Bicyclic MAT2A inhibitor and application thereof

Abstract

Provided is a bicyclic compound represented by formula (I) or a pharmaceutically acceptable salt, an enantiomer, a diastereoisomer, a raceme, an atropisomer, a polymorphic substance, a solvate or an isotope-labeled compound thereof. The compound shown in the formula (I) has MAT2A enzyme inhibitory activity, can be used as a good MAT2A inhibitor, and is further used for preparing drugs for treating and / or preventing MTAP related diseases, especially tumors. # imgabs0 #

Description

Bis-cyclic MAT2A inhibitors and uses thereof

[0001] This application claims priority to Chinese patent application No. 202210828873.6, filed on July 13, 2022, and entitled “Bis-cyclic MAT2A inhibitors and their uses,” the entire contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention relates to MAT2A inhibitors, and specifically to a class of bicyclic compounds represented by the following formula I, pharmaceutical compositions comprising the compounds, and their use in preparing drugs for treating and / or preventing MAT2A-related diseases, particularly tumors. Background Art

[0003] Cancer treatment is a major challenge facing the world today. A major problem with existing common therapies, such as chemotherapy and immunotherapy, is that they often kill not only cancer cells but also produce significant side effects on normal cells and tissues. Therefore, there is an urgent need to develop new treatments that can better target cancer cells.

[0004] Synthetic lethality is defined as the loss of two or more genes leading to cell death, whereas loss of any one gene alone has no effect. In recent years, numerous studies have demonstrated the presence of multiple genetic mutations in cancer cells that render them more susceptible to synthetic lethality therapies. These tumor-specific genetic mutations can enable the use of targeted therapies to kill cancer cells while sparing normal cells.

[0005] Methionine adenosyltransferase 2A (MAT2A) is an enzyme that catalyzes the reaction of methionine (Met) with ATP to produce S-adenosylmethionine (SAM). SAM is the main methyl donor in the body and regulates gene expression through transmethylation of DNA, RNA, and proteins, thereby significantly influencing cell differentiation, growth, and death. Arginine N-methyltransferase 5 (PRMT5) is a methyltransferase that uses SAM as a methyl donor. SAM is crucial for the activity of PRMT5, while 5'methylthioadenosine (MTA) can inhibit PRMT5 activity. MTA is a product of the methionine compensation pathway, which is maintained at a low level in cells through the catalysis of methylthioadenosine phosphorylase (MTAP) to produce 5-methylthioribose-1-phosphate and adenine.

[0006] The MTAP gene is located on chromosome 9, which is deleted in cells of patients with various cancers, including pancreatic cancer, esophageal cancer, bladder cancer, and lung cancer (cBioPortal database). The loss of MTAP leads to the enrichment of MTA in cells, making these cells more dependent on the production of SAM and the activity of MAT2A than normal cells. Studies have shown that inhibiting the expression of MAT2A in MTAP-deficient cancer cells can selectively inhibit cell activity compared to cancer cells with normal MTAP (McDonald et al., 2017 Cell 170, 577-592). At the same time, reducing MAT2A expression can selectively inhibit tumor growth in a mouse xenograft tumor model of MTAP-deficient tumor cells (Marjon et al., 2016 Cell Reports 15 (3), 574-587). These results suggest that MAT2A inhibitors can provide a new and effective treatment for cancer patients, especially those whose tumors contain MTAP deletions.

[0007] Summary of the Invention

[0008] The inventors unexpectedly discovered that the compound of formula (I) of the present invention has an inhibitory effect on MAT2A enzyme activity, and verified its tumor cell activity inhibitory effect through cell experiments. Therefore, the compound of formula (I) can be used as a good MAT2A inhibitor.

[0009] One object of the present invention is to provide a dicyclic compound as shown in formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate, or isotope-labeled compound thereof.

[0010] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds selected from the group consisting of compounds represented by formula (I) or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, atropisomers, polymorphs, solvates, and isotope-labeled compounds thereof, and at least one pharmaceutically acceptable carrier.

[0011] Another object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate, isotope-labeled compound, or pharmaceutical composition thereof for use in the preparation of a medicament for inhibiting MAT2A activity.

[0012] Another object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate, or isotope-labeled compound thereof, and the use of the pharmaceutical composition in the preparation of a drug for treating and / or preventing MAT2A-related diseases, particularly tumors.

[0013] In order to achieve the above-mentioned object, the first aspect of the present invention provides a bicyclic compound as shown in formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof,

[0014] in,

[0015] R 1 Selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylsulfonyl, C3-C7 cycloalkyl, 3-6 membered heterocycloalkyl, cyano, nitro, carboxyl, -NR a R a2 、-NHCOR a 、-OR a 、-SR a , the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3-6 membered heterocycloalkyl is unsubstituted or optionally substituted with one or more substituents selected from D and halogen;

[0016] R a 、R a2 Each independently selected from H, C1-C10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-6 membered heterocycloalkyl, C1-C 10 Alkyl, C3-C substituted by one or more substituents selected from Group A 10 Cycloalkyl; Group A substituents include: D, halogen, C1-C3 alkoxy, hydroxyl, C6-C 10 Aryl, 5-10 membered heteroaryl, unsubstituted or substituted with one or more substituents selected from Group A2 C3-C 10 Cycloalkyl; the A2 group substituents include: D, halogen, hydroxyl, C1-C6 alkyl, C1-C 10 alkoxy;

[0017] R 2 、R 3 Each independently selected from unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C6-C 10 Aryl, unsubstituted or substituted 4-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl; wherein the substitution refers to substitution by one or more substituents selected from Group B, and Group B substituents include: halogen, cyano (-CN), hydroxyl (-OH), oxo (=O), mercapto (-SH), amino (-NH2), nitro (-NO2), 4-6 membered heterocycloalkyl, C1-C4 alkyl unsubstituted or substituted by one or more substituents selected from Group C, C3-C7 cycloalkyl unsubstituted or halogen-substituted, C1-C4 alkoxy unsubstituted or halogen-substituted, -COOH, -CONHR b 、-NHCOR b 、-NHSO2R b ; Group C substituents include: D, halogen, hydroxy, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, C1-C4 alkoxy;

[0018] R b Selected from H, C1-C4 alkyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C6-C 10 Aryl, wherein the R b C1-C4 alkyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C6-C 10 Aryl is unsubstituted or substituted by one or more substituted groups selected from halogen, hydroxyl, and cyano;

[0019] Ring A is a five-membered heteroaromatic ring, wherein at most one of X, Y, and Z is CR4 , the rest are independently selected from N, NR 5 ,O,S;

[0020] R 4 、R 5 are each independently selected from H, D, halogen, amino, C1-C6 alkyl, C3-C6 cycloalkyl; or, R 4 、R 5 Each is independently selected from H, D, halogen, amino, C1-C6 alkyl, C3-C6 cycloalkyl; the C1-C6 alkyl, C3-C6 cycloalkyl is unsubstituted or substituted with hydroxyl.

[0021] In some embodiments, R 1 Selected from C1-C6 alkyl, C3-C7 cycloalkyl, 3-6 membered heterocycloalkyl, -OR a NR a R a2 The C1-C6 alkyl, C3-C7 cycloalkyl, 3-6 membered heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from D and halogen; R a 、R a2 Each independently selected from H, C3-C7 cycloalkyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, wherein the substituents in Group A include: D, halogen, C1-C3 alkoxy, hydroxyl, C6-C 10 Aryl, 5-10 membered heteroaryl, unsubstituted or substituted with one or more substituents selected from Group A2 C3-C 10 Cycloalkyl; the substituents of group A2 include: D, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy.

[0022] In some embodiments, R 1 Selected from C1-C6 alkyl, C3-C7 cycloalkyl, 3-6 membered heterocycloalkyl, -OR a 、-SR a NR a R a2 The C1-C6 alkyl, C3-C7 cycloalkyl, 3-6 membered heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from D and halogen; R a 、R a2 Each independently selected from H, C3-C7 cycloalkyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, wherein the substituents in Group A include: D, halogen, C1-C3 alkoxy, hydroxyl, C6-C 10 Aryl, 5-10 membered heteroaryl, unsubstituted or substituted with one or more substituents selected from Group A2 C3-C 10Cycloalkyl; the substituents of group A2 include: D, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy.

[0023] In some embodiments, R 2 、R 3 Each independently selected from unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C6-C 10 Aryl, unsubstituted or substituted 5-10 membered heteroaryl, the substitution refers to substitution by one or more substituents selected from Group B; the substituents of Group B include: halogen, cyano, hydroxyl, mercapto, nitro, amino, oxo, unsubstituted or substituted 4-6 membered heterocycloalkyl, C1-C4 alkyl unsubstituted or substituted by one or more substituents selected from Group C, unsubstituted or halogen-substituted C3-C7 cycloalkyl, unsubstituted or halogen-substituted C1-C4 alkoxy; the substituents of Group C include: D, halogen, hydroxyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, C1-C4 alkoxy; in particular, the 5-10 membered heteroaryl is selected from benzo 5 membered heteroaryl, benzo 6 membered heteroaryl, 6 membered heteroaryl and 5 membered heteroaryl, 6 membered heteroaryl and 6 membered heteroaryl,

[0024] In some embodiments, R 1 Selected from C2-C6 alkyl, C3-C6 cycloalkyl, -OR a NR a R a2 ; wherein the C2-C6 alkyl and C3-C6 cycloalkyl are unsubstituted or substituted by one or more substituents selected from D and halogen; R a 、R a2 Each is independently selected from H, C3-C6 cycloalkyl, C2-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, wherein the substituents in Group A include: D, halogen, methoxy, hydroxyl, and C3-C6 cycloalkyl.

