 8.5, 2.2 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 5.61 (s, 1H), 5.10 - 4.80 (m, 1H), 3.64 - 3.54 (m, 1H), 3.52 (t, J = 6.8 Hz, 2H), 3.20 (t, J = 6.8 Hz, 2H), 3.12 - 2.96 (m, 1H), 2.49 - 2.40 (m, 1H), 2.06 - 1.97 (m, 1H), 1.95 - 1.85 (m, 1H), 1.78 - 1.64 (m, 2H), 1.65 - 1.53 (m, 1H), 1.03 (d, J = 6.5 Hz, 6H).

[0933] Example 76: Preparation of Compound 76

[0934]

[0935] Referring to the preparation method of Compound 26 in Reference Example 26, replace 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide therein with 5-bromo-6-fluoro-1,3-dihydrobenzo[c]thiophene 2,2-dioxide to obtain the crude product of Compound 76.

[0936] The crude product of Compound 76 was purified by medium and low pressure preparative liquid phase (C18 chromatographic column, acetonitrile / water (30 / 70), and the eluent contained one-thousandth ammonia water) to obtain Compound 76 (110 mg) of Example 76. MS (ESI, [M+H] + ) m / z: 437.1662.

[0937] 1 1H NMR (500 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.22 (s, 1H), 8.10 (d, J = 8.10 Hz, 1H), 7.16 (d, J = 11.70 Hz, 1H), 6.93 (d, J = 7.80 Hz, 1H), 5.77 (s, 1H), 5.03 - 4.96 (m, 1H), 4.41 (s, 2H), 4.36 (s, 2H), 3.60 - 3.56 (m, 1H), 3.08 - 3.03 (m, 1H), 2.48 - 2.43 (m, 1H), 2.05 - 2.00 (m, 1H), 1.94 - 1.86 (m, 1H), 1.76 - 1.65 (m, 2H), 1.62 - 1.56 (m, 1H), 1.04 - 1.03 (m, 6H).

[0938] Example 77: Preparation of Compound 77

[0939]

[0940] Referring to the preparation method of Compound 48 in Reference Example 48, replace 1-methylcyclopropane-1-amine hydrochloride therein with isopropylamine hydrochloride-d7 to obtain Intermediate 77B.

[0941] Referring to the preparation method of Compound 52 in Reference Example 52, replace Intermediate K therein with Intermediate 77B to obtain Compound 77 (80 mg). MS (ESI): m / z 450.1821 [M+H] + 。

[0942] 1 H NMR (500 MHz, DMSO-d6) δ 12.09 (s, 1H), 10.08 (s, 1H), 8.03 (d, J = 8.75 Hz, 1H), 7.42 (s, 2H), 7.34 (s, 1H), 6.91 (s, 1H), 6.08 (s, 1H), 5.00 (m, 1H), 3.11 - 3.04 (m, 1H), 2.49 - 2.42 (m, 1H), 2.05 - 1.98 (m, 1H), 1.95 - 1.86 (m, 1H), 1.79 - 1.66 (m, 2H), 1.65 - 1.56 (m, 1H).

[0943] Example 78: Preparation of Compound 78

[0944]

[0945] Referring to the preparation method of Compound 26 in Reference Example 26, replace Intermediate K therein with Intermediate 77B to obtain Compound 78 (40 mg). MS (ESI): m / z 426.2284 [M+H] + 。

[0946] 1 H NMR (500 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.46 (s, 1H), 7.41 (s, 1H), 7.22 (d, J = 7.95 Hz, 1H), 7.14 (d, J = 8.40 Hz, 1H), 6.92 (d, J = 7.95 Hz, 1H), 5.63 (s, 1H), 4.99 (m, 1H), 4.40 (s, 2H), 4.32 (s, 2H), 3.08 - 3.00 (m, 1H), 2.48 - 2.42 (m, 1H), 2.03 - 1.98 (m, 1H), 1.93 - 1.86 (m, 1H), 1.73 - 1.68 (m, 2H), 1.62 - 1.56 (m, 1H).

