A pyrazole substituted cyclopentyl ester derivative and uses thereof

Abstract

The application relates to a pyrazole-substituted cyclopentyl ester derivative and use thereof, in particular to a compound shown in formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof.

Description

[0001] This application is a divisional application of the application with the application number of 202380036025.4, the application date of April 27, 2023, and the application title of "A pyrazole-substituted cyclopentyl ester derivative and its use".

[0002] Cross-reference to Related Applications

[0003] This application claims priority to and the benefit of Chinese Patent Application No. 202210469621.9, filed April 28, 2022, Chinese Patent Application No. 202210836180.1, filed July 15, 2022, Chinese Patent Application No. 202210999975.4, filed August 19, 2022, Chinese Patent Application No. 202211603669.0, filed December 13, 2022, Chinese Patent Application No. 202310250462.8, filed March 15, 2023, and Chinese Patent Application No. 202310411874.5, filed April 17, 2023, the disclosures of which are incorporated herein by reference in their entireties. TECHNICAL FIELD

[0004] The present application relates to a pyrazole-substituted cyclopentyl ester derivative and its use, in particular to a compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof. BACKGROUND

[0005] Cyclin-dependent kinases (CDKs) belong to the serine / threonine protein kinase family, which 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 control point is the most important, and its regulation is closely related to CDKs. CDKs form a protein kinase complex by combining with cyclins, which can catalyze the phosphorylation of substrates, control the cell cycle progression, and complete DNA replication and mitosis in turn, causing cell division and proliferation. The cell division cycle is regulated by two kinds of regulation: inhibition and promotion, and under normal circumstances, the two are in dynamic balance. However, when the signal to promote cell proliferation is enhanced, or the signal to inhibit cell proliferation is weakened, the balance will be broken, and cell proliferation will be out of control, leading to the occurrence of tumors. Studies have shown that there is overexpression of CDKs in many malignant tumors.

[0006] Studies have shown that CDKs directly involved in cell cycle regulation mainly include CDK1, CDK2, CDK4, and CDK6, playing a crucial role in cell cycle regulation. CDK2 belongs to the CDK family. It is a cell cycle-dependent kinase essential for the completion of G1 phase and the transition from G1 to S phase during cell mitosis. In late G1, CDK2 binds to and activates Cyclin E, promoting continuous phosphorylation of pRb, ensuring the smooth passage of cells through G1 phase and into S phase. E2F inactivation is a prerequisite for S phase completion. In early S phase, CDK2 binds to Cyclin A, inactivating the E2F transcription factor, thereby promoting the smooth completion of S phase. However, sustained E2F activity leads to apoptosis. Therefore, selectively inhibiting CDK2 / Cyclin A activity to increase E2F concentration can lead to cell cycle arrest in S phase or apoptosis, thereby achieving the goal of treating tumor cells. Summary of the Invention

[0007] This application provides the compound of formula (I), its isomers, or pharmaceutically acceptable salts thereof.

[0008]

[0009] in,

[0010] Ring A is selected from C 3-10 Alkane rings, 5-10 membered heteroalkyl rings, benzene rings, naphthalene rings, and benzo[a]carbonyl rings 5-6 Alkane rings, benzene rings, 5-6 membered heteroalkane rings, 5-10 membered heteroaromatic rings, 5-6 membered heteroaromatic rings with C 5-6 Alkyl ring or 5-6 membered heteroaryl ring and 5-6 membered heteroalkyl ring, wherein C 3-10 Alkane rings, 5-10 membered heteroalkyl rings, benzene rings, naphthalene rings, and benzo[a]carbonyl rings 5-6 Alkane rings, benzene rings, 5-6 membered heteroalkane rings, 5-10 membered heteroaromatic rings, 5-6 membered heteroaromatic rings with C 5-6 An alkyl ring or a 5-6 membered heteroaryl ring, with the 5-6 membered heteroalkyl ring optionally and independently bound by one or more R... a replace;

[0011] L 1 and L 2 Each is independently selected from single bonds, -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 selected from H, deuterium, halogen, OH, CN, NH2, 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, said C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted with 1, 2, or 3 R d substituents; 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl is optionally independently substituted with 1 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, said C 1-3 alkyl or C 1-3 alkoxy is optionally independently substituted with 1 or more R z substituents;

[0014] or R 2 and R 3 together with the carbon atoms to which they are attached form a C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, 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- to 6-membered heterocycloalkyl is optionally independently substituted with 1 or more R z substituents;

[0015] each R a is each 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 with 1 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 with 1, 2, or 3 R x substituents; said C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted with 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 with 1 or more R x substituents;

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

[0019] each R e is each 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 with 1 or more R x substituents;

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

[0021] each R y is each 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 with 1 or more substituents selected from deuterium, halogen, OH, CN, or NH2;

[0022] each R z is each 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, in the form of (R) or (S) single enantiomer or enriched in one enantiomeric form;

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

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

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

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

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

[0030] In some embodiments of this 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 them is a group containing a deuterium atom.

[0031] In some embodiments of this application, the phrase "replaced by one or more" is each independently selected from being replaced by 1, 2, 3, 4, 5 or 6.

[0032] In some embodiments of this application, the phrase "replaced by one or more" is each independently selected from being replaced by 1, 2, 3, 4 or 5.

[0033] In some embodiments of this application, the phrase "replaced by one or more" is each independently selected from being replaced by 1, 2, 3 or 4.

[0034] In some embodiments of this application, the phrase "replaced by one or more" is each independently selected from being replaced by 1, 2 or 3.

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

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

[0037] In some embodiments of this application, ring A is selected from C. 3-6 Alkane rings, 5-6 membered heteroalkyl rings, benzene rings, naphthalene rings, and benzo[a]carbonyl rings 5-6 Alkane rings, benzene rings, 5-6 membered heteroalkane rings, 5-10 membered heteroaromatic rings, 5-6 membered heteroaromatic rings with C 5-6 Alkyl ring or 5-6 membered heteroaryl ring and 5-6 membered heteroalkyl ring, wherein C 3-6 Alkane rings, 5-6 membered heteroalkyl rings, benzene rings, naphthalene rings, and benzo[a]carbonyl rings 5-6 Alkane rings, benzene rings, 5-6 membered heteroalkane rings, 5-10 membered heteroaromatic rings, 5-6 membered heteroaromatic rings with C 5-6 An alkyl ring or a 5-6 membered heteroaryl ring, with the 5-6 membered heteroalkyl ring optionally and independently bound by 1, 2, 3 or 4 R groups. a Replace other variables as defined in this application.

[0038] In some embodiments of this application, ring A is selected from C. 3-6 Alkane rings, 5-6 membered heteroalkyl rings, benzene rings, naphthalene rings, and benzo[a]carbonyl rings 5-6 Alkane rings, benzene rings, 5-6 membered heteroalkane rings, 5-6 membered heteroaromatic rings, 5-6 membered heteroaromatic rings with C 5-6 Alkyl ring or 5-6 membered heteroaryl ring and 5-6 membered heteroalkyl ring, wherein C 3-6 Alkane rings, 5-6 membered heteroalkyl rings, benzene rings, naphthalene rings, and benzo[a]carbonyl rings 5-6 Alkane rings, benzene rings, 5-6 membered heteroalkane rings, 5-6 membered heteroaromatic rings, 5-6 membered heteroaromatic rings with C 5-6 An alkyl ring or a 5-6 membered heteroaryl ring, with the 5-6 membered heteroalkyl ring optionally and independently bound by 1, 2, or 3 R groups. a Replace other variables as defined in this application.

[0039] In some embodiments of this application, ring A is selected from 5-6-membered heteroalkane rings, benzene rings, benzene-anchored 5-6-membered heteroalkane rings, 5-6-membered heteroaromatic rings, or 5-6-membered heteroaromatic rings with 5-6-membered heteroalkane rings, wherein the 5-6-membered heteroalkane ring, benzene ring, benzene-anchored 5-6-membered heteroalkane ring, 5-6-membered heteroaromatic ring, or 5-6-membered heteroaromatic ring with 5-6-membered heteroalkane ring is optionally independently bounded by 1, 2, or 3 R's. a Replace other variables as defined in this application.

[0040] In some embodiments of this application, ring A is selected from a 6-membered heteroalkane ring, a benzene ring, a benzene-5-membered heteroalkane ring, a 5-6-membered heteroaromatic ring, or a 6-membered heteroaromatic ring with 5-6-membered heteroalkane ring, wherein the 6-membered heteroalkane ring, benzene ring, benzene-5-membered heteroalkane ring, 5-6-membered heteroaromatic ring, or 6-membered heteroaromatic ring with 5-6-membered heteroalkane ring is optionally independently bounded by 1, 2, or 3 R groups. a Replace other variables as defined in this application.

[0041] In some embodiments of this 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 5-9-membered heteroaromatic ring, or a 6-membered heteroaromatic ring fused to a 5-6-membered heteroalkane ring, wherein the 6-membered heteroalkane ring, benzene ring, benzene ring fused to a 5-membered heteroalkane ring, a 5-9-membered heteroaromatic ring, or a 6-membered heteroaromatic ring fused to a 5-6-membered heteroalkane ring is optionally independently bounded by 1, 2, or 3 R's. a Replace other variables as defined in this application.

[0042] In some further embodiments of this application, ring A is selected from a 6-membered heteroalkane ring, a benzene ring, a benzene ring fused to a 5-membered heteroalkane ring, or a 6-membered heteroaromatic ring fused to a 5-6-membered heteroalkane ring, wherein the 6-membered heteroalkane ring, benzene ring, benzene ring fused to a 5-membered heteroalkane ring, or a 6-membered heteroaromatic ring fused to a 5-6-membered heteroalkane ring is optionally independently bounded by 1, 2, or 3 R groups. a Replace other variables as defined in this application.

[0043] In some embodiments of this application, the 5-10 membered heteroaromatic ring or 5-9 membered heteroaromatic ring in the definition of ring A contains only one or two N atoms, and other variables are as defined in this application.

[0044] In some other embodiments of this application, the 5-10 membered heteroaromatic ring or 5-9 membered heteroaromatic ring in the definition of ring A contains only one N atom, and other variables are as defined in this application.

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

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

[0047] In some embodiments of this 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 heteroaromatic ring, a 6-membered heteroaromatic ring, a 9-membered heteroaromatic 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, wherein the 6-membered heteroalkane ring, benzene ring fused to a 5-membered heteroalkane ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 9-membered heteroaromatic 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 is optionally independently bounded by 1, 2, or 3 R's. a Replace other variables as defined in this application.

[0048] In some embodiments of this application, ring A is selected from a 6-membered heteroalkane ring, a benzene ring, a benzene-5-membered heteroalkane ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 6-membered heteroaromatic ring-5-membered heteroalkane ring, or a 6-membered heteroaromatic ring-6-membered heteroalkane ring, wherein the 6-membered heteroalkane ring, benzene ring, benzene-5-membered heteroalkane ring, 5-membered heteroaromatic ring, 6-membered heteroaromatic ring, 6-membered heteroaromatic ring-5-membered heteroalkane ring, or a 6-membered heteroaromatic ring-6-membered heteroalkane ring is optionally independently bounded by 1, 2, or 3 R's. a Replace other variables as defined in this application.

[0049] In some further embodiments of this 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 heteroaromatic ring fused to a 5-membered heteroalkane ring, or a 6-membered heteroaromatic ring fused to a 6-membered heteroalkane ring, wherein the 6-membered heteroalkane ring, 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 is optionally independently bounded by 1, 2, or 3 R's. a Replace other variables as defined in this application.

[0050] In other embodiments of this application, ring A is selected from a benzo[5-membered heteroalkyl ring, a 6-membered heteroaromatic ring, or a 6-membered heteroaromatic ring, wherein the benzo[5-membered heteroalkyl ring, 6-membered heteroaromatic ring, or 6-membered heteroaromatic ring is optionally independently bounded by 1, 2, or 3 R[] a Instead, the “hetero” mentioned in the 5-membered or 6-membered heteroalkyl 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 this application.

[0051] In other embodiments of this application, ring A is selected from a 6-membered heteroalkyl ring containing 1-3 N atoms, a benzene ring, a 5-membered heteroalkyl ring containing 1-3 N atoms, a 5-membered heteroaromatic ring containing 1-3 N atoms, a 6-membered heteroaromatic ring with only 1 N atom, a 6-membered heteroaromatic ring containing 1-3 N atoms and a 5-membered heteroalkyl ring containing 1-3 N atoms, or a 6-membered heteroaromatic ring containing 1-3 N atoms and a 6-membered heteroalkyl ring containing 1-3 N atoms. Alkyl rings, including six-membered heteroalkyl rings containing 1-3 N atoms, benzene rings, five-membered heteroalkyl rings containing 1-3 N atoms, five-membered heteroaromatic rings containing 1-3 N atoms, six-membered heteroaromatic rings with only one N atom, six-membered heteroaromatic rings containing 1-3 N atoms and five-membered heteroalkyl rings containing 1-3 N atoms, or six-membered heteroaromatic rings containing 1-3 N atoms and six-membered heteroalkyl rings containing 1-3 N atoms, are optionally and independently separated by one, two, or three R atoms. a Replace other variables as defined in this application.

[0052] In some embodiments of this application, ring A is selected from a 6-membered heteroalkyl ring containing 1-3 N atoms, a benzene ring, a 5-membered heteroalkyl 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 and a 5-membered heteroalkyl ring containing 1-3 N atoms, or a 6-membered heteroaromatic ring containing 1-3 N atoms and a 6-membered heteroalkyl ring containing 1-3 N atoms. Alkyl rings, including 6-membered heteroalkyl rings containing 1-3 N atoms, benzene rings, 5-membered heteroalkyl rings containing 1-3 N atoms, 5-membered heteroaromatic rings containing 1-3 N atoms, 6-membered heteroaromatic rings containing 1-3 N atoms, 9-membered heteroaromatic rings containing 1-3 N atoms, 6-membered heteroaromatic rings containing 1-3 N atoms and 5-membered heteroalkyl rings containing 1-3 N atoms, or 6-membered heteroaromatic rings containing 1-3 N atoms and 6-membered heteroalkyl rings containing 1-3 N atoms, optionally and independently composed of 1, 2, or 3 R atoms. a Replace other variables as defined in this application.

[0053] In some embodiments of this application, 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 6-membered heteroaromatic ring containing 1 or 2 N atoms and 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, wherein the six-membered heteroalkyl ring containing one or two N atoms, benzene ring, five-membered heteroalkyl ring containing one or two N atoms, five-membered heteroaromatic ring containing one or two N atoms, six-membered heteroaromatic ring containing one or two N atoms, six-membered heteroaromatic ring containing one or two N atoms and five-membered heteroalkyl ring containing one or two N atoms, or six-membered heteroaromatic ring containing one or two N atoms and six-membered heteroalkyl ring containing one or two N atoms, is optionally and independently composed of one, two, or three R atoms. a Replace other variables as defined in this application.

[0054] In some embodiments of this application, 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 and a benzene ring, 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 and a 5-membered heteroalkyl ring containing 1 N atom, or a 6-membered heteroaromatic ring containing 1 N atom and a 6-membered heteroalkyl ring. The 6-membered heteroalkyl ring containing 1 N atom, benzene ring, 5-membered heteroalkyl ring containing 1 N atom and a benzene ring, 5-membered heteroaromatic ring containing 1 or 2 N atoms, 6-membered heteroaromatic ring containing 1 or 2 N atoms, 6-membered heteroaromatic ring containing 1 N atom and a 5-membered heteroalkyl ring containing 1 N atom, or 6-membered heteroaromatic ring containing 1 N atom and a 6-membered heteroalkyl ring containing 1 N atom may be independently divided by 1, 2, or 3 R atoms. a Replace other variables as defined in this application.

[0055] In other embodiments of this application, 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 and a benzene ring, a 5-membered heteroaromatic ring containing 1 or 2 N atoms, a 6-membered heteroaromatic ring containing only 1 N atom, a 6-membered heteroaromatic ring containing 1 N atom and a 5-membered heteroalkyl ring containing 1 N atom, or a 6-membered heteroaromatic ring containing 1 N atom and a 6-membered heteroalkyl ring containing 1 N atom. The 6-membered heteroalkyl ring containing 1 N atom, benzene ring, 5-membered heteroalkyl ring containing 1 N atom and a benzene ring, 5-membered heteroaromatic ring containing 1 or 2 N atoms, 6-membered heteroaromatic ring containing only 1 N atom, 6-membered heteroaromatic ring containing 1 N atom and a 5-membered heteroalkyl ring containing 1 N atom, or 6-membered heteroaromatic ring containing 1 N atom and a 6-membered heteroalkyl ring containing 1 N atom may be independently divided by 1, 2, or 3 R atoms. a Replace other variables as defined in this application.

[0056] In some embodiments of this application, 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 and a benzene ring, 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 and a 5-membered heteroalkyl ring containing 1 N atom, or a 6-membered heteroaromatic ring containing 1 N atom and a 6-membered heteroalkyl ring. The 6-membered heteroalkyl ring containing 1 N atom, benzene ring, 5-membered heteroalkyl ring containing 1 N atom and a benzene ring, 5-membered heteroaromatic ring containing 1 or 2 N atoms, 6-membered heteroaromatic ring containing 1 or 2 N atoms, 6-membered heteroaromatic ring containing 1 N atom and a 5-membered heteroalkyl ring containing 1 N atom, or 6-membered heteroaromatic ring containing 1 N atom and a 6-membered heteroalkyl ring containing 1 N atom may be independently divided by 1, 2, or 3 R atoms. a Replace other variables as defined in this application.

[0057] In some further embodiments of this application, ring A is selected from a 6-membered heteroalkyl ring containing one N atom, a benzene ring, a 5-membered heteroalkyl ring containing one N atom and a benzene ring, a 5-membered heteroalkyl ring containing one N atom and a 6-membered heteroaromatic ring, or a 6-membered heteroalkyl ring containing one N atom and a 6-membered heteroaromatic ring. The 6-membered heteroalkyl ring containing one N atom, benzene ring, 5-membered heteroalkyl ring containing one N atom and a benzene ring, 5-membered heteroalkyl ring containing one N atom and a 6-membered heteroaromatic ring, or 6-membered heteroalkyl ring containing one N atom is optionally and independently composed of one, two, or three R atoms. a Replace other variables as defined in this application.