[0025] In some embodiments, R 1 Selected from C2-C6 alkyl, C3-C6 cycloalkyl, -OR a 、-SR a NR a R a2 ; wherein the C2-C6 alkyl and C3-C6 cycloalkyl are unsubstituted or substituted by one or more substituents selected from D and halogen; R a 、R a2 Each is independently selected from H, C3-C6 cycloalkyl, C2-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, wherein the substituents in Group A include: D, halogen, methoxy, hydroxyl, and C3-C6 cycloalkyl.

[0026] In some embodiments, R 2 and R 3 Each is independently selected from an unsubstituted or substituted cyclohexyl group, an unsubstituted or substituted phenyl group, and an unsubstituted or substituted 5-10 membered heteroaryl group, wherein the 5-10 membered heteroaryl group is selected from the following structures: The substitution in the unsubstituted or substituted phenyl group, unsubstituted or substituted 5-10 membered heteroaryl group refers to substitution by one or more substituents selected from Group B, and the substituents in Group B include: halogen, cyano, hydroxyl, mercapto, nitro, amino, 4-6 membered heterocycloalkyl, C1-C4 alkyl group which is unsubstituted or substituted by one or more substituents selected from Group C, C3-C7 cycloalkyl group which is unsubstituted or halogen substituted, and C1-C4 alkoxy group which is unsubstituted or halogen substituted; the substituents in Group C include: D, halogen, C3-C6 cycloalkyl group, hydroxyl group, 4-6 membered heterocycloalkyl group, and C1-C4 alkoxy group.

[0027] In some embodiments, R 2 and R 3 Each is independently selected from an unsubstituted or substituted cyclohexyl group, an unsubstituted or substituted phenyl group, and an unsubstituted or substituted 5-10 membered heteroaryl group, wherein the 5-10 membered heteroaryl group is selected from the following structures: The substitution in the unsubstituted or substituted phenyl group, unsubstituted or substituted 5-10 membered heteroaryl group refers to substitution by one or more substituents selected from Group B, and the substituents in Group B include: halogen, cyano, hydroxyl, mercapto, nitro, amino, 4-6 membered heterocycloalkyl, C1-C4 alkyl group which is unsubstituted or substituted by one or more substituents selected from Group C, C3-C7 cycloalkyl group which is unsubstituted or halogen substituted, and C1-C4 alkoxy group which is unsubstituted or halogen substituted; the substituents in Group C include: D, halogen, C3-C6 cycloalkyl group, hydroxyl group, 4-6 membered heterocycloalkyl group, and C1-C4 alkoxy group.

[0028] In some embodiments, R 5 is independently H, D, C1-C3 alkyl or C3-C6 cycloalkyl at each occurrence; or R 5 Each occurrence is independently H, D, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl or C3-C6 cycloalkyl is unsubstituted or substituted with hydroxy.

[0029] In some embodiments, R 1 Select from -OR a and NHR a .

[0030] In some embodiments, R 1 Selected from C2-C6 alkyl, -OR a and NHRa .

[0031] In some embodiments, R a Selected from C3-C6 cycloalkyl, C2-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A; the substituents in Group A include: D, halogen, methoxy, hydroxyl, C3-C6 cycloalkyl.

[0032] In some embodiments, R 2 and R 3 Each independently selected from:

[0033] Or, R 2 and R 3 Each independently selected from:

[0034] Among them, (R 7 ) m Indicates that there are m identical or different R7 substituents on the ring; m is 1, 2 or 3; R 6 and each R 7 Each is independently selected from: H, halogen, cyano, hydroxyl, mercapto, nitro, amino, 4-6 membered heterocycloalkyl, C1-C4 alkyl unsubstituted or substituted by one or more substituents selected from Group C, C3-C7 cycloalkyl unsubstituted or halogen substituted, C1-C4 alkoxy unsubstituted or halogen substituted; Group C substituents include: D, halogen, C3-C6 cycloalkyl, hydroxyl, 4-6 membered heterocycloalkyl, C1-C4 alkoxy; preferably, m is 1 or 2; R 6 and each R 7 Each is independently selected from: H, halogen, cyano, hydroxyl, mercapto, nitro, amino, 4-6 membered heterocycloalkyl, C1-C2 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, cyclopropyl which is unsubstituted or halogen substituted, C1-C2 alkoxy which is unsubstituted or halogen substituted; the substituents of Group C include: D, halogen, C3-C6 cycloalkyl, hydroxyl, 4-6 membered heterocycloalkyl, C1-C4 alkoxy.

[0035] In some embodiments, R 5 is independently at each occurrence H or methyl.

[0036] In some embodiments, R 5 is independently at each occurrence H, methyl or hydroxyethyl.

[0037] In some embodiments, R 1 Select from -OR a 、NHR a ; R aSelected from C3-C6 cycloalkyl, unsubstituted C2-C4 alkyl, halogen-substituted C2-C4 alkyl, cyclopropyl-substituted C2-C4 alkyl, methoxy-substituted C2-C4 alkyl, hydroxy-substituted C2-C4 alkyl.

[0038] In some embodiments, R 1 Selected from C2-C6 alkyl, -OR a 、-SR a 、NHR a ; R a Selected from C3-C6 cycloalkyl, unsubstituted C2-C4 alkyl, halogen-substituted C2-C4 alkyl, cyclopropyl-substituted C2-C4 alkyl, methoxy-substituted C2-C4 alkyl, hydroxy-substituted C2-C4 alkyl.

[0039] In some embodiments, R 2 and R 3 Each independently selected from:

[0040] In some embodiments, R 2 and R 3 Each independently selected from:

[0041] In some embodiments, m is 1, 2, or 3; R 6 and R 7 Each is independently selected from: H, halogen, cyano, hydroxyl, mercapto, nitro, amino, 4-6 membered heterocycloalkyl, C1-C4 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C3-C7 cycloalkyl which is unsubstituted or halogen substituted, C1-C4 alkoxy which is unsubstituted or halogen substituted; the substituents of Group C include: D, halogen, C3-C6 cycloalkyl, hydroxyl, 4-6 membered heterocycloalkyl, C1-C4 alkoxy.

[0042] In some embodiments, m is 1, 2, or 3; R 6 and R 7 Each independently selected from: H, halogen, cyano, hydroxyl, thiol, nitro, amino, C1-C3 alkyl, unsubstituted or substituted by one or more substituents selected from Group C, unsubstituted or halogen-substituted cyclopropyl, unsubstituted or halogen-substituted C1-C2 alkoxy; Group C substituents include: D, halogen, C3-C6 cycloalkyl, hydroxyl, methoxy,

[0043] In some embodiments, R 1 Selected from -OC2H5, -OCH2CF3, -NHCH3, -NHC2H5,

[0044] In some embodiments, R 1 Selected from propyl, -OC2H5, -SC2H5, -OCH2CF3, -NHCH3, -NHC2H5,

[0045] In some embodiments, R 2 Selected from Or, R 2 Selected from Wherein, m is 1, 2 or 3; R 8 and R 9 are each independently selected from H, halogen, CN, methoxy, methyl substituted by one or more halogens, methoxy substituted by one or more halogens, cyclopropyl; preferably, R 2 Selected from Or, R 2 Selected from Among them, R 8 and R 9 Each is independently selected from H, halogen, cyano, methoxy, methyl substituted by one or more halogens, methoxy substituted by one or more halogens, cyclopropyl;

[0046] R 3 Selected from Or, R 3 Selected from Wherein, m is 1, 2 or 3; R 10 and R 11 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyano, methoxy, hydroxy-substituted ethyl, methoxy-substituted ethyl, cyclopropyl,

[0047] In some embodiments, the compound of formula (I) is selected from the following structures:

[0048] Among them, R 1 、R 2 、R 3 、R 4 、R 5 Same as defined above.

[0049] In some embodiments, the compound of formula (I) is selected from the following structures:

[0050] Among them, R 1 、R2 、R 3 、R 5 Same as defined above.

[0051] In some embodiments, the compound represented by formula (I) is selected from the following structures:

[0052] A second aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of one or more compounds selected from the group consisting of compounds represented by formula (I), pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, atropisomers, polymorphs, solvates, and isotope-labeled compounds thereof, and at least one pharmaceutically acceptable carrier. The pharmaceutical composition may optionally further comprise one or more other therapeutic agents.