[0947] Example 79: Preparation of Compound 79

[0948]

[0949] Referring to the preparation method of Compound 13 in Reference Example 13, replace the intermediate 2-bromopyridine therein with 5-bromo-2-cyanopyridine to obtain Compound 79 (70 mg) of Example 79. MS (ESI): m / z 355.1880 [M+H] + 。

[0950] 1H NMR (500 MHz, DMSO-d6) δ 12.15–12.01 (m, 1H), 9.42 (s, 1H), 8.58 (d, 1H), 7.96 (dd, 1H), 7.77 (d, 1H), 6.93 (d, 1H), 5.74 (d, 1H), 5.00 (s, 1H), 3.58 (dd, 1H), 3.13–3.01 (m, 1H), 2.49–2.41 (m, 1H), 2.07–1.98 (m, 1H), 1.96–1.86 (m, 1H), 1.80–1.67 (m, 2H), 1.09–0.98 (m, 6H).

[0951] Example 80: Preparation of Compound 80

[0952]

[0953] 2-Bromo-5-cyanopyridine (178 mg), potassium tert-butoxide (0.146 g), and Intermediate K (0.2 g) were reacted in THF (15 mL) at 80 °C in an oil bath. After the reaction was complete, the solvent was removed by distillation under reduced pressure from the reaction solution, and the residue was separated by column chromatography (eluent: dichloromethane / methanol) to obtain Intermediate 80A (100 mg). MS (ESI): m / z 411.29 [M+H] + 。

[0954] Referring to the preparation method of Compound 79 in Example 79, replace Intermediate 79A therein with 80A to obtain Compound 80 (30 mg) of Example 80. MS (ESI): m / z 355.1882 [M+H] + 。

[0955] 1H NMR (500 MHz, DMSO-d6) δ 8.37 (d, 1H), 7.30–7.21 (m, 1H), 6.92 (d, 1H), 6.68 (d, 1H), 6.45 (s, 1H), 5.01 (t, 1H), 3.57 (h, 1H), 3.16 (p, 1H), 2.47 (dd, 1H), 2.13–2.02 (m, 1H), 1.94–1.89 (m, 1H), 1.81–1.71 (m, 2H), 1.65 (ddd, 4.7 Hz, 1H), 1.03 (t, 6H).

[0956] Experimental Example 1 In vitro kinase inhibitory activity

[0957] 1.1 Determination of CDK2 / CycA2 kinase inhibitory activity

[0958] The CDK2 / CycA2 kinase solution (concentration 0.078 ng / μL) was added to the detection wells at 6 μL per well. Different compounds dissolved in DMSO were added to the detection wells using a nanoliter pipettor to make the final concentration of the compounds 1000 nM - 0.244 nM, with 2 replicates, and a control was set simultaneously. The above system was incubated for 30 minutes. ATP (concentration 50 μM or 5000 μM) and the ULight-Myelin Basic Protein Peptide substrate (manufacturer: PerkinElmer, concentration 0.25 μM) were mixed at a ratio of 1:1 and added to the detection wells at 4 μL per well. After reacting at room temperature for 2 hours, 5 μL of EDTA was added to terminate the reaction, and then 5 μL of the detection antibody (manufacturer: PerkinElmer, concentration 8 nM) was added and incubated at room temperature for 1 hour. Detection was performed using a PerkinElmer Envision multimode microplate reader (excitation 320 nm, emission 615 nm / 665 nm), and four-parameter fitting was used to calculate the IC 50 。

[0959] 1.2 Determination of CDK2 CycE1 kinase inhibitory activity

[0960] CDK2 CycE1 kinase solution (concentration 0.015 ng / μL), add 6 μL per well to the detection wells. Use a nanoliter pipettor to add different compounds dissolved in DMSO to the detection wells to make the final concentration of the compounds 300 nM - 0.07 nM, with 2 replicates, and set a control at the same time. Incubate the above system for 30 minutes. Mix ATP (concentration 50 μM or 5000 μM) with the ULight-Myelin BasicProtein Peptide substrate (manufacturer: PerkinElmer, concentration 0.25 μM) at a ratio of 1:1, and add 4 μL per well to the detection wells; after reacting at room temperature for 2 hours, add 5 μL of EDTA to terminate the reaction, then add 5 μL of the detection antibody (manufacturer: PerkinElmer, concentration 8 nM), and incubate at room temperature for 1 hour; detect using a PerkinElmer Envision multimode microplate reader (excitation 320 nm, emission 615 nm / 665 nm), and use four-parameter fitting to calculate IC 50 。

[0961] The experimental results are shown in Table 1, where A represents: 0 nM < IC 50 ≤ 10 nM; B represents: 10 nM < IC 50 ≤ 50 nM; C represents: 50 nM < IC 50 ≤ 100 nM; D represents: 100 nM < IC 50 ≤ 1000 nM; E represents: 1000 nM < IC 50 。

