Methionine adenosyltransferase 2A inhibitors for the treatment of MTAP-deficient cancers

Abstract

Disclosed is a methionine adenosyltransferase 2A inhibitor represented by formula (I), its preparation method, pharmaceutical composition containing same, and medical use thereof. The compound has excellent MAT2A inhibitory activity. [Formula 1] JPEG2025503186000414.jpg44133

Description

[Technical field]

[0001] The present application relates to compounds for the treatment of cancer, in particular to methionine adenosyltransferase 2A inhibitors, their preparation methods, pharmaceutical compositions containing them, and medical uses thereof. [Background technology]

[0002] Methionine adenosyltransferase (MAT), also known as S-adenosylmethionine synthetase, has a primary biological function of catalyzing the reaction between methionine and ATP to generate the biological methyl donor S-adenosylmethionine (SAM, AdoMet, or SAMe); the MAT-catalyzed reaction is considered to be a critical, rate-limiting step in the methionine metabolic cycle.

[0003] The MAT family includes three family members: MAT1A, MAT2A, and MAT2B. Among them, MAT1A is specifically expressed in human liver, while MAT2A and MAT2B are widely distributed in multiple human tissues. In normal hepatocytes, there is a dynamic balance between MAT1A and MAT2A, which jointly maintain the intracellular SAM homeostasis, whereas in hepatocellular carcinoma (HCC), the expression of MAT1A is abnormally downregulated, whereas the expression of MAT2A is abnormally upregulated. Such gene expression, which is converted from MAT1A to MAT2A, promotes cancer invasion and metastasis, and is closely associated with increased metastasis and poor recurrence-free survival (RFS) in HCC patients. See, for example, Ruizhi Wang et al., Molecular Carcinogenesis 57(9)(2018)1201-1212. In addition to hepatocellular carcinoma, abnormally elevated expression levels of MAT2A are also found in various tumors, such as gastric cancer, colorectal cancer, and pancreatic cancer, and are closely related to the development and progression of tumors. MAT2A plays an important role in the pathogenesis of various tumors, and gene silencing of MAT2A can inhibit the proliferation of cancer cells, such as hepatocellular carcinoma cells or gastric cancer cells, and induce apoptosis of the cells. Therefore, MAT2A has become a drug target for antitumor therapy. For example, see T. Li et al., J. Cancer 7 (10) (2016) 1317-1327; T. Zhang et al., Acta Histochemica 115 (2013) 48-55.

[0004] Furthermore, the literature has reported that MAT2A is a synthetic lethal target in MTAP-deficient cancers. MTAP, or methylthioadenosine phosphorylase (S-methyl-5 ’ -thioadenosine phosphorylase (MTA) is widely distributed in normal tissues and converts 5- ’-methylthioribose-1-phosphate (MTRP) and adenine, and this process is a key link in the body's methionine salvage pathway. The gene encoding human MTAP is located in the chromosome 9p21 region. Studies have shown that the frequency of homozygous deletion of the chromosome 9p21 region in all tumors is about 15%, and the frequency of deletion in different types of tumors is different. Types of cancer with a relatively high frequency of MTAP deletion include glioma, mesothelioma, esophageal cancer, bladder cancer, pancreatic cancer, melanoma, non-small cell lung cancer, head and neck cancer, bile duct cancer, esophageal and gastric cancer, osteosarcoma, diffuse brain glioma, gastric cancer, adrenocortical carcinoma, breast cancer, thymic cancer, hepatocellular carcinoma, ovarian cancer, renal cell carcinoma, etc. In addition, K Marjon et al. have reported that methylthioadenosine phosphorylase (S-methyl-5 ’ We found that cancers lacking MTAP (-thioadenosine phosphorylase, MTAP) are more sensitive to targeting the MAT2A / PRMT5 / RIOK1 signaling pathway (Cell Reports Volume 15, Issue 3, 2016, 574-587). The loss of MTAP inhibits the metabolic pathway of MTA, which leads to a large accumulation of MTA in the body, and the accumulation of large amounts of MTA partially inhibits the activity of PRMT5. MAT2A is a key enzyme that produces SAM in cells, and the inhibition of MAT2A activity reduces SAM, which leads to a shortage of substrates for PRMT5. Therefore, in tumor cells lacking MTAP, the inhibition of MAT2A further inhibits the methylation function of PRMT5, which further leads to defects in RNA cleavage, gene expression and chromosomal integrity, thereby inhibiting tumor cell growth.

[0005] MAT2A is abnormally expressed in various human tumors (liver cancer, pancreatic adenocarcinoma, gastric cancer, colon cancer, etc.), and inhibition of MAT2A can selectively reduce the proliferation ability of MTAP-deficient tumor cells, but has a relatively weak effect on normal cells in which MTAP is normally expressed. Therefore, the development of MAT2A inhibitors can be used as an effective tumor therapeutic tool. Summary of the Invention

[0006] The present application provides effective methionine adenosyltransferase 2A inhibitors, methods for their preparation, pharmaceutical compositions containing them, and their medical uses, particularly for the treatment of MTAP-deficient cancers. In one aspect, the present application provides a compound according to formula (I) or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof.

[0007] [ka] In some embodiments, the compound represented by formula (I) above or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharma- ceutically acceptable salts have the structure represented by formula (IA):

[0008] [ka] In some embodiments, the compound represented by formula (I) above or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharma- ceutically acceptable salts have the structure represented by formula (IB1), (IB2), (IB3), (IB4), or (IB5).

[0009] [ka] In some embodiments, the compound represented by formula (I) above or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharma- ceutically acceptable salts have the structure represented by formula (IC1), (IC2), (IC3), (IC4), or (IC5).

[0010] [ka] In some embodiments, the compound represented by formula (I) above or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharma- ceutically acceptable salt thereof optionally has the following structure:

[0011] [ka] In some embodiments, the compound represented by formula (I) above or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharma- ceutically acceptable salt thereof optionally has the following structure:

[0012] [ka] According to another aspect, the present application provides a process for preparing a compound of formula (I) above.

[0013] According to another aspect, the present application provides a composition comprising a therapeutically effective amount of a compound of formula (I) as defined in any one of the preceding claims, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0014] In another aspect, the present application provides the use of a compound of formula (I) as described in any one of the preceding claims or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharma- ceutically acceptable salt thereof, or a composition as described in any one of the preceding claims, in inhibiting methionine adenosyltransferase 2A (MAT2A), wherein the inhibitory effect may be in vitro inhibition or in vivo inhibition.

[0015] According to another aspect, the present application provides the use of a compound of formula (I) as described in any one of the preceding claims or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharma- ceutically acceptable salt thereof, or a composition as described in any one of the preceding claims, in the manufacture of an inhibitor of methionine adenosyltransferase 2A (MAT2A).

[0016] According to another aspect, the present application provides the use of a compound of formula (I) as defined in any one of the preceding claims or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharma- ceutically acceptable salt thereof, or a composition as defined in any one of the preceding claims, in the treatment and / or prevention of cancer, particularly cancer in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted and / or fully dysfunctional.

[0017] In another aspect, the present application provides the use of a compound of formula (I) as defined in any one of the preceding claims or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharma- ceutically acceptable salt thereof, or a composition as defined in any one of the preceding claims, in the manufacture of a medicament for treating and / or preventing cancer, particularly cancer in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted and / or fully functional.

[0018] According to another aspect, the present application provides a method for treating and / or preventing cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) as defined in any one of the preceding claims or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharma- ceutically acceptable salt thereof, or a composition as defined in any one of the preceding claims, including cancers in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted and / or fully functional.

[0019] The methionine adenosyltransferase 2A inhibitor having a novel structure provided by the present application has excellent inhibitory activity. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] In order to better understand the contents of this application, the following definition of terms is provided.

[0021] The "alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 6-methylhexyl, 7-methylhexyl, 8-methylhexyl, 9-methylhexyl, 10-methylhexyl, 11-methylhexyl, 12-methylhexyl, 13-methylhexyl, 14-methylhexyl, 15-methylhexyl, 16-methylhexyl, 17-methylhexyl, 18-methylhexyl, 19-methylhexyl, 20-methylhexyl, 21-methylhexyl, 22-methylhexyl, 23-methylhexyl, 24-methylhexyl, 25-methylhexyl, 26-methylhexyl, 27-methylhexyl, 28-methylhexyl, 29-methylhexyl, 30-methylhexyl, 31-methylhexyl, 32-methylhexyl, 33-methylhexyl, 34-methylhexyl, 35-methylhexyl, 36-methylhexyl, 37-methylhexyl, 38-methylhexyl, 39-methylhexyl, 40-methylhexyl, 41-methylhexyl, 42-methylhexyl, 43-methylhex Examples of such groups include 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. The alkyl groups may be optionally substituted independently with one or more substituents described herein.

[0022] "Alkylene group" refers to a saturated linear or branched aliphatic hydrocarbon group having two residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a linear or branched alkylene group containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. In any case, the alkylene groups may be optionally and independently substituted with one or more substituents described herein.

[0023] An "alkenyl group" refers to an alkyl group having 2 to 8 carbon atoms and at least one unsaturated site (i.e., a carbon-carbon sp 2 "Alkenyl" refers to a linear or branched monovalent hydrocarbon radical having an alkyl group (-C-C-O) and an alkyl group (-D-C-O) bond, of which the alkenyl radical may be optionally substituted independently with one or more substituents described herein, including radicals having "cis" and "trans" orientations (or "E" and "Z" orientations). Examples include, but are not limited to, vinyl radicals (-CH=CH2), allyl radicals (-CH2CH=CH2), and the like.

[0024] "Alkynyl group" refers to a linear or branched monovalent hydrocarbon group having from 2 to 8 carbon atoms and at least one site of unsaturation (i.e., a carbon-carbon sp triple bond), wherein the alkynyl group may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C≡CH), propynyl (propargyl, -CH2C≡CH), and the like.

[0025] The terms "carbocycle" and "cycloalkyl group", as used interchangeably herein, refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl group ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups, and polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups, each of which may be optionally and independently substituted with one or more substituents described herein.

[0026] "Spirocycloalkyl group" refers to a polycyclic group in which 5-20 membered monocyclic rings share one carbon atom (called a spiro atom), and may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups, with monospirocycloalkyl groups and bisspirocycloalkyl groups being preferred. Non-limiting examples of spirocycloalkyl groups are: [ka] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, and in which one or more rings may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings that constitute the group, the group can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, and is preferably bicyclic or tricyclic. Non-limiting examples of fused cycloalkyl groups are: [ka] The term "bridged cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which any two rings share two carbon atoms that are not directly linked, and which may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings that constitute it, the bridged cycloalkyl group can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, and is preferably a bicyclic, tricyclic or tetracyclic group, and more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups are: [ka]

[0027] The cycloalkyl rings include the above cycloalkyl groups (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, in which the ring connected to the parent structure is a cycloalkyl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.

[0028] "Alkoxy" refers to (alkyl)-O-, where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy and butoxy, where the alkoxy groups may be optionally and independently substituted with one or more substituents described herein.

[0029] The terms "heterocycle" and "heterocyclyl group", as used interchangeably herein, refer to a saturated or partially unsaturated monocyclic or polycyclic ring substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with an oxo group (i.e., to form a sulfoxide or sulfone), but not including the -OO-, -OS- or -SS- ring moieties, and the remaining ring atoms being carbon. Preferably, the ring contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms, and more preferably, 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) ring atoms, of which 1 to 3 (e.g., 1, 2 and 3) are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyl groups include spiroheterocyclyl groups, fused heterocyclyl groups, and bridged heterocyclyl groups, which are optionally and independently substituted with one or more substituents described herein.

[0030] "Spiroheterocyclyl group" refers to a 5-20 membered polycyclic heterocyclyl group in which the monocyclic rings share one atom (called a spiro atom), in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6-14 membered, more preferably 7-10 membered (e.g., 7, 8, 9 or 10 membered). Depending on the number of spiro atoms shared between the rings, spiroheterocyclyl groups are divided into monospiroheterocyclyl groups, bisspiroheterocyclyl groups and polyspiroheterocyclyl groups, and are preferably monospiroheterocyclyl groups and bisspiroheterocyclyl groups. Non-limiting examples of spiroheterocyclyl groups are: [ka]

[0031] "Fused heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which each ring in the system shares a pair of adjacent atoms with another ring in the system, and one or more rings may contain one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Depending on the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl groups, and is preferably bicyclic or tricyclic. Non-limiting examples of fused heterocyclyl groups are: [ka]

[0032] The term "bridged heterocyclyl group" refers to a 5-14 membered polycyclic heterocyclyl group in which any two rings share two atoms that are not directly linked, and may contain one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It is preferably 6-14 membered, more preferably 7-10 membered (e.g., 7, 8, 9 or 10 membered). Depending on the number of rings that constitute it, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, and is preferably bicyclic, tricyclic or tetracyclic. Non-limiting examples of bridged heterocyclyl groups are: [ka]

[0033] The heterocyclyl ring includes a heterocyclyl group as described above (such as a monocyclic, spiro heterocyclic, fused heterocyclic, and bridged heterocyclic ring) fused to an aryl group, a heteroaryl group, or a cycloalkyl ring, in which the ring connected to the parent structure is a heterocyclyl group, non-limiting examples of which are: [ka]

[0034] As used interchangeably herein, an "aromatic ring" or an "aryl group" refers to a 6-14 membered all carbon monocyclic or fused polycyclic (fused polycyclic rings are rings which share adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6-10 membered, such as phenyl and naphthyl groups. The aryl ring includes the above aryl rings fused to a heteroaryl group, heterocyclyl group, or cycloalkyl ring, in which the ring connected to the parent structure is an aryl ring, non-limiting examples of which are: [ka]

[0035] wherein the aryl groups are optionally substituted independently with one or more substituents described herein.

[0036] The terms "heteroaryl ring" and "heteroaryl group", as used interchangeably herein, refer to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms selected from oxygen, sulfur, and nitrogen, and 5 to 14 ring atoms. The heteroaryl group is preferably 5- to 10-membered (e.g., 5-, 6-, 7-, 8-, 9-, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl. The heteroaryl ring includes the heteroaryl group fused to an aryl group, heterocyclyl group, or cycloalkyl ring, in which the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which are: [ka]

[0037] wherein the heteroaryl groups may be optionally substituted independently with one or more substituents described herein, and, if substituted, may be substituted at any available point of attachment.

[0038] The above cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups include residues derived by removing one hydrogen atom from a parent ring atom, or by removing two hydrogen atoms from the same or two different parent ring atoms, i.e., "divalent cycloalkyl groups," "divalent heterocyclyl groups," "arylene groups," and "heteroarylene groups."

[0039] "Cycloalkyloxy" refers to a cycloalkyl-O-, where the cycloalkyl group is as defined above, which may be optionally substituted independently with one or more substituents described herein.

[0040] "Heterocyclyloxy group" refers to a heterocyclyl-O- group, where heterocyclyl is as defined above, which may be optionally substituted independently with one or more substituents described herein.

[0041] An "aryloxy group" refers to an aryl-O- group, where aryl is as defined above, which may be optionally substituted independently with one or more substituents described herein.

[0042] A "heteroaryloxy group" refers to a heteroaryl-O-, where heteroaryl is as defined above, which may be optionally substituted independently with one or more substituents described herein.

[0043] The term "sulfonyl group" refers to -SO2-, which may be optionally substituted with a substituent as described herein, such as an alkylsulfonyl group, a cycloalkylsulfonyl group, a heterocyclylsulfonyl group, or an arylsulfonyl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, and the aryl group are as defined above.

[0044] An "alkylthio group" refers to an alkyl-S- group in which the alkyl group is as defined above.

[0045] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0046] A "cyano group" refers to -CN.

[0047] A "hydroxy group" refers to -OH.

[0048] An "oxo group" or "oxo" refers to "=O".

[0049] A "carboxyl group" refers to -C(=O)OH.

[0050] "Amino group" refers to -NH2, optionally substituted with one or more substituents described herein to form, for example, an alkylamino group, a dialkylamino group, a cycloalkylamino group, a heterocyclylamino group, or an arylamino group, wherein the alkyl, cycloalkyl, heterocyclyl, and aryl groups are defined above.

[0051] An "alkylamino group" refers to an RNH- group, where R is an alkyl group as defined above. For example, a C1 to C6 alkylamino group may be a methylamino group, an ethylamino group, and the like.

[0052] A "dialkylamino group" refers to a RR'N- group, in which R and R' are each alkyl groups as defined above. For example, a di(C1-C6)alkylamino group can be a dimethylamino group, a methylethylamino group, and the like.

[0053] A "urea group" refers to a -NH-C(=O)-NH group, optionally substituted with one or more substituents described herein.

[0054] "Acyl group" refers to a "-C(=O)-" group, which is optionally substituted with any substituent to form an alkylacyl group, an alkoxyacyl group, a cycloalkylacyl group, a heterocyclylacyl group, an arylacyl group, an aminoacyl group, etc., such as a C1-C6 alkylacyl group, a C1-C6 alkoxyacyl group, a cycloalkylacyl group having 3-10 ring atoms, a heterocyclylacyl group having 4-10 ring atoms, an arylacyl group having 6-10 ring atoms, etc., in which the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, and the aryl group are as defined above. For example, the C1-C6 alkylacyl group includes, but is not limited to, a formyl group, an acetyl group, and a 3-methylpentanoyl group.

[0055] The compounds of the present disclosure include their isotopic derivatives. The term "isotopic derivative" refers to a compound having a structure according to the present disclosure, which differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure according to the present disclosure, in which hydrogen is replaced by "deuterium" or "tritium" or fluorine is replaced by 18 F-fluorine labeling ( 18 F isotope) or carbon atoms are replaced by 11 C-, 13 C-, or 14 C-rich carbon ( 11 C-, 13 C- or 14 C-carbon label, 11 C-, 13 C- or 14 Compounds in which the hydrogen atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds may be used, for example, as analytical tools or probes in biological measurements, or as imaging tracers for in vivo diagnosis of disease, or as tracers in pharmacodynamic, pharmacokinetic, or receptor studies. The various deuterated forms of compounds according to the present disclosure are those in which each available hydrogen atom connected to a carbon atom is independently replaced with a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds by referring to the relevant literature. Deuterated forms of compounds may be prepared using commercially available deuterated starting materials, or may be synthesized by conventional techniques with deuterated reagents, including, but not limited to, deuterated borane, tritium borane tetrahydrofuran solution, lithium aluminum deuterated hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds can generally retain activity comparable to non-deuterated compounds, and when deuteration is at a certain site, may obtain better metabolic stability and provide some therapeutic advantages.

[0056] "Optionally," "optionally," or "alternatively" means that the subsequently described event or circumstance may, but may not, occur, and the description includes cases where the event or circumstance occurs and cases where it does not. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but may not, be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0057] "Independently" means that at least two groups (or ring systems) that are present in the structure and have the same or similar range of values ​​can have the same or different meanings in a particular case. For example, if X and Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl, then when X is hydrogen, Y can be hydrogen, halogen, hydroxyl, cyano, alkyl or aryl; similarly, when Y is hydrogen, X can be hydrogen, halogen, hydroxyl, cyano, alkyl or aryl.

[0058] "Substituted" refers to one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in a group being independently replaced with a corresponding number of substituents. A person skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0059] The term "therapeutically effective amount" of a drug or pharmacologically active agent refers to a sufficient dose of the drug or agent to produce a desired effect while being non-toxic. The effective amount is determined by the individual and depends on the age and general condition of the recipient, and also on the specific active agent, and the appropriate effective amount for an individual can be determined by one of ordinary skill in the art through routine testing.

[0060] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, and other components such as physiologically / pharmaceutical acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and contribute to the absorption of the active ingredients to further exert biological activity.

[0061] "Pharmaceutical salts" or "acceptable salts" refer to salts of compounds according to the present disclosure, which are safe and effective when used in a mammalian body and have the desired biological activity. The salts may be prepared separately during the final isolation and purification process of the compounds, or by reacting a suitable group with a suitable base or acid. In general, bases for forming pharmaceutical acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonium. In general, acids for forming pharmaceutical acceptable salts include inorganic acids and organic acids.

[0062] "Solvate" refers to a physical association of a compound of the present disclosure with one or more, preferably one to three, organic or inorganic solvent molecules. Such physical associations include hydrogen bonds. In some cases, the solvate will be isolated, for example, when one or more, preferably one to three, solvent molecules are incorporated into the crystal lattice of a crystalline solid. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are known in the art.

[0063] "Hydrate" refers to a substance formed by combining a compound of the present application or a pharma- ceutically acceptable salt thereof with water through non-covalent intermolecular forces. Common hydrates include (but are not limited to) hemihydrate, monohydrate, dihydrate, trihydrate, etc.

[0064] A "prodrug" is one that can be transformed in the body to yield the active drug compound under physiological conditions, for example, by hydrolysis in blood.

[0065] By "pharmacologically acceptable" it is meant that the compounds, materials, compositions and / or dosage forms can be applied in contact with the tissues of a patient without undue toxicity, irritation, allergic response or other problem or complication, within the scope of reasonable medical judgment, and are effective for the desired use, with a reasonable benefit / risk ratio.

[0066] "Stereoisomers" are compounds that have identical chemical structure but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans), atropisomers, etc.

[0067] "Tautomers" are isomers of a compound that differ from one another in proton position and / or electron distribution. Examples of tautomers include, but are not limited to, enol-keto tautomers, imine-enamine tautomers, amide-imidic acid tautomers, amine-imine tautomers, and tautomeric forms of heteroaryl groups that contain ring atoms bonded to the -NH- portion of the ring and the =N- portion of the ring, such as pyrazole, imidazole, benzimidazole, triazole, pyridotriazole, piperidinotriazole, and tetrazole.

[0068] "In vitro" refers to a biological entity, biological process, or biological reaction in an artificial condition outside the body. For example, a cell grown in vitro should be understood to be a cell grown in an extracorporeal environment such as a test tube, a culture disc, or a microtiter plate.

[0069] According to one aspect, the present application provides a compound according to formula (I) or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharma- ceutically acceptable salt thereof, [ka] Among them, w is CR3 or N; X is CR4 or N; y is CR5 or N; z is CR6 or N; v and u are each independently selected from C or N; JPEG2025503186000018.jpg10115 indicates that it may be a single bond or a double bond, R3 and R5 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, sulfonyl, halogen, cycloalkyl, cyano, amino, acyl, hydroxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, and cycloalkyloxy; optionally, R3 can further comprise one or more R 3a and optionally R5 is further substituted with one or more R 5a Each R 3a and R 5a are each independently selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylamino group, a dialkylamino group, a halogen, a sulfonyl group, a cycloalkyl group, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group, a heteroaryloxy group, a cycloalkyloxy group, a heterocyclyl group, and a heterocyclyloxy group, and optionally, R 3a may further include one or more R 3b is replaced by R 5a may further include one or more R 5b Each R 3b and R 5b are each independently selected from an alkyl group, a halogen atom, a hydroxy group, an alkoxy group, an amino group, and a heterocyclyloxy group; R4 and R6 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, sulfonyl, halogen, cycloalkyl, cyano, amino, and acyl; optionally, R4 can further comprise one or more R 4a and R6 is further substituted with one or more R 6a Each R 4a and R 6aare each independently selected from an alkyl group, a halogen, an amino group, an alkylamino group, and a dialkylamino group; R1 is -X1-R7, where X1 is a bond or an alkylene group, and optionally, X1 is one or more X 1a Replaced by each X 1a are each independently selected from halogen, alkyl groups, and cycloalkyl groups, and R7 is selected from cycloalkyl groups, aryl groups, heteroaryl groups, and heterocyclyl groups, of which R7 is optionally selected from one or more R 7a Each R 7a are each selected from an alkyl group, an alkoxy group, a hydroxy group, a sulfonyl group, a halogen atom, a cyano group, an alkenyl group, an alkynyl group, a carboxyl group, an acyl group, an amino group, a cycloalkyl group, an aryl group, a heterocyclyl group, a heteroaryl group, an oxo group, and a urea group, and optionally R 7a may further include one or more R 7b and R 7b are each selected from a halogen, an alkyl group, an alkoxy group, a hydroxy group, an amino group, an alkenyl group, an alkynyl group, an alkylamino group, a dialkylamino group, a sulfonyl group, a heterocyclyl group, and a heteroaryl group; B is selected from a 5-, 6-, or 7-membered aryl or heteroaryl group, of which B is optionally substituted with one or more R2; Each R2 is independently selected from hydrogen, halogen, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkyloxy group, a heterocyclyl group, a heterocyclyloxy group, an aryl group, a heteroaryl group, a heteroaryloxy group, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group; or two adjacent R2 form a 3- to 7-membered carbocyclic ring, a heterocyclic ring, an aryl ring, or a heteroaryl ring, and optionally the R2 or the 3- to 7-membered carbocyclic ring, a heterocyclic ring, an aryl ring, or a heteroaryl ring formed by two adjacent R2 may further include one or more R 2a Each R 2aare each independently selected from halogen, an alkyl group, a heterocyclyl group, a heterocyclyloxy group, an amino group, a heteroaryl group, a cycloalkyl group, an aryl group, an alkylamino group, a dialkylamino group, a hydroxy group, a sulfonyl group, an alkoxy group, a cyano group, an alkenyl group, an acyl group, an alkynyl group, and an oxo group, and optionally, 2a may further include one or more R 2b Each R 2b are each selected from an alkyl group substituted with 0 to 3 halogens, an amino group, an alkylamino group, a dialkylamino group, an alkoxy group substituted with 0 to 3 halogens, a halogen, a hydroxy group, a heterocyclyl group unsubstituted or substituted with an alkyl group, a cyano group, and an oxo group, and are preferably selected from an alkyl group, an amino group, an alkylamino group, a dialkylamino group, an alkoxy group, a halogen, a hydroxy group, and an oxo group.

[0070] In some embodiments, B is a 6-membered heteroaryl group.

[0071] In some embodiments, B is [ka]

[0072] In some embodiments, B is a 5-membered aryl or heteroaryl group.

[0073] In some embodiments, B is a 5-membered heteroaryl group containing at least two heteroatoms selected from N, O, and S.

[0074] In some embodiments, B is optionally substituted with one or more R2, each R2 being independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, and preferably, the above R2 is selected from hydrogen, halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, and more preferably, R2 is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyano group, a methoxy group, and an oxo group.

[0075] In some embodiments, two adjacent R2 form a 5- to 6-membered carbocyclic, heterocyclic or heteroaryl ring, preferably a 5- to 6-membered heterocyclic or heteroaryl ring, more preferably [ka]

[0076] In some embodiments, the ring structure formed by the R2 or two adjacent R2 may further include one or more R 2a Each R 2aare each independently selected from a halogen, a C1-C6 alkyl group, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an amino group, a heteroaryl group having 5 to 10 ring atoms, a cycloalkyl group having 3 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a C1-C6 alkylamino group, a di(C1-C6)alkylamino group, a hydroxy group, a sulfonyl group, a C1-C6 alkoxy group, a cyano group, a C2-C6 alkenyl group, a C2-C6 alkynyl group and an oxo group, and preferably, each R 2a are each independently selected from a halogen, a C1-C4 alkyl group, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an amino group, a heteroaryl group having 5 to 6 ring atoms, a cycloalkyl group having 3 to 6 ring atoms, an aryl group having 6 to 10 ring atoms, a C1-C3 alkylamino group, a di(C1-C3)alkylamino group, a hydroxy group, a sulfonyl group, a C1-C4 alkoxy group, a cyano group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, and an oxo group, and more preferably, each R 2a are each independently selected from the group consisting of methyl, chlorine, fluorine, phenyl, cyclopropyl, oxo, amino, methylamino, dimethylamino, methoxy, hydroxy, pyridyl, pyrazolyl, and pyrimidinyl, and most preferably each R 2a are each independently selected from a methyl group, chlorine, fluorine, phenyl group, cyclopropyl group, oxo group, amino group, methylamino group, dimethylamino group, methoxy group, hydroxy group, pyridyl group and pyrazolyl group.

[0077] In some embodiments, the R 2a may further include one or more R 2b Each R 2bare each selected from a C1-C3 alkyl group substituted with 0 to 3 halogens, a C1-C3 alkoxy group substituted with 0 to 3 halogens, a halogen, a hydroxy group, a 5- to 6-membered heterocyclyl group unsubstituted or substituted with a C1-C3 alkyl group, a cyano group, and an oxo group, preferably a C1-C3 alkyl group, a C1-C3 alkoxy group, a halogen, a hydroxy group, and an oxo group, and more preferably each R 2b are selected from a methoxy group and a methyl group, respectively.

[0078] In some embodiments, each R 2b is a piperazinyl group which is unsubstituted or substituted with an alkyl group, and is preferably a piperazinyl group substituted with a C1 to C3 alkyl group.

[0079] In some embodiments, each R 2b are each selected from a methoxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a difluoromethoxy group, an N-methylpiperazinyl group, and a cyano group.

[0080] In some embodiments, the R3 is selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a heterocyclyl group having 5 to 10 ring atoms, a heterocyclyloxy group having 5 to 10 ring atoms, and a cycloalkyloxy group having 3 to 10 ring atoms, and preferably, the R3 is selected from hydrogen, a C1-C4 alkyl group, a C2- R3 is selected from a C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 alkoxy group, halogen, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, and a cycloalkyloxy group having 3 to 6 ring atoms, and more preferably, R3 is selected from a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, and a piperidinyloxy group.

[0081] In some embodiments, R3 further comprises one or more R 3a Each R 3a are each independently selected from a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a di(C1-C6 alkyl)amino group, a halogen, a sulfonyl group, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 5 to 10 ring atoms, and a heterocyclyloxy group having 5 to 10 ring atoms, and preferably, 3aare each independently selected from a C1-C3 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C3 alkoxy group, a C1-C3 alkylamino group, a di(C1-C3 alkyl)amino group, a halogen, a sulfonyl group, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, and a heterocyclyloxy group having 5 to 6 ring atoms, and more preferably, 3a are each independently selected from a methyl group and a dimethylamino group.