[0053] In one embodiment of the present invention, the present invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective dose of one or more compounds selected from the group consisting of compounds represented by formula (I), pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, atropisomers, polymorphs, solvates, and isotope-labeled compounds thereof, and one or more other therapeutic agents.

[0054] The compounds of the present invention may be used alone, in combination with other compounds of the present invention or in combination with one or more, preferably one or two, other therapeutic agents, simultaneously or sequentially.

[0055] In a third aspect, the present invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, an enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound, or a pharmaceutical composition thereof in the preparation of a medicament for inhibiting MAT2A activity.

[0056] The fourth aspect of the present invention provides the use of one or more of the compounds of formula (I) or their pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, atropisomers, polymorphs, solvates or isotope-labeled compounds, or pharmaceutical compositions thereof, in the preparation of drugs for treating and / or preventing MTAP-related diseases, particularly tumors.

[0057] Preferably, the tumor includes: MTAP-deficient tumors; MTAP-lowly expressed tumors; MAT2A-abnormally expressed tumors; and other MAT2A-dependent tumors.

[0058] Specifically, the tumors include: breast cancer, lung cancer, glioblastoma, brain cancer and spinal cancer, head and neck cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, heart tumors, germ cell tumors, malignant neuroendocrine tumors, malignant rhabdoid tumors, soft tissue sarcomas, midline tract cancer and unknown primary cancer.

[0059] In one embodiment of the present invention, the present invention provides a method for treating or preventing MAT2A-related diseases, particularly tumors, comprising administering to an individual in need thereof an effective amount of one or more selected from the compounds of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, atropisomers, polymorphs, solvates, and isotopically labeled compounds, or a pharmaceutical composition of the present invention. In some embodiments, the method further comprises administering to an individual in need thereof an effective amount of a second therapeutic agent, wherein the second therapeutic agent is one or more other therapeutic agents.

[0060] In addition, the present invention provides a product or kit comprising one or more compounds of the present invention as defined above, their pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, atropisomers, polymorphs, solvates, isotopically labeled compounds, or a pharmaceutical composition of the present invention. The kit may further comprise one or more other therapeutic agents to constitute a combined preparation for simultaneous, separate, or sequential use in anticancer therapy. DETAILED DESCRIPTION

[0061] Terminology

[0062] In the present invention, unless otherwise specified, the terms used in the present invention have the meanings defined below. Terms not clearly defined in the present invention have the general meanings generally understood by those skilled in the art.

[0063] Singular terms used in the context of the present invention (especially in the context of the claims) should be construed to include the plural referent, unless otherwise specifically indicated herein or clearly contradicted by context.

[0064] A dash ("-") that is not between two letters or symbols indicates the point of attachment of a substituent. For example, -O(C1-C3 alkyl) indicates that the group is attached to the rest of the molecule through an oxygen atom. However, when the point of attachment of a substituent is obvious to one skilled in the art, such as for substituents such as halogen and hydroxy, the "-" may be omitted.

[0065] As used herein, "heteroatom" refers to a nitrogen (N), oxygen (O) or sulfur (S) atom, particularly nitrogen or oxygen, each of which may be substituted or unsubstituted, including oxidized forms thereof. Examples of heteroatoms include, but are not limited to, -O-, -N=, -NR-, -S-, -S(O)- and -S(O)2-, where R is hydrogen, C1-C4 alkyl or a nitrogen protecting group (e.g., benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.). Any heteroatom with unsatisfied valences is deemed to have hydrogen atoms sufficient to satisfy the valences, unless otherwise indicated.

[0066] As used herein, "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine. Preferred halogen substituents are fluorine and chlorine.

[0067] As used herein, "alkyl" refers to a fully saturated, straight-chain or branched, monovalent hydrocarbon group. The alkyl group preferably contains 1-20 carbon atoms, more preferably 1-16 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms, or 1-3 carbon atoms. The number before the alkyl group represents the number of carbon atoms. For example, "C1-C6 alkyl" represents an alkyl group having 1-6 carbon atoms, "C1-C4 alkyl" represents an alkyl group having 1-4 carbon atoms, "C1-C3 alkyl" represents an alkyl group having 1-3 carbon atoms, and so on. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. This definition applies regardless of whether the term "alkyl" appears alone or as part of another group such as haloalkyl, alkoxy, and the like.

[0068] As used herein, "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing at least one double bond. The alkenyl group preferably contains 2-20 carbon atoms, more preferably 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. The number before the alkenyl group represents the number of carbon atoms. Representative examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, heptenyl, octenyl, and the like.

[0069] As used herein, "alkynyl" refers to a linear or branched monovalent hydrocarbon group containing at least one triple bond. The alkynyl group preferably contains 2-20 carbon atoms, more preferably 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. The number before the alkynyl group represents the number of carbon atoms. Representative examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, isopentenyl, hexynyl, heptynyl, octynyl, and the like.

[0070] As used herein, "alkoxy" refers to an alkyl group as defined herein attached through an oxygen bridge, i.e., an alkyl-O- group, with the number preceding the alkoxy group indicating the number of carbon atoms. For example, "C 1- C6 alkoxy" means an alkoxy group having 1 to 6 carbon atoms, i.e. -OC 1-6 Alkyl; "C 1- C4 alkoxy" means an alkoxy group having 1 to 4 carbon atoms, i.e. -OC 1-4 Alkyl; "C 1- C3 alkoxy" means an alkoxy group having 1 to 3 carbon atoms, i.e. -OC 1-3 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0071] As used herein, "cycloalkyl" refers to a saturated or partially saturated non-aromatic carbocyclic ring, including mono-, bi-, or tricyclic rings, preferably having 3-12 ring carbon atoms, more preferably 3-10 ring carbon atoms, such as 3-8, 3-7, 3-6, 4-10, or 4-8 ring carbon atoms. "C3-C8 cycloalkyl" is intended to include C3, C4, C5, C6, C7, and C8 cycloalkyl groups; "C3-C6 cycloalkyl" is intended to include C3, C4, C5, and C6 cycloalkyl groups. Exemplary monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. Exemplary bicyclic cycloalkyl groups include bornyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, etc. Exemplary tricyclic cycloalkyl groups include adamantyl, etc.

[0072] As used herein, "haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, such as 1, 2 or 3 hydrogen atoms, are replaced by halogen, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same as or different from each other. For example, "C1-C4 haloalkyl" is intended to include C1, C2, C3 and C4 haloalkyl groups, and "C1-C3 haloalkyl" is intended to include C1, C2 and C3 haloalkyl groups. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1,1-difluoroethyl, 1,1,-difluoropropyl and 1,1,1-trifluoropropyl. Examples of haloalkyl groups also include "fluoroalkyl", which is intended to include alkyl groups as defined herein in which one or more hydrogen atoms are replaced by fluorine atoms. "Haloalkyl" herein is preferably an alkyl group in which up to three hydrogen atoms are replaced by halogen.

[0073] As used herein, "haloalkoxy" refers to a haloalkyl group as defined above having a specified number of carbon atoms connected by an oxygen bridge, wherein one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, such as 1, 2, or 3 hydrogen atoms, are replaced by halogen. For example, "C1-C6 haloalkoxy" or "C1 to C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy. Examples of haloalkoxy also include "fluoroalkoxy."

[0074] As used herein, "aryl" is a group consisting of one or more fused rings with 6 to 20, preferably 6 to 14, more preferably 6 to 12, and most preferably 6 to 10 ring carbon atoms. 10 Aryl groups include: monocyclic aromatic groups (e.g., phenyl); or fused bicyclic ring systems in which one ring is aromatic and the other ring is aromatic (e.g., naphthalene, biphenyl) or non-aromatic (e.g., dihydroindene, tetrahydronaphthalene). Non-limiting examples of aryl groups include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl, dihydroindene, anthracenyl, and the like.

[0075] As used herein, "heteroaryl" refers to a 5-14 membered, preferably 5-10 membered, more preferably 5-7 membered or 5-6 membered aromatic ring system, including monocyclic or bicyclic or fused polycyclic rings, containing 1-4, preferably 1-3 ring heteroatoms selected from N, O or S, with the remaining ring atoms being carbon atoms. Examples of heteroaryl include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, oxazinyl, oxadiazinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoxazinyl, 2H-chromene, benzopyranyl, benzothiophenyl, indolyl, indazolyl, benzo [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridine, pyrazolo[1,5-a]pyridine, etc.