[0962] Table 1: Inhibitory activities of compounds on CDK2 CycA2 and CDK2 CycE1 kinases

[0963]

[0964]

[0965]

[0966]

Claims

1. A compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from C 3-10 alkane rings, 5- to 10-membered heteroalkane rings, benzene rings, naphthalene rings, benzene ring-fused C 5-6 alkane rings, benzene ring-fused 5- to 6-membered heteroalkane rings, 5- to 10-membered heteroaromatic rings, 5- to 6-membered heteroaromatic ring-fused C 5-6 alkane rings or 5- to 6-membered heteroaromatic ring-fused 5- to 6-membered heteroalkane rings, wherein the C 3-10 alkane rings, 5- to 10-membered heteroalkane rings, benzene rings, naphthalene rings, benzene ring-fused C 5-6 alkane rings, benzene ring-fused 5- to 6-membered heteroalkane rings, 5- to 10-membered heteroaromatic rings, 5- to 6-membered heteroaromatic ring-fused C 5-6 alkane rings or 5- to 6-membered heteroaromatic ring-fused 5- to 6-membered heteroalkane rings are optionally and independently substituted by one or more R a substituents; L 1 and L 2 each independently selected from a single bond, -N(R b )-, -N=, -O-, -S-, -(CH2) m -, -(CD2) m -, -(CHD) m -, -C(=O)-, -S(=O)-, -S(=O)2-, -S(=O)(=N(R b ))-, -S(=O)(R c )-, -P(=O)(R c )- or -P(=O)(NR b R b )-; R 1 selected from H, deuterium, C 1-3 alkyl, C 1-3 alkoxy, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, C 3-6 cycloalkyl, 3-6 membered heteroalkyl, phenyl or 5-6 membered heteroaryl, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R d substituents, and the C 3-6 cycloalkyl, 3-6 membered heteroalkyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted by one or more R e substituents; R 2 、R 3 and R 4 are each independently selected from H, deuterium, halogen, OH, CN, NH2, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted with one or more R z substituents; or R 2 and R 3 together with the jointly linked carbon atom form C 3-6 cycloalkyl or 3-6 membered heteroalkyl, R 4 is selected from H, deuterium, halogen, OH, CN, NH2, C 1-3 alkyl or C 1-3 alkoxy, said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 3-6 membered heteroalkyl is optionally independently substituted by one or more R z substituted; Each R a is independently selected from deuterium, halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by one or more R x substituents; Each R b is independently selected from H, C 1-3 alkyl, C 1-3 alkoxy, -C(=O)H, -S(=O)2C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x ; the C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by one or more R y ; R c Selected from halogen, OH, CN or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally and independently substituted by one or more R x substituents; Each R d is independently selected from deuterium, a halogen, OH, CN or NH2; Each R e is independently selected from deuterium, halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by one or more R x substituents; Each R x is independently selected from deuterium, a halogen, OH, CN or NH2; Each R y is independently selected from deuterium, halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted with one or more substituents selected from deuterium, halogen, OH, CN or NH2; Each R z is independently selected from deuterium, halogen, OH, CN or NH2; m is selected from 1, 2 or 3; The carbon atom with "*" is a chiral carbon atom and exists in the form of a single (R) or (S) enantiomer or an enantiomer-rich form; Alternatively, each L 1 、L 2 、R 1 、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e 、R x 、R y or R z is independently and optionally substituted with one or more substituents.