[0082] In some embodiments, the R 3a may further include one or more R 3b Each R 3b are each independently selected from a C1 to C3 alkyl group, a halogen, a hydroxy group, a C1 to C3 alkoxy group, and an amino group.

[0083] In some embodiments, R4 is selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group; preferably, R4 is selected from hydrogen, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 alkoxy group, a C1-C4 alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, and an acyl group; more preferably, R4 is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, fluorine, chlorine, bromine, and a cyano group.

[0084] In some embodiments, R4 further comprises one or more R 4a Each R 4aare each independently selected from a C1-C6 alkyl group, a halogen, an amino group, a C1-C6 alkylamino group, and a di(C1-C6)alkylamino group, and preferably, 4a are each independently selected from a C1 to C3 alkyl group, a halogen, an amino group, a C1 to C3 alkylamino group, and a di(C1 to C3) alkylamino group.

[0085] In some embodiments, R5 is selected from halogen, a cyano group, an amino group, a hydroxy group, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, and a heteroaryl group having 5 to 10 ring atoms; preferably, R5 is selected from halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 4 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms; more preferably, R5 is selected from chlorine, fluorine, bromine, iodine, a cyano group, an ethyl group, an n-propyl group, an isopropyl group, a methyl group, a cyclopropyl group, a methoxy group, and a cyclopropyloxy group.

[0086] In some embodiments, R5 further comprises one or more R 5a Each R 5a are each independently selected from a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and a hydroxy group, and preferably, 5a are each independently selected from a C1 to C6 alkyl group, a halogen atom, a cyano group, and a cycloalkyl group having 3 to 6 ring atoms, and more preferably, 5a are each independently selected from fluorine and a cyano group.

[0087] In some embodiments, R6 is selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group; preferably, R6 is selected from hydrogen, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 alkoxy group, a C1-C4 alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, and an acyl group; more preferably, R6 is selected from hydrogen, fluorine, chlorine, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, a methoxy group, a cyclopropyloxy group, and a cyano group.

[0088] In some embodiments, R6 further comprises one or more R 6a Each R 6a are each independently selected from a C1-C6 alkyl group, a halogen, an amino group, a C1-C6 alkylamino group, and a di(C1-C6)alkylamino group, and preferably, 6a are each independently selected from a C1 to C3 alkyl group, a halogen, an amino group, a C1 to C3 alkylamino group, and a di(C1 to C3) alkylamino group.

[0089] In some embodiments, R1 is -X1-R7, where X1 is a bond or a methylene group.

[0090] In some embodiments, X is one or more X 1a Replaced by each X 1a are each independently selected from a halogen and a C1 to C3 alkyl group, and are preferably a methyl group.

[0091] In some embodiments, R7 is selected from a cycloalkyl group having 4 to 10 ring atoms, an aryl group having 6 to 12 ring atoms, a heteroaryl group having 5 to 12 ring atoms, and a heterocyclyl group having 3 to 12 ring atoms; Preferably, R7 is selected from the following groups:

[0092] [ka] More preferably, R7 is selected from the following groups:

[0093] [ka]

[0094] In some embodiments, R7 is optionally one or more R 7a Each R 7a are each independently selected from an oxo group, a halogen, a C1-C6 alkyl group, a cycloalkyl group having 3 to 10 ring atoms, a C1-C6 alkoxy group, a cycloalkyloxy group having 3 to 6 ring atoms, a cyano group, an amino group, a hydroxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a sulfonyl group, an acyl group, a carboxyl group, a heterocyclyl group having 3 to 12 ring atoms, a heteroaryl group having 5 to 10 ring atoms, and a urea group, and preferably 7a are each independently selected from an oxo group, a halogen, a C1-C4 alkyl group, a cycloalkyl group having 3 to 6 ring atoms, a C1-C4 alkoxy group, a cycloalkyloxy group having 3 to 4 ring atoms, a cyano group, an amino group, a hydroxy group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a sulfonyl group, an acyl group, a carboxyl group, a heterocyclyl group having 3 to 6 ring atoms, a heteroaryl group having 5 to 6 ring atoms, and a urea group, and more preferably, 7a are each independently selected from fluorine, chlorine, bromine, a hydroxyl group, a cyano group, a methoxy group, a methyl group, a cyclopropyloxy group, and a cyclopropyl group, and are most preferably selected from the above R 7a are each independently selected from fluorine, chlorine, bromine, a hydroxy group, a cyano group, a methoxy group, a methyl group, and a cyclopropyloxy group.

[0095] In some embodiments, R 7a may further include one or more R 7b and R 7b are each selected from a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a hydroxy group, an amino group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkylamino group, a di(C1-C6)alkylamino group, a sulfonyl group, a heterocyclyl group having 3 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms, and preferably, each R 7b are each independently selected from a halogen, a C1-C3 alkyl group, a C1-C3 alkoxy group, a hydroxy group, an amino group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C3 alkylamino group, a di(C1-C3)alkylamino group, a sulfonyl group, a heterocyclyl group having 3 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms, more preferably each R 7b are each independently selected from fluorine, chlorine and bromine.

[0096] In some embodiments, when X1 is a methylene group, R7 is not a substituted or unsubstituted aryl group.

[0097] In some embodiments, R1 is selected from the following structures, including the dotted JPEG2025503186000023.jpg12151 represents the bond between R1 and the parent structure. [ka] In some embodiments, w is CR3, x is CR4, and y is CR5, wherein R3, R4, and R5 are as defined in any one of the above embodiments.

[0098] In some embodiments, when y is CR5, said R5 is not hydrogen.

[0099] In some embodiments, any one of the compounds of formula (I) above or stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharma- ceutically acceptable salts thereof, wherein the compound has the structure of formula (IA): [ka] Among them, m is selected from N, O, S, NR9 and CR9; t is selected from N, O, S, NR8 and CR8; q is selected from N, O, S, NR2 and CR2; JPEG2025503186000026.jpg9122 indicates that the bond may be a single bond or a double bond. Wherein w, x, y, z, v, u, R1 or R2 is as defined in any one of the above embodiments.

[0100] In some embodiments, at least two of m, t, q, v, and u are substituted or unsubstituted heteroatoms, and preferably the heteroatoms are N, O, or S.

[0101] In some embodiments, when X1 is a methylene group, R7 is not a substituted or unsubstituted aryl group.

[0102] In some embodiments, w is CR3, x is CR4, and y is CR5, wherein R3, R4, and R5 are as defined in any one of the above embodiments.

[0103] In some embodiments, when y is CR5, said R5 is not hydrogen.

[0104] In some embodiments, any one of the compounds of formula (I) above or stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharma- ceutically acceptable salts thereof, wherein the compound has a structure as shown in formula (IB1), (IB2), (IB3), (IB4), or (IB5): [ka] represents that the bond may be a single bond or a double bond, Wherein w, x, y, z, v, u, m, t, R1 or R2 is as defined in any one of the above embodiments.

[0105] In some embodiments, in formula (IB1), (IB2), (IB4) or (IB5) above, at least one of v, u, m and t is a substituted or unsubstituted heteroatom, preferably, the heteroatom is N, O or S.

[0106] In some embodiments, in the above formula (IB3), at least two of v, u, m, and t are substituted or unsubstituted heteroatoms; preferably, the heteroatoms are N, O, or S.

[0107] In some embodiments, when X1 is a methylene group, R7 is not a substituted or unsubstituted aryl group.

[0108] In some embodiments, w is CR3, x is CR4, and y is CR5, wherein R3, R4, and R5 are as defined in any one of the above embodiments.

[0109] In some embodiments, when y is CR5, said R5 is not hydrogen.

[0110] In some embodiments, any one of the compounds of formula (I) above or stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharma- ceutically acceptable salts thereof, wherein the compound has a structure as shown in formula (IC1), (IC2), (IC3), (IC4), or (IC5): [ka] represents that the bond may be a single bond or a double bond, Wherein w, x, z, v, u, m, t, R1, R2 or R5 is as defined in any one of the above embodiments.

[0111] In some embodiments, in formula (IC1), (IC2), (IC4) or (IC5), at least one of v, u, m and t is a substituted or unsubstituted heteroatom, preferably, the heteroatom is N, O or S.

[0112] In some embodiments, in formula (IC3), at least two of v, u, m, and t are substituted or unsubstituted heteroatoms; preferably, the heteroatoms are N, O, or S.

[0113] In some embodiments, when X1 is a methylene group, R7 is not a substituted or unsubstituted aryl group.

[0114] In some embodiments, w is CR3 and x is CR4, wherein R3, R4 are as defined in any one of the above embodiments.

[0115] In some embodiments, any one of the compounds of formula (I) above or stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharma- ceutically acceptable salts thereof, wherein ring B of the compound is selected from the following structures: [ka]

[0116] In some embodiments, the compound of any one of the above formula (I) or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharma- ceutically acceptable salts, wherein the compound is selected from the following structures: [ka] Preferably, the compound is selected from the following structures: [ka] Wherein w, x, z, R1, R2 or R5 is as defined in any one of the above embodiments.

[0117] In some embodiments, when X1 is a methylene group, R7 is not a substituted or unsubstituted aryl group.

[0118] In some embodiments, w is CR3 and x is CR4, wherein R3, R4 are as defined in any one of the above embodiments.

[0119] In some embodiments, R2, R8, and R9 described in any one of the above are each independently selected from hydrogen, halogen, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkyloxy group, a heterocyclyl group, a heterocyclyloxy group, an aryl group, a heteroaryl group, a heteroaryloxy group, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group.

[0120] In some embodiments, R2 according to any one of the above is selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, and preferably, R2 is selected from hydrogen, halogen, C R2 is selected from a 1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, and more preferably, R2 is selected from a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyano group, a methoxy group, and an oxo group.

[0121] In some embodiments, R8 and R9 described in any one of the above are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, and preferably, R8 and R9 described above are each independently selected from hydrogen, halogen, a C1-C4 alkyl group, a C1-C4 aryl ... R8 and R9 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyano, methoxy, oxo, cyclopropyl, tetrahydropyrrolyl, tetrahydrofuranyl, phenyl, and propenyl groups.

[0122] In some embodiments, adjacent R8 and R2 form a 3- to 7-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, preferably a 5- to 6-membered carbocyclic, heterocyclic or heteroaryl ring, more preferably a 5- to 6-membered heterocyclic or heteroaryl ring.

[0123] In some embodiments, adjacent R8 and R9 form a 3- to 7-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, preferably a 5- to 6-membered carbocyclic, heterocyclic or heteroaryl ring, more preferably a 5- to 6-membered heterocyclic or heteroaryl ring, for example, [ka]

[0124] In some embodiments, R2 further comprises one or more R 2a is replaced by.

[0125] In some embodiments, R8 further comprises one or more R 8a is replaced by.

[0126] In some embodiments, R9 further comprises one or more R 9a is replaced by.

[0127] In some embodiments, the ring formed by the adjacent R8 and R2 further comprises one or more R 2a or R 8a is replaced by.

[0128] In some embodiments, the ring formed by the adjacent R8 and R9 further comprises one or more R 9a or R 8a is replaced by.

[0129] In some embodiments, any one of the above R 2a , R 9a or R 8a are each independently selected from a halogen, an alkyl group, a heterocyclyl group, a heterocyclyloxy group, an amino group, a heteroaryl group, an acyl group, a cycloalkyl group, an aryl group, an alkylamino group, a dialkylamino group, a hydroxy group, a sulfonyl group, an alkoxy group, a cyano group, an alkenyl group, an alkynyl group, and an oxo group.

[0130] In some embodiments, each R 2a are each independently selected from a halogen, a C1-C6 alkyl group, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an amino group, a heteroaryl group having 5 to 10 ring atoms, a cycloalkyl group having 3 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a C1-C6 alkylamino group, a di(C1-C6)alkylamino group, a hydroxy group, a sulfonyl group, a C1-C6 alkoxy group, a cyano group, a C2-C6 alkenyl group, a C2-C6 alkynyl group and an oxo group, and preferably, each R 2a are each independently selected from a halogen, a C1-C4 alkyl group, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an amino group, a heteroaryl group having 5 to 6 ring atoms, a cycloalkyl group having 3 to 6 ring atoms, an aryl group having 6 to 10 ring atoms, a C1-C3 alkylamino group, a di(C1-C3)alkylamino group, a hydroxy group, a sulfonyl group, a C1-C4 alkoxy group, a cyano group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, and an oxo group, and more preferably, each R 2a are each independently selected from the group consisting of methyl, chlorine, fluorine, phenyl, cyclopropyl, oxo, amino, methylamino, dimethylamino, methoxy, hydroxy, pyridyl, pyrazolyl, and pyrimidinyl, and most preferably each R 2a are each independently selected from a methyl group, chlorine, fluorine, phenyl group, cyclopropyl group, oxo group, amino group, methylamino group, dimethylamino group, methoxy group, hydroxy group, pyridyl group and pyrazolyl group.

[0131] In some embodiments, the R 8a or R 9aare each independently selected from a halogen, a C1-C6 alkyl group, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an amino group, a heteroaryl group having 5 to 10 ring atoms, a cycloalkyl group having 3 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a C1-C6 alkylamino group, a di(C1-C6)alkylamino group, a hydroxy group, a sulfonyl group, a C1-C6 alkoxy group, a cyano group, a C2-C6 alkenyl group, a C2-C6 alkynyl group and an oxo group, and preferably, each R 8a or R 9a are each independently selected from a halogen, a C1-C4 alkyl group, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an amino group, a heteroaryl group having 5 to 6 ring atoms, a cycloalkyl group having 3 to 6 ring atoms, an aryl group having 6 ring atoms, a C1-C3 alkylamino group, a di(C1-C3)alkylamino group, a hydroxy group, a sulfonyl group, a C1-C4 alkoxy group, a cyano group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, and an oxo group, and more preferably each R 8a or R 9a are each independently selected from the group consisting of methyl, chlorine, fluorine, bromine, phenyl, cyclopropyl, oxo, amino, methylamino, dimethylamino, methoxy, hydroxy, pyridyl, pyrazolyl, sulfonyl, morpholinyl, tetrahydrofuranyl, isoxazolyl, and pyrimidinyl, and most preferably each R 8a or R 9a are each independently selected from a methyl group, chlorine, fluorine, bromine, phenyl group, cyclopropyl group, oxo group, amino group, methylamino group, dimethylamino group, methoxy group, hydroxy group, pyridyl group, pyrazolyl group, sulfonyl group, morpholinyl group, tetrahydrofuranyl group, and isoxazolyl group.

[0132] In some embodiments, the R 2a may further include one or more R 2b is replaced by.

[0133] In some embodiments, the R 8a may further include one or more R 8b is replaced by.

[0134] In some embodiments, the R 9a may further include one or more R 9b is replaced by.

[0135] In some embodiments, each R 2b , R 8b or R 9b are each selected from an alkyl group substituted with 0 to 3 halogens, an alkoxy group substituted with 0 to 3 halogens, a halogen, a hydroxy group, a heterocyclyl group unsubstituted or substituted with an alkyl group, a cyano group, and an oxo group, and are preferably selected from an alkyl group, an alkoxy group, a halogen, a hydroxy group, and an oxo group.

[0136] In some embodiments, each R 2b are each selected from a C1-C3 alkyl group substituted with 0 to 3 halogens, a C1-C3 alkoxy group substituted with 0 to 3 halogens, a halogen, a hydroxy group, a 5- to 6-membered heterocyclyl group unsubstituted or substituted with a C1-C3 alkyl group, a cyano group, and an oxo group, preferably a C1-C3 alkyl group, a C1-C3 alkoxy group, a halogen, a hydroxy group, and an oxo group, and preferably each R 2b are selected from a methoxy group and a methyl group, respectively.

[0137] In some embodiments, the R 8b or R 9b are each independently selected from a C1-C3 alkyl group substituted with 0 to 3 halogens, a C1-C3 alkoxy group substituted with 0 to 3 halogens, a halogen, a hydroxy group, a 5- to 6-membered heterocyclyl group unsubstituted or substituted with a C1-C3 alkyl group, a cyano group, and an oxo group, and are preferably a C1-C3 alkyl group, a C1-C3 alkoxy group, a halogen, a hydroxy group, and an oxo group, and are preferably the above R 8b or R 9bare each independently selected from a methoxy group and a methyl group.

[0138] In some embodiments, the R 8b or R 9b are each independently selected from a methoxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a difluoromethoxy group, an N-methylpiperazinyl group, and a cyano group.

[0139] It should be understood that the compounds of formula (I) described herein or stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharma- ceutically acceptable salts thereof include, for example, formula (IA), (IB1), (IB2), (IB3), (IB4), (IB5), (IC1), (IC2), (IC3), (IC4) or (IC5), or include the structure shown in the formula below:

[0140] [ka] The definition of each of the substituents may optionally be derived from any of the above embodiments or combinations of the above embodiments.

[0141] For example, in one embodiment, the compounds described herein or their stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharma- ceutically acceptable salts, including, among others: R3 is selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a heterocyclyl group having 5 to 10 ring atoms, a heterocyclyloxy group having 5 to 10 ring atoms, and a cycloalkyloxy group having 3 to 10 ring atoms, Optionally, R3 further comprises one or more R 3a Each R 3aare each independently selected from a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a di(C1-C6 alkyl)amino group, a halogen, a sulfonyl group, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 5 to 10 ring atoms, and a heterocyclyloxy group having 5 to 10 ring atoms, Optionally, R 3a may further include one or more R 3b Each R 3b are each independently selected from a C1 to C3 alkyl group, a halogen, a hydroxyl group, a C1 to C3 alkoxy group, and an amino group; R4 is selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group; Optionally, R4 further comprises one or more R 4a Each R 4a are each independently selected from a C1-C6 alkyl group, a halogen, an amino group, a C1-C6 alkylamino group, and a di(C1-C6)alkylamino group; R5 is selected from halogen, a cyano group, an amino group, a hydroxy group, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a cycloalkyl group having 3-10 ring atoms, a cycloalkyloxy group having 3-10 ring atoms, a heterocyclyl group having 4-10 ring atoms, and a heteroaryl group having 5-10 ring atoms; Optionally, R5 further comprises one or more R 5a Each R 5aare each independently selected from a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and a hydroxy group; R6 is selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a sulfonyl group, halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group; Optionally, R6 further comprises one or more R 6a Each R 6a are each independently selected from a C1-C6 alkyl group, a halogen, an amino group, a C1-C6 alkylamino group, and a di(C1-C6)alkylamino group; The above R1 is -X1-R7, where X1 is a bond or a methylene group; Optionally, X1 is one or more X 1a Replaced by each X 1a are each independently selected from a halogen and a C1-C3 alkyl group; R7 is selected from a cycloalkyl group having 4 to 10 ring atoms, an aryl group having 6 to 12 ring atoms, a heteroaryl group having 5 to 12 ring atoms, and a heterocyclyl group having 3 to 12 ring atoms; wherein R7 is optionally one or more R 7a Each R 7a are each independently selected from an oxo group, a halogen, a C1-C6 alkyl group, a cycloalkyl group having 3 to 10 ring atoms, a C1-C6 alkoxy group, a cycloalkyloxy group having 3 to 6 ring atoms, a cyano group, an amino group, a hydroxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a sulfonyl group, an acyl group, a carboxyl group, a heterocyclyl group having 3 to 12 ring atoms, a heteroaryl group having 5 to 10 ring atoms, and a urea group; Optionally, R 7a may further include one or more R 7b and R 7bare each selected from a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a hydroxy group, an amino group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkylamino group, a di(C1-C6)alkylamino group, a sulfonyl group, a heterocyclyl group having 3 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms; Among them, when X1 is a methylene group, R7 is not a substituted or unsubstituted aryl group, R2 is selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group; Optionally, R2 may further comprise one or more R 2a Each R 2a are each independently selected from a halogen, a C1-C6 alkyl group, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an amino group, a heteroaryl group having 5 to 10 ring atoms, a cycloalkyl group having 3 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a C1-C6 alkylamino group, a di(C1-C6)alkylamino group, a hydroxy group, a sulfonyl group, a C1-C6 alkoxy group, a cyano group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and an oxo group; Optionally, R 2a may further include one or more R 2b Each R 2bare each selected from a C1-C3 alkyl group substituted with 0 to 3 halogens, a C1-C3 alkoxy group substituted with 0 to 3 halogens, a halogen, a hydroxy group, a 5- to 6-membered heterocyclyl group unsubstituted or substituted with a C1-C3 alkyl group, a cyano group, and an oxo group, and are preferably a C1-C3 alkyl group, a C1-C3 alkoxy group, a halogen, a hydroxy group, and an oxo group; R8 and R9 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group; or adjacent R8 and R9 form a 5- to 6-membered carbocyclic, heterocyclic, or heteroaryl ring; Optionally, R8 may further comprise one or more R 8a Optionally, R9 is further substituted with one or more R 9a and optionally the carbocyclic, heterocyclic or heteroaryl ring from which the adjacent R8 and R9 are formed may further be substituted with one or more R 8a or R 9a is replaced by Above R 8a or R 9a are each independently selected from a halogen, a C1-C6 alkyl group, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an amino group, a heteroaryl group having 5 to 10 ring atoms, a cycloalkyl group having 3 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a C1-C6 alkylamino group, a di(C1-C6)alkylamino group, a hydroxy group, a sulfonyl group, a C1-C6 alkoxy group, a cyano group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and an oxo group; Optionally, R 8amay further include one or more R 8b and optionally substituted with R 9a may further include one or more R 9b and R 8b or R 9b are each independently selected from a C1-C3 alkyl group substituted with 0 to 3 halogens, a C1-C3 alkoxy group substituted with 0 to 3 halogens, a halogen, a hydroxy group, a 5- to 6-membered heterocyclyl group unsubstituted or substituted with a C1-C3 alkyl group, a cyano group, and an oxo group, and are preferably a C1-C3 alkyl group, a C1-C3 alkoxy group, a halogen, a hydroxy group, and an oxo group.

[0142] In one embodiment, the compounds described herein or their stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharma- ceutically acceptable salts, including any of the compounds described herein, including any of the compounds described herein, including any of the compounds described herein, R3 is selected from hydrogen, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 alkoxy group, a halogen, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, and a cycloalkyloxy group having 3 to 6 ring atoms; Optionally, R3 further comprises one or more R 3a Each R 3a are each independently selected from a C1-C3 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C3 alkoxy group, a C1-C3 alkylamino group, a di(C1-C3 alkyl)amino group, a halogen, a sulfonyl group, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, and a heterocyclyloxy group having 5 to 6 ring atoms, Optionally, R 3a may further include one or more R 3b Each R 3b are each independently selected from a C1 to C3 alkyl group, a halogen, a hydroxyl group, a C1 to C3 alkoxy group, and an amino group; R4 is selected from hydrogen, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 alkoxy group, a C1-C4 alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, and an acyl group; Optionally, R4 further comprises one or more R 4a Each R 4a are each independently selected from a C1-C3 alkyl group, a halogen, an amino group, a C1-C3 alkylamino group, and a di(C1-C3)alkylamino group; R5 is selected from halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 4 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms; Optionally, R5 further comprises one or more R 5a Each R 5a are each independently selected from a C1 to C6 alkyl group, a halogen, a cyano group, and a cycloalkyl group having 3 to 6 ring atoms; R6 is selected from hydrogen, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 alkoxy group, a C1-C4 alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, and an acyl group; Optionally, R6 further comprises one or more R 6a Each R 6a are each independently selected from a C1-C3 alkyl group, a halogen, an amino group, a C1-C3 alkylamino group, and a di(C1-C3)alkylamino group; The above R1 is -X1-R7, where X1 is a bond or a methylene group; Optionally, X1 is one or more X 1a is replaced by X 1a is a methyl group, The R7 is selected from the following groups: [ka] Preferably, R7 is selected from the following groups: [ka] wherein R7 is optionally one or more R 7a Each R 7a are each independently selected from an oxo group, a halogen, a C1-C4 alkyl group, a cycloalkyl group having 3 to 6 ring atoms, a C1-C4 alkoxy group, a cycloalkyloxy group having 3 to 4 ring atoms, a cyano group, an amino group, a hydroxy group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a sulfonyl group, an acyl group, a carboxyl group, a heterocyclyl group having 3 to 6 ring atoms, a heteroaryl group having 5 to 6 ring atoms, and a urea group; Optionally, R 7a may further include one or more R 7b and R 7b are each independently selected from a halogen, a C1-C3 alkyl group, a C1-C3 alkoxy group, a hydroxy group, an amino group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C3 alkylamino group, a di(C1-C3)alkylamino group, a sulfonyl group, a heterocyclyl group having 3 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms; Among them, when X1 is a methylene group, R7 is not a substituted or unsubstituted aryl group, R2 is selected from hydrogen, halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group; Optionally, R2 may further comprise one or more R 2a Each R 2a are each independently selected from a halogen, a C1-C4 alkyl group, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an amino group, a heteroaryl group having 5 to 6 ring atoms, a cycloalkyl group having 3 to 6 ring atoms, an aryl group having 6 to 10 ring atoms, a C1-C3 alkylamino group, a di(C1-C3)alkylamino group, a hydroxy group, a sulfonyl group, a C1-C4 alkoxy group, a cyano group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, and an oxo group; Optionally, R 2a may further include one or more R 2b Each R 2b are each selected from a methoxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a difluoromethoxy group, an N-methylpiperazinyl group, and a cyano group, and are preferably a methoxy group or a methyl group, R8 and R9 are each independently selected from hydrogen, halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an aryl group having 6 ring atoms, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group; or adjacent R8 and R9 form a 5- to 6-membered heterocycle or heteroaryl ring, Optionally, R8 may further comprise one or more R 8a Optionally, R9 is further substituted with one or more R 9a and optionally the heterocyclic or heteroaryl ring from which the adjacent R8 and R9 are formed may further be substituted with one or more R 8a or R 9a is replaced by Above R 8a or R 9a are each independently selected from a halogen, a C1-C4 alkyl group, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an amino group, a heteroaryl group having 5 to 6 ring atoms, a cycloalkyl group having 3 to 6 ring atoms, an aryl group having 6 ring atoms, a C1-C3 alkylamino group, a di(C1-C3)alkylamino group, a hydroxy group, a sulfonyl group, a C1-C4 alkoxy group, a cyano group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, and an oxo group; Optionally, R 8a may further include one or more R 8b and optionally substituted with R 9a may further include one or more R 9b and R 8b or R 9bare each independently selected from a methoxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a difluoromethoxy group, an N-methylpiperazinyl group, and a cyano group, and are preferably a methoxy group or a methyl group.

[0143] In one embodiment, the compounds described herein or their stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharma- ceutically acceptable salts, including any of the compounds described herein, including any of the compounds described herein, including any of the compounds described herein, R3 is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, and a piperidinyloxy group; Optionally, R3 further comprises one or more R 3a Each R 3a are each independently selected from a methyl group and a dimethylamino group; Optionally, R 3a may further include one or more R 3b Each R 3b are each independently selected from a C1 to C3 alkyl group, a halogen, a hydroxyl group, a C1 to C3 alkoxy group, and an amino group; R4 is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a fluorine group, a chlorine group, a bromine group, and a cyano group; Optionally, R4 further comprises one or more R 4a Each R 4a are each independently selected from a C1-C3 alkyl group, a halogen, an amino group, a C1-C3 alkylamino group, and a di(C1-C3)alkylamino group; R5 is selected from chlorine, fluorine, bromine, iodine, a cyano group, an ethyl group, an n-propyl group, an isopropyl group, a methyl group, a cyclopropyl group, a methoxy group, and a cyclopropyloxy group; Optionally, R5 further comprises one or more R 5a Each R 5a are each independently selected from fluorine and a cyano group; R6 is selected from hydrogen, fluorine, chlorine, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, a methoxy group, a cyclopropyloxy group, and a cyano group; Optionally, R6 further comprises one or more R 6a Each R 6a are each independently selected from a C1-C3 alkyl group, a halogen, an amino group, a C1-C3 alkylamino group, and a di(C1-C3)alkylamino group; The above R1 is -X1-R7, where X1 is a bond or a methylene group; Optionally, X1 is one or more X 1a is replaced by X 1a is a methyl group, The R7 is selected from the following groups: [ka] Preferably, R7 is selected from the following groups: [ka] wherein R7 is optionally one or more R 7a Each R 7a are each independently selected from fluorine, chlorine, bromine, a hydroxy group, a cyano group, a methoxy group, a methyl group, a cyclopropyloxy group, and a cyclopropyl group, and are preferably selected from fluorine, chlorine, bromine, a hydroxy group, a cyano group, a methoxy group, a methyl group, and a cyclopropyloxy group; Optionally, R 7a may further include one or more R 7b and R 7b are selected from fluorine, chlorine, and bromine, Among them, when X1 is a methylene group, R7 is not a substituted or unsubstituted aryl group, R2 is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyano group, a methoxy group, and an oxo group; Optionally, R2 may further comprise one or more R 2a Each R2a are each independently selected from a methyl group, chlorine, fluorine, phenyl group, cyclopropyl group, oxo group, amino group, methylamino group, dimethylamino group, methoxy group, hydroxy group, pyridyl group, pyrazolyl group, and pyrimidinyl group, and are preferably selected from a methyl group, chlorine, fluorine, phenyl group, cyclopropyl group, oxo group, amino group, methylamino group, dimethylamino group, methoxy group, hydroxy group, pyridyl group, and pyrazolyl group; Optionally, R 2a may further include one or more R 2b Each R 2b are each selected from a methoxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a difluoromethoxy group, an N-methylpiperazinyl group, and a cyano group, and are preferably a methoxy group or a methyl group, The above R8 and R9 are each independently selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyano group, a methoxy group, an oxo group, a cyclopropyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a phenyl group, and a propenyl group, or adjacent R8 and R9 are [ka] Optionally, R8 may further comprise one or more R 8a Optionally, R9 is further substituted with one or more R 9a and optionally, the ring formed by the adjacent R8 and R9 may further be substituted with one or more R 8a or R 9a is replaced by Above R 8a or R 9a are each independently selected from a methyl group, a chlorine group, a fluorine group, a bromine group, a phenyl group, a cyclopropyl group, an oxo group, an amino group, a methylamino group, a dimethylamino group, a methoxy group, a hydroxy group, a pyridyl group, a pyrazolyl group, a sulfonyl group, a morpholinyl group, a tetrahydrofuranyl group, an isoxazolyl group, and a pyrimidinyl group, and preferably each R 8a or R 9aare each independently selected from a methyl group, a chlorine group, a fluorine group, a bromine group, a phenyl group, a cyclopropyl group, an oxo group, an amino group, a methylamino group, a dimethylamino group, a methoxy group, a hydroxy group, a pyridyl group, a pyrazolyl group, a sulfonyl group, a morpholinyl group, a tetrahydrofuranyl group, and an isoxazolyl group; Optionally, R 8a may further include one or more R 8b and optionally substituted with R 9a may further include one or more R 9b and R 8b or R 9b are each independently selected from a methoxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a difluoromethoxy group, an N-methylpiperazinyl group, and a cyano group, and are preferably a methoxy group or a methyl group.