[0076] As used herein, "heterocycloalkyl" refers to a group in which one or more ring carbons of a cycloalkyl group as defined herein are replaced by a heteroatom selected from N, O or S, such as -O-, -N=, -NR-, -S-, -S(=O)- and -S(=O)2-, wherein R is hydrogen, C 1-4Alkyl or nitrogen protecting group (for example, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.). Preferably, heterocycloalkyl is a monocyclic, bicyclic or tricyclic saturated and partially unsaturated non-aromatic ring having 3-20 ring atoms, for example 3-12 ring atoms, for example 3-8 ring atoms, for example 3-6 ring atoms. More preferably, heterocycloalkyl is preferably a 4- to 12-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 4- to 8-membered heterocycloalkyl, more preferably a 4- to 7-membered, 4- to 6-membered or 5- to 6-membered heterocycloalkyl, wherein the heteroatoms are substituted or unsubstituted, for example substituted by C1-C4 alkyl. For example, examples of heterocycloalkyl include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, azepanyl (pyrrolidinyl), tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, pyrazolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, pyrrolidin-2-one, imidazolonyl, piperidinyl (hexahydropyridine), N-methylpiperidinyl, tetrahydropyranyl, oxazinyl, 1,3-oxazinyl, hexahydropyrimidinyl, piperazinyl, piperidinylone, 1,4-dioxa-8-aza-spiro[4.5]decan-8-yl, morpholino, thiomorpholino, thiomorpholino-S-monooxide (sulfanomorpholino), thiomorpholino-S,S-dioxide (sulfonomorpholino), octahydropyrrolo[3,2-b]pyrrolyl, and the like.

[0077] As used herein, the term "oxo" refers to an oxygen atom connected to another atom via a double bond, which can be represented by "=O". The term "-C(=O)" represents a carbonyl group, "-S(=O)" represents a sulfoxide group, and "-S(=O)2" represents a sulfone group.

[0078] As used herein, "optional," "optionally," or "optionally" means that the subsequently described event may or may not occur, and that the description includes instances where the event occurs as well as instances where the event does not occur. For example, "optionally substituted alkyl" includes "unsubstituted alkyl" and "substituted alkyl" as defined herein. "Optionally substituted with halogen" includes instances where "substituted with halogen" and instances where "not substituted with halogen," such as substituted with 0-3 halogens. It will be understood by those skilled in the art that for any group containing one or more substituents, the group does not include any substitution pattern that is sterically impractical, chemically incorrect, synthetically infeasible, and / or inherently unstable.

[0079] As used herein, the terms "substituted", "substituted" or "substituted by" mean that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given substituent group, provided that the normal valence of the given atom is not exceeded. When the substituent is oxo (i.e., =O), two hydrogen atoms on a single atom are replaced by oxygen. Oxo substituents are not present on aromatic moieties. When a ring system (e.g., a carbocycle or heterocycle) is substituted by a carbonyl group or a double bond, it is intended that the carbonyl group or double bond is part of the ring (i.e., within the ring). Such combinations are permitted only if the combination of substituents and / or variables results in a chemically correct and stable compound. A chemically correct and stable compound means that the compound is sufficiently stable to be isolated from a reaction mixture and the chemical structure of the compound can be determined, and then can be formulated into a formulation that at least has practical utility. For example, in the absence of a clear listing of substituents, the terms "substituted", "substituted" or "substituted by" as used herein mean that one or more hydrogen atoms on a given atom or group are independently replaced by one or more, e.g., 1, 2, 3 or 4, substituents. When an atom or group is substituted with multiple substituents, the substituents may be the same or different.

[0080] Unless otherwise indicated, the term "compound of the present invention" or "compound of the present invention" refers to one or more compounds of formula (I) or its subformula as defined herein, such as formula (I-1), (I-2), (I-1-1), (I-2-1), (I-3-1), etc., or a pharmaceutically acceptable salt thereof, as well as all isomers such as stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, conformational isomers (including rotational isomers and atropisomers), tautomers, internal addition products of isomers, prodrugs, and isotopically labeled compounds (including deuterium substitution) and inherently formed moieties (e.g., polymorphs, solvates and / or hydrates). When there is a moiety capable of forming a salt, the salt, in particular a pharmaceutically acceptable salt, is also included. The presence of tautomers or internal addition products of isomers can be identified by those skilled in the art using tools such as NMR. The compounds of formula (I) of the present invention are capable of readily forming tautomers and internal addition products of isomers as depicted herein.

[0081] Those skilled in the art will recognize that the compounds of the present invention may contain chiral centers and as such may exist in different isomeric forms. "Isomers" as used herein refer to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.

[0082] As used herein, "enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term is used to refer to a racemic mixture. When indicating the stereochemistry of the compounds of the present invention, the conventional RS system is used to designate single stereoisomers with two chiral centers of known relative and absolute configuration (e.g., (1S, 2S)); single stereoisomers with known relative configuration but unknown absolute configuration are marked with an asterisk (e.g., (1R*, 2R*)); racemates with two letters (e.g., (1RS, 2RS) is a racemic mixture of (1R, 2R) and (1S, 2S); (1RS, 2SR) is a racemic mixture of (1R, 2S) and (1S, 2R)). "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is indicated according to the Cahn-lngold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-) based on the direction (right-hand or left-hand) in which they rotate plane polarized light at the wavelength of the sodium D line. Alternatively, the resolved compounds can be defined by the respective retention times of the corresponding enantiomers / diastereomers via chiral HPLC.

[0083] Some of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomers that can be defined in terms of absolute stereochemistry as (R)- or (S)-.

[0084] Geometric isomers can occur when a compound contains a double bond or some other feature that imparts a certain amount of structural rigidity to the molecule. If the compound contains a double bond, the substituents can be in either the E or Z conformation. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have either the cis or trans configuration.

[0085] Conformational isomers are isomers that differ by rotation about one or more valence bonds. Rotamers are conformational isomers that differ by rotation about only a single valence bond.

[0086] "Atropisomers" refer to structural isomers based on axial or planar chirality resulting from restricted rotation in a molecule.

[0087] Unless otherwise indicated, the compounds of the present invention are intended to include all such possible isomers, including racemic mixtures, optically active forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0088] The compounds of the present invention can be isolated in optically active or racemic forms. Optically active forms can be prepared by resolution of the racemic form or by synthesis from optically active starting materials. All methods for preparing the compounds of the present invention and intermediates prepared therein are considered part of this invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods such as chromatography or fractional crystallization.

[0089] Depending on the process conditions, the end products of the present invention are obtained in free (neutral) or salt form. Both the free and salt forms of these end products are within the scope of the present invention. If desired, one form of the compound can be converted to the other form. A free base or acid can be converted to a salt; a salt can be converted to a free compound or other salt; a mixture of isomeric compounds of the present invention can be separated into individual isomers.

[0090] As used herein, "pharmaceutically acceptable salts" refers to salts that retain the biological effects and properties of the compounds of the present invention and are not biologically or otherwise undesirable. Non-limiting examples of such salts include non-toxic, inorganic or organic base or acid addition salts of the compounds of the present invention. In many cases, due to the presence of amino and / or carboxyl groups or groups similar thereto, the compounds of the present invention are capable of forming acid salts and / or base salts. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; ammonium, potassium, sodium, calcium, and magnesium salts are particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, particularly, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound (basic or acidic moiety) by conventional chemical methods. Generally, the salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of an appropriate base (e.g., a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K) or by reacting the free base form of the compound with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred where practicable. Other suitable salts can be found in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985), which is incorporated herein by reference.

[0091] As used herein, "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, the like, and combinations thereof, which are well known to those of ordinary skill in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pp. 1289-1329, incorporated herein by reference). Unless any conventional carrier is incompatible with the active ingredient, it is contemplated for use in therapeutic or pharmaceutical compositions.

[0092] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H (ie D), 3 H (ie T), 11 C. 13 C. 14 C. 15 N. 18 F 31 P. 32 P. 35 S. 36 Cl, 125 I. The present invention includes various isotopically labeled compounds as defined herein, for example, wherein radioactive isotopes such as 3 H. 13 C and 14 C. Such isotope-labeled compounds can be used for metabolic studies (using 14 C), reaction kinetics studies (e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or may be used for radiotherapy of an individual. In particular, 18Compounds labeled with F or F may be particularly desirable for use in PET or SPECT studies. Isotopically labeled compounds of the invention can generally be prepared by carrying out the procedures described in the schemes or in the examples and preparations below, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0093] Moreover, the presence of heavier isotopes, especially deuterium (i.e. 2 In some embodiments, the present invention provides a compound of the present invention which is substituted with a deuterium (H or D) or a substituted isotope (D). The substitution can also obtain certain therapeutic benefits caused by greater metabolic stability, such as extending half-life in vivo or reducing dosage requirements or improving therapeutic index. It is understood that deuterium in this context can be regarded as a substituent of a compound of the present invention. The concentration of this type of heavier isotope, particularly deuterium, can be defined by an isotopic enrichment factor. "Isotopic enrichment factor" represents the ratio between the isotopic abundance and the natural abundance of a given isotope.

[0094] As used herein, a "therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that can elicit a biological or medical response in a subject, or improve symptoms, slow or delay progression of a disease, or prevent a disease, etc. A "therapeutically effective amount" can be determined by the attending physician or veterinary practitioner and will vary with factors such as the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, and the judgment of the attending physician or veterinary practitioner.

[0095] As used herein, "subject" refers to an animal. Preferably, the animal is a mammal. Subject also refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a preferred embodiment, the subject is a human.