[0058] In some embodiments of this application, ring A is selected from pyrrolidine rings, pyrazolidine rings, imidazoline rings, tetrahydrothiophene rings, tetrahydrofuran rings, tetrahydropyran rings, thiazoline rings, isothiazolidine rings, oxazolidine rings, isoxazolidine rings, piperidine rings, piperazine rings, morpholine rings, thiazine rings, benzene rings, benzo[a]dioxolane rings, benzo[a]pyrrolidine rings, benzo[a]pyrazolidine rings, benzene[a]imidazoline rings, benzo[a]tetrahydrothiophene rings, benzo[a]tetrahydrofuran rings, benzo[a]tetrahydropyran rings, benzo[a]thiazoline rings, benzo[a]isothiazoline rings, benzo[a]oxazolidine rings, benzo[a]piperidine rings, benzo[a]piperazine rings, benzo[a]morpholine rings, benzo[a]thiazine rings, pyrrole rings, pyrazole rings, imidazoline rings, oxazole rings, isoxazolidine rings, and so on. Azole ring, thiazole ring, isothiazole ring, triazole ring, furan ring, thiophene ring, pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, pyridine ring and pyrrolidine ring, pyridine ring and pyrazolidine ring, pyridine ring and imidazoline ring, pyridine ring and tetrahydrothiophene ring, pyridine ring and tetrahydrofuran ring, pyridine ring and tetrahydropyran ring, pyridine ring and thiazoleidine ring, pyridine ring and isothiazoleidine ring, pyridine ring and isoxazolidine ring, pyridine ring and piperidine ring, pyridine ring and piperazine ring, pyridine ring and morpholine ring, pyridine ring and thiazoleidine ring, pyrazine ring and pyrrolidine ring, pyrazine ring and pyrazolidine ring, pyrazine ring and imidazoline ring, pyrazine ring and tetrahydrothiophene ring, pyrazine ring and tetrahydrofuran ring, pyrazine ring and tetrahydropyran ring, pyrazine ring and thiazoleidine ring, pyrazine ring and thiazoleidine ring, pyrazine Cycloisothiazoline ring, pyrazine cycloisothiazoline ring, pyrazine cycloisothiazoline ring, pyrazine cycloisothiazoline ring, pyrazine cycloisothiazoline ring, pyrazine cycloisothiazoline ring, pyrazine cycloisothiazoline ring, pyrazine cycloisothiazoline ring, pyrimidine ... The rings are pyrrolizidine rings, pyrrolizidine rings, pyrrolizidine rings, imidazo[4,5-b]pyrrolizidine rings, imidazo[4,5-c]pyrrolizidine rings, imidazo[1,2-a]pyrrolizidine rings, imidazo[1,5-a]pyrrolizidine rings, pyrrolizidine rings, pyrrolizidine rings, pyrrolizidine rings, pyrrolizidine rings, pyrrolizidine rings, pyrrolizidine rings, pyrrolizidine rings, pyrrolizidine rings, purine rings, indazine rings, pyrrolizidine rings, pyrrolizidine rings, imidazo[1,2-a]pyridazine rings, imidazo[1,2-c]pyrimidine rings, pyrrolizidine rings, or pyrrolizidine rings, wherein ring A is optionally independently surrounded by 1, 2, or 3 R... a Replace other variables as defined in this application.

[0059] In some embodiments of this application, ring A is selected from piperidine ring, benzene ring, benzene-dioxolane ring, benzene-pyrrolidine ring, benzene-tetrahydrothiophene ring, benzene-isothiazolidinyl ring, imidazole ring, oxazole ring, thiazole ring, pyridine ring, pyridine-tetrahydrofuran ring, pyridine-isothiazolidinyl ring, or pyridine-thiazine ring, wherein ring A is optionally independently bound by 1, 2, or 3 R... a Replace other variables as defined in this application.

[0060] In some embodiments of this application, ring A is selected from piperidine ring, benzene ring, benzene-isothiazoline ring, imidazole ring, oxazole ring, thiazole ring, pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, pyridine-isothiazoline ring, pyridine-isothiazoline ring, pyrrolo[3,2-c]pyridine ring, pyrazolo[4,3-c]pyridine ring, pyrazolo[1,5-a]pyrazine ring, or pyrrolo[1,2-a]pyrazine ring, and ring A is optionally independently bound by 1, 2, or 3 R... a Replace other variables as defined in this application.

[0061] In some further embodiments of this application, ring A is selected from piperidine ring, benzene ring, benzene-isothiazoline ring, imidazole ring, oxazole ring, thiazole ring, pyridine-isothiazoline ring, or pyridine-isothiazoline ring, and ring A is optionally independently bounded by 1, 2, or 3 R... a Replace other variables as defined in this application.

[0062] In other embodiments of this application, ring A is selected from...

[0063]

[0064] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace other variables as defined in this application.

[0065] In other embodiments of this application, ring A is selected from...

[0066]

[0067] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace other variables as defined in this application.

[0068] In some embodiments of this application, ring A is selected from...

[0069]

[0070] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace other variables as defined in this application.

[0071] In some embodiments of this application, ring A is selected from...

[0072] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace other variables as defined in this application.

[0073] In some embodiments of this application, ring A is selected from...

[0074]

[0075] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace other variables as defined in this application.

[0076] In other embodiments of this application, ring A is selected from...

[0077] The ring A can be arbitrarily and independently bounded by 1, 2, 3 or 4 R's. a Replace other variables as defined in this application.

[0078] In some other embodiments of this application, ring A is selected from...

[0079] The ring A can be arbitrarily and independently bounded by 1, 2, 3 or 4 R's. a Replace other variables as defined in this application.

[0080] In some embodiments of this application, ring A is selected from...

[0081] The ring A can be arbitrarily and independently bounded by 1, 2, 3 or 4 R's. a Replace other variables as defined in this application.

[0082] In some embodiments of this application, ring A is selected from...

[0083] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace other variables as defined in this application.

[0084] In some embodiments of this application, ring A is selected from...

[0085] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace other variables as defined in this application.

[0086] In some embodiments of this application, ring A is selected from...

[0087] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace other variables as defined in this application.

[0088] In other embodiments of this application, ring A is selected from...

[0089] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace other variables as defined in this application.

[0090] In other embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace other variables as defined in this application.

[0091] In other embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace other variables as defined in this application.

[0092] In other embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace other variables as defined in this application.

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

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

[0095] In some embodiments of this application, each R a Each is independently selected from deuterium, F, Cl, Br, I, CN, =O, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. x Replace other variables as defined in this application.

[0096] In other embodiments of this application, each R a Each is independently selected from F, Cl, CN, =O, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. x Replace other variables as defined in this application.

[0097] In some embodiments of this application, each R a Each is independently selected from F, Cl, Br, I, =O, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. x Replace other variables as defined in this application.

[0098] In some embodiments of this application, each R a Each is independently selected from F, Cl, Br, I, =O or C. 1-3 Alkyl, the C 1-3 Alkyl groups are optionally and independently surrounded by 1, 2, or 3 R's. x Replace other variables as defined in this application.

[0099] In some embodiments of this application, each R a Each of the halogens is independently selected from F, Cl, CN, =O, methyl or methoxy, wherein the methyl or methoxy group is optionally independently substituted by one, two or three halogens, and other variables are as defined in this application.

[0100] In some embodiments of this application, each R a Each is independently selected from F, =O, or methyl, wherein the methyl group is optionally and independently substituted with 1, 2, or 3 halogens, and other variables are as defined in this application.

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

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

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

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

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

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

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

[0108] In other embodiments of this application, ring A is selected from piperidine rings, benzene rings, benzene-dioxolane rings, benzene-pyrrolidine rings, benzene-tetrahydrothiophene rings, benzene-isothiazoline rings, benzene-thiazine rings, imidazole rings, oxazole rings, thiazole rings, pyridine rings, pyridine-tetrahydrofuran rings, pyridine-isothiazoline rings, or pyridine-thiazine rings, wherein ring A is optionally independently bound by 1, 2, or 3 R... a Replace, each R a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0109] In some further embodiments of this application, ring A is selected from piperidine rings, benzene rings, benzenecyclodioxolane rings, benzenecyclopyrrolidine rings, benzenecyclotetrahydrothiophene rings, benzenecycloisothiazoline rings, benzenecyclothiazine rings, imidazole rings, oxazole rings, thiazole rings, pyridinecyclotetrahydrofuran rings, pyridinecycloisothiazoline rings, or pyridinecyclothiazine rings, wherein ring A is optionally independently bounded by 1, 2, or 3 R... a Replace, each R a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0110] In some embodiments of this application, ring A is selected from piperidine ring, benzene ring, benzo[2-dioxolane] ring, benzo[2-pyrrolidine] ring, benzo[2-tetrahydrothiophene] ring, benzo[2-isothiazoline] ring, imidazole ring, oxazole ring, thiazole ring, pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, pyridine[2-tetrahydrofuran] ring, pyridine[2-isothiazoline] ring, pyridine[2-thiazoline] ring, pyrrolo[3,2-c]pyridine ring, pyrazolo[4,3-c]pyridine ring, pyrazolo[1,5-a]pyrazine ring, or pyrrolo[1,2-a]pyrazine ring, wherein ring A is optionally independently bound by 1, 2, or 3 R... a Replace, each R a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0111] In some embodiments of this application, ring A is selected from piperidine ring, benzene ring, benzene-dioxolane ring, benzene-pyrrolidine ring, benzene-tetrahydrothiophene ring, benzene-isothiazolidinyl ring, imidazole ring, oxazole ring, thiazole ring, pyridine ring, pyridine-tetrahydrofuran ring, pyridine-isothiazolidinyl ring, or pyridine-thiazine ring, wherein ring A is optionally independently bound by 1, 2, or 3 R... a Replace, each R a Each is independently selected from F, Cl, =O, methyl, methoxy, trifluoromethyl, or trifluoromethoxy, and other variables are as defined in this application.

[0112] In some embodiments of this application, ring A is selected from piperidine ring, benzene ring, benzene-isothiazoline ring, imidazole ring, oxazole ring, thiazole ring, pyridine ring, pyridine-isothiazoline ring, or pyridine-thiazine ring, and ring A is optionally independently bounded by 1, 2, or 3 R... a Replace, each R a Each is independently selected from F, =O, methyl, or trifluoromethyl, and other variables are as defined in this application.

[0113] In other embodiments of this application, ring A is selected from...

[0114] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0115] In some other embodiments of this application, ring A is selected from...

[0116] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0117] In some embodiments of this application, ring A is selected from...

[0118] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0119] In some embodiments of this application, ring A is selected from...

[0120] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each is independently selected from F, Cl, =O, methyl, methoxy, trifluoromethyl, or trifluoromethoxy, and other variables are as defined in this application.

[0121] In some embodiments of this application, ring A is selected from...

[0122] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each is independently selected from F, =O, methyl, or trifluoromethyl, and other variables are as defined in this application.

[0123] In some embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0124] In some embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each is independently selected from F, Cl, =O, methyl, methoxy, trifluoromethyl, or trifluoromethoxy, and other variables are as defined in this application.

[0125] In some embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each is independently selected from F, Cl, =O, methyl, methoxy, trifluoromethyl, or trifluoromethoxy, and other variables are as defined in this application.

[0126] In some embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each is independently selected from F, Cl, =O, methyl, methoxy, trifluoromethyl, or trifluoromethoxy, and other variables are as defined in this application.

[0127] In some embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0128] In some embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each is independently selected from F, Cl, =O, methyl, methoxy, trifluoromethyl, or trifluoromethoxy, and other variables are as defined in this application.

[0129] In some embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each is independently selected from F, Cl, =O, methyl, methoxy, trifluoromethyl, or trifluoromethoxy, and other variables are as defined in this application.

[0130] In other embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace other variables as defined in this application.

[0131] In other embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each is independently selected from F, Cl, =O, methyl, methoxy, trifluoromethyl, or trifluoromethoxy, and other variables are as defined in this application.

[0132] In other embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each is independently selected from F, Cl, =O, methyl, methoxy, trifluoromethyl, or trifluoromethoxy, and other variables are as defined in this application.

[0133] In some embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each is independently selected from F or trifluoromethyl, and other variables are as defined in this application.

[0134] In other embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each is independently selected from F or trifluoromethyl, and other variables are as defined in this application.

[0135] In some embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each is independently selected from F, =O, methyl, or trifluoromethyl, and other variables are as defined in this application.

[0136] In some embodiments of this application, ring A is selected from... The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Replace, each R a Each is independently selected from F, =O, methyl, or trifluoromethyl, and other variables are as defined in this application.

[0137] In other embodiments of this application, ring A is selected from...

[0138] Other variables are as defined in this application.

[0139] In some other embodiments of this application, ring A is selected from...

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

[0141]

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

[0143] Other variables are as defined in this application.

[0144] In some embodiments of this application, ring A is selected from...

[0145] Other variables are as defined in this application.

[0146] In some embodiments of this application, ring A is selected from...

[0147] Other variables are as defined in this application.

[0148] In some embodiments of this application, ring A is selected from...

[0149] Other variables are as defined in this application.

[0150] In some embodiments of this application, ring A is selected from...

[0151] Other variables are as defined in this application.

[0152] In some embodiments of this application, ring A is selected from...

[0153] Other variables are as defined in this application.

[0154] In some embodiments of this application, ring A is selected from...

[0155] Other variables are as defined in this application.

[0156] In some embodiments of this application, ring A is selected from...

[0157] Other variables are as defined in this application.

[0158] In some embodiments of this application, ring A is selected from...

[0159] Other variables are as defined in this application.

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

[0161] In some embodiments of this application, ring A is selected from...

[0162] Other variables are as defined in this application.

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

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

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

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

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

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

[0169] In other embodiments of this application, the structural unit Selected from

[0170]

[0171] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R... a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0172] In some other embodiments of this application, the structural unit Selected from

[0173] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R... a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0174] In some embodiments of this application, the structural unit Selected from

[0175]

[0176] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R... a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0177] In some embodiments of this application, the structural unit Selected from

[0178] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R... a Each is independently selected from F, Cl, =O, methyl, methoxy, trifluoromethyl, or trifluoromethoxy, and other variables are as defined in this application.

[0179] In some embodiments of this application, the structural unit Selected from

[0180] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R... a Each is independently selected from F, =O, methyl, or trifluoromethyl, and other variables are as defined in this application.

[0181] In some embodiments of this application, the structural unit Selected from

[0182] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R... a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0183] In some embodiments of this application, the structural unit Selected from

[0184] The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R... a Each is independently selected from F, Cl, =O, methyl, trifluoromethyl or trifluoromethoxy, and other variables are as defined in this application.

[0185] In some embodiments of this application, the structural unit Selected from The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R... a Each is independently selected from F, Cl, =O, methyl, trifluoromethyl or trifluoromethoxy, and other variables are as defined in this application.

[0186] In some embodiments of this application, the structural unit Selected from The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R... a Each is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, with other variables as defined in this application. In some embodiments of this application, each R a Each is independently selected from F, Cl, =O, methyl, trifluoromethyl or trifluoromethoxy, and other variables are as defined in this application.

[0187] In other embodiments of this application, the structural unit Selected from The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R... a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0188] In other embodiments of this application, the structural unit Selected from The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R... a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0189] In other embodiments of this application, the structural unit Selected from The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R...a Each variable is independently selected from F, Cl, CN, =O, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, and other variables are as defined in this application.

[0190] In some embodiments of this application, the structural unit Selected from The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R... a Each is independently selected from F, =O, methyl, or trifluoromethyl, and other variables are as defined in this application.

[0191] In some embodiments of this application, the structural unit Selected from The ring A is optionally and independently bounded by 1, 2 or 3 Rs. a Instead, other variables are as defined in this application. In some embodiments of this application, each R... a Each is independently selected from F, =O, methyl, or trifluoromethyl, and other variables are as defined in this application.

[0192] In other embodiments of this application, the structural unit Selected from

[0193]

[0194] Other variables are as defined in this application.

[0195] In some other embodiments of this application, the structural unit Selected from

[0196]

[0197] Other variables are as defined in this application.

[0198] In some embodiments of this application, the structural unit Selected from

[0199]

[0200] Other variables are as defined in this application.

[0201] In some embodiments of this application, the structural unit Selected from

[0202]

[0203] Other variables are as defined in this application.

[0204] In some embodiments of this application, the structural unit Selected from

[0205] Other variables are as defined in this application.

[0206] In some embodiments of this application, the structural unit Selected from

[0207]

[0208] Other variables are as defined in this application.

[0209] In some embodiments of this application, the structural unit Selected from

[0210] Other variables are as defined in this application.

[0211] In some embodiments of this application, the structural unit Selected from

[0212] Other variables are as defined in this application.

[0213] In some embodiments of this application, the structural unit Selected from

[0214] Other variables are as defined in this application.

[0215] In some embodiments of this application, the structural unit Selected from

[0216] Other variables are as defined in this application.

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

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

[0219] In other embodiments of this application, the structural unit Selected from Other variables are as defined in this application.

[0220] In other embodiments of this application, the structural unit Selected from Other variables are as defined in this application.

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

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

[0223] In some embodiments of this application, L 1 Selected from single bonds, -N(R) b )-, -N=, -O-, -S(=O)2-, -S-, -(CH2) m - or -C(=O)-, other variables are as defined in this application.

[0224] In some embodiments of this application, L 1 Selected from single bonds, -N(R)b )-, -O-, -S(=O)2-, -S-, -(CH2) m - or -C(=O)-, other variables are as defined in this application.