[0144] The present application provides a compound of formula (I) or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharma- ceutically acceptable salt thereof, said compound optionally having the structure:

[0145] [ka] In some embodiments, w is CR3, and R3 is selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a heterocyclyl group having 5 to 10 ring atoms, a heterocyclyloxy group having 5 to 10 ring atoms, and a cycloalkyloxy group having 3 to 10 ring atoms, and preferably, R3 is hydrogen, a C1-C4 alkyl group, , a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 alkoxy group, halogen, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, and a cycloalkyloxy group having 3 to 6 ring atoms, more preferably, R3 is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, and a piperidinyloxy group, Optionally, R3 further comprises one or more R 3a Each R 3a are each independently selected from a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a di(C1-C6 alkyl)amino group, a halogen, a sulfonyl group, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 5 to 10 ring atoms, and a heterocyclyloxy group having 5 to 10 ring atoms, and preferably, 3aare each independently selected from a C1-C3 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C3 alkoxy group, a C1-C3 alkylamino group, a di(C1-C3 alkyl)amino group, a halogen, a sulfonyl group, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, and a heterocyclyloxy group having 5 to 6 ring atoms, and more preferably, 3a are each independently selected from a methyl group and a dimethylamino group; Optionally, R 3a may further include one or more R 3b Each R 3b are each independently selected from a C1 to C3 alkyl group, a halogen, a hydroxy group, a C1 to C3 alkoxy group, and an amino group.

[0146] In some embodiments, x is CR4, and R4 is selected from a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group; preferably, R4 is selected from a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 alkoxy group, a C1-C4 alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, and an acyl group; more preferably, R4 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a fluorine group, a chlorine group, a bromine group, and a cyano group; Optionally, R4 further comprises one or more R 4a Each R 4a are each independently selected from a C1-C6 alkyl group, a halogen, an amino group, a C1-C6 alkylamino group, and a di(C1-C6)alkylamino group, and preferably, 4aare each independently selected from a C1 to C3 alkyl group, a halogen, an amino group, a C1 to C3 alkylamino group, and a di(C1 to C3) alkylamino group.

[0147] In some embodiments, the R5 is selected from a halogen, a cyano group, an amino group, a hydroxy group, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, and a heteroaryl group having 5 to 10 ring atoms; preferably, the R5 is selected from a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 4 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms; more preferably, the R5 is selected from chlorine, fluorine, bromine, iodine, a cyano group, an ethyl group, an n-propyl group, an isopropyl group, a methyl group, a cyclopropyl group, a methoxy group, and a cyclopropyloxy group; Optionally, R5 further comprises one or more R 5a Each R 5a are each independently selected from a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and a hydroxy group, and preferably, 5a are each independently selected from a C1 to C6 alkyl group, a halogen atom, a cyano group, and a cycloalkyl group having 3 to 6 ring atoms, and more preferably, 5a are each independently selected from fluorine and a cyano group.

[0148] In some embodiments, z is CR6 or N, Among them, R6 is selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group, preferably, the above R6 is selected from hydrogen, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 alkoxy group, a C1-C4 alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, and an acyl group, more preferably, the above R6 is selected from hydrogen, fluorine, chlorine, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, a methoxy group, a cyclopropyloxy group, and a cyano group, Optionally, R6 further comprises one or more R 6a Each R 6a are each independently selected from a C1-C6 alkyl group, a halogen, an amino group, a C1-C6 alkylamino group, and a di(C1-C6)alkylamino group, and preferably, 6a are each independently selected from a C1 to C3 alkyl group, a halogen, an amino group, a C1 to C3 alkylamino group, and a di(C1 to C3) alkylamino group.

[0149] In some embodiments, R1 is -X1-R7, where X1 is a bond or a methylene group; Optionally, X1 is one or more X 1a Replaced by each X 1a are each independently selected from halogen and a C1 to C3 alkyl group, and are preferably a methyl group; R7 is selected from a cycloalkyl group having 4 to 10 ring atoms, an aryl group having 6 to 12 ring atoms, a heteroaryl group having 5 to 12 ring atoms, and a heterocyclyl group having 3 to 12 ring atoms; Preferably, R7 is selected from the following groups: [ka] More preferably, R7 is selected from the following groups: [ka] wherein R7 is optionally one or more R 7a Each R 7a are each independently selected from an oxo group, a halogen, a C1-C6 alkyl group, a cycloalkyl group having 3 to 10 ring atoms, a C1-C6 alkoxy group, a cycloalkyloxy group having 3 to 6 ring atoms, a cyano group, an amino group, a hydroxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a sulfonyl group, an acyl group, a carboxyl group, a heterocyclyl group having 3 to 12 ring atoms, a heteroaryl group having 5 to 10 ring atoms, and a urea group, and preferably 7a are each independently selected from an oxo group, a halogen, a C1-C4 alkyl group, a cycloalkyl group having 3 to 6 ring atoms, a C1-C4 alkoxy group, a cycloalkyloxy group having 3 to 4 ring atoms, a cyano group, an amino group, a hydroxy group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a sulfonyl group, an acyl group, a carboxyl group, a heterocyclyl group having 3 to 6 ring atoms, a heteroaryl group having 5 to 6 ring atoms, and a urea group, and more preferably, 7a are each independently selected from fluorine, chlorine, bromine, a hydroxyl group, a cyano group, a methoxy group, a methyl group, a cyclopropyloxy group, and a cyclopropyl group; Optionally, R 7a may further include one or more R 7b and R 7b are each selected from a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a hydroxy group, an amino group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkylamino group, a di(C1-C6)alkylamino group, a sulfonyl group, a heterocyclyl group having 3 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms, and preferably, each R 7bare each independently selected from a halogen, a C1-C3 alkyl group, a C1-C3 alkoxy group, a hydroxy group, an amino group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C3 alkylamino group, a di(C1-C3)alkylamino group, a sulfonyl group, a heterocyclyl group having 3 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms, more preferably each R 7b are each independently selected from fluorine, chlorine and bromine; Among them, when X1 is a methylene group, R7 is not a substituted or unsubstituted aryl group.

[0150] In some embodiments, R8 and R9 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group; or adjacent R8 and R9 form a 5- to 6-membered carbocyclic, heterocyclic, or heteroaryl ring, and preferably, R8 and R9 are each independently selected from hydrogen, halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2- or adjacent R8 and R9 are selected from a C4 alkenyl group, a C2-C4 alkynyl group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an aryl group having 6 ring atoms, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group; or adjacent R8 and R9 form a 5- to 6-membered heterocycle or heteroaryl ring, and more preferably, the above R8 and R9 are each independently selected from a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyano group, a methoxy group, an oxo group, a cyclopropyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a phenyl group, and a propenyl group; or adjacent R8 and R9 are [ka] Forming Optionally, R8 may further comprise one or more R 8a Optionally, R9 is further substituted with one or more R 9a and optionally the carbocyclic, heterocyclic or heteroaryl ring from which the adjacent R8 and R9 are formed may further be substituted with one or more R 8a or R9a is replaced by Above R 8a or R 9a are each independently selected from a halogen, a C1-C6 alkyl group, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an amino group, a heteroaryl group having 5 to 10 ring atoms, a cycloalkyl group having 3 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a C1-C6 alkylamino group, a di(C1-C6)alkylamino group, a hydroxy group, a sulfonyl group, a C1-C6 alkoxy group, a cyano group, a C2-C6 alkenyl group, a C2-C6 alkynyl group and an oxo group, and preferably, each R 8a or R 9a are each independently selected from a halogen, a C1-C4 alkyl group, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an amino group, a heteroaryl group having 5 to 6 ring atoms, a cycloalkyl group having 3 to 6 ring atoms, an aryl group having 6 ring atoms, a C1-C3 alkylamino group, a di(C1-C3)alkylamino group, a hydroxy group, a sulfonyl group, a C1-C4 alkoxy group, a cyano group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, and an oxo group, and more preferably each R 8a or R 9a are each independently selected from a methyl group, a chlorine group, a fluorine group, a bromine group, a phenyl group, a cyclopropyl group, an oxo group, an amino group, a methylamino group, a dimethylamino group, a methoxy group, a hydroxy group, a pyridyl group, a pyrazolyl group, a sulfonyl group, a morpholinyl group, a tetrahydrofuranyl group, an isoxazolyl group, and a pyrimidinyl group; Optionally, R 8a may further include one or more R 8b and optionally substituted with R 9a may further include one or more R 9b and R 8b or R 9bare each independently selected from a C1-C3 alkyl group substituted with 0 to 3 halogens, a C1-C3 alkoxy group substituted with 0 to 3 halogens, a halogen, a hydroxy group, a 5- to 6-membered heterocyclyl group unsubstituted or substituted with a C1-C3 alkyl group, a cyano group, and an oxo group, and are preferably a C1-C3 alkyl group, a C1-C3 alkoxy group, a halogen, a hydroxy group, and an oxo group, and are preferably the above R 8b or R 9b are each independently selected from a methoxy group and a methyl group.

[0151] In another aspect, the present application provides a compound according to formula (I) or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharma- ceutically acceptable salt thereof, said compound having the structure:

[0152] [Table 1] JPEG2025503186000044.jpg200134JPEG2025503186000045.jpg190135JPEG202 5503186000046.jpg197137JPEG2025503186000047.jpg211133JPEG2025503186 000048.jpg208137JPEG2025503186000049.jpg204139JPEG2025503186000050. jpg195132JPEG2025503186000051.jpg207134JPEG2025503186000052.jpg20313 4JPEG2025503186000053.jpg193136JPEG2025503186000054.jpg211135JPEG20 25503186000055.jpg196140JPEG2025503186000056.jpg211138JPEG2025503186 000057.jpg211140JPEG2025503186000058.jpg192136JPEG2025503186000059. jpg210139JPEG2025503186000060.jpg210136JPEG2025503186000061.jpg97137

[0153] In another aspect, the present application provides a method for preparing an exemplary compound, comprising the following pathway or steps:

[0154] Route 1: [ka] In this case, R is an alkyl group.

[0155] Route 2: [ka] In this, X is a halogen, R is a hydrogen or an alkyl group, and M is a boric acid, a borate ester, or a metal.

[0156] According to another aspect, the present application provides a composition comprising a therapeutically effective amount of a compound of formula (I) as defined in any one of the preceding claims, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0157] In another aspect, the present application provides the use of a compound of formula (I) as described in any one of the preceding claims or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharma- ceutically acceptable salt thereof, or a composition as described in any one of the preceding claims, in inhibiting methionine adenosyltransferase 2A (MAT2A), wherein the inhibitory effect may be in vitro inhibition or in vivo inhibition.

[0158] According to another aspect, the present application provides the use of a compound of formula (I) as described in any one of the preceding claims or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharma- ceutically acceptable salt thereof, or a composition as described in any one of the preceding claims, in the manufacture of an inhibitor of methionine adenosyltransferase 2A (MAT2A).

[0159] According to another aspect, the present application provides the use of a compound of formula (I) as defined in any one of the preceding claims or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharma- ceutically acceptable salt thereof, or a composition as defined in any one of the preceding claims, in the treatment and / or prevention of cancer, particularly cancer in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted and / or fully functional, including, but not limited to, colon cancer.

[0160] In another aspect, the present application provides the use of a compound of formula (I) as defined in any one of the preceding claims or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharma- ceutically acceptable salt thereof, or a composition as defined in any one of the preceding claims, in the manufacture of a medicament for treating and / or preventing cancer, particularly cancer in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted and / or fully functional.

[0161] According to another aspect, the present application provides a method for treating and / or preventing cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) as defined in any one of the preceding claims or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharma- ceutically acceptable salt thereof, or a composition as defined in any one of the preceding claims, including cancers in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted and / or fully functional.

[0162] Example 1: Synthesis of Compound B2 [ka] Synthesis of intermediate B2-2: Under a nitrogen gas atmosphere, B2-1 (2 g, 13.19 mmol) and pyridine (1.36 g, 17.15 mmol) were dissolved in ethyl ether (40 mL), and ethyl chloroglyoxylate (2.16 g, 15.83 mmol) was added at 0° C. and stirred for 2 hours. The resulting yellow precipitate was filtered off, washed with water, and dried to obtain a yellow solid (1.5 g, 45%).

[0163] Synthesis of intermediate B2-3: In a nitrogen gas atmosphere, B2-2 (1.0 g, 3.97 mmol), ethylhydrazine hydrochloride (0.50 g, 5.16 mmol) and acetic acid (2.38 g, 39.7 mmol) were dispersed in ethanol (20 mL), heated to 100°C, and reacted for 24 hours with stirring. The mixture was cooled to room temperature, concentrated under reduced pressure, and separated by column chromatography to obtain a brown solid B2-3 (0.3 g, 30.5%).

[0164] Synthesis of product B2: In a nitrogen gas atmosphere, B2-3 (0.2 g, 0.81 mmol), iodobenzene (0.20 g, 0.97 mmol), cuprous iodide (0.031 g, 0.16 mmol), 8-hydroxyquinoline (0.047 g, 0.32 mmol), and potassium phosphate (0.34 g, 1.62 mmol) were dispersed in DMF (10 mL), heated to 110 °C, and reacted for 18 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed twice with saturated ammonium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary dried and purified by column chromatography and preparative thin layer chromatography to obtain a pale pink solid B2 (0.07 g, 27%).

[0165] Example 2: Synthesis of Compound B3 [ka] Following the similar synthetic route as in Example 1, in step 3, 3-iodopyridine was substituted for iodobenzene, and potassium tert-butoxide was substituted for potassium phosphate, to obtain compound B3.

[0166] Example 3: Synthesis of Compound B4 [ka] Following the similar synthetic route as in Example 1, in step 3, 3-fluoroiodobenzene was substituted for iodobenzene, and potassium tert-butoxide was substituted for potassium phosphate, to obtain compound B4.

[0167] Example 4: Synthesis of Compound B5 [ka] Following the similar synthetic route as in Example 1, in step 3, 4-fluoroiodobenzene was substituted for iodobenzene, and potassium tert-butoxide was substituted for potassium phosphate, to obtain compound B5.

[0168] Example 5: Synthesis of Compound B6 [ka] Following the similar synthetic route as in Example 1, in step 3, 2-iodopyrazine was substituted for iodobenzene, and potassium tert-butoxide was substituted for potassium phosphate, to obtain compound B6.

[0169] Example 6: Synthesis of Compound B7 [ka] Following the similar synthetic route as in Example 1, in step 3, 2-iodopyrimidine was substituted for iodobenzene, and potassium tert-butoxide was substituted for potassium phosphate, to obtain compound B7.

[0170] Example 7: Synthesis of Compound B8 [ka] Synthesis of intermediate B8-1 In a nitrogen gas atmosphere, B2-3 (100 mg, 0.40 mmol), 3-methoxyiodobenzene (377.9 mg, 1.61 mmol), cuprous iodide (76.71 mg, 0.40 mmol), 8-hydroxyquinoline (29.03 mg, 0.20 mmol) and potassium tert-butoxide (112.21 mg, 1.01 mmol) were dispersed in DMSO (15 mL) and heated to 135°C and reacted overnight. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was rotary evaporated and purified by column chromatography and preparative thin layer chromatography to obtain a brown solid B8-1 (96.5 mg, 68%).

[0171] Synthesis of product B8: B8-1 (60 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL), and 1.0 M boron tribromide in dichloromethane (0.5 mL, 0.5 mmol) was added dropwise at -78°C under nitrogen gas atmosphere, and the mixture was allowed to react for 3 hours. The mixture was quenched by adding 1 mL of methanol, extracted three times with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary dried, purified by preparative HPLC, and separated to give white solid B8 (32.4 mg, 56%).

[0172] Example 8: Synthesis of Compound B9 [ka] Following the similar synthetic route as in Example 1, in step 3, 3-iodobenzonitrile was substituted for iodobenzene, and potassium tert-butoxide was substituted for potassium phosphate, to obtain compound B9.

[0173] Example 9: Synthesis of Compound B10 [ka] Following the similar synthetic route as in Example 1, in step 3, 4-iodopyridine was substituted for iodobenzene, and potassium tert-butoxide was substituted for potassium phosphate, to obtain compound B10.

[0174] Example 10: Synthesis of Compound B11 [ka] Following the similar synthetic route as in Example 1, in step 3, 4-iodoanisole was substituted for iodobenzene, and potassium tert-butoxide was substituted for potassium phosphate, to obtain compound B11.

[0175] Example 11: Synthesis of Compound B12 [ka] Following the similar synthetic route as in Example 1, in step 2, methylhydrazine sulfate was substituted for ethylhydrazine hydrochloride, and in step 3, 3-iodopyridine was substituted for iodobenzene, to obtain compound B12.

[0176] Example 12: Synthesis of Compound B28 [ka] Following the similar synthetic route as in Example 1, in step 2, p-methoxybenzylhydrazine was substituted for ethylhydrazine hydrochloride, and in step 3, 3-iodopyridine was substituted for iodobenzene, to obtain compound B28.

[0177] Example 13: Synthesis of Compound B13 [ka] Compound B28 (1.0 g, 2.4 mmol) was dissolved in trifluoroacetic acid (20 mL) and reacted at 40° C. for 16 hours with stirring. When the reaction was completed, the reaction solution was concentrated under reduced pressure, adjusted to pH=9 with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL×3), and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane:methanol=20:1) to obtain yellow solid compound B13 (600 mg, 65%).

[0178] Example 14: Synthesis of Compound B14 [ka] Following the similar synthetic route as in Example 1, in step 3, 5-fluoro-3-iodopyridine was substituted for iodobenzene, and potassium tert-butoxide was substituted for potassium phosphate, to obtain compound B14.

[0179] Example 15: Synthesis of Compound B15 [ka] Following the similar synthetic route as in Example 1, in step 3, 3-iodobenzotrifluoride was substituted for iodobenzene, and potassium tert-butoxide was substituted for potassium phosphate, to obtain compound B15.

[0180] Example 16: Synthesis of Compound B16 [ka] According to a synthetic route similar to that of Example 1, in step 1, [ka] In step 2, methylhydrazine sulfate was substituted for ethylhydrazine hydrochloride, and in step 3, 3-iodopyridine was substituted for iodobenzene, and compound B16 was synthesized.

[0181] Example 17: Synthesis of Compound B17 [ka] According to a synthetic route similar to that of Example 1, in step 1, [ka] In step 3, iodobenzene was replaced with 3-iodopyridine to obtain compound B17.

[0182] Example 18: Synthesis of Compound B18 [ka] Synthesis of intermediate B18-2 In a nitrogen gas atmosphere, B18-1 (0.2 g, 1.31 mmol) was dissolved in DMF (2 mL) in an ice-water bath, and a solution of triethylamine (0.15 g, 1.44 mmol) in DMF (1.0 mL) and a solution of di-tert-butyl dicarbonate (0.31 g, 1.44 mmol) in THF (1.5 mL) were gradually added, and the mixture was allowed to warm to room temperature and react overnight. Water was added to dilute the mixture, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary dried and purified by column chromatography to obtain compounds B18-2A (110 mg, 39%) and B18-2B (90 mg, 32%), respectively. B18-2A: 1 H NMR (400 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.45 (s, 1H), 4.61 (s, 2H), 1.68 (s, 9H). B18-2B 1 H NMR (400 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.45 (s, 1H), 4.61 (s, 2H), 1.68 (s, 9H). Synthesis of product B18 In a nitrogen gas atmosphere, B2-3 (100 mg, 0.40 mmol) was dissolved in DMF (3 mL) in an ice-water bath, NaH (20.8 mg, 0.52 mmol, 60% purity) was added, and the mixture was stirred at room temperature for 30 minutes. B18-2A (87 mg, 0.40 mmol) was dissolved in DMF (2 mL) and stirred at room temperature overnight. Water was added to dilute the mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary dried and purified by column chromatography to obtain a pale yellow solid (125 mg, 73%). The obtained solid (100 mg, 0.23 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1.0 mL, 6.71 mmol) was added in an ice-water bath, and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure and purified by preparative HPLC to obtain a white solid (43 mg, 57%).

[0183] Example 19: Synthesis of Compound B19 [ka] According to a synthetic route similar to that of Example 1, in step 1, [ka] In step 3, iodobenzene was replaced with 3-iodopyridine to obtain compound B19.

[0184] Example 20: Synthesis of Compound B20 [ka] Compound B3 (100 mg, 0.31 mmol) and N-chlorosuccinimide (41.04 mg, 0.31 mmol) were added to N-N-dimethylformamide (6 mL), heated to 60°C, and reacted overnight with stirring. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with saturated saline, and the separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to obtain compound B20 (57.6 mg, 52%) as an off-white solid.

[0185] Example 21: Synthesis of Compounds B21 and B22 [ka] Compound B13 (400 mg, 1.35 mmol) and iodoacetonitrile (270 mg, 1.62 mmol) in N,N-dimethylformamide (10 mL) were added with potassium carbonate (465 mg, 3.37 mmol) at room temperature and reacted overnight with stirring at room temperature. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by high-performance liquid preparative chromatography to give white solid compound B21 (4.1 mg, 0.8%) and white solid compound B22 (84.5 mg, 17%), respectively.

[0186] Example 22: Synthesis of Compound B23 [ka] Synthesis of intermediate B23-2: B23-1 (5 g, 32.15 mmol) and 3-aminopyridine (4.13 g, 32.15 mmol) were dissolved in N,N-dimethylformamide (50 mL), potassium tert-butoxide (7.55 g, 67.5 mmol) was added, and the mixture was allowed to react at room temperature for 30 minutes. Water was added, and a solid precipitated. The mixture was filtered under suction, and the filter cake was washed with water, isopropyl alcohol, and isopropyl ether in that order, and then dried to obtain a black solid (4.8 g, 60%).

[0187] Synthesis of intermediate B23-3: To a solution of B23-2 (4.8 g, 19.3 mmol) in acetic acid (50 mL) was added reduced iron powder (5.4 g, 96.4 mmol). The mixture was heated to 80°C and stirred for 2 h. The mixture was cooled to room temperature, adjusted to pH=8 with saturated NaHCO3, and extracted twice with ethyl acetate. The combined organic phase was dried and concentrated under reduced pressure to give B23-3 (4 g, 96%).

[0188] Synthesis of intermediate B23-4: B23-3 (4.0 g, 18.2 mmol) and diethyl oxalate (20 mL) were mixed and heated to reflux overnight and the reaction was monitored for completion by thin layer chromatography. It was cooled to room temperature, filtered, and the filter cake was washed with ethanol and dried to give B23-4 (3 g, 60%).

[0189] Synthesis of intermediate B23-5: B23-4 (1 g, 3.65 mmol) was dissolved in DMF (50 mL), DIPEA (1 g, 7.3 mmol) and POCl3 (1.8 g, 11.68 mmol) were added, and the mixture was heated to 95°C and reacted for 1 hour. The mixture was cooled to room temperature, slowly added to ice water, and extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporated to give a yellow solid B23-5 (800 mg, 74.7%).

[0190] Synthesis of product B23: B23-5 (0.2 g, 0.68 mmol) was dissolved in n-butanol (10 mL), acetohydrazide (0.06 g, 0.81 mmol) was added, and the mixture was heated to 120°C and reacted for 2 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary dried and purified by preparative thin layer chromatography to obtain a white solid B23 (31 mg, 15%).

[0191] Example 23: Synthesis of Compound B29 [ka] Synthesis of intermediate B29-2: B29-1 (500 mg, 2.2 mmol) and 3-aminopyridine (244 mg, 2.6 mmol) were dissolved in N,N-dimethylformamide (10 mL), diisopropylethylamine (568 mg, 4.4 mmol) and HATU (1.2 g, 3.3 mmol) were added, and the mixture was reacted at room temperature for 30 minutes. The mixture was directly spun dry and purified by column chromatography to give B29-2 (450 mg, 70%).

[0192] Synthesis of intermediate B29-3: B29-2 (450 mg, 1.5 mmol) and 2-chloro-6-trifluoromethylpyridine-3-boronic acid (360 mg, 1.6 mmol) were dissolved in 1,4-dioxane (10 mL), and potassium carbonate (621 mg, 4.5 mmol) and Pd(dppf)Cl2 (110 mg, 0.15 mmol) were added. The reaction was carried out at 100 °C for 2 hours under nitrogen gas protection. It was directly rotovapped and purified by column chromatography to give yellow solid B29-3 (150 mg, 25%).

[0193] Synthesis of product B29: B29-3 (100 mg, 0.25 mmol) was dissolved in dimethyl sulfoxide (5 mL), DBU (76 mg, 0.05 mmol) was added, and the mixture was heated to 140° C. and reacted overnight. The reaction solution was separated by reverse phase fractionation to obtain brown solid B29 (23 mg, 25%).

[0194] Example 24: Synthesis of Compound B30 [ka] Following a synthetic route similar to that of Example 23, in step 1, 2-methyl-3-aminopyridine was substituted for 3-aminopyridine, and in step 2, 2-fluoro-4-chlorophenylboronic acid was substituted for 2-chloro-6-trifluoromethylpyridine-3-boronic acid to give compound B30.

[0195] Example 25: Synthesis of Compound B47 [ka] Following a similar synthetic route to Example 1, in step 2, 3-pyridinemethylhydrazine was substituted for ethylhydrazine, and in step 3, 3-iodopyridine was substituted for iodobenzene to give compound B47.

[0196] Example 26: Synthesis of Compound B60 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid; [ka] In step 2, 2-chloro-6-trifluoromethylpyridine-3-phenylboronic acid was replaced with 2-fluoro-4-chlorophenylboronic acid, and Boc was simultaneously eliminated during ring closure in the final step to obtain compound B60.

[0197] Example 27: Synthesis of Compound B72 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid to give compound B72.

[0198] Example 28: Synthesis of compound B139 [ka] Synthesis of intermediate B139-1: Following the preparation method of B29-2 in Example 23, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid to obtain compound B139-1.

[0199] Synthesis of intermediate B139-2: B139-1 (200 mg, 0.7 mmol) and pinacol diborate (220 mg, 0.9 mmol) were dissolved in 1,4-dioxane (2 mL), and potassium acetate (210 mg, 2.1 mmol) and Pd(dppf)Cl2 (52 mg, 0.1 mmol) were added. The mixture was stirred overnight at 100 °C under nitrogen gas protection. It was directly rotary evaporated and purified by column chromatography to give B139-2 (230 mg, 86%) as a brown oil.

[0200] Synthesis of intermediate B139-3: B139-2 (270 mg, 0.82 mmol) and 1-bromo-4-chloro-2,5-difluorobenzene (220 mg, 0.88 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL), and potassium carbonate (350 mg, 2.53 mmol) and Pd(dppf)Cl2 (90 mg, 0.12 mmol) were added. The mixture was stirred overnight at 100 °C under nitrogen gas protection. It was directly rotary evaporated and purified by column chromatography to give B139-3 (140 mg, 98%) as an orange oil.

[0201] Synthesis of product B139: B139-3 (140 mg, 0.40 mmol) was dissolved in N,N-dimethylformamide (5 mL), cesium carbonate (390 mg, 1.20 mmol) was added, and the mixture was heated to 60° C. and stirred for 2 days. The reaction solution was separated by reverse phase fractionation to obtain white solid B139 (46 mg, 34%).

[0202] Example 29: Synthesis of compound B148 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-aminophenol was substituted for 3-aminopyridine to give compound B148.

[0203] Example 30: Synthesis of Compound B171 [ka] Following a synthetic route similar to that of Example 28, in step 2, 1-bromo-4-chloro-2-fluoro-5-methoxybenzene was substituted for 1-bromo-4-chloro-2,5-difluorobenzene to give compound B171.

[0204] Example 31: Synthesis of compound B172 [ka] Following a similar synthetic route to Example 28, in step 2, 2-bromo-5-chloro-1,3-difluorobenzene was substituted for 1-bromo-4-chloro-2,5-difluorobenzene to give compound B172.

[0205] Example 32: Synthesis of compound B176 [ka] Following a similar synthetic route to Example 28, in step 2, 2-bromo-5-chloro-1-fluoro-3-methoxybenzene was substituted for 1-bromo-4-chloro-2,5-difluorobenzene to give compound B176.

[0206] Example 33: Synthesis of compound B178 [ka] Synthesis of intermediate B178-1: Following the procedure for the preparation of B29 in Example 23, 4-bromo-1-p-methoxybenzylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid in step 1 to provide intermediate B178-1.

[0207] Synthesis of product B178: Trifluoroacetic acid (1.5 mL) was slowly added dropwise to a solution of B178-1 (90 mg, 0.18 mmol) in dichloromethane (5 mL) and the mixture was stirred at room temperature overnight. The reaction solution was separated by reverse phase fractionation to give white solid B178 (14 mg, 20%).

[0208] Example 34: Synthesis of Compound B76 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-amino-2-methylpyridine was substituted for 3-aminopyridine to give compound B76.

[0209] Example 35: Synthesis of compounds B179 and B180 [ka] B76 was subjected to chiral resolution (IC-3.0 cm, n-hexane:ethanol=30:70, 25 mL / min, 230 nm) to give B179 (retention time: 8.11 min) and B180 (retention time: 14.98 min).