[0096] As used herein, "inhibit" refers to a reduction or suppression of a particular condition, symptom or disorder or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0097] As used herein, the term "treating" any disease or condition refers, in one embodiment, to ameliorating the disease or condition (i.e., arresting or slowing the progression of the disease or at least one of its clinical symptoms). In another embodiment, "treating" refers to improving at least one physical parameter, which may not be perceptible to the patient. In another embodiment, "treating" refers to modulating the disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both.

[0098] As used herein, "prevention" refers to the administration of one or more pharmaceutical substances, particularly compounds of the present invention and / or pharmaceutically acceptable salts thereof, to an individual with a predisposition to the disease in question, in order to prevent the individual from developing the disease.

[0099] In general, the term "about" is used herein to modify a given numerical value above or below that value by 20%, such as 10%, such as 5%.

[0100] Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0101] Example

[0102] The following examples illustrate the present invention described above, which however do not limit the scope of the invention in any way.The beneficial effects of the combination of the present invention can also be determined by other test models known to those skilled in the art.

[0103] In the present invention, the sources and trade names of the reagents and equipment used are indicated when they first appear. Unless otherwise specified, the same reagents used thereafter are the same as those first indicated. Conventional unlabeled reagents were purchased from Sinopharm Chemical Reagent Co., Ltd.

[0104] Abbreviation meaning:

[0105] DIPEA: N,N-diisopropylethylamine; SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride; TBAF: tetrabutylammonium fluoride; NBS: N-bromosuccinimide; Tf: trifluoromethanesulfonyl; FA: formic acid; BSA: bovine serum albumin; Brij 35: polyoxyethylene lauryl ether; Pd(dppf)Cl2: 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride); NBS: N-bromosuccinimide; PE: petroleum ether; EA: ethyl acetate.

[0106] Example 1: Synthesis of Compound 1

[0107] Step 1: Synthesis of Intermediate 2-1

[0108] In a 100 mL single-necked flask, 5-aminopyrazole 1-1 (8.3 g, 100 mmol) was dissolved in glacial acetic acid (AcOH) (80 mL). Methyl propiolate (8.4 g, 100 mmol) was added with stirring at room temperature and the mixture was refluxed overnight. The reaction solution was concentrated to dryness, EA (150 mL) was added, and stirring was continued for 1.5 h. The mixture was filtered to obtain intermediate 2-1 (4.5 g, yield: 33.3%) as a yellow solid. LCMS (ESI) m / z = 136.2 [M+H] + .

[0109] Step 2: Synthesis of intermediate 3-1

[0110] In a 100 mL single-necked flask, intermediate 2-1 (3.8 g, 28.1 mmol) was dissolved in acetic acid (72.0 mL). Liquid bromine (18.0 g, 112.5 mmol) was added with stirring at room temperature. The reaction was allowed to proceed for 3 hours until completion. The filter cake was collected by filtration and rinsed twice with PE to afford intermediate 3-1 (4.0 g, yield: 66.7%) as a light yellow solid. 1 H NMR (400MHz, DMSO) δ12.14(s,1H),9.82(s,2H),8.29(s,1H),8.03(s,1H).

[0111] Step 3: Synthesis of intermediate 4-1

[0112] In a 100 mL single-necked flask, intermediate 3-1 (2.14 g, 100 mmol) and DIPEA (2.84 g, 220 mmol) were dissolved in tetrahydrofuran (THF) (50 mL). SEMCl (2.0 g, 120 mmol) was added dropwise with stirring at room temperature and allowed to react for 16 h. The reaction solution was poured into water and extracted with EA (100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified on a silica gel flash column (0-30% PE / EA) to obtain intermediate 4-1 (0.8 g, yield: 23.3%) as a waxy solid. LCMS (ESI) m / z = 346.0 [M+H] + .

[0113] Step 4: Synthesis of Intermediate 5-1

[0114] Intermediate 4-1 (0.8 g, 2.32 mmol), 4-methoxyphenylboronic acid pinacol ester (1.085 g, 4.64 mmol), Pd(PPh3)4 (536 mg, 0.464 mmol), potassium carbonate (640 mg, 4.64 mmol), 1,4-dioxane (25 ml), and water (5 ml) were placed sequentially in a 50 mL single-necked flask and stirred at 110°C under N2 protection for 16 h. The reaction mixture was filtered, and the filtrate was concentrated and purified on a silica gel flash column (0-50% PE / EA) to obtain 800 mg of crude intermediate 5-1 as a white solid. 400 mg of the product was separated and purified by prep-HPLC (H2O / ACN, 0.1% formic acid) to obtain intermediate 5-1 (50 mg, yield: 11.6%). LCMS (ESI) m / z = 372.1 [M+H] + .

[0115] Step 5: Synthesis of Intermediate 6-1

[0116] Intermediate 5-1 (40 mg, 0.10 mmol), 5-bromo-2-methyl-2H-indazole (44 mg, 0.2 mmol), trans-N,N'-dimethylcyclohexanediamine (3 mg, 0.02 mmol), cuprous iodide (4 mg, 0.02 mmol), potassium phosphate (44 mg, 0.2 mmol), and dimethyl sulfoxide (DMSO) (5 ml) were placed sequentially in a 50 mL single-necked flask and stirred at 110°C under nitrogen for 16 h. The reaction solution was concentrated to dryness and purified on a silica gel flash column (0-3% methanol (MEOH) / dichloromethane (DCM)) to obtain Intermediate 6-1 (21 mg, yield: 38.9%) as a white solid. LCMS (ESI) m / z = 502.4 [M+H] + .

[0117] Step 6: Synthesis of Compound 1

[0118] Intermediate 6-1 (21 mg, 0.057 mmol) and TBAF tetrahydrofuran solution (5 ml, 5 mmol) were placed sequentially in a 25 mL single-necked flask and stirred at 60°C under N2 protection for 16 h. The reaction solution was concentrated to dryness and analyzed by prep-TLC (DCM / THF = 1 / 1) to afford compound 1 (3 mg, yield: 19.4%) as a white solid. 1 H NMR (400MHz, DMSO) δ12.07(s,1H),8.77(s,1H),8.46(s,1H),8.14(s,1H),7.85(s,1H),7.81(d,J=9.4Hz,1H),7.75( d,J=9.1Hz,1H),7.60(d,J=8.1Hz,2H),6.97(d,J=7.8Hz,2H),4.20(s,3H),3.79(s,3H).LCMS(ESI)m / z=372.2[M+H] + .

[0119] Example 2: Synthesis of Compound 2

[0120] Step 1: Synthesis of intermediate 2-2

[0121] In a 100 mL single-necked flask, 3-amino-4-ethoxycarbonylpyrazole (40 g, 258 mmol) was dissolved in THF (500 mL). The temperature was lowered to 0°C, and DIPEA (40 g, 310 mmol) was added. The mixture was stirred for 15 min, and SEMCl (51.5 g, 310 mmol) was added dropwise. After completion, the mixture was stirred at room temperature for 12 h. The reaction mixture was poured into 1 L of ice-water and extracted with EA. The organic phases were combined and washed with water and saturated brine (200 mL each), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified on a silica gel flash column (EA / PE = 1 / 2) to obtain intermediate 2-2 (55 g, yield: 74.8%) as a light yellow oil. LCMS (ESI) m / z = 286.2 [M+H] + .

[0122] Step 2: Synthesis of intermediate 3-2

[0123] In a 500 mL single-necked flask, intermediate 2-2 (54 g, 189.5 mmol) was dissolved in ethanol (250 mL). Diethyl malonate (113.6 g, 709.5 mmol) was added while stirring at room temperature. The temperature was lowered to 0°C, and a 20% sodium ethoxide (NaOEt) ethanol solution (192.9 g, 567 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to 95°C under N2 protection and stirred for 18 hours. The reaction solution was concentrated to dryness under reduced pressure, added to 200 mL of ice water, and extracted with methanol / DCM (1 / 10). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The product was purified on a silica gel column (DCM / MeOH = 30 / 1) to obtain intermediate 3-2 (50 g, yield: 75.9%) as a light yellow solid. LCMS (ESI) m / z = 354.2 [M+H] + .

[0124] Step 3: Synthesis of intermediate 4-2

[0125] In a 500 mL single-necked flask, intermediate 3-2 (50 g, 141 mmol) was dissolved in 15% aqueous sodium hydroxide solution (350 mL) and heated to 105°C for 15 hours. The reaction solution was cooled to 0°C in an ice-water bath and the pH was adjusted to approximately 5 with 4 M dilute hydrochloric acid. Filtering afforded a white solid, which was then purified on a silica gel flash column (DCM / MeOH = 10:1) to afford intermediate 4-2 (30.8 g, yield: 77.4%) as a white solid. LCMS (ESI) m / z = 282.1 [M+H] + .