[0225] In some embodiments of this application, L 1 Selected from single bonds, -NH-, -N=, -N(C(=O)H)-, -N(C 1-3 Alkyl group, -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -N(S(=O)2C 1-3 Alkyl)- or -C(=O)-, other variables as defined in this application.

[0226] In some embodiments of this application, L 1 Selected from single bonds, -NH-, -N(C(=O)H)-, -N(C 1-3 Alkyl)-, -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -C(=O)-, and other variables as defined in this application.

[0227] In some embodiments of this application, L 1 The variables are selected from single bonds, -NH-, -N=, -N(C(=O)H)-, -N(CH3)-, -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -C(=O)- or -N(S(=O)2CH3)-, and other variables are as defined in this application.

[0228] In other embodiments of this application, L 1 The variables are selected from single bonds, -NH-, -N=, -N(C(=O)H)-, -N(CH3)-, -S(=O)2-, -CH2-, -C(=O)- or -N(S(=O)2CH3)-, and other variables are as defined in this application.

[0229] In some embodiments of this application, L 1 The variables are selected from single bonds, -NH-, -N(C(=O)H)-, -N(CH3)-, -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -C(=O)-, and other variables are as defined in this application.

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

[0231] In some embodiments of this application, L 1 Selected from single bonds, -NH- or -S(=O)2-, and other variables as defined in this application.

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

[0233] In some embodiments of this application, L 1 Selected from single bonds, -NH-, -N(C(=O)H)-, -N(C 1-3 Alkyl)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -C(=O)-, and other variables as defined in this application.

[0234] In some embodiments of this application, L 1 Selected from single bonds, -NH-, -N(C) 1-3 Alkyl)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -C(=O)-, and other variables as defined in this application.

[0235] In some embodiments of this application, L 1 The variables are selected from single bonds, -NH-, -N(C(=O)H)-, -N(CH3)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -C(=O)-, and other variables are as defined in this application.

[0236] In some embodiments of this application, L 1 Selected from single bonds, -NH-, -N(CH3)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -C(=O)-, and other variables as defined in this application.

[0237] In some embodiments of this application, L 1 Selected from single bonds, -NH-, -N(CH3)-, -CH2- or -C(=O)-, and other variables as defined in this application.

[0238] In some embodiments of this application, L 1 Selected from single bonds or -NH-, other variables are as defined in this application.

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

[0240] In some embodiments of this application, L 2 Selected from single bonds, -NH-, -N(C) 1-3 Alkyl group, -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 group, and other variables as defined in this application.

[0241] In some embodiments of this application, L 2 Selected from single bonds, -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)-, and other variables as defined in this application.

[0242] In some embodiments of this application, L 2 Selected from single bonds, -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)-, and other variables as defined in this application.

[0243] In other embodiments of this application, L 2 Selected from single bonds, -NH-, -N(CH3)-, -CH2-CH2-, -C(=O)-, -S(=O)2-, -S(=O)(=NH)-, -S(=O)(CH3)-, -P(=O)(CH3)-, or -P(=O)(NHCH3)-, and other variables as defined in this application.

[0244] In some embodiments of this application, L 2 The variables are selected from single bonds, -NH-, -N(CH3)-, -CH2-CH2-, -C(=O)-, -S(=O)2-, -S(=O)(=NH)-, -P(=O)(CH3)-, or -P(=O)(NHCH3)-, and other variables are as defined in this application.

[0245] In some embodiments of this application, L 2Selected from single bonds, -NH- or -S(=O)2-, and other variables as defined in this application.

[0246] In some embodiments of this application, L 2 Selected from single bonds or -S(=O)2-, other variables are as defined in this application.

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

[0248] In some embodiments of this application, -L 2 -L 1 - Selected from single bonds, -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-, and other variables as defined in this application.

[0249] In some embodiments of this application, -L2 -L 1 - Selected from single bonds, -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-, and other variables as defined in this application.

[0250] In some embodiments of this application, -L 2 -L 1- Selected from single bonds, -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-, and other variables as defined in this application.

[0251] In other embodiments of this application, -L 2 -L 1 - Selected from single bonds, -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)-, and other variables as defined in this application.

[0252] In some embodiments of this application, -L 2 -L1 - Selected from single bonds, -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)-, and other variables as defined in this application.

[0253] In some embodiments of this application, -L 2 -L 1 - Selected from single bonds, -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-, other variables as defined in this application.

[0254] In some embodiments of this application, -L 2 -L 1- Selected from single bonds, -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-, other variables as defined in this application.

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

[0256] In some embodiments of this application, -L 2 -L 1 - Selected from single bonds, -NH-, -CH2- or -S(=O)2-NH-, and other variables as defined in this application.

[0257] In some embodiments of this application, -L 2 -L 1 - Selected from single bonds or -S(=O)2-NH-, other variables are as defined in this application.

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

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

[0260] In some embodiments of this application, -L 2 -L 1 - Selected from single keys, other variables are as defined in this application.

[0261] In some embodiments of this application, R 1 Selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, -NH2, -NH(C) 1-3Alkyl), cyclopropyl, cyclobutyl, cyclopentyl, 4-6 membered heterocyclic alkyl groups containing one or two N, O, or S atoms, or 5-6 membered heteroaryl groups containing one or two N atoms, wherein C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. d Substitution; the 4-6 membered heterocyclic alkyl or 5-6 membered heteroaryl group is optionally independently replaced by 1, 2 or 3 R groups. e Replace other variables as defined in this application.

[0262] In some embodiments of this application, R 1 The group is selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, cyclopentyl, 4-6 membered heterocyclic alkyl groups containing 1 or 2 N, O, or S atoms, or 5-6 membered heteroaryl groups containing 1 or 2 N atoms, wherein the methyl, ethyl, or methoxy group is optionally independently surrounded by 1, 2, or 3 R atoms. d The 4-6-membered heterocyclic alkyl or 5-6-membered heteroaryl group is optionally independently replaced by 1, 2 or 3 R groups. e Replace other variables as defined in this application.

[0263] In some embodiments of this application, R 1 Selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiocyclobutyl, aziridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrothiophene, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thiophene, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, wherein the methyl, ethyl, or methoxy group is optionally independently surrounded by 1, 2, or 3 R groups. d Substitution; the cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiohexacyclobutyl, aziridine, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrothiophene, tetrahydrofuranyl, tetrahydropyranyl, thiazoyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thiophene, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl may optionally be independently replaced by 1, 2, or 3 R groups. e Replace other variables as defined in this application.

[0264] In some embodiments of this application, R 1The radicals are selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, oxacyclobutyl, pyrrolidinyl, pyrazolylyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, oxazolyl, or pyrimidinyl, wherein the methyl, ethyl, or methoxy group is optionally independently surrounded by 1, 2, or 3 R groups. d Substitution; the cyclopropyl, oxacyclobutyl, pyrazolyl, isothiazolyl, isoxazolyl, imidazole, oxazolyl, or pyrimidinyl groups are optionally and independently replaced by 1, 2, or 3 R groups. e Replace other variables as defined in this application.

[0265] In some embodiments of this application, R 1 The derivative is selected from H, methyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, oxacyclobutyl, pyrazolyl, isothiazolyl, isoxazolyl, imidazolyl, oxazolyl, or pyrimidinyl, wherein the methyl, ethyl, or methoxy group is optionally independently surrounded by 1, 2, or 3 R groups. d Substitution; the cyclopropyl, oxacyclobutyl, pyrazolyl, isothiazolyl, isoxazolyl, imidazole, oxazolyl, or pyrimidinyl groups are optionally and independently replaced by 1, 2, or 3 R groups. e Replace other variables as defined in this application.

[0266] In some embodiments of this application, R 1 Selected from H or methyl, other variables are as defined in this application.

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

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

[0269] In some embodiments of this application, each R e Each is independently selected from F, Cl, Br, I, =O or C. 1-3 Alkyl, the C 1-3 Alkyl groups are optionally and independently surrounded by 1, 2, or 3 R's. x Replace other variables as defined in this application.

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

[0271] In some embodiments of this application, each R e Each is independently selected from F, Cl, Br, I, =O or C.1-3 Alkyl groups, and other variables as defined in this application.

[0272] In other embodiments of this application, each R e Each is independently selected from =O or methyl, and other variables are as defined in this application.

[0273] In other embodiments of this application, each R y Each is independently selected from halogens, and other variables are as defined in this application.

[0274] In some embodiments of this application, R 1 The radicals are selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, oxacyclobutyl, pyrrolidinyl, pyrazolylyl, isothiazolyl, isoxazolylyl, pyrazolyl, imidazole, oxazolyl, or pyrimidinyl, wherein the methyl, ethyl, or methoxy radical is optionally independently surrounded by 1, 2, or 3 R radicals. d The cyclopropyl, oxacyclobutyl, pyrazolyl, isothiazolyl, isoxazolyl, imidazole, oxazolyl, or pyrimidinyl groups are optionally and independently replaced by one, two, or three R groups. e Instead, other variables are as defined in this application. In some embodiments of this application, each R... d Each of the R molecules is independently selected from F, Cl, Br, I, and OH. e Selected from F, Cl, Br, I, =O or C 1-3 Alkyl groups; other variables as defined in this application.

[0275] In some embodiments of this application, R 1 Selected from H, methyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, oxacyclobutyl, pyrazolyl, isothiazolyl, isoxazolyl, pyrazolyl, oxazolyl, or pyrimidinyl, wherein the methyl, ethyl, or methoxy group is optionally independently surrounded by 1, 2, or 3 R groups. d The cyclopropyl, oxacyclobutyl, pyrazolyl, isothiazolyl, isoxazolyl, imidazole, oxazolyl, or pyrimidinyl groups are optionally and independently replaced by one, two, or three R groups. e Instead, other variables are as defined in this application. In some embodiments of this application, each R... d Each of the R molecules is independently selected from F, Cl, Br, I, and OH. e Selected from F, Cl, Br, I, =O or C 1-3 Alkyl groups; other variables as defined in this application.

[0276] In some embodiments of this application, R 1The derivative is selected from H, methyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), cyclopropyl, oxacyclobutyl, pyrazolyl, isothiazolyl, isoxazolyl, imidazolyl, oxazolyl, or pyrimidinyl, wherein the methyl, ethyl, or methoxy group is optionally independently surrounded by 1, 2, or 3 R groups. d The cyclopropyl, oxacyclobutyl, pyrazolyl, isothiazolyl, isoxazolyl, imidazole, oxazolyl, or pyrimidinyl groups are optionally and independently replaced by one, two, or three R groups. e Instead, other variables are as defined in this application. In some embodiments of this application, each R... d Each is independently selected from F or OH, and the R e Selected from =O or methyl; other variables are as defined in this application.

[0277] In some embodiments of this application, R 1 Selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3),

[0278] The methyl, ethyl, or methoxy group is optionally independently bound by one, two, or three R groups. d Instead, the

[0279] Optionally independently controlled by 1, 2 or 3 R e Replacement; other variables are as defined in this application. In some embodiments of this application, each R d Each is independently selected from F or OH, each R e Each is independently selected from =O or methyl, and other variables are as defined in this application.

[0280] In other embodiments of this application, R 1 Selected from H, methyl, ethyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3),

[0281]

[0282] The methyl, ethyl, or methoxy group is optionally independently bound by one, two, or three R groups. d Instead, the Optionally independently controlled by 1, 2 or 3 R e Replacement; other variables are as defined in this application. In some embodiments of this application, each R d Each is independently selected from F or OH, each R eEach is independently selected from =O or methyl, and other variables are as defined in this application.

[0283] In some embodiments of this application, R 1 Selected from H, methyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3),

[0284] The methyl or methoxy group is optionally independently surrounded by 1, 2, or 3 R groups. d Instead, the

[0285] Optionally independently controlled by 1, 2 or 3 R e Replacement; other variables are as defined in this application. In some embodiments of this application, each R d Each is independently selected from F or OH, each R e Each is independently selected from =O or methyl, and other variables are as defined in this application.

[0286] In other embodiments of this application, R 1 Selected from H, methyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), The methyl, ethyl, or methoxy group is optionally independently bound by one, two, or three R groups. d Instead, the Optionally independently controlled by 1, 2 or 3 R e Replacement; other variables are as defined in this application. In some embodiments of this application, each R d Each is independently selected from F or OH, each R e Each is independently selected from =O or methyl, and other variables are as defined in this application.

[0287] In some embodiments of this application, R 1 Selected from H, methyl, methoxy, -NH2, -NH(CH3), -NH(CH2CH3), The methyl, ethyl, or methoxy group is optionally independently bound by one, two, or three R groups. d Instead, the Optionally independently controlled by 1, 2 or 3 R e Replacement; other variables are as defined in this application. In some embodiments of this application, each R d Each is independently selected from F or OH, each R eEach is independently selected from =O or methyl, and other variables are as defined in this application.

[0288] In other embodiments of this application, R 1 Selected from H, methyl, -CH2CH2OH, methoxy, -OCF3, -CH2OH, -NH2, -NH(CH3), -NH(CH2CH2OH). Other variables are as defined in this application.

[0289] In some embodiments of this application, R 1 Selected from H, methyl, -CH2CH2OH, methoxy, -OCF3, -CH2OH, -NH2, -NH(CH3), -NH(CH2CH2OH). Other variables are as defined in this application.

[0290] In some embodiments of this application, R 1 Selected from H, methyl, methoxy, -OCF3, -CH2OH, -NH2, -NH(CH3), -NH(CH2CH2OH), Other variables are as defined in this application.

[0291] In some embodiments of this application, R 1 Selected from H, methyl, or methoxy, and other variables as defined in this application.

[0292] In some embodiments of this application, R 1 Selected from methyl, other variables are as defined in this application.

[0293] In some embodiments of this application, R 1 Selected from H, other variables are as defined in this application.

[0294] In some embodiments of this application, each R b Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. x Replace; the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl groups are optionally independently surrounded by 1, 2 or 3 R groups. y Replace other variables as defined in this application.

[0295] In other embodiments of this application, each Rb Each is independently selected from H, -C(=O)H, -S(=O)2CH3, or methyl, wherein the methyl group is optionally independently surrounded by 1, 2, or 3 R groups. x Replace other variables as defined in this application.

[0296] In some embodiments of this application, each R b Each is independently selected from H or C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally and independently surrounded by 1, 2, or 3 R's. x Replace other variables as defined in this application.

[0297] In some embodiments of this application, each R b Each is independently selected from H or methyl, wherein the methyl group is optionally independently surrounded by 1, 2 or 3 R groups. x Replace other variables as defined in this application.

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

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

[0300] In some embodiments of this application, R c Selected from C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally and independently surrounded by 1, 2, or 3 R's. x Replace other variables as defined in this application.

[0301] In some embodiments of this application, R c Selected from methyl, wherein the methyl group is optionally independently surrounded by 1, 2 or 3 R groups. x Replace other variables as defined in this application.

[0302] In some embodiments of this application, R c Selected from methyl, other variables are as defined in this application.

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

[0304] In some embodiments of this application, R 2 R 3 and R 4 Each is independently selected from H, deuterium, or C. 1-3 Alkyl, the C1-3 Alkyl groups are optionally and independently surrounded by 1, 2, or 3 R's. z Replace other variables as defined in this application.

[0305] In some embodiments of this application, R 2 R 3 and R 4 Each is independently selected from H or C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally and independently surrounded by 1, 2, or 3 R's. z Replace other variables as defined in this application.

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

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

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

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

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

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

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

[0313] In some embodiments of this application, R 2 Selected from H, R 3 and R 4 Each is independently selected from methyl groups, and other variables are as defined in this application.

[0314] In other embodiments of this application, R 2 Selected from H, R 3 and R 4 Each is independently selected from methyl and CF3, and other variables are as defined in this application.

[0315] In some embodiments of this application, R 2 Selected from methyl, R 3 and R 4 Each variable is independently selected from H, and other variables are as defined in this application.

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

[0317] In some embodiments of this application, R 2 and R 3 Together with the carbon atoms that are connected, they form C 3-4 Cycloalkyl or 3-4 membered heterocyclic alkyl, R 4 Selected from H or C 1-3 Alkyl, the C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl groups are optionally independently bound by 1, 2 or 3 R groups. z Replace other variables as defined in this application.

[0318] In some embodiments of this application, R 2 and R 3 Together with the carbon atoms they are linked to form cyclopropyl, oxacyclopropyl, or azircyclopropyl, R 4 Selected from H, methyl, or ethyl, wherein the methyl, ethyl, cyclopropyl, oxacyclopropyl, or azircyclopropyl group is optionally independently surrounded by 1, 2, or 3 R groups. z Replace other variables as defined in this application.

[0319] In some embodiments of this application, R 2 and R 3 Together with the carbon atoms that are linked together, they form a cyclopropyl group, R 4 Selected from H or methyl, wherein the methyl or cyclopropyl group is optionally independently surrounded by 1, 2 or 3 R groups. z Replace other variables as defined in this application.

[0320] In some embodiments of this application, R 2 and R 3 Together with the carbon atoms that are linked together, they form a cyclopropyl group, R 4 Selected from methyl, other variables are as defined in this application.

[0321] In some embodiments of this application, R 2 and R 3 Together with the carbon atoms that are linked together, they form a cyclopropyl group, R 4 Selected from H, other variables are as defined in this application.