[0210] Example 36: Synthesis of compound B181 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid; [ka] In the final step, the Boc group was simultaneously eliminated during ring closure to give compound B181.

[0211] Example 37: Synthesis of compound B239 [ka] According to a synthetic route similar to that of Example 33, in step 1, [ka] was substituted for 3-aminopyridine to give compound B239.

[0212] Example 38: Synthesis of compound B245 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-difluoromethylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid; [ka] In the final step, the Boc group was simultaneously eliminated during ring closure to give compound B245.

[0213] Example 39: Synthesis of Compound B250 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-cyclopropylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid; [ka] In the final step, Boc was simultaneously eliminated during ring closure to give compound B250.

[0214] Example 40: Synthesis of compound B254 [ka] Following a synthetic route similar to that of Example 23, in step 1, 5-methyl-4-bromo-1-difluoromethylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid; [ka] In the final step, Boc was simultaneously eliminated during ring closure to give compound B254.

[0215] Example 41: Synthesis of compound B256 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-tritiated methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid; [ka] In the final step, the Boc group was simultaneously eliminated during ring closure to give compound B256.

[0216] Example 42: Synthesis of compound B257 [ka] According to a synthetic route similar to that of Example 28, in step 1, [ka] In the final step, the Boc group was simultaneously eliminated during ring closure to give compound B257.

[0217] Example 43: Synthesis of compound B182 [ka] Following a synthetic route similar to that of Example 23, in step 1, o-chloroaniline was substituted for 3-amino-1-methylpyridine, and 4-bromo-1-methyl-3-carboxypyrazole was substituted for 4-bromo-1-ethyl-3-carboxypyrazole to give compound B182.

[0218] Example 44: Synthesis of compounds B183, B212, and B213 [ka] Following a synthetic route similar to that of Example 23, in step 1, 2-cyclopropyl-3-aminopyridine was substituted for 3-amino-1-methylpyridine, and 4-bromo-1-methyl-3-carboxypyrazole was substituted for 4-bromo-1-ethyl-3-carboxypyrazole to give compound B183.

[0219] B183 was subjected to chiral resolution (REGIS(S,S)WHELK-O1 (250 mm×25 mm, 10 μm), methanol=45%, 70 g / min, 4 min) to give B212 (retention time: 1.97 min) and B213 (retention time: 2.35 min).

[0220] Example 45: Synthesis of Compound B258 [ka] Synthesis of intermediate B258-2: N-bromosuccinimide (3.92 g, 22.04 mmol) was added to a solution of B258-1 (3.0 g, 22.04 mmol) in acetic acid (20 mL). The temperature was raised to 75°C and stirred for 5 hours. The reaction solution was cooled to room temperature and concentrated, and the crude product was separated by column chromatography to obtain a white solid B258-2 (3.5 g, 74%).

[0221] Synthesis of intermediate B258-3: A reaction flask was charged with B258-2 (500 mg, 2.33 mmol), cuprous bromide (280 mg, 2.80 mmol), and acetonitrile (5 mL). tert-Butyl nitrite (720 mg, 6.99 mmol) was added at 0°C and stirred for 4 hours. The reaction solution was diluted with ethyl acetate (50 mL), washed with water (50 mL), and the organic phase was concentrated. The crude product was purified by column chromatography to give the white solid product B258-3 (150 mg, 28%).

[0222] Synthesis of intermediate B258-4: Following a similar synthetic route to B139-2 in Example 28, substituting 1-Boc-4-aminoindazole for 3-aminopyridine, compound B258-4 was obtained.

[0223] Synthesis of intermediate B258-5: A reaction flask was charged with B258-3 (100 mg, 0.43 mmol), B258-4 (150 mg, 0.52 mmol), 1,1 ’ -Bisdiphenylphosphinoferrocenedichloropalladium (31 mg, 0.04 mmol), potassium carbonate (180 mg, 3.90 mmol), 1,4-dioxane (2 mL), and water (0.2 mL) were added. The mixture was stirred at 100° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL), and the organic phase was concentrated. The crude product was purified by column chromatography to give the white solid product B258-5 (100 mg, 59%).

[0224] Synthesis of intermediate B258-6: B258-5 (100 mg, 0.25 mmol), potassium carbonate (96 mg, 0.63 mmol), and N,N-dimethylformamide (1 mL) were added to a reaction flask. The mixture was stirred at 60° C. for 16 hours. The reaction mixture was diluted with dichloromethane (20 mL), washed with water (10 mL), and the organic phase was concentrated to give brown oil B258-6 (70 mg, 74%).

[0225] Synthesis of product B258: To a reaction flask, B258-6 (70 mg, 0.064 mmol), trifluoroacetic acid (0.5 mL), and dichloromethane (1 mL) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL), washed with water (10 mL), and the organic phase was concentrated. The crude product was purified by reverse phase column chromatography to give a white solid, B258 (12 mg, 20%).

[0226] Example 46: Synthesis of Compound B260 [ka] Following a synthetic route similar to that of Example 28, in step 1, N-Boc-4-aminoindazole was substituted for 3-amino-1-methylpyridine, and 4-bromo-1-difluoromethyl-3-carboxypyrazole was substituted for 4-bromo-1-ethyl-3-carboxypyrazole to give compound B260.

[0227] Example 47: Synthesis of Compound B273 [ka] Following a synthetic route similar to that of Example 45, 2-bromo-5-chloro-3-fluoropyridine was substituted for B258-3 to give compound B273.

[0228] Example 48: Synthesis of compound B274 [ka] Synthesis of intermediate B274-2: To a stirred solution of B274-1 (100 mg, 0.5 mmol) in tetrahydrofuran (3 mL), lithium diisopropylamide / tetrahydrofuran (0.5 mL, 1 mmol, 2 mol / L) was added at -78°C, and the mixture was reacted at -78°C for 10 minutes. Iodine (150 mg, 0.6 mmol) was added, and the mixture was allowed to react at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted twice with dichloromethane (10 mL). The organic phases were combined and the solvent was spun to dryness to give the crude product B274-2 (150 mg, 100% yield), which was used directly in the next step.

[0229] Synthesis of product B274: Following a similar synthetic route to Example 45, B274-2 was substituted for B258-3 to give compound B274.

[0230] Example 49: Synthesis of Compounds B332 and B227 [ka] Synthesis of product B332: To a stirred solution of B60 (50 mg, 0.14 mmol) in DMF (1 mL) was added NBS (30 mg, 1.68 mmol). The mixture was allowed to react at room temperature for 1 h. The reaction solution was directly purified by reverse phase column chromatography to give white solid B332 (13 mg, 22%).

[0231] Synthesis of product B227: To a stirred solution of B332 (50 mg, 0.117 mmol) in 1,4-dioxane (1 mL) was added [1,1 ’ -Bis(diphenylphosphino)ferrocene]dichloropalladium (8 mg, 0.01 mmol) and dimethylzinc / toluene solution (0.2 mL, 0.2 mmol, 1 mol / L) were added, and the mixture was heated to 100°C and reacted at room temperature for 3 hours. Water was added to quench the reaction, the solvent was removed by rotary evaporation, and the product was purified by thin layer chromatography to give white solid B227 (6.2 mg, 11%).

[0232] Example 50: Synthesis of Compound B24 [ka] Sodium trifluoromethanesulfonate (274 mg, 2 mmol) was added to a solution of B3 (310 mg, 1 mmol) and TBHP (180 mg, 2 mmol) in DMSO (5 mL). The mixture was heated to 80° C. under nitrogen gas protection and stirred for 72 hours. The temperature was lowered to room temperature, and the reaction solution was directly separated and purified by reverse phase fractionation to give white solid B24 (35 mg, 9%).

[0233] Example 51: Synthesis of Compound B25 [ka] Sodium difluoromethanesulfonate (274 mg, 2 mmol) was added to a solution of B3 (310 mg, 1 mmol) and TBHP (180 mg, 2 mmol) in DMSO (5 mL). The mixture was heated to 80° C. under nitrogen gas protection and stirred for 72 hours. The temperature was lowered to room temperature, and the reaction solution was directly separated and purified by reverse phase fractionation to obtain white solid B25 (15 mg, 4%).

[0234] Example 52: Synthesis of Compound B26 [ka] Following a synthetic route similar to that of Example 50, B12 was substituted for B3 in step 1 to give compound B26.

[0235] Example 53: Synthesis of Compound B27 [ka] Following a similar synthetic route to Example 51, B12 was substituted for B3 in step 1 to give compound B27.

[0236] Example 54: Synthesis of Compound B339 [ka] Following a synthetic route similar to that of Example 28, in step 1, 2-trifluoromethyl-3-aminopyridine was substituted for 3-aminopyridine, and 4-bromo-1-difluoromethyl-3-carboxypyrazole was substituted for 4-bromo-1-methyl-3-carboxypyrazole to give compound B339.

[0237] Example 55: Synthesis of compounds B337, B398, and B399 [ka] Synthesis of compound B337: Following a synthetic route similar to that of Example 28, in step 1, 2-cyclopropyl-3-aminopyridine was substituted for 3-aminopyridine, and 4-bromo-1-difluoromethyl-3-carboxypyrazole was substituted for 4-bromo-1-methyl-3-carboxypyrazole to give compound B337.

[0238] Resolution of products B398 and B399: B337 was subjected to chiral resolution (IB-3.0 cm, n-hexane:ethanol=40:60, 25 mL / min, 214 nm) to give B398 (retention time: 10.2 min) and B399 (retention time: 13.9 min).

[0239] Example 56: Synthesis of Compound B31 [ka] Synthesis of intermediate B31-3: A solution of B31-1 (2.32 g, 10 mmol), B31-2 (1.74 g, 10 mmol), potassium carbonate (4.14 g, 30 mmol) and Pd(dppf)Cl2 (0.73 g, 1 mmol) in dioxane (50 mL) was heated at 100 °C under nitrogen gas protection and stirred for 16 h. After cooling to room temperature, the reaction was directly purified by column chromatography to give brown solid B31-3 (1.2 g, 42%).

[0240] Synthesis of intermediate B31-4 Lithium hydroxide (115 mg, 48 mmol) was added to a mixture of B31-3 (1.13 g, 40 mmol) in tetrahydrofuran (15 mL) / water (20 mL). The mixture was stirred at room temperature for 0.5 hours. After concentrating the reaction solution to dryness, the crude product B31-4 was used directly in the next step.

[0241] Synthesis of intermediate B31-6 To a solution of B31-4 (268 mg, 1 mmol) and B31-5 (122 mg, 1 mmol) in DMF (5 mL), diisopropylethylamine (387 mg, 3 mmol) and HATU (456 mg, 1.2 mmol) were added. The mixture was stirred at 40° C. for 3 hours. The reaction solution was directly purified by column chromatography to give brown oil B31-6 (130 mg, 36%).

[0242] Synthesis of product B31: A mixture of B31-6 (71 mg, 0.2 mmol) and K2CO3 (27 mg, 0.6 mmol) in DMF (3 mL) was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction mixture was directly separated by column chromatography to give white solid B31 (50 mg, 73%).

[0243] Example 57: Synthesis of Compound B32 [ka] Following a synthetic route similar to that of Example 56, in step 3, 2-trifluoromethyl-3-aminopyridine was substituted for 2,4-dimethyl-3-aminopyridine to give compound B32.

[0244] Example 58: Synthesis of Compound B33 [ka] Synthesis of intermediate B33-1: A solution of B31-1 (5.0 g, 21.4 mmol) and Select-F (30.3 g, 85.8 mmol) in acetonitrile (100 mL) was heated to 80° C. under nitrogen gas protection and reacted with stirring for 4 days. The reaction solution was washed with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase was concentrated, and then separated and purified by column chromatography to obtain a white solid B33-1 (1.73 g, 32%).

[0245] Synthesis of product B33: Following a similar synthetic route to Example 56, substituting B33-1 for B31-1 and 3-aminopyridine for 2,4-dimethyl-3-aminopyridine, compound B33 was obtained.

[0246] Example 59: Synthesis of Compound B34 [ka] Following a similar synthetic route to Example 56, in step 1, methyl 4-bromo-2-methyloxazole-5-carboxylate was substituted for B31-1, and in step 3, 3-aminopyridine was substituted for 2,4-dimethyl-3-aminopyridine to give compound B34.

[0247] Example 60: Synthesis of Compound B35 [ka] Following a synthetic route similar to that of Example 56, in step 1, methyl 4-bromo-2-cyclopropylmethyl-5-carboxylate was substituted for B31-1, and in step 3, 3-aminopyridine was substituted for 2,4-dimethyl-3-aminopyridine to give compound B35.

[0248] Example 61: Synthesis of Compounds B36, B37, and B38 [ka] Synthesis of intermediate B36-1: To a solution of B13 (600 mg, 2.02 mmol) and ethyl bromoacetate (405 mg, 2.42 mmol) in DMF (15 mL), potassium carbonate (836 mg, 6.06 mmol) was added and stirred at room temperature for 16 h. The mixture was washed with water, extracted with ethyl acetate, concentrated, and purified by reverse phase separation to give yellow solid B36-1 (200 mg, 19%).

[0249] Synthesis of intermediate B36-2: Lithium hydroxide monohydrate (69 mg, 1.65 mmol) was added to a mixture of B36-1 (210 mg, 0.55 mmol) in tetrahydrofuran (15 mL) / water (2 mL) and stirred at room temperature for 16 hours. The mixture was neutralized with dilute hydrochloric acid (1 M) until it became weakly acidic, and extracted with dichloromethane. After concentrating and drying the organic phase, yellow solid B36-2 (200 mg, 70%) was obtained.

[0250] Synthesis of products B36, B37, B38: To a solution of B36-2 (50 mg, 0.14 mmol), ammonium chloride (11 mg, 0.21 mmol) in DMF (5 mL) was added potassium carbonate (58 mg, 0.42 mmol) and HATU (80 mg, 0.21 mmol). The mixture was stirred at room temperature for 16 h. The mixture was treated with water and extracted with ethyl acetate. The organic phase was concentrated and then purified by reverse phase separation to give white solid B36 (4.0 mg, 6%). Following a similar procedure to the preparation of B36, compounds B37 and B38 were obtained by replacing ammonium chloride with methylamino hydrochloride or dimethylamino hydrochloride, respectively.

[0251] Example 62: Synthesis of Compound B39 [ka] Following a similar synthetic route to Example 1, in step 2, isopropylhydrazine was substituted for ethylhydrazine, and in step 3, 3-iodopyridine was substituted for iodobenzene to give compound B39.

[0252] Example 63: Synthesis of Compounds B40 and B170 [ka] Potassium carbonate (279 mg, 2.02 mmol) was added to a solution of B13 (200 mg, 0.67 mmol) and 1,1-difluoro-2-iodoethane in DMF (8 mL). The mixture was stirred at room temperature for 16 hours, treated with water, and extracted with ethyl acetate. The organic phase was concentrated and then separated by reverse phase fractionation to give white solids B40 (18 mg, 7%) and B170 (69 mg, 27%).

[0253] Example 64: Synthesis of Compound B41 [ka] Following a similar synthetic route to Example 1, in step 2, trifluoroethylhydrazine was substituted for ethylhydrazine, and in step 3, 3-iodopyridine was substituted for iodobenzene to give compound B41.

[0254] Example 65: Synthesis of Compounds B42 and B167 [ka] Following a synthetic route similar to that of Example 63, substituting N,N-dimethyl-3-bromopropylamine for 1,1-difluoro-2-iodoethane in step 2, compounds B42 and B167 were obtained.

[0255] Example 66: Synthesis of Compound B43 [ka] Following a similar synthetic route to Example 63, N,N-dimethyl-2-bromoethylamine was substituted for 1,1-difluoro-2-iodoethane in step 2 to give compound B43.

[0256] Example 67: Synthesis of Compound B46 [ka] Following a similar synthetic route to Example 1, in step 2, hydroxyethylhydrazine was substituted for ethylhydrazine, and in step 3, 3-iodopyridine was substituted for iodobenzene to give compound B46.

[0257] Example 68: Synthesis of Compound B45 [ka] At 0°C, NaH (12 mg, 60%, 0.3 mmol) was added to a DMF solution (15 mL) of B46 (100 mg, 0.3 mmol), and the mixture was stirred at room temperature for 20 minutes. Iodomethane (43 mg, 0.3 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was treated with saturated saline and extracted with ethyl acetate. The organic phase was concentrated and separated by column chromatography to give B45 (38 mg, 30%).

[0258] Example 69: Synthesis of Compounds B48 and B168 [ka] Following a synthetic route similar to that of Example 63, in step 2, 1-methyl-3-methylpyrazole methanesulfonate was substituted for 1,1-difluoro-2-iodoethane to give compound B48 and isomer B168.

[0259] Example 70: Synthesis of Compound B50 [ka] Synthesis of intermediate B50-2: B50-1 (1 g, 7.17 mmol), B31-2 (1.38 g, 7.89 mmol) and sodium carbonate (3 g, 28.68 mmol) were dissolved in a mixture of ethylene glycol dimethyl ether (8 mL) and water (4 mL) with palladium acetate (80 mg, 0.36 mmol) and 2-dicyclohexylphosphino-2 ’ ,6 ’-Dimethoxybiphenyl (29 mg, 0.72 mmol) was added. The reaction solution was stirred at 80° C. for 1 hour under nitrogen gas protection. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and separated by column chromatography to obtain a yellow solid B50-2 (1.2 g, 72%).

[0260] Synthesis of intermediate B50-3: Potassium hydroxide (0.6 g, 10.7 mmol) was added to a suspension of B50-2 (500 mg, 2.14 mmol) in tert-butyl alcohol (20 mL). The mixture was stirred at 120°C for 1.5 hours. After the reaction mixture was cooled to room temperature, 20 mL of water and 6 N hydrochloric acid were added to obtain a suspension, which was filtered and dried in vacuum to obtain a pale yellow solid B50-3 (420 mg, 85%).

[0261] Synthesis of product B50: Copper acetate (0.39 g, 2.16 mmol) was added to a solution of B50-3 (250 mg, 1.08 mmol) and pyridine-3-boronic acid (660 mg, 5.4 mmol) in pyridine (15 mL). The reaction solution was stirred at 100° C. for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and separated by column chromatography to obtain a white solid B50 (7 mg, 2%).

[0262] Example 71: Synthesis of Compound B51 [ka] Following a synthetic route similar to that of Example 56, in step 3, 4-methyl-3-aminopyridine was substituted for 2,4-dimethyl-3-aminopyridine to give compound B51.

[0263] Example 72: Synthesis of Compound B55 [ka] To a mixture of B13 (200 mg, 0.67 mmol) and diethyl bromodifluoromethylphosphate (180 mg, 0.67 mmol) in acetonitrile (10 mL) was added potassium fluoride (78 mg, 1.35 mmol) and stirred at room temperature for 16 h. The reaction was treated with water, extracted with ethyl acetate, and the organic phase was concentrated and separated by reverse phase fractionation to give a yellow solid B55 (46 mg, 18%).

[0264] Example 73: Synthesis of Compound B57 [ka] Following a synthetic route similar to that of Example 56, in step 1, 4-bromo-1-methylpyrazole-3-methylformate was substituted for 4-bromo-1-ethylpyrazole-3-methylformate, and in step 3, 5-aminoindazole was substituted for 2,4-dimethyl-3-aminopyridine to give compound B57.

[0265] Example 74: Synthesis of Compound B58 [ka] Following a synthetic route similar to that of Example 56, in step 1, 4-bromo-1-methylpyrazole-3-methylformate was substituted for 4-bromo-1-ethylpyrazole-3-methylformate, and in step 3, 1-methyl-5-aminopyrazole was substituted for 2,4-dimethyl-3-aminopyridine to give compound B58.

[0266] Example 75: Synthesis of Compound B65 [ka] Following a synthetic route similar to that of Example 56, in step 1, 4-bromo-1-methylpyrazole-3-methylformate was substituted for 4-bromo-1-ethylpyrazole-3-methylformate, and in step 3, 2-methyl-3-aminopyridine was substituted for 2,4-dimethyl-3-aminopyridine to give compound B65.

[0267] Example 76: Synthesis of Compound B68 [ka] Following a synthetic route similar to that of Example 56, in step 1, 4-bromo-1-methylpyrazole-3-methylformate was substituted for 4-bromo-1-ethylpyrazole-3-methylformate, and in step 3, 2-trifluoromethyl-3-aminopyridine was substituted for 2,4-dimethyl-3-aminopyridine to give compound B68.

[0268] Example 77: Synthesis of Compound B69 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-formic acid was substituted for 4-bromo-1-ethylpyrazole-3-formic acid, and in step 2, 2-fluoro-4-trifluoromethylbenzeneboronic acid was substituted for 2-chloro-6-trifluoromethylpyridine-3-boronic acid to give compound B69.

[0269] Example 78: Synthesis of Compound B70 [ka] Synthesis of intermediate B70-1: According to the preparation method of compound B31-3 in Example 56, 4-bromo-1-methylpyrazole-3-methylformate was used instead of 4-bromo-1-ethylpyrazole-3-methylformate to obtain compound B70-1.

[0270] Synthesis of intermediate B70-2: To a solution of B70-1 (300 mg, 1.42 mmol) in toluene (6 mL), water (0.3 mL), potassium phosphate (1.05 g, 4.97 mmol), tricyclohexylphosphine (0.48 M in toluene, 0.295 mL, 0.142 mmol), and palladium acetate (16 mg, 0.071 mmol) were added in that order. The mixture was stirred at 100°C for 4 hours under nitrogen gas protection. After cooling, water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated and separated by column chromatography to give yellow solid B70-2 (211 mg, 86%).

[0271] Synthesis of product B70: Following a synthetic route similar to that of Example 56, B70-2 was substituted for B31-3 and 3-aminopyridine was substituted for B31-5 to give compound B70.

[0272] Example 79: Synthesis of Compound B71 [ka] Synthesis of intermediate B71-2: A mixture of B71-1 (5.0 g, 21 mmol), cyclopropylboronic acid (1.97 g, 23 mmol), Pd(dppf)Cl2 (1.54 g, 2.1 mmol), potassium phosphate (11.1 g, 53 mmol) and tricyclohexylphosphine (1.18 g, 4.2 mmol) in dioxane (100 mL) was heated to 100 °C under nitrogen gas protection and stirred for 17 h. It was treated with water and extracted with ethyl acetate. The organic phase was concentrated and separated by column chromatography to give yellow solid B71-2 (2.52 g, 60%).

[0273] Synthesis of intermediate B71-3: To a solution of B71-2 (2.97 g, 15 mmol) in dichloromethane (60 mL), m-chloroperoxybenzoic acid (5.16 g, 30 mmol) was added and stirred for 17 hours. The reaction mixture was washed with saturated aqueous sodium sulfite solution, concentrated, and purified by column chromatography to obtain yellow solid B71-3 (1.65 g, 51%).

[0274] Synthesis of intermediate B71-4: B71-3 (1.65 g, 7.7 mmol) was heated to 90° C. in phosphorus oxychloride (20 mL) and stirred for 3 h. The phosphorus oxychloride was removed under reduced pressure, and the residue was poured into ice water, treated with saturated aqueous sodium bicarbonate to pH≒8, and extracted with dichloromethane. The organic phase was dried, concentrated, and purified by column chromatography to give yellow solid B71-4 (1.2 g, 67%).

[0275] Synthesis of intermediate B71-6: A mixture of B71-4 (276 mg, 1.2 mmol), B71-5 (480 mg, 1.8 mmol), Pd(dppf)Cl2 (90 mg, 0.12 mmol) and potassium carbonate (498 mg, 3.6 mmol) in dioxane (10 mL) / water (1 mL) was heated to 90° C. under nitrogen gas protection and stirred for 2 h. The reaction was treated with water, extracted with ethyl acetate, concentrated and separated by column chromatography to give yellow solid B71-6 (260 mg, 74%).

[0276] Synthesis of product B71: Following a similar synthetic route to Example 56, B71-6 was substituted for B31-3 and 3-aminopyridine was substituted for B31-5 to give compound B71.

[0277] Example 80: Synthesis of Compound B74 [ka] Following a synthetic route similar to that of Example 78, in step 3, 2-methyl-3-aminopyridine was substituted for 3-aminopyridine to give compound B74.

[0278] Example 81: Synthesis of Compound B75 [ka] Following a synthetic route similar to that of Example 79, in step 6, 2-methyl-3-aminopyridine was substituted for 3-aminopyridine to give compound B75.

[0279] Example 82: Synthesis of Compound B77 [ka] Following the similar synthetic route as in Example 79, in step 4, 1-bromo-2-fluoro-4-trifluoromethoxybenzene was substituted for B71-4, and in step 6, 2-methyl-3-aminopyridine was substituted for 3-aminopyridine, to obtain compound B77.

[0280] Example 83: Synthesis of Compound B78 [ka] Following a similar synthetic route to Example 79, compound B78 was synthesized by replacing B71-4 with 1-bromo-2-fluoro-4-trifluoromethoxybenzene in step 4.

[0281] Example 84: Synthesis of Compound B80 [ka] Following the similar synthetic route to Example 23, compound B80 was synthesized by substituting 4-bromo-1-methyl-pyrazole-3-carboxylic acid for B29-1 and 2-trifluoromethyl-3-aminopyridine for 3-aminopyridine in step 1.

[0282] Example 85: Synthesis of Compound B95 [ka] Synthesis of intermediate B95-1: According to the synthetic route of Example 79, in step 4, 4-boronic acid-1-p-methoxybenzylpyrazole-3-carboxylate was substituted for 4-boronic acid-1-methylpyrazole-3-carboxylate, and in step 6, 2-methyl-3-aminopyridine was substituted for 3-aminopyridine to give intermediate B95-1.

[0283] Synthesis of product B95: Following the synthetic route of Example 33, B95-1 was substituted for B178-1 to obtain B95.

[0284] Example 86: Synthesis of Compound B96 [ka] Compound B96 was synthesized following a similar synthetic route to Example 33, substituting 2-methyl-3-aminopyridine for 3-aminopyridine.

[0285] Example 87: Synthesis of Compound B99 [ka] Compound B99 was synthesized following a similar synthetic route to Example 85, substituting 3-aminopyridine for 2-methyl-3-aminopyridine.

[0286] Example 88: Synthesis of Compound B101 [ka] Synthesis of intermediate B101-1: Following the similar synthetic route to Example 79, compound B101-1 was synthesized by replacing B71-4 with 1-bromo-2-fluoro-4-trifluoromethoxybenzene and B71-5 with 4-boronic acid-1-p-methoxybenzylpyrazole-3-methyl carboxylate in step 4.

[0287] Synthesis of product B101: Following the synthetic route of Example 33, B101-1 was substituted for B178-1 to give B101.

[0288] Example 89: Synthesis of Compound B103 [ka] Compound B103 was synthesized following a similar synthetic route to Example 13, substituting 2-methyl-3-aminopyridine for 3-aminopyridine.

[0289] Example 90: Synthesis of Compound B109 [ka] Following the similar synthetic route to Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylate was substituted for 4-bromo-1-ethylpyrazole-3-carboxylate, and in step 3, trans-4-amino-cyclohexanol was substituted for 2,4-dimethyl-3-aminopyridine, to obtain compound B109.

[0290] Example 91: Synthesis of Compound B117 [ka] Following the similar synthetic route to Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylate was substituted for 4-bromo-1-ethylpyrazole-3-carboxylate, and in step 3, 3-aminomethylpyrazole was substituted for 2,4-dimethyl-3-aminopyridine, to obtain compound B117.

[0291] Example 92: Synthesis of Compound B122 [ka] Following the similar synthetic route to Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylate was substituted for 4-bromo-1-ethylpyrazole-3-carboxylate, and 3-aminomethylimidazole was substituted for 3-aminopyridine, to obtain compound B122.

[0292] Example 93: Synthesis of Compound B123 [ka] Following the similar synthetic route to Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylate was substituted for 4-bromo-1-ethylpyrazole-3-carboxylate, and 3-aminomethylpyrazole was substituted for 3-aminopyridine, to obtain compound B123.

[0293] Example 94: Synthesis of compound B150 [ka] Following the similar synthetic route to Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylate was substituted for 4-bromo-1-ethylpyrazole-3-carboxylate, and 3-hydroxyaniline was substituted for 3-aminopyridine, to obtain compound B150.

[0294] Example 95: Synthesis of Compound B152 [ka] Following the similar synthetic route to Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylate was substituted for 4-bromo-1-ethylpyrazole-3-carboxylate, and in step 3, 3-hydroxyaniline was substituted for 2,4-dimethyl-3-aminopyridine, to obtain compound B152.

[0295] Example 96: Synthesis of Compound B169 [ka] Following the similar synthetic route to Example 79, in step 4, 1-bromo-2-fluoro-4-trifluoromethoxybenzene was substituted for B71-4, and in step 6, 3-hydroxyaniline was substituted for 3-aminopyridine, to obtain compound B169.

[0296] Example 97: Synthesis of Compound B173 [ka] Following the similar synthetic route to Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylate was substituted for 4-bromo-1-ethylpyrazole-3-carboxylate, and in step 3, (S)-3-aminotetrahydrofuran was substituted for 2,4-dimethyl-3-aminopyridine, to obtain compound B173.

[0297] Example 98: Synthesis of compound B174 [ka] Following the similar synthetic route to Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylate was substituted for 4-bromo-1-ethylpyrazole-3-carboxylate, and in step 3, (R)-3-aminotetrahydrofuran was substituted for 2,4-dimethyl-3-aminopyridine, to obtain compound B174.

[0298] Example 99: Synthesis of Compound B175 [ka] Following the similar synthetic route to Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylate was substituted for 4-bromo-1-ethylpyrazole-3-carboxylate, and in step 3, 1,3-dimethyl-5-aminopyrazole was substituted for 2,4-dimethyl-3-aminopyridine, to obtain compound B175.

[0299] Example 100: Synthesis of Compound B177 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and aniline was substituted for 3-aminopyridine to give compound B177.

[0300] Example 101: Synthesis of Compound B184 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-methoxyaniline was substituted for 3-aminopyridine to give compound B184.