2. The compound of formula (I) according to claim 1, its isomer or its pharmaceutically acceptable salt, wherein ring A is selected from C 3-6 alkane ring, 5-6 membered heteroalkane ring, benzene ring, naphthalene ring, benzeno-C 5-6 alkane ring, benzeno-5-6 membered heteroalkane ring, 5-10 membered heteroaromatic ring, 5-6 membered heteroaromatic ring-fused-C 5-6 alkane ring or 5-6 membered heteroaromatic ring-fused-5-6 membered heteroalkane ring, and the C 3-6 alkane ring, 5-6 membered heteroalkane ring, benzene ring, naphthalene ring, benzeno-C 5-6 alkane ring, benzeno-5-6 membered heteroalkane ring, 5-10 membered heteroaromatic ring, 5-6 membered heteroaromatic ring-fused-C 5-6 alkane ring or 5-6 membered heteroaromatic ring-fused-5-6 membered heteroalkane ring is optionally independently substituted by 1, 2, 3 or 4 R a substituents; Alternatively, ring A is selected from a 6-membered heteroalkane ring containing 1 N atom, a benzene ring, a benzene ring fused to a 5-membered heteroalkane ring containing 1 N atom, a 5-membered heteroaromatic ring containing 1 or 2 N atoms, a 6-membered heteroaromatic ring having only 1 N atom, a 6-membered heteroaromatic ring containing 1 N atom fused to a 5-membered heteroalkane ring containing 1 N atom, or a 6-membered heteroaromatic ring containing 1 N atom fused to a 6-membered heteroalkane ring containing 1 N atom, and the 6-membered heteroalkane ring containing 1 N atom, the benzene ring, the benzene ring fused to a 5-membered heteroalkane ring containing 1 N atom, the 5-membered heteroaromatic ring containing 1 or 2 N atoms, the 6-membered heteroaromatic ring having only 1 N atom, the 6-membered heteroaromatic ring containing 1 N atom fused to a 5-membered heteroalkane ring containing 1 N atom, or the 6-membered heteroaromatic ring containing 1 N atom fused to a 6-membered heteroalkane ring containing 1 N atom are each independently optionally substituted with 1, 2, or 3 R a substituents; Alternatively, ring A is selected from a piperidine ring, a benzene ring, a benzo[1,3]dioxole ring, a benzo[1,3]pyrrolidine ring, a benzo[1,3]thiolane ring, a benzo[1,3]isothiazolidine ring, an imidazole ring, an oxazole ring, a thiazole ring, a pyridine ring, a pyrido[2,3-d]tetrahydrofuran ring, a pyrido[2,3-d]isothiazolidine ring or a pyrido[2,3-d]thiazinane ring, and ring A is optionally independently substituted with 1, 2 or 3 R a substituents; Alternatively, the ring A is selected from The ring A is optionally independently substituted by 1, 2 or 3 R a groups; Alternatively, the ring A is selected from The ring A is optionally independently substituted by 1, 2 or 3 R a groups; Alternatively, the ring A is selected from Said ring A is optionally independently substituted by 1, 2, 3 or 4 R a groups.