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

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

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

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

[0326] Ring A is selected from C 3-10 Alkane rings, 5-10 membered heteroalkyl rings, benzene rings, naphthalene rings, and benzo[a]carbonyl rings 5-6 Alkane rings, benzene rings, 5-6 membered heteroalkane rings, 5-6 membered heteroaromatic rings, 5-6 membered heteroaromatic rings with C 5-6 Alkyl ring or 5-6 membered heteroaryl ring and 5-6 membered heteroalkyl ring, wherein C 3-10 Alkane rings, 5-10 membered heteroalkyl rings, benzene rings, naphthalene rings, and benzo[a]carbonyl rings 5-6 Alkane rings, benzene rings, 5-6 membered heteroalkane rings, 5-6 membered heteroaromatic rings, 5-6 membered heteroaromatic rings with C 5-6 An alkyl ring or a 5-6 membered heteroaryl ring, with the 5-6 membered heteroalkyl ring optionally and independently bound by 1, 2, or 3 R groups. a replace;

[0327] L 1and L 2 Each is independently selected from single bonds, -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 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 C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. d Instead, the C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, or 5-6-membered heteroaryl groups are optionally independently bound by 1, 2, or 3 R groups. e replace;

[0329] R 2 R 3 and R 4 Each is 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 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. z replace;

[0330] Or R 2 and R 3 Together with the carbon atoms that are connected, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl, R 4 Selected from H, halogens, 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 3-6 membered heterocycloalkyl groups are optionally independently surrounded by 1, 2 or 3 R groups. z replace;

[0331] Each Ra Each is independently selected from halogens, OH, CN, NH2, =O, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. x replace;

[0332] Each R b Each is independently selected from H and 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 C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. x Replace; the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl groups are optionally independently surrounded by 1, 2 or 3 R groups. y replace;

[0333] R c Selected from halogens, OH, CN, or C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally and independently surrounded by 1, 2, or 3 R's. x replace;

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

[0335] Each R e Each is independently selected from halogens, OH, CN, NH2, =O, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. x replace;

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

[0337] Each R y Each is independently selected from halogens, OH, CN, NH2, =O, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may be independently substituted by one, two, or three substituents selected from halogens, OH, CN, or NH2;

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

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

[0340] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

[0341] This application provides the compound of formula (II), its isomers, or pharmaceutically acceptable salts thereof.

[0342]

[0343] in,

[0344] Ring A is selected from C 3-10 Alkane rings, 5-10 membered heteroalkyl rings, benzene rings, naphthalene rings, and benzo[a]carbonyl rings 5-6 Alkane rings, benzene rings, 5-6 membered heteroalkane rings, 5-6 membered heteroaromatic rings, 5-6 membered heteroaromatic rings with C 5-6 Alkyl ring or 5-6 membered heteroaryl ring and 5-6 membered heteroalkyl ring, wherein C 3-10 Alkane rings, 5-10 membered heteroalkyl rings, benzene rings, naphthalene rings, and benzo[a]carbonyl rings 5-6 Alkane rings, benzene rings, 5-6 membered heteroalkane rings, 5-6 membered heteroaromatic rings, 5-6 membered heteroaromatic rings with C 5-6 An alkyl ring or a 5-6 membered heteroaryl ring, with the 5-6 membered heteroalkyl ring optionally and independently bound by 1, 2, or 3 R groups. a replace;

[0345] L 1 and L 2 Each is independently selected from single bonds, -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 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 C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups.d Instead, the C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, or 5-6-membered heteroaryl groups are optionally independently bound by 1, 2, or 3 R groups. e replace;

[0347] Each R a Each is independently selected from halogens, OH, CN, NH2, =O, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. x replace;

[0348] Each R b Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Alkoxy group, -C(=O)H, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. x Replace; the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl groups are optionally independently surrounded by 1, 2 or 3 R groups. y replace;

[0349] R c Selected from halogens, OH, CN, or C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally and independently surrounded by 1, 2, or 3 R's. x replace;

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

[0351] Each R e Each is independently selected from halogens, OH, CN, NH2, =O, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. x replace;

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

[0353] Each R y Each is independently selected from halogens, OH, CN, NH2, =O, C 1-3 Alkyl or C 1-3 Alkoxy, the C1-3 Alkyl or C 1-3 The alkoxy group may be independently substituted by one, two, or three substituents selected from halogens, OH, CN, or NH2;

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

[0355] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

[0356] In some embodiments of this application, the compound represented by formula (II), its isomers, or pharmaceutically acceptable salts thereof, wherein rings A and R... 1 L 1 and L 2 It can also be defined in the compound shown in formula (I) above.

[0357] In some embodiments of this application, the compound represented by formula (II), its isomers, or pharmaceutically acceptable salts thereof, is selected from the compound represented by formula (II-1).

[0358]

[0359] Among them, rings A and R 1 L 1 and L 2 The compound is defined as shown in formula (II).

[0360] In some embodiments of this application, the compound of formula (II), its isomers, or pharmaceutically acceptable salts thereof are selected from the compounds shown in formula (II-2).

[0361]

[0362] in,

[0363] X is selected from CH or N;

[0364] R 1 R a L 1 and L 2 The compound is defined as shown in formula (II);

[0365] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

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

[0367] In some embodiments of this application, the compound of formula (II), its isomers, or pharmaceutically acceptable salts thereof are selected from the compounds shown in formula (II-2a).

[0368]

[0369] in,

[0370] X is selected from CH or N;

[0371] R 1 R a L 1 and L 2 The compound is defined as shown in formula (II).

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

[0373] In some embodiments of this application, the compound of formula (II), its isomers, or pharmaceutically acceptable salts thereof are selected from the compounds shown in formula (II-3).

[0374]

[0375] in,

[0376] X is selected from CH or N;

[0377] R 1 and R a The compound is defined as shown in formula (II);

[0378] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

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

[0380] In some embodiments of this application, the compound of formula (II), its isomers, or pharmaceutically acceptable salts thereof are selected from the compounds shown in formula (II-3a).

[0381]

[0382] in,

[0383] X is selected from CH or N;

[0384] R 1 and R a The compound is defined as shown in formula (II).

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

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

[0387]

[0388] Among them, rings A and R 1 L 1 and L 2 The compound is defined as shown in formula (I).

[0389] In some embodiments of this 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 implementation schemes in this application are derived from arbitrary combinations of the aforementioned variables.

[0394] On the other hand, this application also provides compounds of the following formula, their isomers, or pharmaceutically acceptable salts thereof.

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403] On the other hand, this application also provides compounds of the following formula, their isomers, or pharmaceutically acceptable salts thereof.

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418] On the other hand, this application also provides a pharmaceutical composition containing a therapeutically or preventively effective amount of the compound described in this application, its isomers, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of this application further includes pharmaceutically acceptable excipients.

[0419] On the other hand, this application also provides the use of the compounds described herein, their isomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the treatment or prevention of CDK2-mediated diseases.

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

[0421] On the other hand, this application also provides the use of the compounds described herein, their isomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the treatment or prevention of CDK2-mediated diseases.

[0422] On the other hand, this application also provides compounds of this application, isomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment or prevention of CDK2-mediated diseases.

[0423] On the other hand, in some embodiments of this application, the CDK2-mediated disease is selected from tumors or cancer.

[0424] In this application, the term "isomer" includes, but is not limited to, stereoisomers or tautomers.

[0425] Technical effect

[0426] The compound in this application, as a novel CDK2 inhibitor, exhibits good inhibitory activity against CDK2-induced signal transduction and demonstrates good inhibitory activity against both CDK2 CycA2 and CDK2 CycE1 kinases. It possesses favorable properties in at least one or more aspects, including in vitro and in vivo inhibitory activity, safety (e.g., low toxicity), and CDK2 selectivity. The compound also exhibits good pharmacokinetic properties and can be developed into a novel class of CDK2 inhibitor drugs.

[0427] Related definitions

[0428] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0429] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0430] The term "pharmaceutically acceptable salt" refers to the salt of the compounds in this application, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this application, with a specific substituent. When the compounds in this application contain relatively acidic functional groups, a base addition salt can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds in this application contain relatively basic functional groups, an acid addition salt can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds in this application contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0431] The pharmaceutically acceptable salts of this application can be synthesized from parent compounds containing an acid radical or a base using conventional chemical methods. Generally, such salts are prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both.

[0432] The compounds of this application may exist in specific stereoisomer forms. This application envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this application.

[0433] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key Represents the relative configuration of the center of a solid.

[0434] The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0435] The compounds of this application may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compound may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds in this application, regardless of radioactivity, are included within the scope of this application.

[0436] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0437] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted 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 aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[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 hydrogen variants, and the number of substituents may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, based on what is chemically feasible.

[0439] The term "substituent" as used herein includes, but is not limited to, the terms "alkyl," "alkoxy," "cycloalkyl," "heterocycloalkyl," "heteroaryl," "alkane," "heteroalkyl," "heteroaryl," etc., as used in the context, and corresponding non-limiting or exemplary groups. Some non-limiting examples of the "substituent" include protium, deuterium, tritium, -OH, -SH, halogen, -NH2, nitro, nitrosyl, -CN, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, and imine group. 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, arylalkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclic, heterocyclicoxy, heterocyclicthio, heterocyclic alkyl, heterocyclic Alkoxy, heterocyclic alkylthio, acyl, acyloxy, carbamate, amide, urea, epoxy, and ester groups, wherein said groups are optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, 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, heterocyclic alkyl, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkyl, heterocyclic alkyloxy, heterocyclic alkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl or aryloxy.

[0440] In some embodiments of this document, the "substituent" is selected from deuterium, tritium, hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, Halogenated -C 1-12 Alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halogenated -C 2-12 alkenyl, 3-12-membered cycloalkenyl, halo-3-12-membered cycloalkenyl, C 2-12 Alkyne group, halogenated -C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated-8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halogenated-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 aryl, 6-10 aryloxy, 6-10 arylthio, 6-10 arylC 1-12 Alkylene, 6-10 aryl C 1-12 Alkoxy, 6-10 aryl C 1-12 Alkylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, 5-10 heteroarylalkylene, 5-10 heteroarylalkoxy, 5-10 heteroarylalkylthio, 3-12 heterocyclic, 3-12 heterocyclic oxy, 3-12 heterocyclic thio, 3-12 heterocyclic C 1-12 Alkylene, 3-12 membered heterocyclic C 1-12 Alkoxy, 3-12 membered heterocyclic C 1-12 Alkylthio, C 1-12 Acyl group, C 1-12 Acyloxy group, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 The ester group and oxo group, wherein the substituent is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, diC 1-12 Alkylamino, halogenated C 1-12 Alkylamino, Halogenated diC 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12Alkyl group, -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 group, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl group, -S(O)2N(C) 1-12 Alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic alkyl group, 3-12-membered heterocyclic alkyl group C 1-12 Alkylene, 3-12-membered heterocyclic alkyloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryl C 1-12 alkylene, 5-10 heteroaryloxy, 6-10 aryl, 6-10 aryl C 1-12 Alkylene or 6-10 aryloxy groups.

[0441] C in this article m-n This means that the 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 This means that the group can have 1 carbon atom, 2 carbon atoms, 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 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0443] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

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

[0445] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the text indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0446] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups 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" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 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" on its own or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

[0449] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It 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 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

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

[0451] Unless otherwise specified, the term "3-6 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(p is 1 or 2). It is a monocyclic system. Furthermore, regarding the "3-6 membered heterocyclic alkyl", the heteroatom can occupy the connection position between the heterocyclic alkyl and the rest of the molecule. The 3-6 membered heterocyclic alkyl includes 3-membered, 4-membered, 5-membered, and 6-membered heterocyclic alkyl, etc. Examples of 3-6 membered heterocyclic alkyl include, but are not limited to, oxetyl, thiopropyl, aziryl, azirylbutyl, oxetyl, thiobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiophene (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrothiophene 1,1,-dioxide-3-yl, tetrahydrothiophene 1,1,-dioxide-2-yl, tetrahydrofuranyl (including... Including tetrahydrofuran-2-yl, tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazine (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxane, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl or homopiperidinyl, etc.

[0452] Unless otherwise specified, the term "5-6-membered heteroaryl" refers to a cyclic group consisting of 5 to 6 ring atoms with a conjugated π-electron system, wherein 1, 2, or 3 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C=O, NO, and S(O)). p (where p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or carbon atom. The 5-6 membered heteroaryl group includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and 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-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), etc.

[0453] Unless otherwise specified, the term "C" 3-10"Alkane ring" refers to a saturated hydrocarbon ring composed of 3 to 10 carbon atoms, including monocyclic and bicyclic systems, where bicyclic systems include spirocyclic, fused, and bridged rings. The C 3-10 Alkyl rings include C 3-6 C 3-5 C 4-8 C 4-6 C 4-5 C 5-8 Or C 5-6 Alkyl rings; they can be monovalent, divalent, or polyvalent. C 3-10 Examples of alkyl rings include, but are not limited to, cyclopropane rings, cyclobutane rings, cyclopentane rings, cyclohexane rings, cycloheptane rings, norbornene rings, [2.2.2]bicyclooctane rings, etc.

[0454] Unless otherwise specified, the term "5-10 membered heteroalkyl ring" refers to a saturated cyclic group consisting 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 remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C=O, NO, and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding this "5-10 membered heteroalkane ring," the heteroatom can occupy the connection position between the heteroalkane ring and the rest of the molecule. The 5-10 membered heteroalkane ring includes 5-6 membered heteroalkane rings, etc. Examples of 5-10 membered heteroalkyl rings include, but are not limited to, nitrogen-containing butane rings, oxo-containing butane rings, thio-containing butane rings, pyrrolidine rings, pyrazolidine rings, imidazoline rings, tetrahydrothiophene rings (including tetrahydrothiophene-2-rings and tetrahydrothiophene-3-rings, etc.), tetrahydrofuran rings (including tetrahydrofuran-2-rings, etc.), tetrahydropyran rings, piperidine rings (including 1-piperidine rings, 2-piperidine rings and 3-piperidine rings, etc.), piperazine rings (including 1-piperidine rings and 2-piperidine rings, etc.), morpholine rings (including 3-morpholine rings and 4-morpholine rings, etc.), dioxane rings, dithiazine rings, isoxazolidine rings, isothiazolidine rings, 1,2-oxazine rings, 1,2-thiazine rings, hexahydropyridazine rings, high-piperidine rings, or dioxane-heptane rings, etc. It should be understood that the term "5-10 membered heteroane ring" includes cases where the cyclic heteroatom is oxidized, for example when a substituent is represented as selected from... At that time, it contains at least The specific structure.

[0455] Unless otherwise specified, the term "benzocyclohexane" refers to... 5-6 "Alkane ring" or "benzo5-6 membered heteroalkyl ring" respectively represent the benzene ring and the C-ring. 5-6 Fused bicyclic rings formed from alkyl rings or 5-6 membered heteroalkyl rings, for example: wait.

[0456] Unless otherwise specified, the term "5-6 quinary heterocyclic cyclopentadienylene ring" refers to a cyclic cyclopentadienylene ring with a cyclic cyclopentadienylene ring. 5-6 In "alkane ring" or "5-6 membered heteroaromatic ring and 5-6 membered heteroalkane ring", the symbols represent 5-6 membered heteroaromatic ring and C, respectively. 5-6 Fused bicyclic rings formed from alkyl rings or 5-6 membered heteroalkyl rings, for example: wait.

[0457] Unless otherwise specified, the term "5-10 membered heteroaromatic ring" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder 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 (where p is 1 or 2). It can be a monocyclic, fused bicyclic, or fused tricyclic system, wherein each ring is aromatic. The 5-10 membered heteroaromatic ring can be attached to the rest of the molecule via heteroatoms or carbon atoms. The 5-10 membered heteroaromatic rings include 5-8, 5-7, 5-6, 5, and 6 membered heteroaromatic rings, etc. Examples of the 5-10 membered heteroaromatic rings include, but are not limited to, pyrrole rings (including N-pyrrole, 2-pyrrole, and 3-pyrrole rings, etc.), pyrazole rings (including 2-pyrrole and 3-pyrrole rings, etc.), imidazole rings (including N-imidazolium, 2-imidazolium, 4-imidazolium, and 5-imidazolium rings, etc.), oxazole rings (including 2-oxazole, 4-oxazole, and 5-oxazole rings, etc.), triazole rings (1H-1,2,3-triazole rings, 2H-1,2,3-triazole rings, 1H-1,2,4-triazole rings, and 4H-1,2,4-triazole rings, etc.), tetrazolium rings, isoxazole rings (3-isooxazole rings, 4-isooxazole rings, and 5-isooxazole rings, etc.), and thiazole rings (including 2-thiazole rings, 4-thiazole rings, etc.). The rings include azole rings and 5-thiazole rings, furan rings (including 2-furan rings and 3-furan rings), thiophene rings (including 2-thiophene rings and 3-thiophene rings), pyridine rings (including 2-pyridine rings, 3-pyridine rings and 4-pyridine rings), pyrazine rings, pyrimidine rings (including 2-pyrimidine rings and 4-pyrimidine rings), benzothiazole rings (including 5-benzothiazole rings), purine rings, benzimidazole rings (including 2-benzimidazole rings), benzoxazole rings, indole rings (including 5-indole rings), isoquinoline rings (including 1-isoquinoline rings and 5-isoquinoline rings), quinoxaline rings (including 2-quinoxaline rings and 5-quinoxaline rings), and quinoline rings (including 3-quinoline rings and 6-quinoline rings).

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

[0459] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0460] (i) Suppress the disease or disease state, that is, curb its development;

[0461] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0462] The term “prevention” means administering the compound or formulation described in this 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 mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0463] The term "therapeutic or preventive effective amount" means (i) the amount of the compound of this application used to treat a particular disease, condition, or disorder; or (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the occurrence of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic or preventive effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0464] The therapeutic or preventative dose of the compound may be determined based on factors such as the specific intended use for treatment or prevention, the manner of administration, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the compound in the pharmaceutical composition may not be fixed and depends on various factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compound may be provided in a physiologically buffered aqueous solution containing about 0.1–10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 0.001 mg / kg to about 1000 mg / kg body weight / day. The dosage is likely to depend on variables such as the type and severity of the disease or condition, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation, and the route of administration. The effective dose can be obtained by extrapolation from dose-response curves derived from in vitro or animal model testing systems.

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

[0466] "Pharmaceutical composition" means containing one or more of the compounds described in this application, their isomers or pharmaceutically acceptable salts thereof, and other components such as physiologically / pharmaceuticalally acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0467] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients.

[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 excipients well known in the art.

[0469] The compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.