[0301] Example 102: Synthesis of Compound B185 [ka] Following a synthetic route similar to that of Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and in step 3, 4-methoxyaniline was substituted for 2,4-dimethyl-3-aminopyridine to give compound B185.

[0302] Example 103: Synthesis of Compound B186 [ka] Following a synthetic route similar to that of Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and in step 3, 4-difluoromethoxyaniline was substituted for 2,4-dimethyl-3-aminopyridine to give compound B186.

[0303] Example 104: Synthesis of compound B187 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 4-methoxyaniline was substituted for 3-aminopyridine to give compound B187.

[0304] Example 105: Synthesis of Compound B188 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 4-difluoromethoxyaniline was substituted for 3-aminopyridine to give compound B188.

[0305] Example 106: Synthesis of Compound B189 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1,5-dimethylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid and 2-methyl-3-aminopyridine was substituted for 3-aminopyridine to give compound B189.

[0306] Example 107: Synthesis of Compound B190 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-difluoromethoxyaniline was substituted for 3-aminopyridine to give compound B190.

[0307] Example 108: Synthesis of Compound B191 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-cyclopropylmethylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid and 2-methyl-3-aminopyridine was substituted for 3-aminopyridine to give compound B191.

[0308] Example 109: Synthesis of Compound B192 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-cyanoaniline was substituted for 3-aminopyridine to give compound B192.

[0309] Example 110: Synthesis of Compound B193 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid and 3-fluoroaniline was substituted for 3-aminopyridine to give compound B193.

[0310] Example 111: Synthesis of Compound B194 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-difluoromethylaniline was substituted for 3-aminopyridine to give compound B194.

[0311] Example 112: Synthesis of Compound B195 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 2,6-difluoroaniline was substituted for 3-aminopyridine to give compound B195.

[0312] Example 113: Synthesis of Compound B196 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid and 2-chloro-3-aminopyridine was substituted for 3-aminopyridine to give compound B196.

[0313] Example 114: Synthesis of Compound B197 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 4-aminomethylpyrazole was substituted for 3-aminopyridine to give compound B197.

[0314] Example 115: Synthesis of Compound B198 [ka] Following a synthetic route similar to that in Example 23, in step 1, 4-bromo-1,5-dimethylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid to give compound B198.

[0315] Example 116: Synthesis of Compound B199 [ka] Following a synthetic route similar to that in Example 23, in step 1, 4-bromo-1-cyclopropylmethylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid to give compound B199.

[0316] Example 117: Synthesis of Compound B200 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3,5-difluoroaniline was substituted for 3-aminopyridine to give compound B200.

[0317] Example 118: Synthesis of Compound B201 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3,5-difluoro-4-hydroxyaniline was substituted for 3-aminopyridine to give compound B201.

[0318] Example 119: Synthesis of Compound B202 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-amino-5-fluoropyridine was substituted for 3-aminopyridine to give compound B202.

[0319] Example 120: Synthesis of Compound B203 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid and 2-methoxy-3-aminopyridine was substituted for 3-aminopyridine to give compound B203.

[0320] Example 121: Synthesis of Compound B204 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-(3-tetrahydrofuran)pyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid to give compound B204.

[0321] Example 122: Synthesis of Compound B205 [ka] Following a synthetic route similar to that of Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and in step 3, [ka] was substituted for 2,4-dimethyl-3-aminopyridine to give compound B205.

[0322] Example 123: Synthesis of Compound B206 [ka] Following a synthetic route similar to that of Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and in step 3, [ka] was substituted for 2,4-dimethyl-3-aminopyridine to give compound B206.

[0323] Example 124: Synthesis of compound B207 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 2-cyano-3-aminopyridine was substituted for 3-aminopyridine to give compound B207.

[0324] Example 125: Synthesis of Compound B208 [ka] Following a synthetic route similar to that of Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and in step 3, [ka] was substituted for 2,4-dimethyl-3-aminopyridine to give compound B208.

[0325] Example 126: Synthesis of Compound B209 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid; [ka] was substituted for 3-aminopyridine to give compound B209.

[0326] Example 127: Synthesis of Compound B210 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-(4-tetrahydropyran)pyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid to give compound B210.

[0327] Example 128: Synthesis of Compound B211 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-cyclopropylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 2-methyl-3-aminopyridine was substituted for 3-aminopyridine to give compound B211.

[0328] Example 129: Synthesis of Compound B214 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid; [ka] was substituted for 3-aminopyridine to give compound B214.

[0329] Example 130: Synthesis of Compound B215 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-cyclopropylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid to give compound B215.

[0330] Example 131: Synthesis of compound B216 [ka] Synthesis of intermediate B216-1: Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-p-methoxybenzyl-5-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid to give compound B216-1.

[0331] Synthesis of product B216: Following the synthetic route of Example 33, B216-1 was substituted for B178-1 to give B216.

[0332] Example 132: Synthesis of Compound B333 [ka] Synthesis of intermediate B333-2: Compound B333-1 (2 g, 11.59 mmol) and triethylamine (2.35 g, 23.18 mmol) were added to an ethanol (10 mL) solution, and N-methylpiperazine (1.2 g, 11.94 mmol) was added under stirring conditions. The reaction solution was heated to 80°C and stirred overnight. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated to obtain yellow oily product B333-2 (2 g, 73%).

[0333] Synthesis of intermediate B333-3: Compound B333-2 (2 g, 7.99 mmol) was added to a solution of ethanol (20 mL), and sodium borohydride (1 g, 26.43 mmol) was added under stirring conditions, and the reaction was stirred at room temperature overnight. The reaction was filtered and concentrated to give the off-white solid product B333-3 (1.5 g, 90%).

[0334] Synthesis of intermediate B333-4: Compound B333-3 (1.5 g, 7.20 mmol) was added to a solution of phosphorus oxychloride (6 mL), and the temperature was raised to 80° C. and stirred for 4 hours. Water was added to the reaction solution, and the ethyl acetate was adjusted to pH 7-9 with a saturated aqueous sodium carbonate solution, separated, extracted with ethyl acetate, and the organic phase was washed with water and saturated saline, concentrated, and separated by column chromatography to obtain a pale yellow oily product B333-4 (0.7 g, 42%).

[0335] Synthesis of intermediate B333-5: Compound 4-bromopyrazole-3-carboxylate methyl (450 mg, 2.05 mmol) and potassium carbonate (850 mg, 6.15 mmol) were added to a solution of N,N-dimethylformamide (5 mL), and compound B333-4 (700 mg, 2.16 mmol) was added under stirring conditions and stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, concentrated, and separated by column chromatography to obtain pale yellow oily product B333-5 (0.7 g, 86%).

[0336] Synthesis of intermediate B333-6: Compound B333-5 (700 mg, 1.77 mmol), 2,5-difluoro-3-chlorophenylboronic acid (700 mg, 2.55 mmol), potassium carbonate (730 mg, 5.28 mmol) and 1,1 ’-Di(diphenylphosphino)ferrocenedichloropalladium(II) (120 mg, 0.16 mmol) was added to a mixture of dioxane (10 mL) and water (1 mL), and the mixture was purged with nitrogen gas three times. The mixture was heated to 100°C and stirred overnight. The reaction solution was concentrated and then separated by column chromatography to obtain a pale yellow oily product B333-6 (600 mg, 73%).

[0337] Synthesis of product B333 Following a similar synthetic route to Example 56, B333-6 was substituted for B31-3, [ka] was substituted for 2,4-dimethyl-3-aminopyridine, and finally a further deprotection reaction was carried out to give compound B333.

[0338] Example 133: Synthesis of Compound B268 [ka] Synthesis of intermediate B268-1: 4-Bromopyrazole-3-carboxylate methyl (1 g, 4.88 mmol) and potassium carbonate (2.02 g, 5.37 mmol) were added to a solution of N,N-dimethylformamide (10 mL), and 2-fluoro-5-pyridylmethyl chloride (780 mg, 2.16 mmol) was added under stirring conditions and stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was concentrated and separated by column chromatography to obtain a pale yellow oily product B268-1 (0.5 g, 65%).

[0339] Synthesis of intermediate B268-2: B268-1 (0.5 g, 1.59 mmol) was added to a solution of N,N-dimethylformamide (5 mL), and under stirring conditions, cesium carbonate (1.55 g, 4.77 mmol) and methylpiperazine (290 mg, 2.86 mmol) were added, and the reaction was stirred overnight at 80° C. The reaction solution was directly separated by column chromatography to give colorless oil B268-2 (0.5 g, 79%).

[0340] Synthesis of product B268 Following a similar synthetic route to Example 132, B268-2 was substituted for B333-5 to give compound B268.

[0341] Example 134: Synthesis of Compound B336 [ka] Following a synthetic route similar to that of Example 28, in step 1, 5-bromo-1-methylimidazole-4-carboxylic acid was substituted for 4-bromo-1-methylpyrazole-3-carboxylic acid and 2-cyclopropyl-3-aminopyridine was substituted for 3-aminopyridine to give compound B336.

[0342] Example 135: Synthesis of Compound B376 [ka] Following a similar synthetic route to Example 28, in step 1, 5-bromo-1-methylimidazole-4-carboxylic acid was substituted for 4-bromo-1-methylpyrazole-3-carboxylic acid and 1-aminonaphthalene was substituted for 3-aminopyridine to give compound B376.

[0343] Example 136: Synthesis of Compound B340 [ka] Following a synthetic route similar to that of Example 28, in step 1, 2-cyclopropyl-3-aminopyridine was substituted for 3-aminopyridine to give compound B340.

[0344] Example 137: Synthesis of Compound B370 [ka] Following a synthetic route similar to that of Example 28, in step 1, 1-aminonaphthalene was substituted for 3-aminopyridine to give compound B370.

[0345] Example 138: Synthesis of Compound B371 [ka] Following a synthetic route similar to that of Example 28, in step 1, 8-aminoquinoline was substituted for 3-aminopyridine to give compound B371.

[0346] Example 139: Synthesis of Compound B373 [ka] Following a synthetic route similar to that of Example 45, substituting 1-aminonaphthalene for 1-Boc-4-aminoindazole, compound B373 was obtained.

[0347] Example 140: Synthesis of Compound B217 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 5-methyl-3-aminopyridine was substituted for 3-aminopyridine to give compound B217.

[0348] Example 141: Synthesis of compound B218 [ka] Synthesis of intermediate B218-1: Methyl 4-bromopyrazole-3-carboxylate (2 g, 9.76 mmol), 6-methoxy-3-boronic acid (2.5 g, 16.45 mmol), copper acetate (2 g, 10 mmol), 2,2-bipyridine (1.5 g, 9.6 mmol), sodium carbonate (2.5 g, 23.59 mmol), and dichloroethane (10 mL) were added to the reaction flask. The mixture was stirred at 70°C for 16 hours. The reaction solution was filtered, the organic phase was concentrated, and the crude product was separated and purified by column chromatography to obtain a white solid B218-1 (0.5 g, 16%).

[0349] Synthesis of intermediate B218-2: B218-1 (0.5 g, 1.61 mmol), lithium hydroxide (0.2 g, 8.35 mmol), methanol (5 mL), and water (5 mL) were added to a reaction flask. The mixture was stirred at 60° C. for 16 hours. The reaction mixture was concentrated, adjusted to pH 1, extracted with ethyl acetate, washed with saturated saline, and the organic phase was concentrated to obtain brown oily product B218-2 (0.5 g, 79%).

[0350] Synthesis of product B218: Following a synthetic route similar to that of Example 23, in step 1, B218-2 was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid and aniline was substituted for 3-aminopyridine to give compound B218.

[0351] Example 142: Synthesis of compound B219 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-aminobenzamide was substituted for 3-aminopyridine to give compound B219.

[0352] Example 143: Synthesis of Compound B220 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 2-amino-6-methylpyridine was substituted for 3-aminopyridine to give compound B220.

[0353] Example 144: Synthesis of Compound B221 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-amino-5-hydroxypyridine was substituted for 3-aminopyridine to give compound B221.

[0354] Example 145: Synthesis of Compound B222 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid and 3-amino-5-cyanopyridine was substituted for 3-aminopyridine to give compound B222.

[0355] Example 146: Synthesis of Compound B223 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-amino-6-methylpyridine was substituted for 3-aminopyridine to give compound B223.

[0356] Example 147: Synthesis of compounds B224 and B225 [ka] Synthesis of product B224: Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-aminobenzoic acid methyl was substituted for 3-aminopyridine to give compound B224.

[0357] Synthesis of product B225: B224 (100 mg, 0.3 mmol), lithium hydroxide (18 mg, 0.8 mmol), methanol (2 mL), and water (2 mL) were added to a reaction flask and stirred at 60° C. for 16 hours. The reaction mixture was acidified with hydrogen chloride in dioxane (4 M), diluted with dichloromethane (50 mL), and washed with water. The organic phase was concentrated and purified by reverse phase column chromatography to give white solid B225 (8 mg, 8%).

[0358] Example 148: Synthesis of compound B227 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 2-aminopyrazine was substituted for 3-aminopyridine to give compound B227.

[0359] Example 149: Synthesis of compound B226 [ka] Following a synthetic route similar to that of Example 56, in step 1, 4-bromo-1-cyclopropylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and in step 3, 2-methyl-3-aminopyridine was substituted for 2,4-dimethyl-3-aminopyridine to give compound B226.

[0360] Example 150: Synthesis of Compound B228 [ka] Following a similar synthetic route to Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-hydroxy-4-fluoro-aniline was substituted for 3-aminopyridine to give compound B228.

[0361] Example 151: Synthesis of Compound B229 [ka] Following a synthetic route similar to that of Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and in step 3, (S)-3-aminotetrahydropyran was substituted for 2,4-dimethyl-3-aminopyridine to give compound B229.

[0362] Example 152: Synthesis of Compound B230 [ka] Following a synthetic route similar to that of Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and in step 3, (R)-3-aminotetrahydropyran was substituted for 2,4-dimethyl-3-aminopyridine to give compound B230.

[0363] Example 153: Synthesis of Compound B231 [ka] Synthesis of intermediate B231-1: Methyl 4-bromopyrazole-3-carboxylate (2 g, 9.76 mmol), 6-methoxy-3-pyridine borate (1.49 g, 2.44 mmol), copper acetate (1.21 g, 3.17 mmol), 2,2-bipyridine (1.68 g, 10.74 mmol), sodium carbonate (2.07 g, 19.52 mmol), and dichloroethane (10 mL) were added to the reaction flask. The mixture was stirred at 70°C for 16 hours. The reaction solution was filtered, the organic phase was concentrated, and the crude product was purified by column chromatography to obtain the white solid product B231-1 (1.2 g, 78%).

[0364] Synthesis of product B231: Following a synthetic route similar to that of Example 23, in step 1, B231-1 was substituted for B29-1 and aniline was substituted for 3-aminopyridine to give compound B231.

[0365] Example 154: Synthesis of compound B234 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-aminobenzamide was substituted for 3-aminopyridine to give compound B234.

[0366] Example 155: Synthesis of Compound B235 [ka] Following a synthetic route similar to that of Example 56, in step 1, 4-bromo-1-methylpyrazole-3-carboxylate was substituted for 4-bromo-1-ethylpyrazole-3-carboxylate, and in step 3, 4-aminomethylpyrazole was substituted for 2,4-dimethyl-3-aminopyridine to give compound B235.

[0367] Example 156: Synthesis of Compounds B236 and B237 [ka] Synthesis of compound B237: B177 (400 mg, 1.16 mmol), N-bromosuccinimide (310 mg, 1.74 mmol), and N,N-dimethylformamide (5 mL) were added to a reaction flask. The mixture was stirred at 60° C. for 16 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated saline, dried, and purified by column chromatography to obtain the white solid product B237 (300 mg, 61%).

[0368] Synthesis of compound B236: A reaction flask was charged with B237 (150 mg, 0.35 mmol), p-methoxyphenylboronic acid (80 mg, 0.52 mmol), [1,1 ’ -Bis(di-tert-butylphosphino)ferrocene]dichloropalladium (23 mg, 0.035 mmol), potassium fluoride (61 mg, 1.05 mmol), 1,4-dioxane (3 mL), and water (0.6 mL) were added. The mixture was stirred at 80° C. for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and the organic phase was concentrated. The crude product was purified by column chromatography to give the white solid product B236 (50 mg, 31%).

[0369] Example 157: Synthesis of compound B238 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 1-(3-pyrazolyl)-ethylamine was substituted for 3-aminopyridine to give compound B238.

[0370] Example 158: Synthesis of Compound B240 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-amino-5-difluoromethylpyridine was substituted for 3-aminopyridine to give compound B240.

[0371] Example 159: Synthesis of Compounds B241 and B244 [ka] Synthesis of intermediate B244-2: To a stirred solution of compound B244-1 (2 g, 9.76 mmol) in DMF (10 mL), 2-(7-azobenzotriazole)-N,N,N ’ ,N ’ -Tetramethyluronium hexafluorophosphate (4.15 g, 10.93 mmol) and N,N-diisopropylethylamine (1.83 g, 14.14 mmol) were added and stirred at room temperature for 0.5 hours. Then, 3-aminopyridine (1.5 g, 15.9 mmol) was added to the mixture and stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to give the orange solid product B244-2 (2.2 g, 80%).

[0372] Synthesis of compound B244-3: Compound B244-2 (2 g, 7.11 mmol), 2,6-dichloro-3-pyridineboronic acid (1.7 g, 8.86 mmol), potassium fluoride (1.25 g, 21.51 mmol) and dichloro[1,1 ’ -Bis(di-tert-butylphosphine)ferrocenepalladium(II) (400 mg, 0.086 mmol) was added to a mixture of dioxane (10 mL) and water (1 mL), and the mixture was purged with nitrogen gas three times. The mixture was heated to 80°C and stirred overnight. The reaction solution was directly concentrated and then separated by column chromatography to obtain black oily product B244-3 (2 g, 80%).

[0373] Synthesis of compound B244: 1,8-Diazacyclo[5,4,0]undecene-7 (2.1 g, 13.79 mmol) was added to a stirred solution of compound B244-3 (1.6 g, 4.6 mmol) in dimethyl sulfoxide (8 mL), and the mixture was purged with nitrogen gas three times. The mixture was heated to 120°C and stirred overnight. Water was added to the reaction solution, which was then extracted with dichloromethane. The organic phases were combined, washed with water, washed with saturated saline, dried over sodium sulfate, concentrated, and separated by column chromatography to obtain white solid B244 (500 mg, 35%).

[0374] Synthesis of compound B241: Compound B244 (40 mg, 0.13 mmol), 2,2-difluoroethylamine (11 mg, 0.13 mmol), potassium carbonate (50 mg, 0.36 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 0.09 mmol) and 2-dicyclohexylphosphino-2 ’ ,4 ’ ,6 ’ -Triisopropylbiphenyl (40 mg, 0.08 mmol) was added to DMF (2 mL) and purged with nitrogen gas three times. The mixture was heated to 80° C. and stirred overnight. The reaction mixture was directly separated by column chromatography to give an off-white solid B241 (24 mg, 54%).

[0375] Example 160: Synthesis of Compound B242 [ka] Compound B244 (80 mg, 0.26 mmol), potassium carbonate (120 mg, 0.86 mmol), tris(dibenzylideneacetone)dipalladium (24 mg, 0.026 mmol) and 2-dicyclohexylphosphino-2 ’ ,4 ’ ,6 ’-Triisopropylbiphenyl (82 mg, 0.17 mmol) was added to a mixture of ethanol (1 mL) and the mixture was purged with nitrogen gas three times. The mixture was heated to 80°C and stirred overnight. The reaction solution was separated by reverse phase column chromatography to obtain a white solid B242 (28 mg, 33%).

[0376] Example 161: Synthesis of Compound B243 [ka] Synthesis of intermediate B243-1: Following a synthetic route similar to that of intermediate B33-4 in Example 58, in step 1, methyl 4-bromo-1-methylpyrazole-3-carboxylate was substituted for B31-1, and in step 2, 2-chloro-6-trifluoromethylpyridine-3-boronic acid was substituted for B31-2 to give compound B243-1.

[0377] Synthesis of compound B243: 1,8-Diazacyclo[5,4,0]undecene-7 (170 mg, 1.12 mmol) was added to a stirred solution of B243-1 (150 mg, 0.38 mmol) in DMSO (3 mL). The temperature was raised to 120° C. and the mixture was stirred overnight. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was concentrated and separated by column chromatography to obtain the white solid product B243 (23 mg, 12%).

[0378] Example 162: Synthesis of Compound B251 [ka] Following a synthetic route similar to that of Example 159, substituting ethylamine for 2,2-difluoroethylamine in step 4, compound B251 was obtained.

[0379] Example 163: Synthesis of Compound B252 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-difluoromethyl-5-methylpyrazole-3-carboxylic acid was substituted for B29-1 to give compound B252.

[0380] Example 164: Synthesis of Compound B253 [ka] B244 (40 mg, 0.13 mmol), 2,2-difluoroethanol (30 mg, 0.37 mmol), potassium carbonate (60 mg, 0.43 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.022 mmol) and 2-dicyclohexylphosphino-2 ’ ,4 ’ ,6 ’ -Triisopropylbiphenyl (60 mg, 0.13 mmol) was added to the mixture in DMF (1 mL). The mixture was purged with nitrogen gas three times, heated to 80° C., and stirred overnight. The reaction mixture was directly separated by column chromatography to give the off-white solid product B253 (35 mg, 76%).

[0381] Example 165: Synthesis of Compound B255 [ka] Following a synthetic route similar to that of Example 23, in step 1, 4-bromo-1-difluoromethylpyrazole-3-carboxylic acid was substituted for B29-1 to give compound B255.

[0382] Example 166: Synthesis of Compound B263 [ka] Synthesis of intermediate B263-1: Following a synthetic route similar to that of Example 28, substituting 4-bromo-1-p-methoxybenzylpyrazole-3-carboxylic acid for 4-bromo-1-methylpyrazole-3-carboxylic acid and 1-Boc-4-aminoindazole for 3-aminopyridine, intermediate B263-1 was synthesized.

[0383] Synthesis of compound B263: Following a method similar to the preparation of B178 in Example 33, B263 was synthesized.

[0384] Example 167: Synthesis of Compound B267 [ka] Following a synthetic route similar to that of Example 133, in step 1, 2-chloromethyl-6-fluoropyridine was substituted for 3-chloromethyl-6-fluoropyridine to give compound B267.

[0385] Example 168: Synthesis of compounds B342, B388, and B389 [ka] 1) Synthesis of product B342: Following a synthetic route similar to that in Example 28, substituting 2-trifluoromethyl-3-aminopyridine for 3-aminopyridine, compound B342 was obtained.

[0386] 2) Resolution of products B388 and B389: B342 was subjected to chiral resolution (IA-3.0 cm, n-hexane / ethanol=50:50, 25 mL / min, 230 nm) to give B388 (retention time: 9.79 min) and B389 (retention time: 14.33 min).

[0387] Example 169: Synthesis of Compound B348 [ka] Following a synthetic route similar to that of Example 45, substituting 1-Boc-3-aminoindazole with 2-cyclopropyl-3-aminopyridine, compound B348 was obtained.

[0388] Example 170: Synthesis of Compound B372 [ka] Synthesis of intermediate B372-1: Following a method similar to the preparation of B29-2 in Example 23, substituting 5-bromo-1-methylimidazole-4-carboxylic acid for B29-1 and 1-Boc-3-aminoindazole for 3-aminopyridine, compound B372-1 was obtained.

[0389] Synthesis of intermediate B372-2: A reaction flask was charged with B372-1 (0.5 g, 1.19 mmol), (4-chloro-2,5-difluorobenzene)boronic acid (0.34 g, 1.78 mmol), [1,1 ’ -Bis(di-tert-butylphosphino)ferrocene]dichloropalladium (87 mg, 0.12 mmol), potassium fluoride (490 mg, 3.57 mmol), 1,4-dioxane (2.5 mL), and water (0.5 mL) were added. The mixture was stirred at 80° C. under nitrogen gas protection for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and the organic phase was concentrated. The crude product was purified by column chromatography to give the white solid product B372-2 (70 mg, 8%).

[0390] Synthesis of intermediate B372-3: B372-2 (70 mg, 0.14 mmol), cesium fluoride (110 mg, 0.70 mmol), and N,N-dimethylformamide (1 mL) were added to a reaction flask. The mixture was stirred at 80° C. for 16 hours. The reaction mixture was diluted with dichloromethane, washed with water, and the organic phase was concentrated. The crude product was purified by column chromatography to give yellow solid B372-3 (60 mg, 89%).

[0391] Synthesis of compound B372: B372-3 (60 mg, 0.13 mmol), trifluoroacetic acid (0.5 mL), and dichloromethane (0.5 mL) were added to a reaction flask. The mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated and then purified by reverse phase column chromatography to obtain white solid B372 (22 mg, 43%).

[0392] Example 171: Synthesis of Compound B351 [ka] Following a synthetic route similar to that of Example 170, substituting 2-trifluoromethyl-3-aminopyridine for 1-Boc-3-aminoindazole, compound B351 was obtained.

[0393] Example 172: Synthesis of Compound B374 [ka] Following a synthetic route similar to that of Example 45, substituting 1-Boc-3-aminoindazole with 8-aminoquinoline, compound B374 was obtained.

[0394] Example 173: Synthesis of Compound B375 [ka] Following a similar synthetic route to Example 170, in step 1, 2-fluoro-4-chloro-5-cyanophenylboronic acid pinacol ester was substituted for 4-chloro-2,5-difluorophenylboronic acid to give compound B375.

[0395] Example 174: Synthesis of Compound B377 [ka] Following a synthetic route similar to that of Example 170, substituting 1-Boc-3-aminoindazole with 8-aminoquinoline, compound B377 was obtained.

[0396] Example 175: Synthesis of Compound B378 [ka] Following a similar synthetic route to Example 170, substituting 2-fluoro-4-chloro-5-cyanophenylboronic acid pinacol ester for 4-chloro-2,5-difluorophenylboronic acid and 1-aminonaphthalene for 1-Boc-3-aminoindazole, compound B378 was obtained.

[0397] Example 176: Synthesis of Compound B379 [ka] Following a synthetic route similar to that of Example 170, substituting 2-fluoro-4-chloro-5-cyanophenylboronic acid pinacol ester for 4-chloro-2,5-difluorophenylboronic acid and 8-aminoquinoline for 1-Boc-3-aminoindazole, compound B379 was obtained.

[0398] Example 177: Synthesis of Compound B381 [ka] Following a synthetic route similar to that of Example 28, substituting 2-methyl-4-aminoindazole for 2-methyl-3-aminopyridine, compound B381 was obtained.

[0399] Example 178: Synthesis of Compound B382 [ka] Following a synthetic route similar to that of Example 28, substituting 2-methyl-7-aminoindazole for 2-methyl-3-aminopyridine, compound B382 was obtained.

[0400] Example 179: Synthesis of Compound B394 [ka] Synthesis of intermediate B394-1: Following a synthetic route similar to Example 45, substituting 4-bromo-1-methylpyrazole-3-carboxylic acid with 4-bromo-1-benzylpyrazole-3-carboxylic acid, intermediate B394-1 was obtained.

[0401] Synthesis of compound B394: Following similar preparation conditions as B178 in Example 33, compound B394 was obtained.

[0402] Example 180: Synthesis of Compound B400 [ka] Following a similar method to the synthesis of B253 in Example 164, B186 was substituted for B244 to give compound B400.

[0403] Example 181: Synthesis of Compound B401 [ka] Following a synthetic method similar to that of Example 23, in step 1, 5-bromo-1-methylimidazole-4-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 6-aminoquinoline was substituted for 3-aminopyridine to give compound B401.

[0404] Example 182: Synthesis of Compound B402 [ka] Following a synthetic method similar to that of Example 23, in step 1, 5-bromo-1-methylimidazole-4-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 2-aminoquinoline was substituted for 3-aminopyridine to give compound B402.

[0405] Example 183: Synthesis of Compound B403 [ka] Following a synthetic method similar to that of Example 23, in step 1, 5-bromo-1-methylimidazole-4-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 3-aminoquinoline was substituted for 3-aminopyridine to give compound B403.

[0406] Example 184: Synthesis of Compound B404 [ka] Following a synthetic method similar to that of Example 23, in step 1, 5-bromo-1-methylimidazole-4-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 2-aminonaphthalene was substituted for 3-aminopyridine to give compound B404.

[0407] Example 185: Synthesis of Compound B405 [ka] Following a synthetic method similar to that of Example 23, in step 1, 5-bromo-1-methylimidazole-4-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 2-amino-1,5-dinaphthyridine was substituted for 3-aminopyridine to give compound B405.

[0408] Example 186: Synthesis of Compound B408 [ka] Following a synthetic method similar to that of Example 23, in step 1, 5-bromo-1-methylimidazole-4-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 5-aminoquinoline was substituted for 3-aminopyridine to give compound B408.

[0409] Example 187: Synthesis of Compound B407 [ka] Following a synthetic method similar to that of Example 23, in step 1, 5-bromo-1-methylimidazole-4-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 8-aminoisoquinoline was substituted for 3-aminopyridine to give compound B407.

[0410] Example 188: Synthesis of Compound B409 [ka] Following a synthetic method similar to that in Example 33, substituting o-chloroaniline for 3-aminopyridine, compound B409 was obtained.

[0411] Example 189: Synthesis of Compound B410 [ka] Following a synthetic method similar to that of Example 23, in step 1, 4-bromo-2-methylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and o-chloroaniline was substituted for 3-aminopyridine to give compound B410.

[0412] Example 190: Synthesis of Compound B406 [ka] Following a synthetic method similar to that of Example 23, in step 1, 5-bromo-1-methylimidazole-4-carboxylic acid was substituted for 4-bromo-1-ethylpyrazole-3-carboxylic acid, and 4-aminoisoquinoline was substituted for 3-aminopyridine to give compound B406.

[0413] Example 191: Synthesis of Compound B286 [ka] Following a synthetic method similar to that of Example 45, 4-bromo-1-p-methoxybenzylpyrazole-3-carboxylic acid was substituted for 4-bromo-1-methylpyrazole-3-carboxylic acid to give compound B286.