3. The compound of formula (I) according to claim 1, its isomer or its pharmaceutically acceptable salt, wherein L 1 is selected from a single bond, -N(R b )-, -N=, -O-, -S(=O)2-, -S-, -(CH2) m -, or -C(=O)-; or, L 1 is selected from a single bond, -NH-, -N=, -N(C(=O)H)-, -N(CH3)-, -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -C(=O)- or -N(S(=O)2CH3)-; or, L 1 is selected from a single bond, -NH-, -N=, -N(C(=O)H)-, -N(CH3)-, -S(=O)2-, -CH2-, -C(=O)- or -N(S(=O)2CH3)-; Alternatively, said L 1 is selected from -NH-; The L 2 is selected from a single bond, -NH-, -N(C 1-3 alkyl)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -C(=O)-, -S(=O)-, -S(=O)2-, -S(=O)(=NH)-, -S(=O)(C 1-3 alkyl)-, -P(=O)(C 1-3 alkyl)-, -P(=O)(NH2)- or -P(=O)(NH(C 1-3 alkyl)); or, the L 2 is selected from a single bond, -NH-, -N(CH3)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -C(=O)-, -S(=O)-, -S(=O)2-, -S(=O)(=NH)-, -S(=O)(CH3)-, -P(=O)(CH3)-, -P(=O)(NH2)- or -P(=O)(NHCH3)-; or, a single bond, -NH-, -N(CH3)-, -CH2-CH2-, -C(=O)-, -S(=O)2-, -S(=O)(=NH)-, -S(=O)(CH3)-, -P(=O)(CH3) or -P(=O)(NHCH3)-; or, L 2 is selected from a single bond or -S(=O)2-; -L 2 -L 1 -selected from a single bond, -NH-, -N(CH3)-, -C(=O)-, -CH2-, -CH2-CH2-, -S(=O)2-, -CH2-NH-, -NH-CH2- -CH2-N(CH3)-, -CH2-N(C(=O)H)-, -N(CH3)-CH2-, -N(C(=O)H)-CH2-, -C(=O)-CH2-, -CH2-C(=O)-, -C(=O)-NH-, -NH-C(=O)-, -NH-S(=O)2-, -S(=O)2-NH-, -N(CH3)-S(=O)2-, -N(S(=O)2CH3)-S(=O)2-, -S(=O)2-N(S(=O)2CH3)-, -S(=O)(CH3)=N-, -S(=O)2-N(CH3)-, -N(CH3)-C(=O)-, -C(=O)-N(CH3)-, -NH-S(=O)(=NH)-, -S(=O)(=NH)-NH-, -S(=O)(=NH)-, -P(=O)(CH3)-, -CH2-S(=O)(=NH)-, -S(=O)(=NH)-CH2-, -CH2-P(=O)(CH3)-, -P(=O)(CH3)-CH2-, -NH-P(=O)(CH3)-, -P(=O)(CH3)-NH-, -NH-P(=O)(NHCH3)-, -P(=O)(NHCH3)-NH-, -NH-P(=O)(NH2)-, -P(=O)(NH2)-NH-, -CH2-P(=O)(NHCH3)-, -P(=O)(NHCH3)-CH2-, -N(CH3)-CH2-CH2-, -N(C(=O)H)-CH2-CH2-, -CH2-CH2-N(CH3)-, -CH2-CH2-N(C(=O)H)-, -NH-CH2-CH2- or -CH2-CH2-NH-; or, -L 2 -L 1 - selected from a single bond, -NH-, -CH2-, -S(=O)2-, -N(CH3)-CH2-, -NH-C(=O)-, -NH-C(=O)-, -S(=O)2-NH-, -NH-S(=O)2- -S(=O)(CH3)=N-, -S(=O)2-N(CH3)-, -C(=O)-NH-, -C(=O)-N(CH3)-, -S(=O)(=NH)-NH-, -S(=O)(=NH)-, -P(=O)(CH3)-, -CH2-S(=O)(=NH)-, -P(=O)(CH3)-CH2-, -P(=O)(CH3)-NH-, -P(=O)(NHCH3)-NH-, -CH2-CH2-N(CH3)-, -CH2-CH2-N(C(=O)H)-, -CH2-CH2-NH- or -S(=O)2-N(S(=O)2CH3)-; or, a single bond, -NH-, -CH2-, -S(=O)2-, -N(CH3)-CH2-, -NH-C(=O)-, -N(CH3)-C(=O)-, -S(=O)2-NH-, -NH-S(=O)2-, -S(=O)(CH3)=N-, -S(=O)2-N(CH3)-, -C(=O)-NH-, -C(=O)-N(CH3)-, -S(=O)(=NH)-NH-, -S(=O)(=NH)-, -P(=O)(CH3)-, -S(=O)(=NH)-CH2-, -P(=O)(CH3)-CH2-, -P(=O)(CH3)-NH-, -P(=O)(NHCH3)-NH-, -CH2-CH2-N(CH3)-, -CH2-CH2-N(C(=O)H)-, -CH2-CH2-NH- or -S(=O)2-N(S(=O)2CH3)-; or, -L 2 -L 1 - selected from a single bond or -S(=O)2-NH-.

4. The compound of formula (I) according to claim 1, its isomer or its pharmaceutically acceptable salt, wherein R 1 is selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, cyclopentyl, a 4-6 membered heterocycloalkyl containing 1 or 2 atoms selected from N, O, S atoms or a 5-6 membered heteroaryl containing 1 or 2 N atoms, and the methyl, ethyl or methoxy is optionally independently substituted by 1, 2 or 3 R d substituents, and the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R e substituents; or, R 1 is selected from H, C 1-3 alkyl, C 1-3 alkoxy, -NH2, -NH(C 1-3 alkyl), cyclopropyl, cyclobutyl, cyclopentyl, a 4-6 membered heterocycloalkyl containing 1 or 2 atoms selected from N, O, S atoms or a 5-6 membered heteroaryl containing 1 or 2 N atoms, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R d substituents; the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R e substituents; or, the R 1 is selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, pyrazolyl, oxazolyl or pyrimidinyl, and the methyl, ethyl or methoxy is optionally independently substituted by 1, 2 or 3 R d substituents; the cyclopropyl, oxetanyl, pyrazolidinyl, isothiazolidinyl, isoxazolidinyl, imidazolyl, oxazolyl or pyrimidinyl is optionally independently substituted by 1, 2 or 3 R e substituents; Alternatively, said R 1 is selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), The methyl, ethyl or methoxy group is optionally independently substituted by 1, 2 or 3 R d groups, and the Optionally independently substituted by 1, 2 or 3 R e groups; Alternatively, R 1 is selected from H, methyl, -CH2CH2OH, methoxy, -OCF3, -CH2OH, -NH2, -NH(CH3), -NH(CH2CH2OH), Alternatively, said R 1 is selected from H, methyl, -CH2CH2OH, methoxy, -OCF3, -CH2OH, -NH2, -NH(CH3), -NH(CH2CH2OH), Alternatively, said R 1 is selected from H, methyl or methoxy.