[0126] Step 4: Synthesis of intermediate 5-2

[0127] In a 100 mL single-necked bottle, intermediate 4-2 (30.8 g, 109.5 mmol) was dissolved in dimethylformamide (DMF) (200 mL). Triethylamine (TEA) (33.2 g, 328.5 mmol) was added, followed by the addition of N-phenylbis(trifluoromethylsulfonyl)imide (46.9 g, 131.4 mmol) in portions. The mixture was allowed to react at room temperature for 16 hours. The reaction solution was poured into 1 L of ice water and extracted with EA. The organic phases were combined, washed once with water and saturated brine (100 mL each), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified on a silica gel flash column (PE / EA = 2:1) to obtain intermediate 5-2 (10.1 g, yield: 22.3%) as a white solid. 1 H NMR (400MHz, DMSO) δ12.41(s,1H),8.60(s,1H),6.41(s,1H),5.55(s,2H),3.66-3.55(m,2H),0.93-0.84(m,2H),0.01-0.02(m,9H).

[0128] Step 5: Synthesis of intermediate 6-2

[0129] In a 25 mL single-necked flask, intermediate 5-2 (5.0 g, 12.1 mmol) was dissolved in DMF (25 mL). TEA (1.35 g, 13.3 mmol) was added, and ethylamine tetrahydrofuran solution (13.3 ml, 26.6 mmol, 2 M) was slowly added dropwise. The mixture was stirred at room temperature overnight. The reaction solution was poured into 250 mL of ice water and extracted with EA. The organic phases were combined, washed once with water and once with saturated sodium chloride (50 mL each), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified on a silica gel flash column (DCM / MeOH = 40 / 1) to obtain intermediate 6-2 (1.1 g, yield: 29.5%) as a white solid. 1 H NMR (400MHz, DMSO) δ10.63(s,1H),8.21(s,1H),6.90(t,J=5.2Hz,1H),5.43(d,J=4.0Hz,2H),4.88(d,J=5.6Hz ,1H),3.57(t,J=8.2Hz,2H),3.15(d,J=4.4Hz,2H),1.24(t,J=7.2Hz,3H),0.89(t,J=8.0Hz,2H),0.02(s,9H).

[0130] Step 6: Synthesis of intermediate 7-2

[0131] In a 25 mL single-necked flask, intermediate 6-2 (1.1 g, 3.57 mmol) was dissolved in THF (15 mL), and NBS (634 mg, 3.57 mmol) was added. The mixture was allowed to react at room temperature for 2 h. The reaction solution was poured into ice water and extracted with DCM / methanol (10 / 1). The organic layers were combined, washed once with water and once with saturated brine (20 mL each), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel flash column (DCM / MeOH = 25 / 1) to obtain intermediate 7-2 (1.1 g, yield: 79.6%) as a white solid. 1 H NMR (400MHz, DMSO) δ11.31(s,1H),8.62(s,1H),6.36(t,J=6.0Hz,1H),5.48(s,2 H),3.67-3.55(m,4H),1.27(t,J=7.2Hz,3H),0.90(t,J=8.0Hz,2H),0.01(s,9H).

[0132] Step 7: Synthesis of intermediate 8-2

[0133] Intermediate 7-2 (1.0 g, 2.58 mmol), 4-methoxyphenylboronic acid pinacol ester (1.2 g, 5.16 mmol), Pd(dppf)Cl2 (209 mg, 0.258 mmol), potassium carbonate (712 mg, 5.16 mmol), 1,4-dioxane (25 ml), and water (5 ml) were placed sequentially in a 50 mL single-necked flask. Under nitrogen protection, the mixture was heated to 100°C and stirred for 16 h. The reaction solution was concentrated to dryness, and the crude product was purified by silica gel flash column chromatography (DCM / methanol = 30 / 1) to obtain intermediate 8-2 (550 mg, yield: 51.4%) as a white solid. 1 H NMR (400MHz, DMSO) δ10.90(s,1H),8.49(s,1H),7.12(d,J=8.4Hz,2H),6.98(d,J=8.4Hz,2H),5.45(s,2H),5.21(t,J=6.0Hz ,1H),3.80(s,3H),3.60(dd,J=10.8,5.3Hz,2H),3.33-3.28(m,2H),1.07(t,J=7.2Hz,3H),0.92-0.87(m,2H),0.01(s,9H).

[0134] Step 8: Synthesis of Intermediate 9-2

[0135] Intermediate 8-2 (200 mg, 0.48 mmol), 5-bromo-2-methyl-2H-indazole (204 mg, 0.96 mmol), trans-N,N'-dimethylcyclohexanediamine (7 mg, 0.048 mmol), cuprous iodide (9 mg, 0.048 mmol), potassium phosphate (204.5 mg, 1 mmol), and DMSO (25 ml) were placed sequentially in a 50 mL single-necked flask. The mixture was heated to 130°C and stirred for 16 h under N2 protection. The reaction mixture was poured into ice water and extracted with DCM / methanol (10 / 1). The organic layers were combined and washed once with water and once with saturated brine (25 mL each), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified on a silica gel flash column (DCM / MeOH = 30 / 1) to obtain Intermediate 9-2 (100 mg, yield: 38.3%) as a white solid. LCMS (ESI) m / z = 545.2 [M+H] + .

[0136] Step 9: Synthesis of Compound 2

[0137] In a 25 mL single-necked vial, intermediate 9-2 (100 mg, 1.83 mmol) was dissolved in 4 M HCl / 1,4-dioxane (15 mL) and allowed to react at room temperature for 2 h. The reaction mixture was poured into ice water and the pH adjusted to neutral with aqueous sodium bicarbonate. Extraction was performed with DCM / methanol (10 / 1). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by prep-HPLC (H2O / CAN, 0.1% FA). Freeze-dried, compound 2 (31.77 mg, 41.8% yield) was obtained as a white solid. 1 H NMR (400MHz, DMSO) δ13.03(s,1H),8.35(s,2H),7.60(d,J=13.2Hz,2H),7.16(d,J=8.8Hz,2H),7.07(dd,J=9.2,2.0Hz,1H),6 .95(d,J=8.8Hz,2H),5.27(s,1H),4.19(s,3H),3.77(s,3H),3.36(m,2H),1.09(t,J=7.2Hz,3H).LCMS(ESI)m / z=415.2[M+H] + .

[0138] Compounds 5, 6, 7, 9, 10, 11, and 16 were prepared using the synthetic method of Example 2.

[0139] Example 3: Synthesis of Compound 4

[0140] Step 1: Synthesis of intermediate 2-4

[0141] In a 25 mL autoclave, 4-2 (2.5 g, 8.9 mmol) was dissolved in a 25 mL, 2 M solution of methylamine in THF. The mixture was heated to 100°C and allowed to react overnight. The reaction solution was concentrated to give the crude product, which was purified by silica gel flash column chromatography (0-2% methanol / DCM) to afford intermediate 2-4 (1.0 g, yield: 38.3%) as a white solid. 1 H NMR (400MHz, DMSO) δ10.64(s,1H),8.14(s,1H),7.05(d,J=4.8Hz,1H),5.44(s,2H),4. 86(s,1H),3.61-3.54(m,2H),2.78(d,J=4.8Hz,3H),0.93-0.85(m,2H),-0.00(s,9H).

[0142] Step 2: Synthesis of intermediate 3-4

[0143] In a 25 mL single-necked flask, intermediate 2-4 (1.0 g, 3.4 mmol) was dissolved in THF (15 mL), and NBS (604 mg, 3.4 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated to dryness to obtain the crude product, which was purified by silica gel flash column chromatography (0-3% methanol / DCM) to obtain intermediate 3-4 (760 mg, yield: 60.3%) as a white solid. LCMS (ESI) m / z = 373.1 [M+H] + .

[0144] Step 3: Synthesis of intermediate 4-4

[0145] Intermediate 3-4 (373 mg, 1.0 mmol), 4-methoxyphenylboronic acid pinacol ester (468 mg, 2 mmol), Pd(dppf)Cl2 (81 mg, 0.1 mmol), potassium carbonate (276 mg, 2 mmol), 1,4-dioxane (15 ml), and water (3 ml) were placed sequentially in a 50 mL single-necked flask and stirred at 90°C under N2 protection for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was purified on a silica gel flash column (0-3% methanol / DCM) to obtain Intermediate 4-4 (180 mg, yield: 45%) as a white solid. LCMS (ESI) m / z = 401.2 [M+H] + .

[0146] Step 4: Synthesis of intermediate 5-4

[0147] Intermediate 4-4 (80 mg, 0.2 mmol), 5-bromo-2-methyl-2H-indazole (84 mg, 0.4 mmol), trans-N,N'-methylcyclohexanediamine (3 mg, 0.02 mmol), cuprous iodide (8 mg, 0.04 mmol), potassium phosphate (55 mg, 0.4 mmol), and DMSO (6 ml) were placed sequentially in a 10 mL microwave tube and microwave-heated at 110°C for 3 h under nitrogen. The reaction mixture was poured into water and extracted with 50 mL of methanol / DCM (1 / 10). The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified on a silica gel flash column (0-2% methanol / DCM) to afford Intermediate 5-4 (75 mg, yield: 75.5%) as a white solid. LCMS (ESI) m / z = 531.3 [M+H] + .