[0470] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

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

[0472] An important consideration in synthetic route planning in this field is to select appropriate protecting groups for reactive functional groups (such as amino groups in this application). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

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

[0474] Route 1:

[0475]

[0476] in,

[0477] R 1 L 2 The definition of ring A is as described above;

[0478] Y is selected from halogens (e.g., bromine).

[0479] Route 2:

[0480]

[0481] in,

[0482] R 1 The definition of ring A is as described above;

[0483] Y is selected from halogens (e.g., bromine).

[0484] For clarity, this application is further illustrated with examples, but these examples are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification. Detailed Implementation

[0485] The present application is described in detail below with reference to embodiments, but this does not imply any adverse limitation on the present application. The present application has been described in detail herein, and specific embodiments thereof are disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific implementations of the present application without departing from the spirit and scope thereof.

[0486] Example 1: Preparation of Compound 1

[0487]

[0488] 6-Bromopyridin-3-amine (0.50 g), diisopropylethylamine (0.49 g), and methanesulfonic anhydride (1.01 g) were reacted in dichloromethane (5 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction mixture under reduced pressure, and 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), and potassium phosphate (203 mg) were reacted in dioxane (10 mL) under nitrogen protection using a microwave at 120 °C. After the reaction was complete, the mixture was filtered and concentrated to give intermediate 1B (365 mg). MS (ESI): m / z 557.3 [M+H] + .

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

[0491] Intermediate 1C (95 mg) was reacted in formic acid (5 mL) at 70 °C with stirring. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. The residue was adjusted to alkaline pH with sodium bicarbonate aqueous solution, causing solid precipitation. The mixture was filtered, and the filter cake was slurried with methanol to obtain compound 1 (47 mg) from Example 1. MS (ESI): m / z 423.2 [M+H] + .

[0492] 1 H NMR(500MHz,DMSO-d6)δ11.80(s,1H),9.21(s,1H),9.14(s,1H),7.98(d,J=2.7Hz,1H),7 .42(dd,J=8.9,2.7Hz,1H),7.27(s,1H),6.94(d,J=7.8Hz,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=6.7Hz,6H).

[0493] Example 2: Preparation of Compound 2

[0494]

[0495] Referring to the preparation method of the compound in Example 1, 6-bromopyridine-3-amine was replaced with 6-bromo-N-methylpyridine-3-amine to obtain crude compound 2.

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

[0497] 1H NMR (500MHz, DMSO-d6) δ11.85(s,1H),9.28(s,1H),8.12(d,J=2.7Hz,1H),7.59(dd,J= 9.0,2.8Hz,1H),7.28(s,1H),6.95(d,J=7.8Hz,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=6.2Hz,6H).

[0498] Example 3: Preparation of Compound 3

[0499]

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

[0501] The crude compound 3 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 3 (10 mg). MS (ESI): m / z 440.2 [M+H] + .

[0502] 1 H NMR(500MHz,DMSO-d6)δ11.73(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=5.35Hz,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 reacted in dichloromethane (5 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction mixture under reduced pressure, and intermediate 4A (396 mg) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 229.0 [M+H] + .

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

[0507] The crude compound 4 was purified by medium-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 (500MHz, DMSO-d6) δ11.85(s,1H),9.29(s,1H),8.06(d,J=2.6Hz,1H),7.52(dd,J=9.1,2. 7Hz,1H),7.29(d,J=7.9Hz,1H),6.95(d,J=7.8Hz,1H),6.15(s,1H),5.13–4.92(m,1H),3.58( h,J=6.7Hz,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=6.7,2.6Hz,6H).

[0509] Example 5: Preparation of Compound 5

[0510]

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

[0512] Under nitrogen protection, triphenylphosphine (18.19 g) and hexachloroethane (16.42 g) were reacted in chloroform (90 ml) at 73 °C with stirring for 6 h. The mixture was then cooled to room temperature, and triethylamine (10.50 g) was added, followed by stirring at room temperature for 15 min. The mixture was then cooled to 0 °C, and a chloroform (10 ml) solution of intermediate 5A (12.10 g) was added, followed by stirring at 0 °C for 0.5 h. A tetrahydrofuran (10 ml) solution of 6-bromopyridine-3-amine (2.00 g) and triethylamine (11.70 g) was added, followed by stirring at 0 °C. After the reaction was complete, the solvent was evaporated under reduced pressure. Water and dichloromethane were added to the residue, and the mixture was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (developing solvent: petroleum ether / ethyl acetate) to obtain intermediate 5B (1.60 g).

[0513] Following the preparation method of intermediate 1B in 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 hydrochloric acid solution (0.6 mL, 4 mol / L) were added to 10 mL of dichloromethane and stirred at room temperature. After the reaction was complete, a saturated sodium bicarbonate aqueous solution was added to adjust the pH to 9-10. The mixture was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain intermediate 5D (0.05 g). This intermediate was used directly in the next reaction without further purification.

[0515] Intermediate 5D (0.05 g) was reacted in formic acid (20 mL) at 70 °C with stirring. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and the mixture was separated by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (25 / 75), eluent containing 0.1% ammonia) to obtain compound 5 (6 mg). MS (ESI): m / z 373.2 [M+H] + .

[0516] 1H NMR(500MHz,DMSO)δ11.77(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-Bromopyridine-3-amine (500 mg), triethylamine (731 mg), and acetic anhydride (590 mg) were reacted in dichloromethane (5 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction mixture under reduced pressure, and compound 6A (0.528 g) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 214.85 [M+H] + .

[0520] Referring to the preparation method of compound 2 in Example 2, intermediate 2A was replaced with intermediate 6A to obtain crude compound 6.

[0521] The crude compound 6 was slurryed with methanol to give compound 6 (46 mg). MS (ESI): m / z 387.2144 [M+H] + .

[0522] 1H NMR(500MHz,DMSO-d6)δ11.74(s,1H),9.76(s,1H),8.93(s,1H),8.27(s,1H),7.70(d ,J=8.20Hz,1H),7.26(s,1H),6.95(d,J=7.10Hz,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 = 6.40Hz, 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 reacted in dichloromethane (15 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction mixture under reduced pressure, and intermediate 7A (0.66 g) was obtained by column chromatography (electrolyte: petroleum ether / ethyl acetate). MS (ESI): m / z 325.0 [MH] - .

[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 in an oil bath at 120 °C. After the reaction was complete, the mixture was filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 7B (208 mg). MS (ESI): m / z 556.3 [M+H] + .

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

[0528] Referring to the preparation method of compound 1 in Example 1, intermediate 1C was replaced with intermediate 7C to obtain crude compound 7.

[0529] The crude compound 7 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 7 (40 mg). MS (ESI): m / z 442.2 [M+H) + .

[0530] 1 H NMR (500MHz, DMSO-d6) δ11.67(s,1H),9.10(s,1H),8.27(s,1H),7.28(d,J=8.30H z,2H),7.11-6.99(m,2H),6.95(d,J=7.8Hz,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=6.60Hz,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 reacted in dichloromethane (20 mL) with stirring at 50 °C. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and intermediate 8A (758 mg) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 276.9 [M+H] + .

[0534] 1 H NMR (500MHz, DMSO-d6): δ10.17(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-(dicyclohexylphosphine)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (65 mg), (2-dicyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) chloride (100 mg), and potassium phosphate (330 mg) were reacted in 1,4-dioxane (50 mL) under nitrogen protection in an oil bath at 110 °C. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. The resulting residue 8B was not further purified and was directly added to the next reaction step.

[0536] Referring to the preparation method of compound 1 in Example 1, intermediate 1C was replaced with intermediate 8B to obtain crude compound 8.

[0537] The crude compound 8 was initially purified by column chromatography (developing solvent: dichloromethane / methanol), followed by purification by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (40 / 60), eluent containing 0.1% ammonia) to obtain compound 8 (10 mg). MS (ESI): m / z 449.1965 [M+H] + .

[0538] 1 H NMR (500MHz, DMSO-d6): δ11.81(s,1H),9.13(brs,1H),9.13(s,1H),7.99(s,1H),7.43 (d,J=7.60Hz,1H),7.26(s,1H),6.94(d,J=7.05Hz,1H),6.08(s,1H),4.99(s,1H),3.6 1-3.52(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=6.25Hz,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 Example 1, intermediate 1A was replaced with 2-bromo-5-methoxypyridine to obtain crude compound 9.

[0542] The crude compound 9 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 9 (18 mg). MS (ESI): m / z 360.2031 [M+H] + .

[0543] 1 H NMR (500MHz, DMSO-d6) δ11.68(s,1H),8.76(s,1H),7.84(s,1H),7.27(d,J=12 .5Hz,2H),6.95(d,J=7.0Hz,1H),6.03(s,1H),4.99(s,1H),3.73(s,3H),3.58 (dd,J=13.3,6.4Hz,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=6.4Hz,6H).

[0544] Example 10: Preparation of Compound 10

[0545]

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

[0547] Referring to the preparation method of compound 1 in Example 1, intermediate 1A was replaced with intermediate 10A to obtain crude compound 10.

[0548] The crude compound 10 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (25 / 75), eluent containing 0.1% ammonia) to obtain compound 10 (60 mg). MS (ESI): m / z 404.2458 [M+H] + .

[0549] 1H NMR(500MHz,DMSO-d6)δ11.73(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=6.3Hz,6H).

[0550] Example 11: Preparation of Compound 11

[0551]

[0552] Referring to the preparation method of compound 1 in Example 1, 6-bromopyridine-3-amine was replaced with 6-chloro-2-(trifluoromethyl)pyridine-3-amine to obtain crude compound 11.

[0553] The crude compound 11 was purified by column chromatography (developing solvent: dichloromethane / methanol (96 / 4)) to give compound 11 (40 mg). MS (ESI): m / z 491.1687 [M+H] + .

[0554] 1 H NMR (500MHz, DMSO-d6) δ11.97(s,1H),9.75(s,1H),9.26(s,1H),7.70(d,J=8.9Hz,1H),7.48(d,J=9.1Hz,1H),6.92(d,J=7.8Hz,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=5.7Hz,6H).

[0555] Example 12: Preparation of Compound 12

[0556]

[0557] 6-Bromopyridine-3-amine (1000 mg), sodium tert-butoxide (1666 mg), and 1-bromo-2-methoxyethane (1606 mg) were reacted in acetonitrile (10 mL) with stirring at 80 °C. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and 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 reacted in dichloromethane (5 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction mixture under reduced pressure, and 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 added to toluene / tert-butanol (35 mL, 5:1 (v / v)). After addition, the mixture was stirred at 120 °C. The reaction was completed, filtered, and the solvent was removed from the filtrate under reduced pressure. Intermediate 12C (224 mg) was obtained by column chromatography (developing solvent: dichloromethane / methanol). MS (ESI): m / z 559.58 [M+H] + .

[0560] Intermediate 12C (224 mg) was reacted in formic acid (10 ml) with stirring at 70 °C. After the reaction was complete, the mixture was concentrated, and the residue was adjusted to alkaline pH with saturated sodium bicarbonate aqueous solution. Extraction was performed with dichloromethane, and the residue was dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. The filtrate was purified by preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to give compound 12 (105 mg). MS (ESI): m / z 434.2403 [M+H] + .

[0561] 1H NMR(500MHz,DMSO-d6)δ11.85(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=7.4Hz,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),2.0 3-1.99(m,1H),1.93-1.85(m,1H),1.76-1.68(m,2H),1.63-1.57(m,1H),1.03(d,J=6.5Hz,6H).

[0562] Example 13: Preparation of Compound 13

[0563]

[0564] Referring to the preparation method of compound 12 in Example 12, intermediate 12B was replaced with 2-bromopyridine and intermediate K1 was replaced with intermediate K to obtain crude compound 13.

[0565] The crude compound 13 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (28 / 72), eluent containing 0.1% ammonia) to obtain compound 13 (50 mg). MS (ESI): m / z 330.1927 [M+H] + .

[0566] 1 H NMR (500MHz, DMSO-d6): δ11.79(s,1H),9.04(s,1H),8.09(d,J=3.95Hz,1H),7.51(t,J =7.50Hz,1H),7.24(s,1H),6.95(d,J=7.25Hz,1H),6.66(t,J=5.40Hz,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=6.30Hz,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 added to dichloromethane (10 mL). After addition, the mixture was stirred at room temperature. Once the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and 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 reacted in acetonitrile (10 mL) with stirring at 80 °C. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and 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 Example 12, intermediate 12B was replaced with intermediate 14B and intermediate K1 was replaced with intermediate K to obtain crude compound 14.

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

[0573] 1 H NMR(500MHz,DMSO-d6)δ11.79(s,1H),9.08(s,1H),8.30(d,J=2.7Hz,1H),7.86-7.85(m,1H), 7.30(s,1H),6.95(d,J=7.7Hz,1H),6.06(s,1H),4.99(m,1H),3.78(t,J=7.0Hz,2H),3.61-3.5 4(m,1H),3.08-2.97(m,1H),2.47(d,J=7.2Hz,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=6.4Hz,6H).

[0574] Example 15: Preparation of Compound 15

[0575]

[0576] Referring to the preparation method of compound 1 in Example 1, 6-bromopyridine-3-amine was replaced with 2-amino-5-bromopyridine to obtain crude compound 15.

[0577] The crude compound 15 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (22 / 78), eluent containing 0.1% ammonia) to obtain compound 15 (13 mg). MS (ESI): m / z 423.1810 [M+H] + .

[0578] 1 H NMR (500MHz, DMSO-d6) δ8.05 (d, J = 2.9Hz, 1H), 7.83 (s, 1H), 7.49-7.37 (m, 1H), 6. 96(d,J=7.8Hz,1H),6.53(d,J=8.8Hz,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=6.5Hz,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 reacted in acetonitrile (20 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and intermediate 16A (800 mg) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 268.04 [MH] - .

[0582] Referring to the preparation method of compound 1 in Example 1, intermediate 1A was replaced with intermediate 16A and intermediate K was replaced with intermediate K1 to obtain crude compound 16.

[0583] The crude compound 16 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 16 (60 mg). MS (ESI): m / z 440.5 [M+H] + .

[0584] 1 H NMR(500MHz,DMSO-d6)δ12.00(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=7.8Hz,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=4.1Hz,3H),2.04-2.00(m,1 H), 1.96-1.86 (m, 1H), 1.76-1.67 (m, 2H), 1.64-1.56 (m, 1H), 1.03 (d, J = 6.6Hz, 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 reacted in dichloromethane (30 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and intermediate 17A (200 mg) was obtained by column chromatography (evolving solvent: dichloromethane / methanol). MS (ESI): m / z 251.02 [M+H] + .

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

[0589] The crude compound 17 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (40 / 60), eluent containing 0.1% ammonia) to obtain compound 17 (30 mg). MS (ESI): m / z 423.1813 [M+H] + .

[0590] 1H NMR (500MHz, DMSO-d6): δ8.78(s,1H),7.66(d,J=8.85Hz,1H),6.95(d,J=7.40Hz, 1H),6.58(s,1H),6.24(dd,J=1.50,5.80Hz,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=6.50Hz,6H).

[0591] Example 18: Preparation of Compound 18

[0592]

[0593] Sodium hydride (1.3 g) and 6-bromo-3-pyridinemethanol (2.0 g) were added to N,N-dimethylformamide (20 mL) at 0 °C and stirred for half an hour. Iodomethane (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 mixture. The mixture was extracted with ethyl acetate, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Intermediate 18A (1.6 g) was obtained by column chromatography (electrolyte: petroleum ether / ethyl acetate). MS (ESI): m / z 202.0 [M+H] + .

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

[0595] The crude compound 18 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (35 / 65), eluent containing 0.1% ammonia) to obtain compound 18 (19 mg). MS (ESI): m / z 374.2188 [M+H] + .

[0596] 1H NMR(500MHz,DMSO-d6)δ11.79(s,1H),9.09(s,1H),8.04(s,1H),7.49(d,J=8.1Hz,1H), 7.26(d,J=7.3Hz,1H),6.95(d,J=6.9Hz,1H),6.10(s,1H),5.00(s,1H),4.26(s,2H),3.5 8(dd,J=13.3,6.7Hz,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=6.4Hz,6H).

[0597] Example 19: Preparation of Compound 19

[0598]

[0599] Referring to the preparation method of compound 17 in Example 17, 2-bromo-4-aminopyridine was replaced with 5-amino-2-bromopyrimidine to obtain crude compound 19.

[0600] The crude compound 19 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (40 / 60), eluent containing 0.1% ammonia) to obtain compound 19 (32 mg). MS (ESI): m / z 424.1760 [M+H] + .

[0601] 1 H NMR (500MHz, DMSO-d6): δ9.37(s,1H),8.17(s,2H),6.95(d,J=7.45Hz,1H),6.20(s,1H),4.99(s,1H),3.61-3.53(m,1H),3.04-3.00(m,1 H),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=6.50Hz,6H).

[0602] Example 20: Preparation of Compound 20

[0603]

[0604] In Example 12, compound 12 (80 mg) was reacted in dilute hydrochloric acid (1 M, 5 mL) with stirring at 50 °C. After the reaction was complete, the solvent was removed from the reaction solution 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, and the solvent was removed from the filtrate under reduced pressure. The filtrate was purified by preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 20 (25 mg). MS (ESI): m / z 403.2455 [M+H] + .

[0605] 1 H NMR(500MHz,DMSO-d6)δ11.60(s,1H),8.43(s,1H),7.57(d,J=2.9Hz,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=6.6Hz,6H).

[0606] Example 21: Preparation of compound 21

[0607]

[0608] Intermediate K1 (200 mg), 6-chloro-2,3-dihydrofuran[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 reacted in toluene / tert-butanol (35 mL, 5:1 (v / v)) under nitrogen protection with stirring at 120 °C. After the reaction was complete, the mixture was filtered, the solvent was removed by vacuum distillation, and intermediate 21A (108 mg) was obtained by column chromatography (developing solvent: dichloromethane / methanol). MS (ESI): m / z 428.51 [M+H] + .