5. The compound of formula (I) according to claim 1, its isomers or its pharmaceutically acceptable salts, wherein R 2 , R 3 and R 4 are each independently selected from H, deuterium or C 1-3 alkyl, and the C 1-3 alkyl is optionally independently substituted by 1, 2 or 3 R z ; or R 2 , R 3 and R 4 are each independently selected from H, deuterium, methyl, -CD3, difluoromethyl, trifluoromethyl or ethyl; or R 2 , R 3 and R 4 are each independently selected from H, deuterium, methyl, -CD3, or trifluoromethyl; or R 2 is selected from H or deuterium, and R 3 and R 4 are each independently selected from methyl, -CD3 or trifluoromethyl; or said R 2 and R 3 together with the jointly connected carbon atom form a C 3-4 cycloalkyl or 3- to 4-membered heterocycloalkyl, R 4 is selected from H or C 1-3 alkyl, the C 1-3 alkyl, C 3-4 cycloalkyl or 3- to 4-membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R z substituents; or R 2 and R 3 together with the jointly connected carbon atom form a cyclopropyl, R 4 is selected from H or methyl, and the methyl or cyclopropyl is optionally independently substituted by 1, 2 or 3 R z substituents.

6. A compound represented by formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from C 3-10 alkane ring, 5-10 membered heteroalkane ring, benzene ring, naphthalene ring, benzene ring fused to C 5-6 alkane ring, benzene ring fused to 5-6 membered heteroalkane ring, 5-10 membered heteroaromatic ring, 5-6 membered heteroaromatic ring fused to C 5-6 alkane ring or 5-6 membered heteroaromatic ring fused to 5-6 membered heteroalkane ring, wherein the C 3-10 alkane ring, 5-10 membered heteroalkane ring, benzene ring, naphthalene ring, benzene ring fused to C 5-6 alkane ring, benzene ring fused to 5-6 membered heteroalkane ring, 5-10 membered heteroaromatic ring, 5-6 membered heteroaromatic ring fused to C 5-6 alkane ring or 5-6 membered heteroaromatic ring fused to 5-6 membered heteroalkane ring is optionally independently substituted by 1, 2 or 3 R a substituents; L 1 and L 2 each independently selected from a single bond, -N(R b )-, -O-, -S-, -(CH2) m -, -C(=O)-, -S(=O)-, -S(=O)2-, -S(=O)(=N(R b ))-, -P(=O)(R c )- or -P(=O)(NR b R b ); R 1 selected from H, C 1-3 alkyl, C 1-3 alkoxy, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R d substituents, and the C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R e substituents; Each R a is independently selected from halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x substituents; Each R b is independently selected from H, C 1-3 alkyl, C 1-3 alkoxy, -C(=O)H, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x groups; the C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R y groups; R c Selected from halogen, OH, CN or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally and independently substituted by 1, 2 or 3 R x substituents; Each R d is independently selected from halogen, OH, CN or NH2; Each R e is independently selected from halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted by 1, 2 or 3 R x substituents; Each R x is independently selected from halogen, OH, CN or NH2; Each R y is independently selected from halogen, OH, CN, NH2, =O, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted with 1, 2 or 3 substituents selected from halogen, OH, CN or NH2; m is selected from 1, 2 or 3; The carbon atom with "*" is a chiral carbon atom and exists in the form of a single (R) or (S) enantiomer or an enantiomer-rich form.

7. The compound represented by formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 16, which is selected from the compounds represented by formula (II-1), Among them, Ring A, R 1 , L 1 and L 2 as defined in claim 16 8. A compound of the following formula, an isomer thereof, or a pharmaceutically acceptable salt thereof, or selected from a compound of the following formula, an isomer thereof, or a pharmaceutically acceptable salt thereof, 9. A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-8; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

10. Use of the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating or preventing a CDK2-mediated disease.

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