[0148] Step 5: Synthesis of Compound 4

[0149] In a 25 mL single-necked flask, intermediate 5-4 (75 mg, 0.14 mmol) was dissolved in 4 mol / L hydrogen chloride in dioxane (5 mL) and stirred at room temperature for 2 h. The reaction mixture was poured into 10 mL of water and the pH was adjusted to neutral with aqueous sodium bicarbonate. Extraction was performed with 50 mL of DCM / methanol (10 / 1). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification was performed by prep-HPLC (water / acetonitrile, 0.1% NH3.H2O), and freeze-dried to afford compound 4 (6.83 mg, yield: 12.1%) as a white solid. 1 H NMR (400MHz, DMSO) δ13.02 (s, 1H), 8.36 (s, 2H), 7.61 (d, J = 12.0Hz, 2H), 7.15 (d, J = 8.4Hz, 2H), 7.06 (dd, J1 = 9.2Hz, J2 = 2. 0Hz,1H),6.94(d,J=8.4Hz,2H),5.61(s,1H),4.19(s,3H),3.77(s,3H),2.99(d,J=4.4Hz,3H).LCMS(ESI)m / z=401.1[M+H] + .

[0150] Example 4: Synthesis of Compound 3

[0151] Step 1: Synthesis of intermediate 2-3

[0152] In a 25 mL single-necked bottle, 4-2 (2.0 g, 7.1 mmol) was dissolved in DMF (25 mL). Sodium bicarbonate (1.2 g, 14.2 mmol) and iodoethane (EtI) (1.66 g, 10.7 mmol) were added and reacted at 45°C overnight. The reaction solution was poured into ice water and extracted with EA (100 mL). The organic layers were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified on a silica gel flash column (0-80% EA / PE) to obtain intermediate 2-3 (0.2 g, yield: 9.1%) as a white solid. 1 HNMR(400MHz,DMSO)δ11.37(s,1H),8.30(s,1H),5.52(s,1H),5.44(s,2H),4.17(q,J= 7.2Hz,2H),3.62-3.55(m,2H),1.41(t,J=7.2Hz,3H),0.91-0.85(m,2H),-0.00(s,9H).

[0153] Step 2: Synthesis of intermediate 3-3

[0154] In a 25 mL single-necked flask, intermediate 2-3 (0.2 g, 0.645 mmol) was dissolved in THF (15 mL), and NBS (120 mg, 0.677 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was poured into water and extracted with 50 mL of DCM / methanol (10 / 1). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by silica gel flash column chromatography (0-4% methanol / DCM) to obtain intermediate 3-3 (205 mg, yield: 82.3%) as a white solid. 1 HNMR(400MHz,DMSO)δ12.01(s,1H),8.77(s,1H),5.49(s,2H),4.63(q,J=7.2Hz,2H ),3.67-3.59(m,2H),1.44(t,J=7.2Hz,3H),0.94-0.85(m,2H),0.02--0.04(m,9H).

[0155] Step 3: Synthesis of intermediate 4-3

[0156] Intermediate 3-3 (205 mg, 0.53 mmol), 4-methoxyphenylboronic acid pinacol ester (247 mg, 1.06 mmol), Pd(dppf)Cl2 (43 mg, 0.053 mmol), potassium carbonate (146 mg, 1.06 mmol), 1,4-dioxane (15 ml), and water (3 ml) were placed sequentially in a 50 mL single-necked flask. Under nitrogen protection, the mixture was heated to 100°C and stirred for 16 h. The reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel flash column (0-2% methanol / DCM) to obtain intermediate 4-3 (150 mg, yield: 68.5%) as a white solid. 1 H NMR(400MHz, DMSO)11.62(s,1H),8.61(s,1H),7.24(d,J=8.8Hz,2H),6.92(d,J=8.8Hz,2H),5.47(s,2H),4.32(q,J=7.2Hz ,2H),3.79(s,3H),3.65-3.57(m,2H),1.21(t,J=7.2Hz,3H),0.93-0.86(m,2H),-0.00(s,9H).LCMS(ESI)m / z=416.2[M+H] + .

[0157] Step 4: Synthesis of intermediate 5-3

[0158] Intermediate 4-3 (130 mg, 0.31 mmol), 5-bromo-2-methyl-2H-indazole (131 mg, 0.62 mmol), trans-N,N'-methylcyclohexanediamine (4.4 mg, 0.03 mmol), cuprous iodide (9 mg, 0.048 mmol), potassium phosphate (131.0 mg, 0.62 mmol), and DMSO (8 ml) were placed sequentially in a 20 mL microwave tube and microwave-dried at 110°C for 3 h under nitrogen. The reaction solution was poured into water and extracted with 50 mL of methanol / DCM (1 / 10). The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified on a silica gel flash column (0-3% methanol / DCM) to afford Intermediate 5-3 (100 mg, yield: 58.8%) as a white solid. LCMS (ESI) m / z = 546.2 [M+H] + .

[0159] Step 5: Synthesis of compound 3

[0160] In a 25 mL single-necked flask, intermediate 5-3 (100 mg, 0.183 mmol) was dissolved in 4 mol / L hydrogen chloride in dioxane (5 mL) and stirred at room temperature for 2 h. The reaction mixture was poured into 10 mL of water and the pH was adjusted to neutral with aqueous sodium bicarbonate. Extraction was performed with 50 mL of DCM / methanol (10 / 1). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification was performed by prep-HPLC (water / acetonitrile, 0.1% FA) and freeze-dried to afford 3 (9.0 mg, yield: 11.84%) as a white solid. 1 H NMR (400MHz, DMSO) δ13.29(s,1H),8.48(s,1H),8.40(s,1H),7.76-7.57(m,2H),7.27(d,J=8.8Hz,2H),7.10(dd,J1=9.2Hz,J2=2.0 Hz,1H),6.89(d,J=8.8Hz,2H),4.40(q,J=6.8Hz,2H),4.21(s,3H),3.76(s,3H),1.23(t,J=7.2Hz,3H).LCMS(ESI)m / z=416.1[M+H] + .

[0161] Using the synthetic method of Example 4, compounds 13, 14, 15, 17-26, 33-34, 37-38, 40-41, 46-48, 54, 57-58, 60, 62, 65-66, 84, 86-87, 90, 92, 101-102, 111, 114, 116-118, 124-128, 131-133, 137, 139, 141, and 142 were prepared.

[0162] Trifluoroacetate of compound 35:

[0163] The synthetic method of Example 4 was used, except that 4-methoxyphenylboronic acid pinacol ester in the third step was replaced with 4-chlorophenylboronic acid pinacol ester, 5-bromo-2-methyl-2H-indazole in the fourth step was replaced with 1-(azetidin-3-yl)-6-iodo-1H-benzo[d]imidazole, and the mobile phase FA purified by prep-HPLC in the fifth step was replaced with trifluoroacetic acid to obtain the trifluoroacetate salt of compound 35. 1H NMR(400MHz,MeOD)δ8.83(s,1H),8.46(d,J=9.1Hz,1H),7.92-7.82(dd,J=23.1,14.3Hz,2H),7.46-7.25(m,5H), 5.90-5.63(m,1H),4.81-4.58(m,4H),4.51(q,J=7.0Hz,2H),1.33(t,J=7.0Hz,3H).LCMS(ESI)m / z=460.85[M+H] + .

[0164] Example 5: Synthesis of Compound 12

[0165] Step 1: Synthesis of intermediate 2-12

[0166] In a 25 mL single-necked flask, 4-2 (2.0 g, 7.1 mmol) and potassium carbonate (1.96 g, 14.2 mmol) were dissolved in DMF (25 mL). 2,2,2-Trifluoroethyl trifluoromethanesulfonate solution (3.3 g, 14.2 mmol) was added to the reaction mixture and stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with EA (100 mL). The organic layers were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified on a silica gel flash column (0-60% EA) to obtain intermediate 2-12 (0.6 g, yield: 51.9%) as a white solid. 1 HNMR(400MHz,DMSO)δ11.53(s,1H),8.35(s,1H),5.70(s,1H),5.41(s,2H),4.91(q,J=8.8Hz ,2H),3.54(t,J=8.0Hz,2H),0.83(t,J=8.0Hz,2H),-0.05(s,9H).LCMS(ESI)m / z=363.9[M+H] + .

[0167] Step 2: Synthesis of Intermediate 3-12

[0168] In a 25 mL single-necked flask, intermediate 2-12 (0.6 g, 1.36 mmol) was dissolved in THF (15 mL). NBS (0.24 g, 1.36 mmol) was added and stirred at room temperature for 2 h. The reaction solution was slowly added dropwise to ice water. A large amount of solid precipitated and was filtered. The filter cake was purified by silica gel flash column chromatography (0-4% methanol / DCM) to obtain intermediate 3-12 (600 mg, yield: 93.7%) as a white solid. 1HNMR(400MHz,DMSO)δ12.23(s,1H),8.76(s,1H),5.50(s,2H),5.26(q,J=8.5Hz,2H),3.68- 3.57(m,2H),0.89(dd,J1=10.6Hz,J2=5.6Hz,2H),-0.00(s,9H).LCMS(ESI)m / z=441.9[M+H] + .