[0609] Intermediate 21A (108 mg) was reacted in formic acid (5 ml) with stirring at 70 °C. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. The pH of the residue was adjusted to alkaline with a saturated sodium bicarbonate aqueous solution, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was slurried with methanol to give compound 21 (49 mg). MS (ESI): m / z 372.2036 [M+H] + .

[0610] 1 H NMR (500MHz, DMSO-d6) δ11.74(s,1H),8.89(s,1H),7.37(d,J=8.0Hz,1H),6.94(d ,J=7.9Hz,1H),6.79(d,J=7.9Hz,1H),6.01(s,1H),5.00(s,1H),4.49(t,J=8.4Hz ,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=6.6Hz,6H).

[0611] Example 22: Preparation of compound 22

[0612]

[0613] 1-N-methanesulfonyl-4-piperidinone (264 mg), intermediate K1 (200 mg), and acetic acid (42.8 mg) were reacted in 1,2-dichloroethane (15 mL) under nitrogen protection with stirring 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 from the reaction solution under reduced pressure, and intermediate 22A (300 mg) was obtained by column chromatography (evolving solvent: dichloromethane / methanol). MS (ESI): m / z 470.6 [M+H] + .

[0614] Intermediate 22A (200 mg) was reacted in formic acid (10 mL) at 110 °C with stirring. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. The residue was adjusted to alkaline pH with triethylamine, and the solvent was removed again under reduced pressure. The crude compound 22 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 22 (37 mg). MS (ESI): m / z 414.5 [M+H] + .

[0615] 1H NMR(500MHz,DMSO-d6)δ11.17(s,1H),6.94(d,J=7.8Hz,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,1 H),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=6.5Hz,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 reacted in dichloromethane (85 mL) under nitrogen protection with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction mixture under reduced pressure. Dichloromethane and a saturated aqueous solution of ammonium chloride were added to the residue. The organic phase was separated, dried, filtered, and the solvent was removed from the filtrate under reduced pressure to give 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 reacted in toluene / tert-butanol (30 mL, 5:1 (v / v)) under nitrogen protection with stirring at 120 °C. After the reaction was complete, the mixture was filtered, the solvent was removed from the filtrate under reduced pressure, and intermediate 23B (1.00 g) was obtained by column chromatography (developing solvent: dichloromethane / methanol).

[0620] Intermediate 23B (0.12 g) was reacted in formic acid (20 mL) at 70 °C with stirring. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. The residue was intermediate 23C, which was not further purified and directly fed into the next reaction step.

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

[0622] 1 H NMR(500MHz,DMSO-d6)δ11.80(s,1H),9.06(s,1H),8.67(s,1H),7.43(d,J=12.4H z,1H),7.11(t,J=8.9Hz,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=6.3Hz,6H).

[0623] Example 24: Preparation of compound 24

[0624]

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

[0626] The crude compound 24 was purified by column chromatography (developing solvent: dichloromethane / methanol (96 / 4)) to give compound 24 (106 mg). MS (ESI): m / z 441.1722 [M+H] + .

[0627] 1H NMR(500MHz,DMSO-d6)δ11.95(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=7.8Hz,1H),6.06(s,1H),5.04-4.96(m,1H),3.6 1-3.54(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=6.6,2.4Hz,6H).

[0628] Example 25: Preparation of compound 25

[0629]

[0630] Referring to the preparation method of compound 16A in Example 16, the methylamine hydrochloride was replaced with ammonia to obtain compound 25A.

[0631] Referring to the preparation method of compound 16 in Example 16, intermediate 16A was replaced with intermediate 25A and intermediate K1 was replaced with intermediate K to obtain crude compound 25.

[0632] The crude compound 25 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 25 (50 mg). MS (ESI): m / z 426.5 [M+H] + .

[0633] 1 H NMR(500MHz,DMSO-d6)δ11.96(s,1H),8.62(s,1H),8.19(t,J=8.5Hz,1H),7.50 (d,J=9.9Hz,2H),7.17(s,2H),6.94(d,J=7.8Hz,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=6.5Hz,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), and potassium phosphate (960 mg) were added to N,N-dimethylformamide (20 ml). After addition, the mixture was stirred at 110 °C. The reaction was completed, filtered, and the solvent was removed from the filtrate under reduced pressure. Intermediate 26A (655 mg) was obtained by column chromatography (developing solvent: dichloromethane / methanol). MS (ESI): m / z 475.33 [M+H] + .

[0637] Intermediate 26A (108 mg) was reacted in formic acid (10 ml) with stirring at 70 °C. After the reaction was complete, the solvent was removed from the reaction solution 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, and the solvent was removed from the filtrate under reduced pressure. The filtrate was purified by preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to give compound 26 (140 mg). MS (ESI): m / z 419.1753 [M+H] + .

[0638] 1H NMR(500MHz,DMSO-d6)δ11.73(s,1H),8.48(s,1H),7.41(s,1H),7.22(d,J=8.4Hz,1 H),7.14(d,J=8.4Hz,1H),6.95(d,J=7.9Hz,1H),5.63(s,1H),4.99(m,1H),4.41(s,2 H),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 Example 1, 6-bromopyridine-3-amine was replaced with 2-amino-5-bromotrifluorotoluene to obtain compound 27A.

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

[0643] The crude compound 27 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 27 (60 mg). MS (ESI): m / z 490.3 [M+H] + .

[0644] 1 H NMR(500MHz,DMSO-d6)δ11.87(s,1H),9.04(s,1H),8.80(s,1H),7.90(s,1H),7.46-7. 45(m,1H),7.34(d,J=8.7Hz,1H),6.95(d,J=7.9Hz,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=6.1Hz,6H).

[0645] Example 28: Preparation of compound 28

[0646]

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

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

[0649] Referring to the preparation method of compound 14 in Example 14, intermediate 14B was replaced with compound 28B to obtain crude compound 28.

[0650] The crude compound 28 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (25 / 75), eluent containing 0.1% ammonia) to obtain compound 28 (25 mg). MS (ESI): m / z 449.1964 [M+H] +.

[0651] 1 H NMR(500MHz,DMSO-d6)δ11.81(s,1H),9.17(s,1H),8.02(d,J=2.1Hz,1H),7.55-7.47(m,1H), 7.33(s,1H),6.93(d,J=6.8Hz,1H),6.08(s,1H),5.00(s,1H),3.66(t,J=6.6Hz,2H),3.62-3.5 4(m,1H),3.43(t,J=7.6Hz,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=6.4Hz,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 reacted in tetrahydrofuran (150 ml) with stirring at room temperature. After the reaction was complete, the mixture was filtered, and the solvent was removed from the filtrate under reduced pressure to give 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 reacted in 1,4-dioxane (200 ml) with stirring at room temperature. After the reaction was complete, the mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. Intermediate 29B (3.63 g) was obtained by column chromatography (developing solvent: dichloromethane / methanol). MS (ESI): m / z 323.16 [M+H] + .

[0656] Intermediate 29B (3.63 g) and 3,3-dimethyl-1-(trifluoromethyl)-1,2-benzoiodoxopentane (4.17 g) were reacted in dichloromethane (100 ml) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure to give intermediate 29C (4.00 g). MS (ESI): m / z 391.25 [M+H] + .

[0657] Intermediate 29C (4.00 g) was reacted in nitromethane (50 ml) with stirring at 120 °C. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, 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 reacted in toluene / tert-butanol (35 mL, 5:1 (v / v)) under nitrogen protection with stirring at 120 °C. After the reaction was complete, the mixture was filtered, the solvent was removed from the filtrate under reduced pressure, and intermediate 29E (120 mg) was obtained by column chromatography (developing solvent: 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 reacted in tetrahydrofuran (5 mL) under a hydrogen atmosphere with stirring at room temperature. After the reaction was complete, the mixture was filtered, and the solvent was removed from the filtrate under reduced pressure to give 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 reacted in dichloromethane (5 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure to give compound 29G (90 mg). MS (ESI): m / z 641.31 [M+H] + .

[0661] Intermediate 29G (90 mg) was reacted in formic acid (5 ml) with stirring at 90 °C. After the reaction was complete, the solvent was removed from the reaction solution 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, and the solvent was removed from the filtrate under reduced pressure to give intermediate 29H (70 mg). MS (ESI): m / z 585.18 [M+H] + .

[0662] Intermediate 29H (70 mg), sodium carbonate (70 mg), and water were reacted in methanol (5 ml) and water (1 ml) at 70 °C with stirring. After the reaction was complete, methanol was removed under reduced pressure. The residue was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The filtrate was purified by preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to give compound 29 (20 mg). MS (ESI): m / z 507.1638 [M+H] + .

[0663] 1 H NMR(500MHz,DMSO-d6)δ11.92(s,1H),9.62(s,1H),9.26(s,1H),7.58(d,J=8.6Hz ,1H),6.97(d,J=8.6Hz,1H),6.90(d,J=7.9Hz,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=6.7Hz,6H).

[0664] Example 30: Preparation of compound 30

[0665]

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

[0667] Referring to the preparation method of compound 1 in Example 1, intermediate 1A was replaced with intermediate 30A to obtain crude compound 30.

[0668] The crude compound 30 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (18 / 82), eluent containing 0.1% ammonia) to obtain compound 30 (30 mg). MS (ESI): m / z 457.1422 [M+H] + .

[0669] 1H NMR(500MHz,DMSO-d6)δ11.94(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=8.8Hz,1H),6.04(s,1H),5.00(s,1H),3.62-3.5 3(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=4.8Hz,6H).

[0670] Example 31: Preparation of compound 31

[0671]

[0672] Referring to the preparation method of compound 29D in Example 29, intermediate 29C was reacted in nitromethane and then subjected to column chromatography to obtain intermediate 31A.

[0673] Referring to the preparation method of compound 29 in Example 29, intermediate 29D was replaced with intermediate 31A to obtain crude compound 31.

[0674] The crude compound 31 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 31 (13 mg). MS (ESI): m / z 507.1638 [M+H] + .

[0675] 1 H NMR(500MHz,DMSO-d6)δ11.99(s,1H),9.60(s,1H),9.28(s,1H),8.12(s,1H) ,7.64(s,1H),6.93(d,J=7.2Hz,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=6.3Hz,6H).

[0676] Example 32: Preparation of compound 32

[0677]

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

[0679] Referring to the preparation method of compound 23 in Example 23, intermediate 23A was replaced with compound 32A to obtain crude compound 32.

[0680] The crude compound 32 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (24 / 76), eluent containing 0.1% ammonia) to obtain compound 32 (25 mg). MS (ESI): m / z 458.1670 [M+H] + .

[0681] 1 H NMR(500MHz,DMSO-d6)δ11.87(s,1H),9.29(s,1H),8.47(s,1H),8.13-8.09(m,1 H),7.14-7.10(m,1H),6.93(d,J=7.1Hz,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=6.3Hz,6H).

[0682] Example 33: Preparation of compound 33

[0683]

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

[0685] Referring to the preparation method of compound 16 in Example 16, intermediate K1 was replaced with intermediate K to obtain crude compound 33.

[0686] The crude compound 33 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 33 (40 mg). MS (ESI): m / z 426.3 [M+H] + .

[0687] 1H NMR (500MHz, DMSO-d6) δ11.96(s,1H),9.15(s,1H),7.54(t,J=8.7Hz,1H),7.43(dd,J=13. 9,2.1Hz,1H),7.27(s,2H),7.03(dd,J=8.8,2.1Hz,1H),6.94(d,J=7.8Hz,1H),5.69(d,J=2 .2Hz,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=6.8Hz,6H).

[0688] Example 34: Preparation of compound 34

[0689]

[0690] Referring to the preparation method of compound 16A in Example 16, methylamine hydrochloride was replaced with ammonia, and 4-bromo-3-fluorobenzenesulfonyl chloride was replaced with 4-bromo-2-fluorobenzenesulfonyl chloride to prepare compound 34A.

[0691] Referring to the preparation method of compound 16 in Example 16, intermediate K1 was replaced with intermediate K2 to obtain crude compound 34.

[0692] The crude compound 34 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 34 (25 mg). MS (ESI): m / z 426.3 [M+H] + .

[0693] 1 H NMR (500MHz, DMSO-d6) δ11.96 (s, 1H), 8.61 (s, 1H), 8.18 (t, J = 8.4Hz, 1H), 7. 57–7.45(m,2H),7.16(s,2H),6.93(d,J=7.9Hz,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 Example 14, 6-bromo-N-methylpyridin-3-amine was replaced with 4-bromo-2-fluoroaniline to obtain crude compound 35.

[0697] The crude compound 35 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 35 (30 mg). MS (ESI): m / z 430.2246 [M+H] + .

[0698] 1 H NMR (500MHz, DMSO-d6) δ11.79(s,1H),8.66(s,1H),7.41(d,J=13.9Hz,1H),7.13(t,J=8.8H z,1H),7.03–6.88(m,2H),5.62(s,1H),4.99(s,1H),3.65(t,J=7.0Hz,2H),3.60-3.56(m,1H ),3.07-3.00(m,1H),2.49–2.426(m,1H),2.38(t,J=8.0Hz,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=6.5Hz,6H).

[0699] Example 36: Preparation of compound 36

[0700]

[0701] 1-(6-bromopyridin-3-yl)ethane-1-one (3.00 g) and liquid bromine (0.90 mL) were reacted in hydrobromic acid (45 mL) under nitrogen protection at 70 °C with stirring. After the reaction was complete, diethyl ether was added, and the mixture was stirred for 30 min. The mixture was then filtered, and the filter cake was dried to give intermediate 36A (4.00 g). MS (ESI): m / z 277.88 [M+H] + .

[0702] Intermediate 36A (3.00 g) was reacted in formamide (20 mL) by microwave at 150 °C. After the reaction was complete, the mixture was poured into water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (developing solvent: 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 Example 12, intermediate 12B was replaced with intermediate 36B to obtain crude compound 36.

[0704] The crude compound 36 was purified by slurry extraction with methanol to obtain compound 36 (28 mg). MS (ESI): m / z 397.1988 [M+H] + .

[0705] 1 H NMR(500MHz,DMSO-d6)δ11.84(s,1H),9.27(s,1H),8.55(s,1H),8.48(s,1H),8.43 (s,1H),7.89(d,J=8.2Hz,1H),7.35(s,1H),6.94(d,J=6.8Hz,1H),6.12(s,1H),5.0 0(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,1 H), 1.94-1.86 (m, 1H), 1.78-1.68 (m, 2H), 1.66-1.57 (m, 1H), 1.03 (d, J = 5.9Hz, 6H).

[0706] Example 37: Preparation of compound 37

[0707]

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

[0709] The crude compound 37 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (28 / 72), eluent containing 0.1% ammonia) to obtain compound 37 (156 mg). MS (ESI): m / z 458.1674 [M+H] + .

[0710] 1H NMR(500MHz,DMSO-d6)δ11.84(s,1H),9.31(s,1H),8.31(s,1H),7.80-7.76(m,1 H),7.02-6.98(m,1H),6.93(d,J=7.1Hz,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=6.4Hz,6H).

[0711] Example 38: Preparation of compound 38

[0712]

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

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

[0715] Compound 38 (100 mg) was purified by acetonitrile slurry extraction. MS (ESI): m / z 396.2147 [M+H] + .

[0716] 1H NMR(500MHz,DMSO-d6)δ11.86(s,1H),9.42(s,1H),8.38(d,J=2.6Hz,1H),8.09(s,1H),7.81 (dd,J=9.0,2.8Hz,1H),7.61(s,1H),7.36(d,J=8.9Hz,1H),7.09(s,1H),6.94(d,J=7.2Hz,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=6.4Hz,6H).

[0717] Example 39: Preparation of compound 39

[0718]

[0719] Referring to the preparation method of compound 26 in Example 26, the 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide was replaced with 4-bromo-1,2-methylenedioxybenzene to obtain crude compound 39.

[0720] The crude compound 39 was purified by medium-low pressure preparative liquid chromatography (C18 column, nitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 39 (28 mg). MS (ESI): m / z 373.1869 [M+H] + .

[0721] 1 H NMR(500MHz,DMSO-d6)δ11.60(s,1H),8.09(s,1H),7.09(s,1H),6.93(d,J= 7.2Hz,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),1.9 3–1.85(m,1H),1.75-1.65(m,2H),1.61-1.55(m,1H),1.03(d,J=6.4Hz,6H).

[0722] Example 40: Preparation of Compound 40

[0723]

[0724] Referring to the preparation method of compound 23 in Example 23, 4-bromo-2-fluoroaniline was replaced with 4-bromo-2-chloroaniline to obtain crude compound 40.

[0725] The crude compound 40 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 40 (70 mg). MS (ESI): m / z 456.1470 [M+H] + .

[0726] 1 H NMR(500MHz,DMSO-d6)δ11.80(s,1H),9.08(s,1H),8.64(s,1H),7.68(s,1H),7.19(d ,J=8.7Hz,1H),7.13(d,J=8.1Hz,1H),6.94(d,J=8.2Hz,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=6.4Hz,6H).

[0727] Example 41: Preparation of compound 41

[0728]

[0729] Referring to the preparation method of compound 26 in Example 26, the 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide was replaced with 4-bromophenyldimethylphosphorus oxide to obtain crude compound 41.

[0730] The crude compound 41 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 41 (120 mg). MS (ESI): m / z 405.2055 [M+H] + .

[0731] 1H NMR(500MHz,DMSO-d6)δ11.83(s,1H),8.68(s,1H),7.53-7.49(m,2H),7.39-7.37 (m,2H),6.94(d,J=7.9Hz,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=6.7Hz,6H).

[0732] Example 42: Preparation of compound 42

[0733]

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

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

[0736] The crude compound 42 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 42 (10 mg). MS (ESI): m / z 384.20 [M+H] + .

[0737] 1H NMR(500MHz,DMSO-d6)δ11.51(s,1H),10.04(s,1H),7.97(s,1H),7.26(s,1H) ,7.10-7.08(m,1H),6.94(d,J=7.9Hz,1H),6.62(d,J=8.3Hz,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 reacted in water (80 mL) with stirring at 90 °C. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure to give intermediate 43A (10.00 g).