[0414] Example 192: Synthesis of Compound B293 [ka] Following a synthetic method similar to that of Example 45, substituting 4-bromo-1-methylpyrazole-3-carboxylic acid with 4-bromo-1-(1-methylpyrazole-3-methyl)pyrazole-3-carboxylic acid, compound B293 was obtained.

[0415] Example 193: Synthesis of Compound B393 [ka] Following a synthetic method similar to that of Example 45, substituting 4-bromo-1,5-dimethylpyrazole-3-carboxylic acid for 4-bromo-1-methylpyrazole-3-carboxylic acid, compound B393 was obtained.

[0416] Example 194: Synthesis of Compound B396 [ka] Following a synthetic method similar to that of Example 45, substituting 4-bromo-1-cyclopropylmethylpyrazole-3-carboxylic acid for 4-bromo-1-methylpyrazole-3-carboxylic acid, compound B396 was obtained.

[0417] Example 195: Synthesis of Compound B412 [ka] B257 (0.15 g, 0.41 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N-chlorosuccinimide (0.11 g, 0.82 mmol) was added while stirring, and the mixture was reacted for 16 hours with stirring at 25° C. LCMS showed the reaction was complete, and the reaction solution was filtered to obtain the filtrate, which was purified by reverse phase column chromatography (0.05% aqueous formic acid / acetonitrile) to give the white product B412 (7 mg, 4.22%).

[0418] Example 196: Synthesis of Compound B413 [ka] B257 (0.15 g, 0.41 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N-bromosuccinimide (0.15 g, 0.82 mmol) was added while stirring, and the mixture was reacted for 16 hours with stirring at 25° C. LCMS showed the reaction was complete, and the reaction solution was filtered to obtain the filtrate, which was purified by reverse phase column chromatography (0.05% aqueous formic acid / acetonitrile) to give the white product B413 (33 mg, 18%).

[0419] Example 197: Synthesis of Compound B414 [ka] Synthesis of intermediate B414-2: B414-1 (5.00 g, 19.62 mmol), cyclopropylboronic acid (1.85 g, 21.58 mmol) and potassium phosphate (10.41 g, 49.05 mmol) were added to a solution of 1,4-dioxane (50 mL), and the mixture was purged with nitrogen gas three times. ’ -Bis(diphenylphosphino)ferrocene]dichloropalladium (1.44 g, 1.96 mmol) and tricyclohexylphosphine (1.11 g, 3.92 mmol) were added and the mixture was stirred at 90° C. for 6 hours. LCMS showed the reaction was complete, and the reaction was poured into water, extracted with dichloromethane (50 mL×2), concentrated, and purified by column chromatography (petroleum ether / dichloromethane) to give white oil B414-2 (2.3 g, 39%). m / z [M+H] + =215.9.

[0420] Synthesis of intermediate B414-3: B414-2 (2 g, 9.26 mmol) was added to a solution of dichloromethane (40 mL), and m-chloroperoxybenzoic acid (3.2 g, 18.52 mmol) was added in portions with stirring at 0° C., and then the reaction was carried out at 25° C. for 16 hours. LCMS showed the reaction was complete. The reaction was poured into water, extracted with ethyl acetate (25 mL×2), and concentrated to give white oil B414-3 (0.53 g, 22%). m / z [M+H] + =231.9.

[0421] Synthesis of intermediate B414-4: B414-3 (0.53 g, 2.28 mmol) was added to a solution of phosphorus oxychloride (15 mL) and reacted for 12 hours with stirring at 80° C. LCMS showed the reaction was complete, and the reaction solution was poured into ice water, extracted with ethyl acetate (10 mL×2), and concentrated to give colorless oil B414-4 (0.11 g, yield: 16.53%). m / z [M+H] + =249.9.

[0422] Synthesis of intermediate B414-5: 4-Bromo-1-methylpyrazole-3-carboxylic acid (0.3 g, 1.46 mmol) was added to a solution of N,N-dimethylformamide (5 mL), and 1-naphthylamine (0.23 g, 1.61 mmol), 2-(7-azabenzotriazole)-N,N,N ’ ,N ’ -Tetramethyluronium hexafluorophosphate (0.61 g, 1.61 mmol) and N,N-diisopropylethylamine (0.57 g, 4.38 mmol) were added and reacted at 25°C overnight. LCMS showed the reaction was complete, and the reaction solution was poured into water and extracted with ethyl acetate (20 mL x 2). The organic phases were combined and concentrated to give a brown solid B414-5 (0.21 g, 43%). m / z [M+H] + =330.1.

[0423] Synthesis of intermediate B414-6: B414-5 (0.21 g, 0.64 mmol) was dissolved in 1,4-dioxane (4 mL), and bis(pinacolato)diboron (0.24 g, 0.96 mmol) and potassium acetate (0.19 g, 1.92 mmol) were added while stirring. After purging with nitrogen gas three times, the mixture was cooled to room temperature and cooled to room temperature. ’ -Bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g, 0.06 mmol) was added and the reaction was stirred for 6 hours at 100° C. The reaction was shown to be complete by LCMS and purified by column chromatography (ethyl acetate / petroleum ether) to give a white solid B414-6 (0.15 g, 63%).

[0424] Synthesis of intermediate B414-7: B414-4 (0.1 g, 0.40 mmol), B414-6 (0.15 g, 0.40 mmol) and potassium fluoride (0.07 g, 1.2 mmol) were added to a mixture of 1,4-dioxane (20 mL) and water (0.5 mL), and the atmosphere was replaced with nitrogen gas three times. ’ -Bis(diphenylphosphino)ferrocene]dichloropalladium (0.026 g, 0.04 mmol) was added and the reaction was stirred at 90° C. for 12 hours. LCMS showed the reaction was complete, and the reaction solution was poured into water, extracted with dichloromethane (50 mL×2), concentrated, and purified by column chromatography (petroleum ether / dichloromethane) to give white oil B414-7 (40 mg, 24%). m / z [M+H] + =421.1.

[0425] Synthesis of product B414: B414-7 (40 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (2 mL), potassium fluoride (17 mg, 0.29 mmol) was added while stirring, and the mixture was reacted for 16 hours with stirring at 80° C. LCMS showed the reaction was complete, and the reaction solution was filtered to obtain the filtrate, which was then purified by reverse phase column chromatography (0.05% aqueous formic acid / acetonitrile) to obtain the white product B414 (3 mg, 8%).

[0426] Example 198: Synthesis of Compound B391 [ka] Following a method similar to the synthesis of compound B258 in Example 45, in step 1, 4-amino-2-trifluoromethylbenzonitrile was substituted for B258-1 to give B391.

[0427] Example 199: Synthesis of Compound B283 [ka] Following a method similar to the synthesis of compound B258 in Example 45, substituting 4-bromo-1-methylpyrazole-3-carboxylic acid with 4-bromo-1-difluoromethylpyrazole-3-carboxylic acid, compound B283 was obtained.

[0428] Example 200: Synthesis of Compound B281 [ka] Following a synthetic method similar to that of Example 48, in step 1, 6-chloro-2-trifluoromethylnicotinonitrile was substituted for B274-1 to give compound B281.

[0429] Example 201: Synthesis of Compound B284 [ka] Following a synthetic method similar to that of Example 45, substituting 4-bromo-1-cyclopropylpyrazole-3-carboxylic acid for 4-bromo-1-methylpyrazole-3-carboxylic acid, compound B284 was obtained.

[0430] Example 202: Synthesis of Compound B411 [ka] B257 (0.15 g, 0.41 mmol) was dissolved in acetonitrile (2 mL), and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluorophonate) (0.23 g, 0.66 mmol) was added while stirring, and the mixture was reacted for 36 hours with stirring at 25° C. The reaction solution was filtered, and the filtrate was separated by reverse phase column chromatography to obtain a white product B411 (10 mg, 6%).

[0431] The nuclear magnetic and mass spectrometric data of exemplary compounds of the present application are shown below.

[0432] [Table 2] JPEG2025503186000284.jpg200149JPEG2025503186000285.jpg195150JPEG2025503186000286.jpg210149JPEG2025503186000287.jpg211149JPEG2025503186000288.jpg189148JPEG2025503186000289.jpg201149JPEG2025503186000290.jpg208148JPEG2025503186000291.jpg194150JPEG2025503186000292.jpg209148JPEG2025503186000293.jpg190146JPEG2025503186000294.jpg200150JPEG2025503186000295.jpg196146JPEG2025503186000296.jpg199149JPEG2025503186000297.jpg194147JPEG2025503186000298.jpg191150JPEG2025503186000299.jpg193148JPEG2025503186000300.jpg195146JPEG2025503186000301.jpg210150JPEG2025503186000302.jpg197147JPEG2025503186000303.jpg209144JPEG2025503186000304.jpg209147JPEG2025503186000305.jpg208144JPEG2025503186000306.jpg194150JPEG2025503186000307.jpg208148JPEG2025503186000308.jpg205148JPEG2025503186000309.jpg208148JPEG2025503186000310.jpg207149JPEG2025503186000311.jpg192150JPEG2025503186000312.jpg209149JPEG2025503186000313.jpg184150JPEG2025503186000314.jpg184150JPEG2025503186000315.jpg188150JPEG2025503186000316.jpg193149JPEG2025503186000317.jpg185150JPEG2025503186000318.jpg184149JPEG20255031860003 19.jpg192150JPEG2025503186000320.jpg196150JPEG2025503186000321.jpg212150JPEG20255031860 00322.jpg196147JPEG2025503186000323.jpg204149JPEG2025503186000324.jpg201150JPEG20255031 86000325.jpg207150JPEG2025503186000326.jpg198150JPEG2025503186000327.jpg201150JPEG202550 3186000328.jpg207149JPEG2025503186000329.jpg197144JPEG2025503186000330.jpg196150JPEG202 5503186000331.jpg211148JPEG2025503186000332.jpg197150JPEG2025503186000333.jpg203145JPEG2 025503186000334.jpg200150JPEG2025503186000335.jpg203150JPEG2025503186000336.jpg189149JP EG2025503186000337.jpg188150JPEG2025503186000338.jpg211150JPEG2025503186000339.jpg25149.

[0433] Experimental Example 1 Biological activity test of the compound of the present application MAT2A inhibitory activity MAT2A catalyzed the reaction of L-methionine with ATP to produce S-adenosylmethionine (SAM), inorganic phosphate, and inorganic diphosphate. Malachite green reacted with inorganic phosphate to produce a green product, and the content of inorganic phosphate in the sample could indirectly reflect the enzyme activity of MAT2A.

[0434] The compounds to be measured were prepared in DMSO and diluted 2-fold so that the final initial concentration in the reaction system was 1000 nM, with a 1:3 ratio, resulting in a total of 10 gradient dilutions. The above compounds to be measured at different concentrations were transferred to a 384-well plate. An experimental buffer (50 mM HEPES pH 7.5, 50 mM KCl, 10 mM MgCl2, 10 mM DTT) was prepared. 2× MAT2A recombinant protein was prepared in the buffer and added to the 384-well plate. A mixed solution of 2× L-methionine and ATP was prepared in the buffer and added to the 384-well plate to start the enzyme reaction and react for 60 minutes at room temperature. 20 μL of colorimetric detection reagent was added to the above system, incubated at room temperature for 15 minutes, and absorbance was detected at 630 nm. The inhibition rate of the compound against the enzyme activity was calculated, and the inhibition rate value and the logarithm of the compound concentration were fitted with nonlinear regression (dose response-variable slope) to obtain the IC of the compounds to be measured. 50 Got the value.

[0435] The present application uses the above-mentioned measurement method to test compounds pending measurement and obtain IC 50 Compounds pending measurement were assessed according to the magnitude of the IC values: (A) below 100 nM, (B) between 100 nM and 1 μM, (C) above 1 μM, and (NT) not tested. 50 The values ​​were as shown in Table 3.

[0436] Cellular Symmetric Dimethylarginine (SDMA) Assay MAT2A catalyzed the reaction of L-methionine with ATP to generate SAM, inorganic phosphate, and inorganic diphosphate. SAM is an important methyl donor and substrate of arginine methyltransferase 5 (PRMT5). PRMT5 catalyzed the SDMA modification of multiple proteins in cells. ICW (In-cell Western) detected the intracellular SDMA modification level, which indirectly reflected the inhibition of the target compound on intracellular MAT2A enzyme activity.

[0437] In this application, human colon cancer cell line HCT116 and the corresponding HCT116-MTAP knockout cell line were seeded in 96-well cell culture plates at appropriate cell densities. After 24 hours, the cells were treated with the compounds to be measured at a maximum concentration of 6 μM, diluted 1:4 times in six gradients, and a DMSO-treated group was also set up. The cells were cultured for 4 days in a 37°C / 5% CO2 incubator. To test the inhibitory activity of the compounds to be measured against tumor cell SDMA, the medium was discarded, the plate was washed three times with PBST, and then fixed with 4% paraformaldehyde at room temperature for 20 minutes. The fixative was discarded, the plate was washed three times with PBST, and each well was blocked with a dedicated blocking solution at room temperature for 2 hours. The blocking solution was discarded, the plate was washed three times with PBST, and then incubated with SDMA antibody at 4°C overnight. The next day, the plates were washed three times with PBST, and the secondary antibodies and DRAQ5 were diluted to appropriate concentrations in blocking solution and incubated at room temperature for 2 hours. The plates were washed three times with PBST, and the fluorescent signals at 700 nm and 800 nm were detected using a Li-COR Odyssey dual-color near-infrared laser imager.

[0438] The data were then processed and the 800 nm / 700 nm ratios of each well were statistically analyzed after subtracting the corresponding background values ​​for each well, and a nonlinear regression model was used to plot the S dose-inhibition rate curves and calculate the IC 50 The values ​​were calculated by fitting.

[0439] Inhibition Rate (%) = (1-SDMA dose / SDMA DMSO control) × 100. SDMA dose is the value for the drug-treated group, and SDMA DMSO control is the value for the DMSO control group.

[0440] In the above measurements, exemplary compounds disclosed herein were tested and scored according to the following scores for SDMA IC 50 Inhibition was determined. As shown in Table 3, (A) less than 200 nM, (B) between 200 nM and 1 μM, (C) between 1 μM and 3 μM, (D) greater than 3 μM, and (NT) not tested.

[0441] [Table 3] JPEG2025503186000341.jpg210147JPEG2025503186000342.jpg209145JPEG202 5503186000343.jpg209147JPEG2025503186000344.jpg209145JPEG20255031860 00345.jpg209144JPEG2025503186000346.jpg209145JPEG2025503186000347.j pg209146JPEG2025503186000348.jpg210150JPEG2025503186000349.jpg209148

[0442] As can be seen from Table 3, most of the compounds had good inhibitory activity against MAT2A protein, good SDMA inhibitory activity against MATP knockout HCT116 cells, and a certain selectivity against MATP wild-type HCT116 cells.

[0443] Measurement of tumor cell proliferation inhibition HCT116-MTAP knockout (- / -), HCT116-MTAP wild-type (+ / +), DOHH-2 or Hut-78 cell lines were treated with the target compounds for 5 days, and the inhibition of the target compounds on the growth of tumor cell lines was evaluated by detecting ATP levels using Promega's CellTiter-Glo reagent kit.

[0444] In this application, HCT116-MTAP knockout (- / -) cell line, HCT116-MTAP wild type (+ / +) cell line, DOHH-2 cell line or Hut-78 cell line were seeded in 96-well cell culture plates at appropriate cell density. After 24 hours, the cells were treated with the compounds to be tested at the highest concentration of 10 μM, diluted 1:3 times in 10 gradients, and a DMSO treatment group was also set up. The cells were cultured for 5 days in a 37°C / 5% CO2 incubator. To test the proliferation inhibition of the compounds to be tested against tumor cells, the cells were equilibrated at room temperature for 10 minutes, and then 30 μL of cell proliferation detection reagent CellTiter-Glo (CTG) was added to each well, shaken for 2 minutes, and then incubated in the dark for 15 minutes. Chemiluminescence values ​​were read using a Thermo Varioskan LUX-3020 multifunction microplate reader and converted into a proliferation index to calculate the inhibition rate of compounds against tumor cell proliferation. The inhibition rate values ​​and the logarithm of compound concentrations were fitted with nonlinear regression (dose response-variable slope) to obtain the IC of the compounds. 50 Got the value. In the above assays, exemplary compounds disclosed herein were tested and scored according to the following criteria: IC 50 Inhibition was determined as shown in Table 4: (A) below 500 nM, (B) between 500 nM and 2 μM, (C) above 2 μM, and (NT) not tested.

[0445] [Table 4] JPEG2025503186000351.jpg206147JPEG2025503186000352.jpg207148JPEG202 5503186000353.jpg207144JPEG2025503186000354.jpg207146JPEG20255031860 00355.jpg207146JPEG2025503186000356.jpg207144JPEG2025503186000357.j pg207147JPEG2025503186000358.jpg207146JPEG2025503186000359.jpg207147

[0446] As can be seen from Table 4, most of the compounds had good proliferation inhibitory activity against MATP knockout HCT116 cells and a certain selectivity against MATP wild-type HCT116 cells. They also showed good antiproliferative activity against MATP-deficient tumor cells DOHH2 and Hut-78.

[0447] Experimental Example 2 Liver microsome stability test The phase 1 metabolic stability of pending compounds was evaluated in CD-1 mice, Sprague-Dawley rats, beagle dogs, cynomolgus monkeys, and human liver microsomes.

[0448] Testing system: Animal and human liver microsomes used in the test system were purchased from Xenotech, Corning or other quality suppliers and stored in a refrigerator below -60°C prior to use.

[0449] A brief introduction to the experiment: The samples and control compounds were incubated with animal and human liver microsomes at 37±1°C for a set period of time, with a maximum incubation time of 60 min. At the designated time points, samples were removed and the reaction was stopped with acetonitrile or other organic solvents containing an internal standard. After centrifugation, the resulting supernatant was measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0450] Testing Method: Preparation of buffer solutions Dissolve 73.21 g of potassium dihydrogen phosphate trihydrate and 10.78 g of potassium dihydrogen phosphate in 4000 mL of ultrapure water. Adjust the pH value of the solution to between 7.40±0.10 with 10% phosphoric acid or 1 M potassium hydroxide to a final concentration of 100 mM.

[0451] Preparation of working fluid The sample powder was prepared into a stock solution of a given concentration in DMSO or other organic solvent and then further diluted with the appropriate organic solvent.

[0452] The control compounds testosterone, diclofenac and propafenone were prepared as 10 mM stock solutions in DMSO and then further diluted in the appropriate organic solvent.

[0453] Preparation of liver microsomal solution Microsomes of each species were diluted to a working concentration of 2× with 100 mM potassium phosphate buffer, and the final concentration of microsomes in the reaction system was 0.5 mg / mL.

[0454] Preparation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) regenerating system Appropriate amounts of nicotinamide adenine phosphate dinucleotide (NADP) and isocitrate (ISO) powders were weighed, dissolved in magnesium chloride solution, and mixed uniformly by shaking. Appropriate amounts of isocitrate dehydrogenase (IDH) were added and mixed uniformly by gently inverting. The final concentrations in the reaction system were 1 mM NADP, 1 mM magnesium chloride, 6 mM ISO, and 1 unit / mL IDH, respectively.

[0455] Preparation of stop solution A stop solution was prepared using acetonitrile or other organic solvent containing an internal standard (tolbutamide or other appropriate compound). The prepared stop solution was stored in a refrigerator at 2-8 °C.

[0456] Incubation Process Incubations were completed in 96-well plates. Eight incubation plates were prepared, designated T0, T5, T15, T30, T45, T60, Blank60, and NCF60. The corresponding reaction time points for the first six plates were 0, 5, 15, 30, 45, and 60 minutes, respectively. No sample or control compound was added to the Blank60 plate, and it was sampled after 60 minutes of incubation. In the NCF60 plate, potassium phosphate buffer was incubated for 60 minutes instead of NADPH regenerating system solution. All condition samples were in triplicate.

[0457] After mixing the microsomes with the sample or control compound, the incubation plates Blank60, T5, T15, T30, T45 and T60, except for T0 and NCF60, were pre-incubated in a water bath at 37°C for about 10 minutes. The stop solution was added to the incubation plate T0, followed by the NADPH regenerating system working solution, and 98 μL of potassium phosphate buffer was added to each sample well of the incubation plate NCF60 to start the reaction. After the pre-incubation of the incubation plates Blank60, T5, T15, T30, T45 and T60 was completed, 98 μL of the NADPH regenerating system working solution was added to each sample well to start the reaction. The reaction temperature was 37±1°C, the final reaction volume was 200 μL, and the reaction system contained 0.5 mg / mL microsomes, 1.0 μM substrate, 1 mM NADP, 6 mM ISO and 1 unit / mL IDH.

[0458] At 5, 15, 30, 45 and 60 minutes, respectively, the reaction was terminated by adding cold stop solution containing an internal standard to the reaction plate.

[0459] After completion of the reaction, all reaction plates were shaken uniformly and centrifuged at 3220×g for 20 minutes at 4° C. The supernatant was diluted at a certain ratio and then subjected to LC-MS / MS analysis.

[0460] Sample analysis Sample analysis was performed using liquid chromatography-tandem mass spectrometry (LC-MS / MS) without standard curves and quality control samples. Semiquantitative measurements were performed using the ratio of the analyte peak area to the internal standard peak area. Retention times of the analytes and internal standards, chromatogram acquisition, and chromatogram integration were processed using the software Analyst (Sciex, Framingham, Massachusetts, USA).

[0461] The CV of the internal standard peak areas in each matrix in each analytical batch should be within 20%.

[0462] Data analysis The ratio of the compound to the internal standard peak area in the following formula was converted into a residual rate to determine the in vitro elimination rate constant ke of the compound.

number

[0463] CL (liver) =(CL int(liver) ×Q h ) / (CL int(liver) +Q h ) The parameters in the formula are shown in Table 5.

[0464] [Table 5]

[0465] Liver microsomal stability data for some compounds are shown in Table 6.

[0466] [Table 6]

[0467] Experimental Example 3 Hepatocyte metabolic stability test This example was used to test the metabolic stability of compounds in hepatocytes.

[0468] 0.5 x 10 using pre-warmed medium 6After preparing a 1000μL / mL hepatocyte suspension, 198μL of pre-warmed cell suspension was added to a 96-well plate. 2μL of compounds to be measured were added to each well of the 96-well plate to a final concentration of 1μM, and two parallel wells were set up. For the T=0 min sample, the compounds and cells were thoroughly and homogenously mixed for 1 min, and then 25μL of the sample was immediately taken and added to 125μL of stop solution (acetonitrile solution containing 200ng / mL tolbutamide and 200ng / mL labetalol) in an ice bath and mixed homogenously. At the same time, all plates were placed in a 37℃, 5% CO2 incubator, and the shaker was set to 600 rpm. At the time points of 15, 30, 60 and 90 minutes of incubation, the samples were mixed uniformly, and 25 μL of the sample was taken and added to 125 μL of stop solution (acetonitrile solution containing 200 ng / mL tolbutamide and 200 ng / mL labetalol) in an ice bath, mixed uniformly, and then shaken at 500 rpm for 10 minutes. Then, the samples were centrifuged at 3220×g for 20 minutes at 4°C. After the centrifugation, 80 μL of the supernatant was taken from each well and transferred to another 96-well plate containing 240 μL of ultrapure water. Then, the samples were analyzed by LC-MS / MS, and the internal clearance (CLint) and half-life (T1 / 2) were calculated.

[0469] Hepatocyte metabolic stability data for some compounds are shown in Table 7.

[0470] [Table 7]

[0471] Test Example 4 Pharmacokinetic study in rats In this example, the pharmacokinetic behavior of the compound in SD rats was examined after administration by intravenous injection (IV) and oral gavage (PO).

[0472] On the day of administration, the rats were weighed and the dose volume was calculated. Three rats were included in each group. For each compound, two groups were tested: one group was administered a single dose intravenously, and the other group was administered a single dose by oral gavage. Whole blood samples were collected at the designated time points (0.25, 0.5, 1, 2, 4, 8, and 24 h after administration) by jugular vein blood collection. After collection, the blood samples were immediately transferred to tagged commercial sample tubes containing K2-EDTA (0.85-1.15 mg) and then centrifuged (3200×g, 4°C, 10 min) and plasma was collected. The plasma was transferred to pre-cooled centrifuge tubes, flash frozen in dry ice, and then stored in an ultra-low temperature refrigerator at or below -60°C until LC-MS / MS analysis was performed.

[0473] Plasma concentrations were measured using an LC-MS / MS method. The plasma drug concentration data of the compounds were processed with a noncompartmental model using WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. The linear-logarithmic trapezoidal method was used to calculate the relevant pharmacokinetic parameters.

[0474] The pharmacokinetic results of some compounds in rats are shown in Table 8.

[0475] [Table 8]

[0476] As can be seen from the results in Table 8, the compounds of the present invention had good oral exposure and oral bioavailability in rats.

[0477] Experimental Example 5 Pharmacokinetic study in mice In this example, the pharmacokinetic behavior of the compound in BALB / c mice was examined following administration by intravenous injection (IV) and oral gavage (PO).

[0478] On the day of administration, the actual body weight of the mice was weighed and the administration volume was calculated. Two groups of mice, nine in each group, were tested for each compound, one group was administered a single dose intravenously and the other group was administered a single dose by oral gavage. Whole blood samples were collected at the designated time points (0.25, 0.5, 1, 2, 4, 8, and 24 h after administration) by retro-orbital blood collection. After collection, the blood samples were immediately transferred to tagged commercial sample tubes containing K2-EDTA (0.85-1.15 mg) and then centrifuged (3200×g, 4°C, 10 min) and plasma was collected. The plasma was transferred to pre-cooled centrifuge tubes, flash frozen in dry ice, and then stored in an ultra-low temperature refrigerator at -60°C or lower until LC-MS / MS analysis was performed.

[0479] Plasma concentrations were measured using an LC-MS / MS method. The plasma drug concentration data of the compounds were processed with a noncompartmental model using WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. The linear-logarithmic trapezoidal method was used to calculate the relevant pharmacokinetic parameters.

[0480] The pharmacokinetic results of some compounds in mice are shown in Table 9.

[0481] [Table 9]

[0482] As can be seen from the results in Table 9, the compounds of the present invention have good oral exposure and oral bioavailability in mice, among which B60, B181, B245, B254, B256, B257 and B258 have higher AUC and longer half-life (T1 / 2), and B258 has a higher Vz value and better tissue distribution.

[0483] Experimental Example 6 hERG Inhibition Test HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at a culture temperature of 37°C and a CO2 concentration of 5%.TM After digestion with Express, centrifugation was performed to reduce the cell density to 2 x 10 6 After adjusting the concentration to 1000 cells / mL, the cells were gently mixed for 15-20 min on a room temperature equilibrated shaker and subjected to patch clamp testing in the instrument. The prepared cell medium was replaced with extracellular solution. The intracellular and extracellular solutions were aspirated from the liquid pool and added to the intracellular pool, cell and test substance pool of the QPlate chip, respectively. Whole-cell patch clamp recorded the voltage stimulation of the whole-cell hERG potassium current, and the test data were collected and stored by Qpatch. The compounds were started at 30 μM and diluted 3-fold, and six concentration points were set, with each drug concentration administered twice for at least 5 minutes. The current detected by each cell in the compound-free external solution was detected independently and repeated twice using at least two cells at each concentration as an autologous control group. All electrophysiological tests were performed at room temperature.

[0484] Data analysis was performed by first standardizing the currents affected by each drug concentration and the blank control current (Peak tail current compound / Peak tail current vehicle ), then the inhibition rate (1-Peak tail current compound / Peak tail current vehicle The mean and standard error were calculated for each concentration, and the median inhibitory concentration of each compound was calculated.

number

[0485] The hERG inhibitory activity data of some compounds are shown in Table 10.

[0486] [Table 10] As can be seen from the results in Table 10, the compounds of the present invention had no hERG inhibitory activity.

[0487] Experimental Example 7 Cytochrome oxidase P450 inhibition test 1) Preparation of buffer solutions: 100 mM K-Buffer: 9.5 mL of stock solution A was mixed with 40.5 mL of stock solution B, the total volume was adjusted to 500 mL with ultrapure water, and the buffer was titrated to pH 7.4 with KOH or H3PO4.

[0488] Source A (1 M potassium dihydrogen phosphate): 136.5 g potassium dihydrogen phosphate in 1 L water Stock solution B (1 M potassium dihydrogen phosphate): 174.2 g potassium dihydrogen phosphate in 1 L water 2) Preparation of test specimen The test article powder was prepared as a stock solution at a fixed concentration in DMSO or other organic solvent and then further diluted with the appropriate organic solvent.

[0489] 3) In vitro incubation The in vitro incubation system of liver microsomes for CYP450 enzyme metabolic phenotype research is a biochemical reaction in which redox coenzymes and enzyme-specific selective inhibitors are added to the prepared liver microsomes under conditions simulating physiological temperature and physiological environment.

[0490] 4) Detection of prototype drugs or metabolites The concentrations of the prototype drugs or their metabolites during the incubation were measured using LC-MS / MS.

[0491] The CYP inhibitory activity data of some compounds are shown in Table 11.

[0492] [Table 11] As can be seen from the results in Table 11, the compounds of the present invention had no CYP hepatic enzyme inhibitory activity.

[0493] Experimental Example 8 PXR activation test In this example experiment, the activating effect of compounds on PXR was tested.

[0494] Add 100 µL of DPX2 stable transfected cells (4.5 × 10) to each well of a 96-well cell culture plate. 5 Cells / mL, prepared in Puracyp medium) were inoculated into the wells, and then the 96-well plate was placed in a 37°C incubator. After 24 hours, the 96-well plate was removed from the incubator, and the medium was replaced with 100 μL of the ready-to-test compounds (final concentrations of 10 μM and 30 μM), the positive control compound rifampicin (final concentration of 10 μM) and DMSO treatment group (final concentration of 0.1%), and three parallel wells were set up. The test plate was returned to the incubator. After 24 hours, the medium was replaced with freshly prepared ready-to-test compounds and rifampicin solutions, and the test plate was returned to the incubator. After 48 hours of compound treatment, the test plate was removed from the incubator, the medium in the wells was discarded, washed twice with PBS, and 1× CellTiter-Fluor was added to the wells. TM 50 μL of medium containing Cell Viability Assay reagent was added and incubated at 37°C for 30 minutes. The test plate was removed and equilibrated to room temperature, and the fluorescent signal was detected by a microplate reader under the conditions of 400 nm excitation light / 505 nm emission light. Then, 50 μL of medium containing ONE-Glo Assay reagent was added to each well, shaken to mix evenly, incubated at room temperature for 5 minutes, and chemiluminescence was detected by a microplate reader. The data was analyzed to evaluate the activating effect of the compounds waiting to be measured on PXR.