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

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

[0744] Intermediate 43C (0.63 g) and bromine (0.46 g) were reacted in acetic acid (8 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and intermediate 43D (0.75 g) was obtained by column chromatography (developing solvent: petroleum ether / ethyl acetate). MS (ESI): m / z 246.0 [MH] - .

[0745] Intermediate 43D (0.75 g), potassium carbonate (0.83 g), and benzyl bromide (0.54 g) were reacted in DMF (10 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation, and intermediate 43E (800 mg) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 335.95 [MH] - .

[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 reacted in N,N-dimethylformamide (20 mL) under nitrogen protection with stirring at 110 °C. 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 reacted in methanol (20 mL) with hydrogen purging and stirred at room temperature. 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 with ethanol (1 mL) and dilute hydrochloric acid (1 N, 20 mL) in a microwave-controlled reaction at 100 °C. After the reaction was complete, the solvent was removed from the reaction solution 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, and the solvent was removed from the filtrate under reduced pressure. The filtrate was purified by preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to give compound 43 (9 mg). MS (ESI): m / z 420.1701 [M+H] + .

[0749] 1H NMR(500MHz,DMSO-d6)δ11.61(s,1H),9.74(s,1H),8.18(s,1H),7.37(s,1H),7.15(d,J=8 .6Hz,1H),6.94(d,J=7.7Hz,1H),6.71(d,J=8.6Hz,1H),5.57(s,1H),4.99(s,1H),4.43(s, 2H),3.61-3.55(m,1H),3.03(q,J=8.7Hz,1H),2.44(dt,J=14.3,7.4Hz,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=6.7,2.3Hz,6H).

[0750] Example 44: Preparation of compound 44

[0751]

[0752] Referring to the preparation method of compound 1B in Example 1, 6-bromopyridine-3-amine was replaced with 3-amino-2-methoxy-6-bromopyridine to obtain crude intermediate 44B.

[0753] Referring to the preparation method of compound 1 in Example 1, intermediate 1C was replaced with intermediate 44B to obtain crude compound 44.

[0754] The crude compound 44 was purified by column chromatography (developing solvent: dichloromethane / methanol (90 / 10)) to give compound 44 (39 mg). MS (ESI): m / z 531.27 [M+H] + .

[0755] 1 H NMR(500MHz,DMSO-d6)δ12.17(s,1H),9.12(s,1H),9.00(s,1H),7.78(s,1H),6.91( d,J=7.8Hz,1H),6.54(s,1H),5.00(d,J=8.6Hz,1H),4.01(s,3H),3.64-3.48(m,1H) ,3.26(s,3H),3.11(q,J=8.7Hz,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=6.2Hz,6H).

[0756] Example 45: Preparation of compound 45

[0757]

[0758] Referring to the preparation method of compound 1 in Example 1, intermediate 1A was replaced with intermediate 44A to obtain crude compound 45.

[0759] The crude compound 45 was purified by column chromatography (developing solvent: dichloromethane / methanol (90 / 10)) to give compound 45 (55 mg). MS (ESI): m / z 453.29 [M+H] + .

[0760] 1 H NMR (500MHz, DMSO-d6) δ11.84(s,1H),9.18(s,1H),8.72(s,1H),7.33(d,J=8.3Hz,1H),6. 92(d,J=7.9Hz,1H),6.79-6.62(m,1H),6.23(s,1H),5.00(d,J=7.8Hz,1H),3.90(s,3H),3 .58(dt,J=13.8,7.0Hz,1H),3.08-3.02(m,1H),2.88(s,3H),2.48-2.40(m,1H),2.05-1.9 6(m,1H),1.95-1.84(m,1H),1.80-1.66(m,2H),1.64-1.60(m,1H),1.02(d,J=6.6Hz,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 reacted in dichloromethane (50 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and the intermediate 46A (0.37 g) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z: 422.1 [M+Na] + .

[0764] 1 H NMR (500MHz, DMSO-d6) δ7.81-7.83(m,2H),7.71-7.68(m,2H),1.36(s,18H).

[0765] Referring to the preparation method of compound 23 in Example 23, 23A was replaced with 46A, and formic acid was replaced with ethanol / 1N dilute hydrochloric acid (1 / 5) to obtain crude compound 46.

[0766] The crude compound 46 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 46 (13 mg). MS (ESI): m / z 372.2035 [M+H] + .

[0767] 1 H NMR(500MHz,DMSO-d6)δ11.51(s,1H),10.04(s,1H),7.97(s,1H),7.26(s,1H),7.10 -7.08(m,1H),6.94(d,J=7.9Hz,1H),6.62(d,J=8.3Hz,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] Following the preparation method of compound 7 in Example 7, 4-bromoaniline was replaced 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 with ethanol (2 mL) and dilute hydrochloric acid (1 N, 20 mL) in a microwave-safe mixture at 100 °C. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. The residue was adjusted to alkaline pH with a saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 47 (30 mg). MS (ESI): m / z 506.1693 [M+H] + .

[0772] 1H NMR(500MHz,DMSO-d6)δ11.86(s,1H),9.12(s,1H),8.75(s,1H),7.70(s,1H),7.22(d, J=8.8Hz,1H),7.14-7.12(m,1H),6.93(d,J=7.8Hz,1H),5.60(d,J=2.2Hz,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=6.5Hz,6H).

[0773] Example 48: Preparation of compound 48

[0774]

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

[0776] Intermediate 48A (0.40 g) and palladium on carbon (5% palladium content, 50% water content (w / w), 0.30 g) were reacted in tetrahydrofuran (5 mL) and ethyl acetate (5 mL) under a hydrogen atmosphere with stirring at room temperature. After the reaction was complete, the mixture was filtered and concentrated to give 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 added to N,N-dimethylformamide (10 mL). After addition, the reaction was stirred at 110 °C under nitrogen protection. The reaction was completed, filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to give intermediate 48C (0.20 g). MS (ESI): m / z 487.29 [M+H] + .

[0778] Intermediate 48C (0.20 g) was reacted in ethanol (2 mL) and dilute hydrochloric acid (1 N, 20 mL) under microwave stirring at 100 °C. After the reaction was complete, the solvent was removed from the reaction solution 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 preparative liquid chromatography (C18 column, acetonitrile / water (20 / 80), eluent containing 0.1% ammonia) to obtain compound 48 (15 mg). MS (ESI): m / z 431.1745 [M+H] + .

[0779] 1 H NMR (500MHz, DMSO) δ11.69(s,1H),8.46(s,1H),7.36(d,J=22.0Hz,2H),7.20(d,J=8.1Hz,1H) ,7.13(d,J=8.4Hz,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] Following the preparation method of intermediate 26A in Example 26, intermediate K was replaced with intermediate K2 to obtain intermediate 49A (120 mg). MS (ESI): m / z 475.50 [M+H] + .

[0783] Following the preparation method of compound 47 in Example 47, intermediate 47C was replaced with intermediate 49A to obtain compound 49 (40 mg). MS (ESI): m / z 419.1756 [M+H] + .

[0784] 1 H NMR(500MHz,DMSO-d6)δ11.73(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=7.05Hz,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,1 H),1.92-1.88(m,1H),1.75-1.68(m,2H),1.62-1.56(m,1H),1.03(d,J=6.35Hz,6H).

[0785] Example 50: Preparation of Compound 50

[0786]

[0787] Referring to the preparation method of compound 47 in Example 47, 4-bromo-2-trifluoromethoxyaniline was replaced with 4-bromo-2-trifluoromethylaniline, and intermediate K was replaced with intermediate K2 to obtain crude compound 50.

[0788] The crude compound 50 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 50 (20 mg). MS (ESI): m / z 490.1742 [M+H] + .

[0789] 1H NMR(500MHz,DMSO-d6)δ11.86(s,1H),9.04(s,1H),8.77(s,1H),7.89(s,1H),7.46-7. 45(m,1H),7.34(d,J=8.7Hz,1H),6.92(d,J=7.9Hz,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=6.1Hz,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 reacted in dichloromethane (30 mL) and stirred overnight at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and the intermediate 51A (1.05 g) was obtained by column chromatography (developing solvent: petroleum ether / ethyl acetate).

[0793] 1 H NMR (500MHz, DMSO-d6) δ7.47 (s, 1H), 7.38-7.36 (m, 1H), 7.18 (d, J = 8.55Hz, 1H), 3.94 (t, J = 8.40Hz, 2H), 3.12 (t, J = 8.45Hz, 2H), 3.01 (s, 3H).

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

[0795] 1H NMR(500MHz,DMSO-d6)δ11.62(s,1H),8.21(s,1H),7.34(s,1H),7.11-7.06(m,2H ),6.95(d,J=7.35Hz,1H),5.58(s,1H),4.99(s,1H),3.86(t,J=8.35Hz,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=6.40Hz,6H).

[0796] Example 52: Preparation of compound 52

[0797]

[0798] Following the preparation method of compound 16 in Example 16, the methylamine hydrochloride was replaced with ammonia, and intermediate K1 was replaced with intermediate K, yielding intermediate 52B (210 mg). MS (ESI): m / z 499.48 [M+H] + .

[0799] Following the preparation method of compound 47 in Example 47, intermediate 47C was replaced with intermediate 52B to obtain compound 52 (60 mg). MS (ESI): m / z 443.42 [M+H] + .

[0800] 1 H NMR(500MHz,DMSO-d6)δ12.10(s,1H),10.10(s,1H),8.04(d,J=8.7Hz,1H),7. 43(s,2H),7.34(s,1H),6.94(d,J=7.7Hz,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=6.8Hz,6H).

[0801] Example 53: Preparation of compound 53

[0802]

[0803] Referring to the preparation method of compound 48 in Example 48, 1-methylcyclopropane-1-amine hydrochloride was replaced with methylamine hydrochloride to obtain crude compound 53.

[0804] The crude compound 53 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 53 (55 mg). MS (ESI): m / z 391.46 [M+H] + .

[0805] 1 H NMR(500MHz,DMSO-d6)δ11.73(s,1H),8.48(s,1H),7.41(s,1H),7.22-7.21(m,1H), 7.13(d,J=8.4Hz,1H),6.92(d,J=5.3Hz,1H),5.62(d,J=2.2Hz,1H),5.08-4.88(m,1 H),4.40(s,2H),4.32(s,2H),3.07-3.00(m,1H),2.55(d,J=4.6Hz,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, the 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide was replaced with 1-bromo-4-methylsulfonylbenzene to obtain crude compound 54.

[0809] The crude compound 54 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 54 (20 mg). MS (ESI, [M+H)) + )m / z:407.1748.

[0810] 1H NMR(500MHz,DMSO-d6)δ9.13(s,1H),7.73-7.64(m,2H),7.50-7.39(m,2H),6.94(d,J=7.2Hz,1H),5.75(s,1H),5.13-4.9 7(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 Example 47, 4-bromo-2-trifluoromethoxyaniline was replaced with 4-bromo-2-methoxyaniline to obtain crude compound 55.

[0814] The crude compound 55 was purified by column chromatography (developing solvent: dichloromethane / methanol (90 / 10)) to give compound 55 (44 mg). MS (ESI): m / z 452.28 [M+H] + .

[0815] 1 H NMR(500MHz,DMSO-d6)δ11.75(s,1H),8.72-8.44(m,1H),8.38(s,1H),7.19(s,1H),6.97( d,J=8.6Hz,1H),6.94(d,J=7.9Hz,1H),6.77(d,J=8.6Hz,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=6.3Hz,6H).

[0816] Example 56: Preparation of Compound 56

[0817]

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

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

[0820] Intermediate 56B (2.58 g) was dissolved in polyphosphoric acid (50 ml) and reacted with stirring at 140 °C. After the reaction was complete, the mixture was allowed to return 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 [MH] - .

[0821] Intermediate 56C (2.00 g) and sodium borohydride (2.89 g) were dissolved in tetrahydrofuran (50 ml). Boron trifluoride diethyl ether (12.00 g) was added at -10 °C, and the mixture was stirred 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 [MH] - .

[0822] Following the preparation method of compound 47 in 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 Example 47, intermediate 47C was replaced with intermediate 56E to obtain crude compound 56.

[0824] The crude compound 56 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (33 / 67), eluent containing 0.1% ammonia) to obtain compound 56 (40 mg). MS (ESI): m / z 420.1693 [M+H] + .

[0825] 1H NMR(500MHz,DMSO-d6)δ11.90(s,1H),8.99(s,1H),7.58-7.38(m,3H),7.30(d ,J=8.6Hz,1H),6.94(d,J=7.8Hz,1H),5.71(s,1H),4.99(q,J=7.2,6.1Hz,1H), 4.29(s,2H),3.58(h,J=7.0Hz,1H),3.07(q,J=8.7Hz,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 Example 14, the intermediate 6-bromo-N-methylpyridine-3-amine was replaced with 3-amino-6-bromo-2-chloropyridine to obtain crude compound 57.

[0829] The crude compound 57 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (32 / 68), eluent containing 0.1% ammonia) to obtain compound 57 (9 mg). MS (ESI): m / z 447.1904 [M+H] + .

[0830] 1 H NMR (500MHz, DMSO-d6): δ11.89(s,1H),9.64(s,1H),9.44(s,1H),7.67(d,J=8.7Hz ,1H),7.28(d,J=8.7Hz,1H),6.93(d,J=7.7Hz,1H),6.03(s,1H),5.08-4.91(m,1H) ,3.58(h,J=6.8Hz,1H),3.05(p,J=8.7,8.3Hz,1H),2.46(q,J=7.2Hz,1H),2.02(m, 1H),1.89(m,2H),1.78-1.55(m,3H),1.03(d,J=6.8Hz,6H),0.78(d,J=6.1Hz,4H).

[0831] Example 58: Preparation of Compound 58

[0832]

[0833] Referring to the preparation method of compound 16 in Example 16, the methylamine hydrochloride was replaced with 2-benzyl-1-ethylamine, the 4-bromo-3-fluorobenzenesulfonyl chloride was replaced with 4-bromo-2-fluorobenzenesulfonyl chloride, and the intermediate K1 was replaced with K, to obtain crude intermediate 58C.

[0834] The crude intermediate 58C was separated into product 58C (150 mg) by column chromatography (developing solvent: dichloromethane / methanol). MS (ESI): m / z 560.29 [M+H] + .

[0835] Under hydrogen atmosphere, palladium on carbon (5% palladium content, 50% water content (w / w), 70 mg) and intermediate 58C (150 mg) were reacted in methanol (10 mL) at room temperature with stirring. After the reaction was complete, the mixture was filtered, concentrated, and purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 58 (23 mg). MS (ESI): m / z 470.29 [M+H] + .

[0836] 1 H NMR(500MHz,DMSO-d6)δ11.98(s,1H),8.67(s,1H),8.17(s,1H),7.59-7.38(m,2H),7.35(s, 1H),6.93(d,J=7.8Hz,1H),5.83(s,1H),5.00(s,1H),4.66(s,1H),3.58(q,J=8.5,7.7Hz,1H ),3.36(t,J=6.4Hz,2H),3.13-2.99(m,1H),2.76(t,J=6.3Hz,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=6.6Hz,6H).

[0837] Example 59: Preparation of compound 59

[0838]

[0839] Referring to the preparation method of compound 26 in Example 26, the 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide was replaced with ((4-bromophenyl)imino)dimethyl-λ 6 - Cyclic sulfone, yielding crude compound 59.

[0840] The crude compound 59 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (34 / 66), eluent containing 0.1% ammonia) to obtain compound 59 (8 mg). MS (ESI, [M+H)) + )m / z:420.2058.

[0841] 1 H NMR(500MHz,DMSO-d6)δ11.56(s,1H),7.92(s,1H),7.14-7.13(m,2H),6.95-6.94(m,1H),6.7 7-6.75(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=6.85Hz,6H).

[0843] Example 60: Preparation of Compound 60

[0844]

[0845] Following the preparation method of compound 22 in Example 22, the 1-N-methanesulfonyl-4-piperidinone was replaced with tert-butyl 4-oxoperidinyl-1-carboxylate to obtain 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 reacted in dichloromethane (20 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction solution 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 reacted in dichloromethane (10 mL) with stirring at room temperature. The solvent was removed from the reaction solution 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 Example 47, intermediate 47C was replaced with intermediate 60D to obtain crude compound 60.

[0849] The crude compound 60 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (32 / 68), eluent containing 0.1% ammonia) to obtain compound 60 (8 mg). MS (ESI, [M+H)) + )m / z:480.2387.

[0850] 1 H NMR(500MHz,DMSO-d6)δ11.12(s,1H),8.31(s,1H),7.76(s,1H),6.91(d,J =7.6Hz,1H),5.22(s,1H),4.94(m,2H),3.91(s,3H),3.60-3.53(m,1H),3.3 8-3.35(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 iodophenyl ester (1.7 g), and cyanamide (0.4 g) were reacted in dichloromethane (30 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and intermediate 61A (1.1 g) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). 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 solution was filtered, concentrated, and 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 50 mL solution of dichloromethane containing 1.2 g of 61B. The mixture was stirred at room temperature until complete. After the reaction was finished, the solvent was removed from the reaction solution under reduced pressure, and the intermediate 61C (1.5 g) was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). MS (ESI): m / z 329.99 [MH] - .

[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 reacted in dioxane (40 mL) under nitrogen protection with stirring at 100 °C. After the reaction was complete, the mixture 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 reacted in 1.0 M hydrochloric acid aqueous solution (10 mL) with stirring at 100 °C. 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 removed from the filtrate under reduced pressure. The filtrate was purified by preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to give compound 61 (100 mg). MS (ESI): m / z 406.25 [M+H] + .

[0858] 1 H NMR (500MHz, DMSO-d6) δ11.90(s,1H),8.92(s,1H),7.74–7.63(m,2H),7.42(d,J=7. 8Hz,2H),6.94(d,J=7.8Hz,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=1.1Hz,3H),2.48–2.43(m,1H),2.05–1.99(m,1 H),1.96–1.84(m,1H),1.75–1.69(m,2H),1.64–1.60(m,1H),1.03(d,J=6.8Hz,6H).

[0859] Example 62: Preparation of compound 62

[0860]

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

[0862] The crude compound 62 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 62 (40 mg). MS (ESI): m / z 432.24 [M+H] + .

[0863] 1 H NMR(500MHz,DMSO-d6)δ11.89(s,1H),8.91(s,1H),7.64(d,J=8.6Hz,2H),7.41(d,J=8.5Hz,2H),6 .94(d,J=7.8Hz,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=6.4Hz,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-pyrazole-5-yl)carbamate (2.00 g), triethylamine (1.70 g), and bis(2,5-dioxopyrrolidine-1-yl) carbonate (4.30 g) were reacted in acetonitrile (20 mL) with stirring at 40 °C. After the reaction was complete, the solvent was removed by vacuum distillation, and the mixture was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to give intermediate 63A (1.73 g). MS (ESI): m / z 499.32 [M+H] + .

[0867] N,N-diisopropylethylamine (1.02 g), 1,1,1-trifluoropropyl-2-amine (0.36 g), and intermediate 63A (1.00 g) were reacted in dichloromethane (20 mL) with stirring at 35 °C. After the reaction was complete, the mixture 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) and palladium on carbon (5% palladium content, 50% water content (w / w), 0.34 g) were reacted in tetrahydrofuran (8 mL) and ethyl acetate (8 mL) under a hydrogen atmosphere with stirring at room temperature. After the reaction was complete, the mixture was filtered and concentrated to give 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), and potassium phosphate (0.44 g) were added to N,N-dimethylformamide (10 mL). After addition, the reaction was stirred at 110 °C under nitrogen protection. The reaction was completed, filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to give intermediate 63D (0.23 g). MS (ESI): m / z 529.28 [M+H] + .

[0870] Intermediate 63D (0.23 g) was reacted in ethanol (2 mL) and dilute hydrochloric acid (1 N, 20 mL) under microwave stirring at 100 °C. After the reaction was complete, the solvent was removed from the reaction solution 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 separated by column chromatography (developing solvent: dichloromethane / methanol) to obtain intermediate 63E (70 mg). MS (ESI): m / z 473.14 [M+H] + .

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

[0872] 1H NMR(500MHz,DMSO-d6)δ11.75(s,1H),8.47(s,1H),7.82(d,J=8.95Hz,1H),7.4 0(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,1 H),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 H NMR(500MHz,DMSO-d6)δ11.75(s,1H),8.47(s,1H),7.82(d,J=8.95Hz,1H),7.4 0(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,1 H),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] Following the preparation method of compound 33 in Example 33, 4-bromo-2-fluorobenzenesulfonyl chloride was replaced with 4-bromobenzenesulfonyl chloride to prepare compound 65 (35 mg). MS (ESI): m / z 408.1709 [M+H] + .

[0878] 1H NMR(500MHz,DMSO-d6)δ11.86(s,1H),8.85(s,1H),7.61-7.59(m,2H),7.39(d, J=8.40Hz,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=6.40Hz,6H).

[0879] Example 66: Preparation of Compound 66

[0880]

[0881] Following the preparation method of compound 33 in Example 33, 4-bromo-2-fluorobenzenesulfonyl chloride was replaced with 4-bromo-2-trifluoromethylbenzenesulfonyl chloride to prepare compound 66 (35 mg). MS (ESI): m / z 476.1585 [M+H] + .

[0882] 1 H NMR(500MHz,DMSO-d6)δ12.03(s,1H),9.28(s,1H),8.00(s,1H),7.93(d,J=8.90H z,1H),7.58-7.57(m,1H),7.30(s,2H),6.93(d,J=7.15Hz,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=6.45Hz,6H).

[0883] Example 67: Preparation of Compound 67

[0884]

[0885] Referring to the preparation method of compound 48 in Example 48, 1-methylcyclopropane-1-amine hydrochloride was replaced with cyclopropylamine to obtain crude compound 67.

[0886] The crude compound 67 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 67 (20 mg). MS (ESI): m / z 417.1596 [M+H] + .

[0887] 1 H NMR(500MHz,DMSO-d6)δ11.72(s,1H),8.46(s,1H),7.40(s,1H),7.21(d,J= 9.8Hz,2H),7.13(d,J=8.4Hz,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 Example 1, 1A was replaced with 6-chloro-N-cyclopropylpyridine-3-sulfonamide to obtain crude compound 68 of Example 68.

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

[0892] 1H NMR (500MHz, DMSO-d6) δ12.02(s,1H),9.85(s,1H),8.46(d,J=2.5Hz,1H),7.83(dd,J=8.9,2.5Hz,1 H),7.70(s,1H),7.34(s,1H),6.93(d,J=7.8Hz,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=6.9,2.8Hz,6H),0.57–0.42(m,2H),0.38–0.35(m,2H).

[0893] Example 69: Preparation of Compound 69

[0894]

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

[0896] 1 H NMR(500MHz,DMSO-d6)δ12.05(s,1H),9.93(s,1H),8.41(d,J=1.30Hz,1H),7.82(dd ,J=2.15,8.90Hz,1H),7.35(s,1H),6.93(d,J=6.85Hz,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] Referring to the preparation method of compound 61 in Example 61, the 4-bromoanisole was replaced with 4-bromo-2-fluoro-1-methylthiobenzene to obtain the crude product of compound 70 in Example 70.

[0900] The crude compound 70 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 70 (80 mg) of Example 70. MS (ESI): m / z 424.23 [M+H] + .

[0901] 1 H NMR(500MHz,DMSO-d6)δ11.98(s,1H),9.20(s,1H),7.61(t,J=8.7Hz,1H),7.44(d,J =13.7Hz,1H),7.07(d,J=8.8Hz,1H),6.94(d,J=7.8Hz,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 reacted in dichloromethane (20 mL) with stirring in an ice bath. The reaction was completed, and the mixture was concentrated to give intermediate 71A (1.90 g).

[0905] Intermediate 71A (1.80 g), N,N-diisopropylethylamine (2.93 g), and methanesulfonic anhydride (3.95 g) were reacted in dichloromethane (20 mL) with stirring at room temperature. After the reaction was complete, the mixture was concentrated and separated by column chromatography (eluent: petroleum ether / ethyl acetate) to give intermediate 71B (2.0 g). MS (ESI): m / z 315.97 [MH] - .

[0906] Intermediate 71B (0.46 g), intermediate K (0.3 g), methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene][2'-amino-1,1'-biphenyl]palladium(II)dichloromethane adduct (0.18 g), and cesium carbonate (0.95 g) were reacted in dioxane (20 mL) under nitrogen protection at 110 °C with stirring. 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 sodium carbonate aqueous solution (10 mL) were added to 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 reacted in ethanol (1 mL) and dilute hydrochloric acid (1 N, 15 mL) under microwave stirring at 100 °C. After the reaction was complete, the solvent was removed by vacuum distillation. The residue was adjusted to alkaline pH with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (developing solvent: dichloromethane / methanol) to obtain intermediate 71 (100 mg). MS (ESI): m / z 488.1787 [M+H] + .

[0909] 1 H NMR(500MHz,DMSO-d6)δ11.83(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=7.10Hz,6H).

[0910] Example 72: Preparation of Compound 72

[0911]

[0912] Following the preparation method of compound 1 in Example 1, but replacing 1A with 4-bromobenzonitrile, compound 72 (60 mg) was obtained. MS (ESI): m / z 354.1923 [M+H] + .

[0913] 1 H NMR(500MHz,DMSO-d6)δ11.96(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, the 4-bromoanisole was replaced with 1-bromo-3-chloro-4-(methylthio)benzene to obtain crude compound 73.

[0917] The crude compound 73 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 73 (50 mg) of Example 73. MS (ESI): m / z 440.15 [M+H] + .

[0918] 1H NMR(500MHz,DMSO-d6)δ11.98(s,1H),9.15(s,1H),7.85(d,J=8.8Hz,1H),7.71(s,1H),7 .31-7.22(m,1H),6.94(d,J=7.8Hz,1H),5.68(s,1H),5.00(s,1H),4.20(s,1H),3.62-3. 55(m,1H),3.13(d,J=1.2Hz,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=6.6,2.2Hz,6H).

[0919] Example 74: Preparation of Compound 74

[0920]

[0921] 5-Bromo-2-nitrobenzaldehyde (3.00 g) and diethylaminosulfur trifluoride (3.15 g) were reacted in dichloromethane (20 mL) with stirring in an ice bath. The reaction was completed, and the mixture was concentrated to give intermediate 74A (3.00 g).

[0922] Intermediate 74A (3.00 g), zinc powder (3.89 g), and ammonium chloride (3.82 g) were added to methanol (30 mL). After addition, the mixture was stirred at room temperature. The reaction was completed, 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 added to dichloromethane (20 mL). After addition, the mixture was stirred at room temperature. The reaction was completed, concentrated, and separated by column chromatography (eluent: petroleum ether / ethyl acetate) to give 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 added to dioxane (20 mL). After addition, the mixture was stirred at 100 °C under nitrogen protection. The reaction was completed, filtered, concentrated, and separated by column chromatography (eluent: dichloromethane / methanol) to obtain intermediate 74D (0.30 g).

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

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

[0927] 1 H NMR(500MHz,DMSO-d6)δ11.83(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=6.25Hz,6H).

[0928] Example 75: Preparation of Compound 75

[0929]

[0930] Referring to the preparation method of compound 26 in Example 26, the 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 crude compound 75.

[0931] The crude compound 75 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 75 (60 mg) of Example 75. MS (ESI): m / z 419.23 [M+H] + .

[0932] 1 H NMR(500MHz,DMSO-d6)δ11.82(s,1H),8.82(s,1H),7.93(s,1H),7.38(dd,J=8.5,2.2Hz,1H), 7.29(d,J=8.5Hz,1H),6.95(d,J=7.8Hz,1H),5.61(s,1H),5.10-4.80(m,1H),3.64-3.54(m,1 H),3.52(t,J=6.8Hz,2H),3.20(t,J=6.8Hz,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=6.5Hz,6H).

[0933] Example 76: Preparation of Compound 76

[0934]

[0935] Referring to the preparation method of compound 26 in Example 26, the 5-bromo-1,3-dihydrobenzo[c]thiophene-2,2-dioxide was replaced with 5-bromo-6-fluoro-1,3-dihydrobenzo[c]thiobenzene-2,2-dioxide to obtain crude compound 76.

[0936] The crude compound 76 was purified by medium-low pressure preparative liquid chromatography (C18 column, acetonitrile / water (30 / 70), eluent containing 0.1% ammonia) to obtain compound 76 (110 mg) of Example 76. MS (ESI, [M+H)) was then used to purify the crude compound 76. + )m / z:437.1662.

[0937] 1 H NMR(500MHz,DMSO-d6)δ11.80(s,1H),8.22(s,1H),8.10(d,J=8.10Hz,1H),7.16(d, J=11.70Hz,1H),6.93(d,J=7.80Hz,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 Example 48, 1-methylcyclopropane-1-amine hydrochloride was replaced with isopropylamine hydrochloride-d7 to obtain intermediate 77B.

[0941] Following the preparation method of compound 52 in Example 52, intermediate K was replaced with intermediate 77B to obtain compound 77 (80 mg). MS (ESI): m / z 450.1821 [M+H] + .

[0942] 1 H NMR(500MHz,DMSO-d6)δ12.09(s,1H),10.08(s,1H),8.03(d,J=8.75Hz,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] Following the preparation method of compound 26 in Example 26, intermediate K was replaced with intermediate 77B to obtain compound 78 (40 mg). MS (ESI): m / z 426.2284 [M+H] + .

[0946] 1 H NMR(500MHz,DMSO-d6)δ11.72(s,1H),8.46(s,1H),7.41(s,1H),7.22(d,J= 7.95Hz,1H),7.14(d,J=8.40Hz,1H),6.92(d,J=7.95Hz,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] Following the preparation method of compound 13 in Example 13, the intermediate 2-bromopyridine was replaced 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(500MHz,DMSO-d6)δ12.15–12.01(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 vacuum distillation, and intermediate 80A (100 mg) was obtained by column chromatography (evolving solvent: dichloromethane / methanol). MS (ESI): m / z 411.29 [M+H] + .

[0954] Following the preparation method of compound 79 in Example 79, intermediate 79A was replaced with 80A to obtain compound 80 (30 mg) of Example 80. MS (ESI): m / z 355.1882 [M+H] + .

[0955] 1H NMR(500MHz,DMSO-d6)δ8.37(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,4.7Hz,1H),1.03(t,6H).

[0956] Experimental Example 1: In vitro kinase inhibitory activity

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

[0958] CDK2 / CycA2 kinase solution (0.078 ng / µl) was added to each well at a rate of 6 µL. Different compounds dissolved in DMSO were added to the wells using a nanoparticle pipette to achieve a final concentration of 1000 nM - 0.244 nM. Two replicates were used, and a control was included. The mixture was incubated for 30 minutes. ATP (50 µM or 5000 µM) and Ultra-Myelin Basic Protein Peptide substrate (PerkinElmer, 0.25 µM) were mixed 1:1 and added to each well at a rate of 4 µL. After reacting at room temperature for 2 hours, 5 µL of EDTA was added to terminate the reaction, followed by 5 µL of detection antibody (PerkinElmer, 8 nM). The mixture was incubated at room temperature for 1 hour. Detection was performed using a PerkinElmer Envision multi-mode microplate reader (excitation 320 nm, emission 615 nm / 665 nm). The IC50 was calculated using a four-parameter fitting method. 50 .

[0959] 1.2 Assay of CDK2 CycE1 kinase inhibitory activity

[0960] CDK2 CycE1 kinase solution (0.015 ng / μL) was added to each well at a rate of 6 μL. Different compounds dissolved in DMSO were added to the wells using a nanoparticle pipette to achieve a final concentration of 300 nM–0.07 nM. Two replicates were used, and a control was included. The above system was incubated for 30 minutes. ATP (50 μM or 5000 μM) and Ultra-Myelin Basic Protein Peptide substrate (PerkinElmer, 0.25 μM) were mixed 1:1 and added to each well at a rate of 4 μL. After reacting at room temperature for 2 hours, 5 μL of EDTA was added to terminate the reaction, followed by 5 μL of detection antibody (PerkinElmer, 8 nM). The mixture was incubated at room temperature for 1 hour. Detection was performed using a PerkinElmer Envision multi-mode microplate reader (excitation 320 nm, emission 615 nm / 665 nm). A four-parameter fitting method was used to calculate the IC50. 50 .

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

[0962] Table 1: Inhibitory activity of compounds against CDK2 CycA2 and CDK2 CycE1 kinases

[0963]

[0964]

[0965]

[0966]

Claims

1. The compound represented by formula (II), its stereoisomers, or its pharmaceutically acceptable salts, in, Ring A is selected from a benzene ring and a 5-membered heteroalkane ring. The 5-membered heteroalkane ring is a saturated cyclic group composed of 5 ring atoms. One ring atom of the 5-membered heteroalkane ring is a heteroatom selected from S, and the rest are carbon atoms, wherein the sulfur heteroatom is oxidized to S(O). p p is 2, and the 5-membered benzo[a]cyclopentaane ring is optionally surrounded by 1, 2, or 3 R[a] ions. a replace; L 1 and L 2 Each is independently selected from a single bond; R 1 Selected from H or C 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. d replace; Each R a Each is independently selected from halogens, OH, CN, NH2, =O, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently surrounded by 1, 2, or 3 R groups. x replace; Each R d Each is independently selected from halogens, OH, CN, or NH2; Each R x Each is independently selected from halogens, OH, CN, or NH2; Carbon atoms marked with "*" are chiral carbon atoms, existing as a single enantiomer (R) or (S) or enriched with one enantiomer.

2. The compound of formula (I) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein R 1 Selected from H or methyl.

3. The compound of formula (I) according to claim 2, its stereoisomers or pharmaceutically acceptable salts thereof, wherein R 1 Selected from H.

4. The compound of formula (I) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein each R a Each is independently selected from F, Cl, Br, I, =O or C. 1-3 Alkyl, the C 1-3 Alkyl groups are optionally and independently surrounded by 1, 2, or 3 R's. x replace.

5. The compound of formula (I) according to claim 4, its stereoisomers or pharmaceutically acceptable salts thereof, wherein each R a Each is independently selected from F, =O, or methyl, and the methyl group is optionally and independently substituted with 1, 2, or 3 halogens.

6. The compound of formula (I) according to claim 5, its stereoisomers or pharmaceutically acceptable salts thereof, wherein each R a Each is independently selected from F, =O, methyl, or trifluoromethyl.

7. The compound of formula (I) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein each R d Each is independently selected from F, Cl, Br, I or OH.

8. The compound of formula (I) according to claim 7, its stereoisomers or pharmaceutically acceptable salts thereof, wherein each R d Each is independently selected from F or OH.

9. The compound of formula (I) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein each R x Each is independently selected from halogens.

10. The compound of formula (I) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein ring A is selected from a benzene ring and a 5-membered heteroalkyl ring, the 5-membered heteroalkyl ring being a saturated cyclic group consisting of 5 ring atoms, one ring atom of the 5-membered heteroalkyl ring being a heteroatom selected from S, and the remainder being carbon atoms, wherein the sulfur heteroatom is oxidized to S(O). p p is 2.

11. The compound of formula (II) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, selected from the compound of formula (II-1), in, Rings A and R 1 L 1 and L 2 As defined in any one of claims 1-10.

12. Compounds of the following formula, their stereoisomers, or pharmaceutically acceptable salts thereof, 13. A compound of the following formula, its stereoisomer, or a pharmaceutically acceptable salt thereof, having the following structure:

14. A pharmaceutical composition comprising a therapeutically or preventively effective amount of any one of the compounds of claims 1-13, its stereoisomers, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

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