[0495] PXR activation data for some compounds are shown in Table 12.

[0496] [Table 12] As can be seen from the results in Table 12, the compounds of the present invention have relatively weak PXR activation activity at 10 μM and moderate PXR activation activity at 30 μM. Among them, the activation activity of B181 and B257 against PXR at 30 μM was also very weak, much lower than other compounds.

[0497] Experimental Example 9 Mouse tumor pharmacodynamic model In this example experiment, the in vivo efficacy of compounds was tested following administration by oral gavage (PO) in a mouse xenograft tumor model.

[0498] Human colorectal adenocarcinoma HCT116-MTAP-KO cells were cultured in McCoy's medium containing 10% fetal bovine serum, 1% penicillin and streptomycin. ’ The monolayers were cultured in vitro in 5A medium at 37°C and 5% CO2. Subculture was performed three times a week by pancreatin digestion. When the cells reached 80%-90% saturation, they were harvested, counted, and inoculated. 0.1 mL (5 × 10 6 HCT116-MTAP-KO cells (1000 cells / mL) were inoculated subcutaneously into the right dorsal region of each mouse. On day 16 after cell inoculation, the mean tumor volume was 154 mm 3 The mice were randomly divided into groups and administered the drug by gavage once a day, while recording the changes in body weight and tumor volume. After a certain number of days from administration, the experiment was terminated. The changes in tumor volume and body weight of the mice were statistically analyzed. AG270 (CAS:2201056-66-6) was the positive control compound.

[0499] [Table 13] Human pancreatic cancer KP-4 cells were cultured in vitro in monolayer in 1640 medium containing 10% fetal bovine serum, 1% penicillin and streptomycin at 37°C and 5% CO2. Subculture was performed three times a week by pancreatin digestion. When the cells reached 80%-90% saturation, they were harvested, counted, and inoculated. 0.1 mL (5 × 106 Each mouse was inoculated with KP-4 cells (100 x 100 mm2) subcutaneously into the right dorsal region. On the 34th day after cell inoculation, the mean tumor volume was 154 mm2. 3 The mice were randomly divided into groups and administered the drug by gavage once a day, while recording the changes in body weight and tumor volume. The experiment was terminated 29 days after administration. The changes in tumor volume and body weight of the mice were statistically analyzed. AG270 (CAS:2201056-66-6) was the positive control compound.

[0500] [Table 14] As can be seen from the results in Tables 13 and 14, the compounds of the present invention have good internal pharmacological effects.

[0501] Experimental Example 10: Saturation solubility test of samples in FaSSIF solution Experimental procedure Preparation of FaSSIF solution Preparation of buffer (pH 6.5): Approximately 0.21 g of sodium hydroxide, approximately 2.24 g of sodium dihydrogen phosphate dihydrate, and 3.09 g of sodium chloride were weighed out and dissolved in 500 mL of water, and the pH was adjusted to 6.5 with 1 N sodium hydroxide or 1 N hydrochloric acid.

[0502] 112 mg of FaSSIF solid was weighed into a 50 mL measuring flask, and the above-mentioned buffer solution was added to dissolve and dilute up to the graduation mark. The flask was shaken uniformly and allowed to stand at room temperature for 2 h or more.

[0503] Sample preparation Sample: Approximately 1 mg of sample was taken, 1 mL of FaSSIF solution was added, the mixture was stirred at room temperature overnight, centrifuged, and the supernatant was collected for sampling analysis.

[0504] Control solution: Approximately 1.5 mg of sample was precisely weighed into a 50 mL measuring flask, dissolved by adding DMF, diluted to the scale, and mixed uniformly to obtain the control solution.

[0505] Preparation of mobile phase Mobile phase A: 1000 mL of purified water was accurately weighed, 1 mL of formic acid was added, and the mixture was mixed uniformly and degassed by ultrasonication to obtain mobile phase A.

[0506] Mobile phase B: acetonitrile.

[0507] Chromatographic conditions (Table 15) [Table 15] result The main component peak of the control product and the peak in the sample that matched its retention time were integrated, and the concentration in the FaSSIF solution was calculated by the external standard method. The test results are shown in Table 16.

[0508] [Table 16] As can be seen from the results in Table 15, the compounds of the present invention had good solubility.

[0509] It should be understood that the above examples are illustrative and are not intended to encompass all possible embodiments within the scope of the claims. Various modifications and changes can be made based on the above examples without departing from the scope of the present disclosure. Similarly, the technical features of the above examples can be combined in any combination to form further examples of the present application that are not explicitly described. Therefore, the above examples merely illustrate some embodiments of the present application and do not limit the scope of the claims of the present application.

Claims

1. A compound of formula (I) or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof, 【Chemistry 1】 Among them, w is CR ３ or N, X is CR ４ or N, y is CR ５ or N, z is CR ６ or N, v and u are each independently selected from C or N; 【change】 represents that the bond may be a single bond or a double bond, R ３ and R ５ are each independently selected from hydrogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a sulfonyl group, a halogen, a cycloalkyl group, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group, a heteroaryloxy group, a heterocyclyl group, a heterocyclyloxy group, and a cycloalkyloxy group, and optionally, R ３ may further include one or more R ３ａ and optionally substituted with R ５ may further include one or more R ５ａ and each R ３ａ and R ５ａ are each independently selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylamino group, a dialkylamino group, a halogen, a sulfonyl group, a cycloalkyl group, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group, a heteroaryloxy group, a cycloalkyloxy group, a heterocyclyl group, and a heterocyclyloxy group, and optionally, R ３ａ may further include one or more R ３ｂ is substituted with R ５ａ may further include one or more R ５ｂ and each R ３ｂ and R ５ｂ are each independently selected from an alkyl group, a halogen atom, a hydroxy group, an alkoxy group, an amino group, and a heterocyclyloxy group; R ４ and R ６ are each independently selected from hydrogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group, a cyano group, an amino group, and an acyl group, and optionally, R ４ may further include one or more R ４ａ is substituted with R ６ may further include one or more R ６ａ and each R ４ａ and R ６ａ are each independently selected from an alkyl group, a halogen, an amino group, an alkylamino group, and a dialkylamino group; R １ is -X １ -R ７ Among them, X １ is a bond or an alkylene group, and optionally １ is one or more X １ａ and each X １ａ are each independently selected from a halogen, an alkyl group, and a cycloalkyl group, ７ is selected from a cycloalkyl group, an aryl group, a heteroaryl group, and a heterocyclyl group, among which R ７ optionally one or more R ７ａ and each R ７ａ are each selected from an alkyl group, an alkoxy group, a hydroxy group, a sulfonyl group, a halogen, a cyano group, an alkenyl group, an alkynyl group, a carboxyl group, an acyl group, an amino group, a cycloalkyl group, an aryl group, a heterocyclyl group, a heteroaryl group, an oxo group, and a urea group, and optionally, R ７ａ may further include one or more R ７ｂ and R ７ｂ are each selected from a halogen, an alkyl group, an alkoxy group, a hydroxy group, an amino group, an alkenyl group, an alkynyl group, an alkylamino group, a dialkylamino group, a sulfonyl group, a heterocyclyl group, and a heteroaryl group; B is selected from 5-, 6-, or 7-membered aryl or heteroaryl groups, of which B optionally includes one or more R ２ is replaced by Each R ２ are each independently selected from hydrogen, halogen, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkyloxy group, a heterocyclyl group, a heterocyclyloxy group, an aryl group, a heteroaryl group, a heteroaryloxy group, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, or two adjacent R ２ form a 3- to 7-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, optionally ２ Or two adjacent R ２ The 3- to 7-membered carbocyclic, heterocyclic, aryl or heteroaryl ring formed may further include one or more R ２ａ and each R ２ａ are each independently selected from halogen, an alkyl group, a heterocyclyl group, a heterocyclyloxy group, an amino group, a heteroaryl group, a cycloalkyl group, an aryl group, an alkylamino group, a dialkylamino group, a hydroxy group, a sulfonyl group, an alkoxy group, a cyano group, an alkenyl group, an acyl group, an alkynyl group, and an oxo group, and optionally ２ａ may further include one or more R ２ｂ and each R ２ｂ are each selected from an alkyl group substituted with 0 to 3 halogens, an amino group, an alkylamino group, a dialkylamino group, an alkoxy group substituted with 0 to 3 halogens, a halogen, a hydroxy group, a heterocyclyl group unsubstituted or substituted with an alkyl group, a cyano group, and an oxo group, and are preferably selected from an alkyl group, an amino group, an alkylamino group, a dialkylamino group, an alkoxy group, a halogen, a hydroxy group, and an oxo group, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and a pharma- ceutically acceptable salt thereof.

2. The B is 【Chemistry 2】 wherein B is optionally one or more R ２ or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof.

3. The compound has the structure shown in formula (IA): 【Chemistry 3】 Among them, m is N, O, S, NR ９ and C.R. ９ Selected from t is N, O, S, NR ８ and C.R. ８ Selected from q is N, O, S, NR ２ and C.R. ２ Selected from Each R ２ , R ８ , R ９ are each independently selected from hydrogen, halogen, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkyloxy group, a heterocyclyl group, a heterocyclyloxy group, an aryl group, a heteroaryl group, a heteroaryloxy group, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, or adjacent R ８ and R ２ form a 3- to 7-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, or adjacent R ８ and R ９ forms a 3- to 7-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, Optionally, the R ２ may further include one or more R ２ａ is replaced by Optionally, the R ８ may further include one or more R ８ａ is replaced by Optionally, the R ９ may further include one or more R ９ａ is replaced by Optionally, the adjacent R ８ and R ２ The 3- to 7-membered carbocyclic, heterocyclic, aryl or heteroaryl ring formed may further include one or more R ２ａ Or R ８ａ is replaced by Optionally, the adjacent R ８ and R ９ The 3- to 7-membered carbocyclic, heterocyclic, aryl or heteroaryl ring formed may further include one or more R ９ａ Or R ８ａ is replaced by Each of the R ２ａ , R ９ａ Or R ８ａ are each independently selected from a halogen, an alkyl group, a heterocyclyl group, a heterocyclyloxy group, an amino group, a heteroaryl group, an acyl group, a cycloalkyl group, an aryl group, an alkylamino group, a dialkylamino group, a hydroxy group, a sulfonyl group, an alkoxy group, a cyano group, an alkenyl group, an alkynyl group, and an oxo group; Optionally, the R ２ａ may further include one or more R ２ｂ is replaced by Optionally, the R ８ａ may further include one or more R ８ｂ is replaced by Optionally, the R ９ａ may further include one or more R ９ｂ is replaced by Each R ２ｂ , R ８ｂ Or R ９ｂ are each selected from an alkyl group substituted with 0 to 3 halogens, an alkoxy group substituted with 0 to 3 halogens, a halogen, a hydroxy group, a heterocyclyl group unsubstituted or substituted with an alkyl group, a cyano group and an oxo group, preferably selected from an alkyl group, an alkoxy group, a halogen, a hydroxy group and an oxo group, or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharma- ceutically acceptable salt thereof.

4. The compound has the formula (IB １ ), (IB ２ ), (IB ３ ), (IB ４ ) or (IB ５ ) 【Chemistry 4】 Of these, m is N, O, S, NR ９ and C.R. ９ Selected from t is N, O, S, NR ８ and C.R. ８ Selected from Among them, R ８ Or R ９ are each independently selected from hydrogen, halogen, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkyloxy group, a heterocyclyl group, a heterocyclyloxy group, an aryl group, a heteroaryl group, a heteroaryloxy group, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, or adjacent R ８ and R ９ form a 3- to 7-membered carbocyclic, heterocyclic or heteroaryl ring, and optionally, ８ may further include one or more R ８ａ and optionally, R ９ may further include one or more R ９ａ and optionally, the adjacent R ８ and R ９ The 3- to 7-membered carbocyclic, heterocyclic or heteroaryl ring formed may further include one or more R ８ａ Or R ９ａ and R ８ａ Or R ９ａ are each independently selected from a halogen, an alkyl group, a heterocyclyl group, a heterocyclyloxy group, an amino group, a heteroaryl group, a cycloalkyl group, an aryl group, an alkylamino group, a dialkylamino group, a hydroxyl group, an acyl group, a sulfonyl group, an alkoxy group, a cyano group, an alkenyl group, an alkynyl group, and an oxo group, and optionally, ８ａ may further include one or more R ８ｂ and optionally, R ９ａ may further include one or more R ９ｂ and R ８ｂ Or R ９ｂ are each independently selected from an alkyl group substituted with 0 to 3 halogens, an alkoxy group substituted with 0 to 3 halogens, a halogen, a hydroxy group, a heterocyclyl group unsubstituted or substituted with an alkyl group, a cyano group, and an oxo group, and are preferably selected from an alkyl group, an alkoxy group, a halogen, a hydroxy group, and an oxo group; Among them, the formula (IB １ ), (IB ２ ), (IB ４ ) or (IB ５ In the formula (IB), at least one of v, u, m and t is a substituted or unsubstituted heteroatom; ３ wherein at least two of v, u, m and t are substituted or unsubstituted heteroatoms; Among them, y is CR ５ If R ５ is not hydrogen, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof.

5. The compound has the formula (IC １ ), (I.C. ２ ), (I.C. ３ ), (I.C. ４ ) or (IC ５ ) 【Chemistry 5】 Among them, the formula (IC １ ), (I.C. ２ ), (I.C. ４ ) or (IC ５ In the formula (IC), at least one of v, u, m and t is a substituted or unsubstituted heteroatom; ３ wherein at least two of v, u, m and t are substituted or unsubstituted heteroatoms; Of these, w is CR ３ and x is CR ４ and Among them, R ５ is a halogen, a cyano group, an amino group, a hydroxyl group, C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ an alkynyl group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, a heteroaryl group having 5 to 10 ring atoms, optionally with R ５ may further include one or more R ５ａ and each R ５ａ are each independently C １ ~C ６ Alkyl group, C １ ~C ６ selected from an alkoxy group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, a hydroxy group, an alkylamino group, a dialkylamino group, and an oxo group; The R １ is -X １ -R ７ Among them, X １ is a bond or a methylene group, and optionally, １ is one or more X １ａ and each X １ａ each independently represents a halogen and C １ ~C ３ alkyl group, ７ is selected from a cycloalkyl group having 4 to 10 ring atoms, an aryl group having 6 to 12 ring atoms, a heteroaryl group having 5 to 12 ring atoms, and a heterocyclyl group having 3 to 12 ring atoms, among which R ７ optionally one or more R ７ａ and each R ７ａ each independently represents an oxo group, a halogen, or C １ ~C ６ Alkyl groups, cycloalkyl groups having 3 to 10 ring atoms, C １ ~C ６ Alkoxy group, cycloalkyloxy group having 3 to 6 ring atoms, cyano group, amino group, hydroxy group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ alkynyl, sulfonyl, acyl, carboxyl, heterocyclyl having 3 to 12 ring atoms, heteroaryl having 5 to 10 ring atoms, and urea; optionally R ７ａ may further include one or more R ７ｂ and R ７ｂ are halogen and C, respectively. １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, hydroxy group, amino group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Alkylamino group, di(C １ ~C ６ ) an alkylamino group, a sulfonyl group, a heterocyclyl group having 3 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms, among which X １ is a methylene group, R ７ is not a substituted or unsubstituted aryl group, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof.

6. The ring B is selected from the following structures: 【Chemistry 6】 6. The compound according to claim 1, 3 to 5, or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, or a pharma- ceutically acceptable salt thereof.

7. The compound optionally has the structure: 【Chemistry 7】 7. The compound according to claim 1, 3 to 6, or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, or a pharma- ceutically acceptable salt thereof.

8. The compound optionally has the structure: 【Chemistry 8】 8. The compound according to claim 1, 3 to 7, or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, or a pharma- ceutically acceptable salt thereof.

9. w is CR ３ and R ３ is hydrogen, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ is selected from an alkoxy group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a heterocyclyl group having 5 to 10 ring atoms, a heterocyclyloxy group having 5 to 10 ring atoms, and a cycloalkyloxy group having 3 to 10 ring atoms, and preferably ３ is hydrogen, C １ ~C ４ Alkyl group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ４ is selected from an alkoxy group, a halogen atom, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, and a cycloalkyloxy group having 3 to 6 ring atoms, and more preferably, ３ is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, and a piperidinyloxy group; Optionally, R ３ may further include one or more R ３ａ and each R ３ａ are each independently C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylamino group, di(C １ ~C ６ a) an alkyl) amino group, a halogen atom, a sulfonyl group, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 5 to 10 ring atoms, and a heterocyclyloxy group having 5 to 10 ring atoms, and preferably, ３ａ are each independently C １ ~C ３ Alkyl group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ３ Alkoxy group, C １ ~C ３ Alkylamino group, di(C １ ~C ３ is preferably selected from the group consisting of an alkyl)amino group, a halogen atom, a sulfonyl group, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, and a heterocyclyloxy group having 5 to 6 ring atoms, more preferably the group consisting of the above R ３ａ are each independently selected from a methyl group and a dimethylamino group; Optionally, R ３ａ may further include one or more R ３ｂ and each R ３ｂ are each independently C １ ~C ３ Alkyl group, halogen, hydroxyl group, C １ ~C ３ 9. The compound according to claim 1 , wherein the aryl group is selected from the group consisting of an alkoxy group and an amino group, or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharma- ceutically acceptable salt thereof.

10. x is CR ４ and the above R ４ is hydrogen, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ is selected from the group consisting of an alkylthio group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group, and is preferably selected from the group consisting of an alkylthio group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group. ４ is hydrogen, C １ ~C ４ Alkyl group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ４ Alkoxy group, C １ ~C ４ is selected from the group consisting of an alkylthio group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, and an acyl group, and more preferably, ４ is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a fluorine group, a chlorine group, a bromine group, and a cyano group; Optionally, R ４ may further include one or more R ４ａ and each R ４ａ are each independently C １ ~C ６ Alkyl group, halogen, amino group, C １ ~C ６ Alkylamino groups and di(C １ ~C ６ ) alkylamino groups, preferably the above R ４ａ are each independently C １ ~C ３ Alkyl group, halogen, amino group, C １ ~C ３ Alkylamino groups and di(C １ ~C ３ 10. The compound according to claim 1, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of aryl, aryloxy ...

11. The R ５ is a halogen, a cyano group, an amino group, a hydroxyl group, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ is selected from the group consisting of an alkoxy group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, and a heteroaryl group having 5 to 10 ring atoms, and is preferably selected from the group consisting of the above R ５ is halogen, C １ ~C ６ Alkyl group, C １ ~C ６ is selected from the group consisting of an alkoxy group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 4 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms, and more preferably, ５ is selected from chlorine, fluorine, bromine, iodine, a cyano group, an ethyl group, an n-propyl group, an isopropyl group, a methyl group, a cyclopropyl group, a methoxy group, and a cyclopropyloxy group; Optionally, R ５ may further include one or more R ５ａ and each R ５ａ are each independently C １ ~C ６ Alkyl group, C １ ~C ６ is selected from the group consisting of an alkoxy group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and a hydroxy group, and is preferably selected from the group consisting of the above R ５ａ are each independently C １ ~C ６ is selected from the group consisting of an alkyl group, a halogen atom, a cyano group, and a cycloalkyl group having 3 to 6 ring atoms, and more preferably, ５ａ are each independently selected from fluorine and a cyano group, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof according to any one of claims 1 to 10.

12. The z is CR ６ or N, Among them, R ６ is hydrogen, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ is selected from the group consisting of an alkylthio group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group, and is preferably selected from the group consisting of an alkylthio group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group. ６ is hydrogen, C １ ~C ４ Alkyl group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ４ Alkoxy group, C １ ~C ４ is selected from the group consisting of an alkylthio group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, and an acyl group, and more preferably, ６ is selected from hydrogen, fluorine, chlorine, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, a methoxy group, a cyclopropyloxy group, and a cyano group; Optionally, R ６ may further include one or more R ６ａ and each R ６ａ are each independently C １ ~C ６ Alkyl group, halogen, amino group, C １ ~C ６ Alkylamino groups and di(C １ ~C ６ ) alkylamino groups, preferably the above R ６ａ are each independently C １ ~C ３ Alkyl group, halogen, amino group, C １ ~C ３ Alkylamino groups and di(C １ ~C ３ 12. The compound according to claim 1, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of aryl, aryloxy ...

13. The R １ is -X １ -R ７ Among them, X １ is a bond or a methylene group, Optionally, the above X １ is one or more X １ａ and each X １ａ each independently represents a halogen and C １ ~C ３ alkyl group, preferably methyl group; The above R ７ is selected from a cycloalkyl group having 4 to 10 ring atoms, an aryl group having 6 to 12 ring atoms, a heteroaryl group having 5 to 12 ring atoms, and a heterocyclyl group having 3 to 12 ring atoms; Preferably, the above R ７ is selected from the following groups: 【Chemistry 9】 More preferably, the above R ７ is selected from the following groups: 【Chemistry 10】 Among them, R ７ optionally one or more R ７ａ and each R ７ａ each independently represents an oxo group, a halogen, or C １ ~C ６ Alkyl groups, cycloalkyl groups having 3 to 10 ring atoms, C １ ~C ６ Alkoxy group, cycloalkyloxy group having 3 to 6 ring atoms, cyano group, amino group, hydroxy group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ is selected from the group consisting of an alkynyl group, a sulfonyl group, an acyl group, a carboxyl group, a heterocyclyl group having 3 to 12 ring atoms, a heteroaryl group having 5 to 10 ring atoms, and a urea group, and is preferably selected from the group consisting of an alkynyl group, a sulfonyl group, an acyl group, a carboxyl group, a heterocyclyl group having 3 to 12 ring atoms, a heteroaryl group having 5 to 1 ７ａ each independently represents an oxo group, a halogen, or C １ ~C ４ Alkyl groups, cycloalkyl groups having 3 to 6 ring atoms, C １ ~C ４ Alkoxy groups, cycloalkyloxy groups having 3 to 4 ring atoms, cyano groups, amino groups, hydroxy groups, C ２ ~C ４ Alkenyl group, C ２ ~C ４ is selected from the group consisting of an alkynyl group, a sulfonyl group, an acyl group, a carboxyl group, a heterocyclyl group having 3 to 6 ring atoms, a heteroaryl group having 5 to 6 ring atoms, and a urea group, and more preferably, ７ａ are each independently selected from fluorine, chlorine, bromine, a hydroxyl group, a cyano group, a methoxy group, a methyl group, a cyclopropyloxy group, and a cyclopropyl group, and are most preferably selected from the above R ７ａ are each independently selected from fluorine, chlorine, bromine, a hydroxyl group, a cyano group, a methoxy group, a methyl group, and a cyclopropyloxy group; Optionally, R ７ａ may further include one or more R ７ｂ and R ７ｂ are halogen and C, respectively. １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, hydroxy group, amino group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Alkylamino group, di(C １ ~C ６ ) selected from an alkylamino group, a sulfonyl group, a heterocyclyl group having 3 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms, preferably each R ７ｂ each independently represents a halogen, C １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy group, hydroxy group, amino group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ３ Alkylamino group, di(C １ ~C ３ ) an alkylamino group, a sulfonyl group, a heterocyclyl group having 3 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms, more preferably each R ７ｂ are each independently selected from fluorine, chlorine and bromine; Among them, X １ is a methylene group, R ７ is not a substituted or unsubstituted aryl group, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof.

14. The R ２ is hydrogen, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ is selected from the group consisting of an alkynyl group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group and an oxo group, and preferably ２ is hydrogen, halogen, C １ ~C ４ Alkyl group, C １ ~C ４ Alkoxy group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ is selected from an alkynyl group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group and an oxo group, and more preferably, ２ is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyano group, a methoxy group, and an oxo group; Optionally, the R ２ may further include one or more R ２ａ and each R ２ａ each independently represents a halogen, C １ ~C ６ alkyl groups, heterocyclyl groups having 4 to 10 ring atoms, heterocyclyloxy groups having 4 to 10 ring atoms, amino groups, heteroaryl groups having 5 to 10 ring atoms, cycloalkyl groups having 3 to 10 ring atoms, aryl groups having 6 to 10 ring atoms, C １ ~C ６ Alkylamino group, di(C １ ~C ６ ) an alkylamino group, a hydroxyl group, a sulfonyl group, C １ ~C ６ Alkoxy group, cyano group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ alkynyl and oxo groups, preferably each R ２ａ each independently represents a halogen, C １ ~C ４ alkyl groups, heterocyclyl groups having 5 to 6 ring atoms, heterocyclyloxy groups having 5 to 6 ring atoms, amino groups, heteroaryl groups having 5 to 6 ring atoms, cycloalkyl groups having 3 to 6 ring atoms, aryl groups having 6 to 10 ring atoms, C １ ~C ３ Alkylamino group, di(C １ ~C ３ ) an alkylamino group, a hydroxyl group, a sulfonyl group, C １ ~C ４ Alkoxy group, cyano group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ More preferably, each R ２ａ are each independently selected from a methyl group, a chlorine group, a fluorine group, a phenyl group, a cyclopropyl group, an oxo group, an amino group, a methylamino group, a dimethylamino group, a methoxy group, a hydroxy group, a pyridyl group, a pyrazolyl group, and a pyrimidinyl group, and most preferably each R ２ａ are each independently selected from a methyl group, a chlorine group, a fluorine group, a phenyl group, a cyclopropyl group, an oxo group, an amino group, a methylamino group, a dimethylamino group, a methoxy group, a hydroxy group, a pyridyl group, and a pyrazolyl group; Optionally, the R ２ａ may further include one or more R ２ｂ and each R ２ｂ Each is C substituted with 0 to 3 halogens. １ ~C ３ Alkyl group, C substituted with 0 to 3 halogens １ ~C ３ Alkoxy group, halogen, hydroxy group, unsubstituted or C １ ~C ３ is selected from a 5- to 6-membered heterocyclyl group substituted with an alkyl group, a cyano group, and an oxo group, and is preferably C １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy groups, halogens, hydroxy groups and oxo groups, more preferably each R ２ｂ are selected from a methoxy group and a methyl group, respectively, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof according to any one of claims 1 to 13.

15. The R ８ , R ９ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ an alkynyl group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, or an adjacent R ８ and R ９ forms a 5- to 6-membered carbocyclic, heterocyclic or heteroaryl ring, and preferably ８ , R ９ are each independently hydrogen, halogen, or C １ ~C ４ Alkyl group, C １ ~C ４ Alkoxy group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ an alkynyl group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an aryl group having 6 ring atoms, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, or an adjacent R ８ and R ９ forms a 5- to 6-membered heterocycle or heteroaryl ring, and more preferably, ８ , R ９ are each independently selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyano group, a methoxy group, an oxo group, a cyclopropyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a phenyl group, and a propenyl group, or adjacent R ８ and R ９ teeth, 【Chemistry 11】 Forming Optionally, the above R ８ may further include one or more R ８ａ and optionally substituted with the above R ９ may further include one or more R ９ａ and optionally, the adjacent R ８ and R ９ The carbocyclic, heterocyclic or heteroaryl ring formed by may further include one or more R ８ａ Or R ９ａ is replaced by The above R ８ａ Or R ９ａ each independently represents a halogen, C １ ~C ６ alkyl groups, heterocyclyl groups having 4 to 10 ring atoms, heterocyclyloxy groups having 4 to 10 ring atoms, amino groups, heteroaryl groups having 5 to 10 ring atoms, cycloalkyl groups having 3 to 10 ring atoms, aryl groups having 6 to 10 ring atoms, C １ ~C ６ Alkylamino group, di(C １ ~C ６ ) an alkylamino group, a hydroxyl group, a sulfonyl group, C １ ~C ６ Alkoxy group, cyano group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ alkynyl and oxo groups, preferably each R ８ａ Or R ９ａ each independently represents a halogen, C １ ~C ４ an alkyl group, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an amino group, a heteroaryl group having 5 to 6 ring atoms, a cycloalkyl group having 3 to 6 ring atoms, an aryl group having 6 ring atoms, C １ ~C ３ Alkylamino group, di(C １ ~C ３ ) an alkylamino group, a hydroxyl group, a sulfonyl group, C １ ~C ４ Alkoxy group, cyano group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ More preferably, each R ８ａ Or R ９ａ are each independently selected from the group consisting of methyl, chlorine, fluorine, bromine, phenyl, cyclopropyl, oxo, amino, methylamino, dimethylamino, methoxy, hydroxy, pyridyl, pyrazolyl, sulfonyl, morpholinyl, tetrahydrofuranyl, isoxazolyl, and pyrimidinyl, and most preferably each R ８ａ Or R ９ａ are each independently selected from a methyl group, a chlorine group, a fluorine group, a bromine group, a phenyl group, a cyclopropyl group, an oxo group, an amino group, a methylamino group, a dimethylamino group, a methoxy group, a hydroxy group, a pyridyl group, a pyrazolyl group, a sulfonyl group, a morpholinyl group, a tetrahydrofuranyl group, and an isoxazolyl group; Optionally, the above R ８ａ may further include one or more R ８ｂ and optionally substituted with the above R ９ａ may further include one or more R ９ｂ and R ８ｂ Or R ９ｂ each independently represents C substituted with 0 to 3 halogens １ ~C ３ Alkyl group, C substituted with 0 to 3 halogens １ ~C ３ Alkoxy group, halogen, hydroxy group, unsubstituted or C １ ~C ３ is selected from a 5- to 6-membered heterocyclyl group substituted with an alkyl group, a cyano group, and an oxo group, and is preferably C １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy groups, halogens, hydroxy groups and oxo groups, and preferably the above R ８ｂ Or R ９ｂ are each independently selected from a methoxy group and a methyl group, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharma- ceutically acceptable salt thereof according to any one of claims 3 to 14.

16. w is CR ３ and x is CR ４ and y is CR ５ and z is CR ６ or N, The R ３ is hydrogen, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ selected from an alkoxy group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a heterocyclyl group having 5 to 10 ring atoms, a heterocyclyloxy group having 5 to 10 ring atoms, and a cycloalkyloxy group having 3 to 10 ring atoms; Optionally, R ３ may further include one or more R ３ａ and each R ３ａ are each independently C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylamino group, di(C １ ~C ６ a)amino group, a halogen atom, a sulfonyl group, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 5 to 10 ring atoms, and a heterocyclyloxy group having 5 to 10 ring atoms; Optionally, R ３ａ may further include one or more R ３ｂ and each R ３ｂ are each independently C １ ~C ３ Alkyl group, halogen, hydroxyl group, C １ ~C ３ selected from an alkoxy group and an amino group; The R ４ is hydrogen, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ selected from an alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group; Optionally, R ４ may further include one or more R ４ａ and each R ４ａ are each independently C １ ~C ６ Alkyl group, halogen, amino group, C １ ~C ６ Alkylamino groups and di(C １ ~C ６ ) alkylamino groups; The R ５ is a halogen, a cyano group, an amino group, a hydroxyl group, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ selected from an alkoxy group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, and a heteroaryl group having 5 to 10 ring atoms; Optionally, R ５ may further include one or more R ５ａ and each R ５ａ are each independently C １ ~C ６ Alkyl group, C １ ~C ６ selected from an alkoxy group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and a hydroxy group; The R ６ is hydrogen, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ selected from an alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group; Optionally, R ６ may further include one or more R ６ａ and each R ６ａ are each independently C １ ~C ６ Alkyl group, halogen, amino group, C １ ~C ６ Alkylamino groups and di(C １ ~C ６ ) alkylamino groups; The R １ is -X １ -R ７ Among them, X １ is a bond or a methylene group, Optionally, the above X １ is one or more X １ａ and each X １ａ each independently represents a halogen and C １ ~C ３ selected from alkyl groups, The R ７ is selected from a cycloalkyl group having 4 to 10 ring atoms, an aryl group having 6 to 12 ring atoms, a heteroaryl group having 5 to 12 ring atoms, and a heterocyclyl group having 3 to 12 ring atoms; Among them, R ７ optionally one or more R ７ａ and each R ７ａ each independently represents an oxo group, a halogen, or C １ ~C ６ Alkyl groups, cycloalkyl groups having 3 to 10 ring atoms, C １ ~C ６ Alkoxy group, cycloalkyloxy group having 3 to 6 ring atoms, cyano group, amino group, hydroxy group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ selected from an alkynyl group, a sulfonyl group, an acyl group, a carboxyl group, a heterocyclyl group having 3 to 12 ring atoms, a heteroaryl group having 5 to 10 ring atoms, and a urea group; Optionally, R ７ａ may further include one or more R ７ｂ and R ７ｂ are halogen and C, respectively. １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, hydroxy group, amino group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Alkylamino group, di(C １ ~C ６ ) selected from alkylamino groups, sulfonyl groups, heterocyclyl groups having 3 to 6 ring atoms, and heteroaryl groups having 5 to 6 ring atoms; Among them, X １ is a methylene group, R ７ is not a substituted or unsubstituted aryl group, The R ２ is hydrogen, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ selected from an alkynyl group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group and an oxo group; Optionally, the above R ２ may further include one or more R ２ａ and each R ２ａ each independently represents a halogen, C １ ~C ６ alkyl groups, heterocyclyl groups having 4 to 10 ring atoms, heterocyclyloxy groups having 4 to 10 ring atoms, amino groups, heteroaryl groups having 5 to 10 ring atoms, cycloalkyl groups having 3 to 10 ring atoms, aryl groups having 6 to 10 ring atoms, C １ ~C ６ Alkylamino group, di(C １ ~C ６ ) an alkylamino group, a hydroxyl group, a sulfonyl group, C １ ~C ６ Alkoxy group, cyano group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ selected from an alkynyl group and an oxo group; Optionally, the above R ２ａ may further include one or more R ２ｂ and each R ２ｂ Each is C substituted with 0 to 3 halogens. １ ~C ３ Alkyl group, C substituted with 0 to 3 halogens １ ~C ３ Alkoxy group, halogen, hydroxy group, unsubstituted or C １ ~C ３ is selected from a 5- to 6-membered heterocyclyl group substituted with an alkyl group, a cyano group, and an oxo group, and is preferably C １ ~C ３ Alkyl group, C １ ~C ３ alkoxy groups, halogens, hydroxy groups and oxo groups; The R ８ , R ９ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ an alkynyl group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, or an adjacent R ８ and R ９ forms a 5- to 6-membered carbocyclic, heterocyclic or heteroaryl ring; Optionally, the above R ８ may further include one or more R ８ａ and optionally substituted with the above R ９ may further include one or more R ９ａ and optionally, the adjacent R ８ and R ９ The carbocyclic, heterocyclic or heteroaryl ring formed by may further include one or more R ８ａ Or R ９ａ is replaced by The above R ８ａ Or R ９ａ each independently represents a halogen, C １ ~C ６ alkyl groups, heterocyclyl groups having 4 to 10 ring atoms, heterocyclyloxy groups having 4 to 10 ring atoms, amino groups, heteroaryl groups having 5 to 10 ring atoms, cycloalkyl groups having 3 to 10 ring atoms, aryl groups having 6 to 10 ring atoms, C １ ~C ６ Alkylamino group, di(C １ ~C ６ ) an alkylamino group, a hydroxyl group, a sulfonyl group, C １ ~C ６ Alkoxy group, cyano group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ selected from an alkynyl group and an oxo group; Optionally, the above R ８ａ may further include one or more R ８ｂ and optionally substituted with the above R ９ａ may further include one or more R ９ｂ and R ８ｂ Or R ９ｂ each independently represents C substituted with 0 to 3 halogens １ ~C ３ Alkyl group, C substituted with 0 to 3 halogens １ ~C ３ Alkoxy group, halogen, hydroxy group, unsubstituted or C １ ~C ３ is selected from a 5- to 6-membered heterocyclyl group substituted with an alkyl group, a cyano group, and an oxo group, and is preferably C １ ~C ３ Alkyl group, C １ ~C ３ 16. The compound according to any one of claims 3 to 15, wherein the aryl group is an alkoxy group, a halogen atom, a hydroxy group, or an oxo group, or a stereoisomer, a tautomer, a solvate, a hydrate, a prodrug, a stable isotope derivative, or a pharma- ceutically acceptable salt thereof.

17. w is CR ３ and x is CR ４ and y is CR ５ and z is CR ６ or N, The R ３ is hydrogen, C １ ~C ４ Alkyl group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ４ selected from an alkoxy group, a halogen, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, and a cycloalkyloxy group having 3 to 6 ring atoms; Optionally, R ３ may further include one or more R ３ａ and each R ３ａ are each independently C １ ~C ３ Alkyl group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ３ Alkoxy group, C １ ~C ３ Alkylamino group, di(C １ ~C ３ a)amino group, a halogen atom, a sulfonyl group, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, and a heterocyclyloxy group having 5 to 6 ring atoms; Optionally, R ３ａ may further include one or more R ３ｂ and each R ３ｂ are each independently C １ ~C ３ Alkyl group, halogen, hydroxyl group, C １ ~C ３ selected from an alkoxy group and an amino group; The R ４ is hydrogen, C １ ~C ４ Alkyl group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ４ Alkoxy group, C １ ~C ４ selected from an alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, and an acyl group; Optionally, R ４ may further include one or more R ４ａ and each R ４ａ are each independently C １ ~C ３ Alkyl group, halogen, amino group, C １ ~C ３ Alkylamino groups and di(C １ ~C ３ ) alkylamino groups; The R ５ is halogen, C １ ~C ６ Alkyl group, C １ ~C ６ selected from an alkoxy group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 4 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms; Optionally, R ５ may further include one or more R ５ａ and each R ５ａ are each independently C １ ~C ６ selected from an alkyl group, a halogen, a cyano group, and a cycloalkyl group having 3 to 6 ring atoms; The R ６ is hydrogen, C １ ~C ４ Alkyl group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ４ Alkoxy group, C １ ~C ４ selected from an alkylthio group, a sulfonyl group, a halogen, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, and an acyl group; Optionally, R ６ may further include one or more R ６ａ and each R ６ａ are each independently C １ ~C ３ Alkyl group, halogen, amino group, C １ ~C ３ Alkylamino groups and di(C １ ~C ３ ) alkylamino groups; The R １ is -X １ -R ７ Among them, X １ is a bond or a methylene group, Optionally, the above X １ is one or more X １ａ is replaced by X １ａ is a methyl group, The above R ７ is selected from the following groups: 【Chemistry 12】 Preferably, the above R ７ is selected from the following groups: 【Chemistry 13】 Among them, R ７ optionally one or more R ７ａ and each R ７ａ each independently represents an oxo group, a halogen, or C １ ~C ４ Alkyl groups, cycloalkyl groups having 3 to 6 ring atoms, C １ ~C ４ Alkoxy groups, cycloalkyloxy groups having 3 to 4 ring atoms, cyano groups, amino groups, hydroxy groups, C ２ ~C ４ Alkenyl group, C ２ ~C ４ selected from an alkynyl group, a sulfonyl group, an acyl group, a carboxyl group, a heterocyclyl group having 3 to 6 ring atoms, a heteroaryl group having 5 to 6 ring atoms, and a urea group; Optionally, R ７ａ may further include one or more R ７ｂ and R ７ｂ each independently represents a halogen, C １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy group, hydroxy group, amino group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ３ Alkylamino group, di(C １ ~C ３ ) selected from alkylamino groups, sulfonyl groups, heterocyclyl groups having 3 to 6 ring atoms, and heteroaryl groups having 5 to 6 ring atoms; Among them, X １ is a methylene group, R ７ is not a substituted or unsubstituted aryl group, The R ２ is hydrogen, halogen, C １ ~C ４ Alkyl group, C １ ~C ４ Alkoxy group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ selected from an alkynyl group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group and an oxo group; Optionally, the above R ２ may further include one or more R ２ａ and each R ２ａ each independently represents a halogen, C １ ~C ４ alkyl groups, heterocyclyl groups having 5 to 6 ring atoms, heterocyclyloxy groups having 5 to 6 ring atoms, amino groups, heteroaryl groups having 5 to 6 ring atoms, cycloalkyl groups having 3 to 6 ring atoms, aryl groups having 6 to 10 ring atoms, C １ ~C ３ Alkylamino group, di(C １ ~C ３ ) an alkylamino group, a hydroxyl group, a sulfonyl group, C １ ~C ４ Alkoxy group, cyano group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ selected from an alkynyl group and an oxo group; Optionally, the above R ２ａ may further include one or more R ２ｂ and each R ２ｂ are each selected from a methoxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a difluoromethoxy group, an N-methylpiperazinyl group, and a cyano group, and are preferably a methoxy group or a methyl group, The R ８ , R ９ are each independently hydrogen, halogen, or C １ ~C ４ Alkyl group, C １ ~C ４ Alkoxy group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ an alkynyl group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an aryl group having 6 ring atoms, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, or an adjacent R ８ and R ９ forms a 5- to 6-membered heterocyclic or heteroaryl ring; Optionally, the above R ８ may further include one or more R ８ａ and optionally substituted with the above R ９ may further include one or more R ９ａ and optionally, the adjacent R ８ and R ９ The heterocycle or heteroaryl ring formed by may further include one or more R ８ａ Or R ９ａ is replaced by The above R ８ａ Or R ９ａ each independently represents a halogen, C １ ~C ４ an alkyl group, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an amino group, a heteroaryl group having 5 to 6 ring atoms, a cycloalkyl group having 3 to 6 ring atoms, an aryl group having 6 ring atoms, C １ ~C ３ Alkylamino group, di(C １ ~C ３ ) an alkylamino group, a hydroxyl group, a sulfonyl group, C １ ~C ４ Alkoxy group, cyano group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ selected from an alkynyl group and an oxo group; Optionally, the above R ８ａ may further include one or more R ８ｂ and optionally substituted with the above R ９ａ may further include one or more R ９ｂ and R ８ｂ Or R ９ｂ are each independently selected from a methoxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a difluoromethoxy group, an N-methylpiperazinyl group, and a cyano group, and are preferably a methoxy group or a methyl group.

18. w is CR ３ and x is CR ４ and y is CR ５ and z is CR ６ or N, The R ３ is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, and a piperidinyloxy group; Optionally, R ３ may further include one or more R ３ａ and each R ３ａ are each independently selected from a methyl group and a dimethylamino group; Optionally, R ３ａ may further include one or more R ３ｂ and each R ３ｂ are each independently C １ ~C ３ Alkyl group, halogen, hydroxyl group, C １ ~C ３ selected from an alkoxy group and an amino group; The R ４ is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a fluorine group, a chlorine group, a bromine group, and a cyano group; Optionally, R ４ may further include one or more R ４ａ and each R ４ａ are each independently C １ ~C ３ Alkyl group, halogen, amino group, C １ ~C ３ Alkylamino groups and di(C １ ~C ３ ) alkylamino groups; The R ５ is selected from chlorine, fluorine, bromine, iodine, a cyano group, an ethyl group, an n-propyl group, an isopropyl group, a methyl group, a cyclopropyl group, a methoxy group, and a cyclopropyloxy group; Optionally, R ５ may further include one or more R ５ａ and each R ５ａ are each independently selected from fluorine and a cyano group; The R ６ is selected from hydrogen, fluorine, chlorine, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, a methoxy group, a cyclopropyloxy group, and a cyano group; Optionally, R ６ may further include one or more R ６ａ and each R ６ａ are each independently C １ ~C ３ Alkyl group, halogen, amino group, C １ ~C ３ Alkylamino groups and di(C １ ~C ３ ) alkylamino groups; The R １ is -X １ -R ７ Among them, X １ is a bond or a methylene group, Optionally, the above X １ is one or more X １ａ is replaced by X １ａ is a methyl group, The above R ７ is as defined in claim 17, Among them, R ７ optionally one or more R ７ａ and each R ７ａ are each independently selected from fluorine, chlorine, bromine, a hydroxy group, a cyano group, a methoxy group, a methyl group, a cyclopropyloxy group, and a cyclopropyl group, and are preferably selected from fluorine, chlorine, bromine, a hydroxy group, a cyano group, a methoxy group, a methyl group, and a cyclopropyloxy group; Optionally, R ７ａ may further include one or more R ７ｂ and R ７ｂ are selected from fluorine, chlorine, and bromine, Among them, X １ is a methylene group, R ７ is not a substituted or unsubstituted aryl group, The R ２ is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyano group, a methoxy group, and an oxo group; Optionally, the above R ２ may further include one or more R ２ａ and each R ２ａ are each independently selected from a methyl group, chlorine, fluorine, phenyl group, cyclopropyl group, oxo group, amino group, methylamino group, dimethylamino group, methoxy group, hydroxy group, pyridyl group, pyrazolyl group, and pyrimidinyl group, and are preferably selected from a methyl group, chlorine, fluorine, phenyl group, cyclopropyl group, oxo group, amino group, methylamino group, dimethylamino group, methoxy group, hydroxy group, pyridyl group, and pyrazolyl group; Optionally, the above R ２ａ may further include one or more R ２ｂ and each R ２ｂ are each selected from a methoxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a difluoromethoxy group, an N-methylpiperazinyl group, and a cyano group, and are preferably a methoxy group or a methyl group, The R ８ , R ９ are each independently selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyano group, a methoxy group, an oxo group, a cyclopropyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a phenyl group, and a propenyl group, or adjacent R ８ and R ９ teeth, 【Chemistry 14】 Forming Optionally, the above R ８ may further include one or more R ８ａ and optionally substituted with the above R ９ may further include one or more R ９ａ and optionally, the adjacent R ８ and R ９ was formed 【Chemistry 15】 may further include one or more R ８ａ Or R ９ａ is replaced by The above R ８ａ Or R ９ａ are each independently selected from a methyl group, a chlorine group, a fluorine group, a bromine group, a phenyl group, a cyclopropyl group, an oxo group, an amino group, a methylamino group, a dimethylamino group, a methoxy group, a hydroxy group, a pyridyl group, a pyrazolyl group, a sulfonyl group, a morpholinyl group, a tetrahydrofuranyl group, an isoxazolyl group, and a pyrimidinyl group, and preferably each R ８ａ Or R ９ａ are each independently selected from a methyl group, a chlorine group, a fluorine group, a bromine group, a phenyl group, a cyclopropyl group, an oxo group, an amino group, a methylamino group, a dimethylamino group, a methoxy group, a hydroxy group, a pyridyl group, a pyrazolyl group, a sulfonyl group, a morpholinyl group, a tetrahydrofuranyl group, and an isoxazolyl group; Optionally, the above R ８ａ may further include one or more R ８ｂ and optionally substituted with the above R ９ａ may further include one or more R ９ｂ and R ８ｂ Or R ９ｂ are each independently selected from a methoxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a difluoromethoxy group, an N-methylpiperazinyl group, and a cyano group, and are preferably a methoxy group or a methyl group.

19. The compound optionally has the structure: 【Chemistry 16】 Of these, x, w, z, and R １ , R ５ , R ８ , R ９ is defined in any one of claims 1, 3 to 5, and R ４ is not H, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof.

20. w is CR ３ and R ３ is hydrogen, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ is selected from an alkoxy group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a heterocyclyl group having 5 to 10 ring atoms, a heterocyclyloxy group having 5 to 10 ring atoms, and a cycloalkyloxy group having 3 to 10 ring atoms, and preferably ３ is hydrogen, C １ ~C ４ Alkyl group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ４ is selected from an alkoxy group, a halogen atom, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, and a cycloalkyloxy group having 3 to 6 ring atoms, and more preferably, ３ is selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, and a piperidinyloxy group; Optionally, R ３ may further include one or more R ３ａ and each R ３ａ are each independently C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylamino group, di(C １ ~C ６ a) an alkyl) amino group, a halogen atom, a sulfonyl group, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 5 to 10 ring atoms, and a heterocyclyloxy group having 5 to 10 ring atoms, and preferably, ３ａ are each independently C １ ~C ３ Alkyl group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ３ Alkoxy group, C １ ~C ３ Alkylamino group, di(C １ ~C ３ is preferably selected from the group consisting of an alkyl)amino group, a halogen atom, a sulfonyl group, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, an acyl group, a hydroxy group, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, and a heterocyclyloxy group having 5 to 6 ring atoms, more preferably the group consisting of the above R ３ａ are each independently selected from a methyl group and a dimethylamino group; Optionally, R ３ａ may further include one or more R ３ｂ and each R ３ｂ are each independently C １ ~C ３ Alkyl group, halogen, hydroxyl group, C １ ~C ３ 20. The compound of claim 19, wherein the R is selected from the group consisting of an alkoxy group, an amino group, and an aryl group.

21. The compound of claim 19, wherein the R is an aryl group, ...

21. x is CR ４ and the above R ４ is C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ is selected from the group consisting of an alkylthio group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group, and is preferably selected from the group consisting of an alkylthio group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group. ４ is C １ ~C ４ Alkyl group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ４ Alkoxy group, C １ ~C ４ is selected from the group consisting of an alkylthio group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, and an acyl group, and more preferably, ４ is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a fluorine group, a chlorine group, a bromine group, and a cyano group; Optionally, R ４ may further include one or more R ４ａ and each R ４ａ are each independently C １ ~C ６ Alkyl group, halogen, amino group, C １ ~C ６ Alkylamino groups and di(C １ ~C ６ ) alkylamino groups, preferably the above R ４ａ are each independently C １ ~C ３ Alkyl group, halogen, amino group, C １ ~C ３ Alkylamino groups and di(C １ ~C ３ 21. The compound according to claim 19, wherein the compound is selected from the group consisting of aryl, aryloxy ...

22. The R ５ is a halogen, a cyano group, an amino group, a hydroxyl group, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ is selected from the group consisting of an alkoxy group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, and a heteroaryl group having 5 to 10 ring atoms, and is preferably selected from the group consisting of the above R ５ is halogen, C １ ~C ６ Alkyl group, C １ ~C ６ is selected from the group consisting of an alkoxy group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 4 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms, and more preferably, ５ is selected from chlorine, fluorine, bromine, iodine, a cyano group, an ethyl group, an n-propyl group, an isopropyl group, a methyl group, a cyclopropyl group, a methoxy group, and a cyclopropyloxy group; Optionally, R ５ may further include one or more R ５ａ and each R ５ａ are each independently C １ ~C ６ Alkyl group, C １ ~C ６ is selected from the group consisting of an alkoxy group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and a hydroxy group, and is preferably selected from the group consisting of the above R ５ａ are each independently C １ ~C ６ is selected from the group consisting of an alkyl group, a halogen atom, a cyano group, and a cycloalkyl group having 3 to 6 ring atoms, and more preferably, ５ａ are each independently selected from fluorine and a cyano group, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof according to any one of claims 19 to 21.

23. The z is CR ６ or N, Among them, R ６ is hydrogen, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ is selected from the group consisting of an alkylthio group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group, and is preferably selected from the group consisting of an alkylthio group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 10 ring atoms, a cyano group, an amino group, and an acyl group. ６ is hydrogen, C １ ~C ４ Alkyl group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ４ Alkoxy group, C １ ~C ４ is selected from the group consisting of an alkylthio group, a sulfonyl group, a halogen atom, a cycloalkyl group having 3 to 6 ring atoms, a cyano group, an amino group, and an acyl group, and more preferably, ６ is selected from hydrogen, fluorine, chlorine, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, a methoxy group, a cyclopropyloxy group, and a cyano group; Optionally, R ６ may further include one or more R ６ａ and each R ６ａ are each independently C １ ~C ６ Alkyl group, halogen, amino group, C １ ~C ６ Alkylamino groups and di(C １ ~C ６ ) alkylamino groups, preferably the above R ６ａ are each independently C １ ~C ３ Alkyl group, halogen, amino group, C １ ~C ３ Alkylamino groups and di(C １ ~C ３ 23. The compound according to any one of claims 19 to 22, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of aryl, aryloxy ...

24. The R １ is -X １ -R ７ Among them, X １ is a bond or a methylene group, Optionally, the above X １ is one or more X １ａ and each X １ａ each independently represents a halogen and C １ ~C ３ alkyl group, preferably methyl group; The above R ７ is selected from a cycloalkyl group having 4 to 10 ring atoms, an aryl group having 6 to 12 ring atoms, a heteroaryl group having 5 to 12 ring atoms, and a heterocyclyl group having 3 to 12 ring atoms; Preferably, the above R ７ is selected from the following groups: 【Chemistry 17】 More preferably, the above R ７ is selected from the following groups: 【Chemistry 18】 Among them, R ７ optionally one or more R ７ａ and each R ７ａ each independently represents an oxo group, a halogen, or C １ ~C ６ Alkyl groups, cycloalkyl groups having 3 to 10 ring atoms, C １ ~C ６ Alkoxy group, cycloalkyloxy group having 3 to 6 ring atoms, cyano group, amino group, hydroxy group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ is selected from the group consisting of an alkynyl group, a sulfonyl group, an acyl group, a carboxyl group, a heterocyclyl group having 3 to 12 ring atoms, a heteroaryl group having 5 to 10 ring atoms, and a urea group, and is preferably ... ７ａ each independently represents an oxo group, a halogen, or C １ ~C ４ Alkyl groups, cycloalkyl groups having 3 to 6 ring atoms, C １ ~C ４ Alkoxy groups, cycloalkyloxy groups having 3 to 4 ring atoms, cyano groups, amino groups, hydroxy groups, C ２ ~C ４ Alkenyl group, C ２ ~C ４ is selected from the group consisting of an alkynyl group, a sulfonyl group, an acyl group, a carboxyl group, a heterocyclyl group having 3 to 6 ring atoms, a heteroaryl group having 5 to 6 ring atoms, and a urea group, and more preferably, ７ａ are each independently selected from fluorine, chlorine, bromine, a hydroxyl group, a cyano group, a methoxy group, a methyl group, a cyclopropyloxy group, and a cyclopropyl group; Optionally, R ７ａ may further include one or more R ７ｂ and R ７ｂ are halogen and C, respectively. １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, hydroxy group, amino group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C １ ~C ６ Alkylamino group, di(C １ ~C ６ ) selected from an alkylamino group, a sulfonyl group, a heterocyclyl group having 3 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms, preferably each R ７ｂ each independently represents a halogen, C １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy group, hydroxy group, amino group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ Alkynyl group, C １ ~C ３ Alkylamino group, di(C １ ~C ３ ) an alkylamino group, a sulfonyl group, a heterocyclyl group having 3 to 6 ring atoms, and a heteroaryl group having 5 to 6 ring atoms, more preferably each R ７ｂ are each independently selected from fluorine, chlorine and bromine; Among them, X １ is a methylene group, R ７ is not a substituted or unsubstituted aryl group, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof.

25. The R ８ , R ９ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ an alkynyl group, a cycloalkyl group having 3 to 10 ring atoms, a cycloalkyloxy group having 3 to 10 ring atoms, a heterocyclyl group having 4 to 10 ring atoms, a heterocyclyloxy group having 4 to 10 ring atoms, an aryl group having 6 to 10 ring atoms, a heteroaryl group having 5 to 10 ring atoms, a heteroaryloxy group having 5 to 10 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, or an adjacent R ８ and R ９ forms a 5- to 6-membered carbocyclic, heterocyclic or heteroaryl ring, and preferably ８ , R ９ are each independently hydrogen, halogen, or C １ ~C ４ Alkyl group, C １ ~C ４ Alkoxy group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ an alkynyl group, a cycloalkyl group having 3 to 6 ring atoms, a cycloalkyloxy group having 3 to 6 ring atoms, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an aryl group having 6 ring atoms, a heteroaryl group having 5 to 6 ring atoms, a heteroaryloxy group having 5 to 6 ring atoms, a cyano group, an amino group, an acyl group, a sulfonyl group, and an oxo group, or an adjacent R ８ and R ９ forms a 5- to 6-membered heterocycle or heteroaryl ring, and more preferably, ８ , R ９ are each independently selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyano group, a methoxy group, an oxo group, a cyclopropyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a phenyl group, and a propenyl group, or adjacent R ８ and R ９ teeth, 【Chemistry 19】 Forming Optionally, the above R ８ may further include one or more R ８ａ and optionally substituted with the above R ９ may further include one or more R ９ａ and optionally, the adjacent R ８ and R ９ The carbocyclic, heterocyclic or heteroaryl ring formed by may further include one or more R ８ａ Or R ９ａ is replaced by The above R ８ａ Or R ９ａ each independently represents a halogen, C １ ~C ６ alkyl groups, heterocyclyl groups having 4 to 10 ring atoms, heterocyclyloxy groups having 4 to 10 ring atoms, amino groups, heteroaryl groups having 5 to 10 ring atoms, cycloalkyl groups having 3 to 10 ring atoms, aryl groups having 6 to 10 ring atoms, C １ ~C ６ Alkylamino group, di(C １ ~C ６ ) an alkylamino group, a hydroxyl group, a sulfonyl group, C １ ~C ６ Alkoxy group, cyano group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ alkynyl and oxo groups, preferably each R ８ａ Or R ９ａ each independently represents a halogen, C １ ~C ４ an alkyl group, a heterocyclyl group having 5 to 6 ring atoms, a heterocyclyloxy group having 5 to 6 ring atoms, an amino group, a heteroaryl group having 5 to 6 ring atoms, a cycloalkyl group having 3 to 6 ring atoms, an aryl group having 6 ring atoms, C １ ~C ３ Alkylamino group, di(C １ ~C ３ ) an alkylamino group, a hydroxyl group, a sulfonyl group, C １ ~C ４ Alkoxy group, cyano group, C ２ ~C ４ Alkenyl group, C ２ ~C ４ More preferably, each R ８ａ Or R ９ａ are each independently selected from a methyl group, a chlorine group, a fluorine group, a bromine group, a phenyl group, a cyclopropyl group, an oxo group, an amino group, a methylamino group, a dimethylamino group, a methoxy group, a hydroxy group, a pyridyl group, a pyrazolyl group, a sulfonyl group, a morpholinyl group, a tetrahydrofuranyl group, an isoxazolyl group, and a pyrimidinyl group; Optionally, the above R ８ａ may further include one or more R ８ｂ and optionally substituted with the above R ９ａ may further include one or more R ９ｂ and R ８ｂ Or R ９ｂ each independently represents C substituted with 0 to 3 halogens １ ~C ３ Alkyl group, C substituted with 0 to 3 halogens １ ~C ３ Alkoxy group, halogen, hydroxy group, unsubstituted or C １ ~C ３ is selected from a 5- to 6-membered heterocyclyl group substituted with an alkyl group, a cyano group, and an oxo group, and is preferably C １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy groups, halogens, hydroxy groups and oxo groups, and preferably the above R ８ｂ Or R ９ｂ are each independently selected from a methoxy group and a methyl group, or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, and pharma- ceutically acceptable salt thereof according to any one of claims 19 to 24.

26. A compound or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof, said compound being selected from: 【Table 1】 The compound or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharma- ceutically acceptable salts.

27. 27. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents, or excipients.

28. Use of a compound according to any one of claims 1 to 26 or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, in the inhibition of methionine adenosyltransferase 2A (MAT2A) or in the manufacture of a methionine adenosyltransferase 2A (MAT2A) inhibitor drug.

29. Use of a compound according to any one of claims 1 to 26 or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, in the treatment and / or prevention of cancer or in the manufacture of a medicament for the treatment and / or prevention of cancer, comprising Preferably, the cancer comprises one in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted and / or completely non-functional.

30. A method for treating and / or preventing cancer, comprising administering to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, preferably comprising administering to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotope derivative and pharma- ceutically acceptable salt thereof, wherein the cancer comprises one in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted and / or completely non-functional.

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