[0169] Step 3: Synthesis of Intermediate 4-12

[0170] Intermediate 3-12 (200 mg, 0.426 mmol), 4-methoxyphenylboronic acid pinacol ester (200 mg, 0.852 mmol), Pd(dppf)Cl2 (34.5 mg, 0.043 mmol), potassium carbonate (117 mg, 0.852 mmol), 1,4-dioxane (15 ml), and water (3 ml) were placed sequentially in a 50 mL single-necked flask. The mixture was stirred at 100°C under nitrogen for 16 h. The mixture was filtered, and the filtrate was concentrated and purified on a silica gel flash column (0-3% methanol / DCM) to obtain Intermediate 4-12 (95 mg, 47.5% yield) as a white solid. LCMS (ESI) m / z = 470.0 [M+H] + .

[0171] Step 4: Synthesis of intermediate 5-12

[0172] Intermediate 4-12 (95 mg, 0.2 mmol), 5-bromo-2-methyl-2H-indazole (85 mg, 0.4 mmol), trans-N,N'-dimethylcyclohexanediamine (6 mg, 0.04 mmol), cuprous iodide (8 mg, 0.04 mmol), potassium phosphate (85 mg, 0.4 mmol), and DMSO (8 ml) were placed sequentially in a 20 mL microwave tube and microwave-dried at 110°C for 3 h under nitrogen. The reaction solution was poured into water and extracted with 50 mL of methanol / DCM (1 / 10). The organic layers were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified on a silica gel flash column (0-3% methanol / DCM) to obtain Intermediate 5-12 (80 mg, yield: 65.8%) as a white solid. LCMS (ESI) m / z = 600.2 [M+H] + .

[0173] Step 5: Synthesis of compound 12

[0174] In a 25 mL single-necked flask, intermediate 5-12 (80 mg, 0.133 mmol) was dissolved in 4 M hydrogen chloride (1,4-dioxane) (6 mL) and stirred at room temperature for 4 h. The reaction mixture was poured into water and the pH was adjusted to neutral with aqueous sodium bicarbonate. Extraction was performed with 50 mL of DCM / methanol (10 / 1). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The product was analyzed by prep-HPLC (water / acetonitrile, 0.1% FA) and freeze-dried to afford compound 12 (31.53 mg, 50.4% yield) as a white solid. 1 H NMR (400MHz, DMSO) δ13.38(s,1H),8.51(s,1H),8.41(s,1H),7.72(s,1H),7.67(d,J=9.2Hz,1H),7.28(d,J=8.8Hz,2H),7.11(d d, J1=9.2Hz, J2=2.0Hz, 1H), 6.91 (d, J=8.8Hz, 2H), 4.98 (q, J=8.8Hz, 2H), 4.21 (s, 3H), 3.77 (s, 3H). LCMS (ESI) m / z=470.1[M+H] + .

[0175] Compounds 27-29, 46-47, 49, 52-54, 89, 93, and 99 were prepared using the synthetic method of Example 5.

[0176] Example 6: Synthesis of Compounds 31 and 45

[0177] In a 25 mL single-necked flask, compound 14 (50 mg, 0.011 mmol) and cesium carbonate (7 mg, 0.022 mmol) were dissolved in 3 mL of acetone. Methyl iodide (4 mg, 0.03 mmol) was added and stirred at room temperature for 1 h. The reaction solution was concentrated to dryness to obtain the crude product, which was purified by prep-TLC (DCM / MeOH = 20 / 1) and freeze-dried to give compound 31 (15 mg, yield: 29.1%) as a white solid; and compound 45 (35 mg, yield: 67.9%) as a white solid.

[0178] Compound 31: 1H NMR (400MHz, DMSO) δ8.49(s,1H),8.14(s,1H),7.86(d,J=1.3Hz,1H),7.74(d,J =9.0Hz,1H),7.40(d,J=8.8Hz,2H),7.26(t,J=76.0Hz,1H),7.24(dd,J=9.0,2.0 Hz,1H),7.13(d,J=8.7Hz,2H),4.46(q,J=7.0Hz,2H),4.22(s,3H),3.05(s,3H),1.25(t,J=7.0Hz,3H).LCMS(ESI)m / z=466.0[M+H] + .

[0179] Compound 45: 1 H NMR (400MHz, DMSO) δ8.57(s,1H),8.40(s,1H),7.68(d,J=1.4Hz,1H),7.65(d,J=9.0Hz,1H),7.40(d,J=8.7Hz,2H),7.26(t,J=76.0Hz,1H),7. 13(d,J=8.6Hz,2H),7.10(d,J=1.9Hz,1H),4.42(d,J=7.0Hz,2H),4.20(s,3H),3.83(s,3H),1.25(t,J=7.0Hz,3H).LCMS(ESI)m / z=466.0[M+H] + .

[0180] Example 7: Synthesis of Compound 50

[0181] Step 1: Synthesis of Intermediate 2-50

[0182] In a 250 mL single-necked flask, 4-2 (4 g, 14.2 mol) was dissolved in DMF (50 mL). Sodium carbonate (3 g, 28.4 mol) and bromomethylcyclopropane (6.72 g, 49.7 mol) were added. The mixture was heated to 90°C and stirred for 3 h. Upon completion of the reaction, the reaction solution was poured into water. The precipitated solid was filtered to obtain the crude product. The crude product was purified using a silica gel flash column (0-2% methanol) to obtain intermediate 2-50 (1.5 g, yield: 31.5%) as a white solid. LCMS (ESI) m / z = 336.1 [M+H] + .

[0183] Step 2: Synthesis of Intermediate 3-50

[0184] In a 50 mL single-necked flask, intermediate 2-50 (1.5 g, 4.47 mmol) was dissolved in THF (20 mL). NBS (0.84 g, 4.7 mmol) was added portionwise at room temperature and allowed to react for 2 h. The reaction mixture was poured into ice water and extracted with EA (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified on a silica gel flash column (0-100% EA) to afford intermediate 3-50 (1.35 g, yield: 73.6%) as a light yellow solid. LCMS (ESI) m / z = 414.0 [M+H] + .

[0185] Step 3: Synthesis of Intermediate 4-50

[0186] Intermediate 3-50 (1.25 g, 3 mmol), 4-chlorophenylboronic acid pinacol ester (1.43 g, 11.6 mmol), Pd(dppf)Cl2 (0.24 g, 0.58 mmol), potassium carbonate (0.83 g, 11.6 mmol), 1,4-dioxane (15 mL), and water (3 mL) were placed sequentially in a 100 mL single-necked flask. The temperature was raised to 100°C under nitrogen protection and the reaction was continued for 16 h. The reaction solution was concentrated and purified by silica gel flash column (PE:EA = 1:1) to obtain Intermediate 4-50 (0.55 g, yield: 41%) as a light yellow solid. LCMS (ESI) m / z = 446.1 [M+H] + .

[0187] Step 4: Synthesis of Intermediate 5-50

[0188] Intermediate 4-50 (550 mg, 1.23 mmol), 5-bromo-2-methyl-2H-indazole (516 mg, 2.46 mmol), trans-N,N'-dimethylcyclohexanediamine (20 mg, 0.12 mmol), cuprous iodide (47 mg, 0.246 mmol), potassium phosphate (524 mg, 2.46 mmol), and DMSO (10 ml) were placed sequentially in a 50 mL single-necked flask. The temperature was raised to 130°C under N2 protection and the reaction was allowed to proceed overnight. The reaction solution was concentrated to dryness to obtain the crude product, which was purified on a silica gel flash column (3% methanol / DCM) to obtain Intermediate 5-50 (420 mg, yield: 59.1%) as a white solid. LCMS (ESI) m / z = 576.2 [M+H] + .

[0189] Step 5: Synthesis of Compound 50

[0190] In a 50 mL single-necked flask, intermediate 5-50 (420 mg, 0.73 mmol) was dissolved in 4 M hydrochloric acid / 1,4-dioxane (10 mL) and allowed to react at room temperature for 4 h. The reaction solution was poured into water and the pH was adjusted to alkaline with aqueous ammonia. Extraction was performed with 50 mL of DCM / methanol (10 / 1). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification was performed by prep-HPLC (water / acetonitrile, 0.1% NH3.H2O), and freeze-dried to afford the final product, compound 50 (164.39 mg, 50.5% yield), as a white solid. 1 H NMR (400MHz, DMSO) δ13.33(s,1H),8.52(s,1H),8.40(s,1H),7.74-7.61(m,2H),7.45-7.33(m,4H),7.11(d,J=8.9Hz,1H),4. 28(d,J=6.6Hz,2H),4.20(s,3H),1.18-1.04(m,1H),0.50(d,J=7.3Hz,2H),0.29(d,J=4.0Hz,2H).LCMS(ESI)m / z=446.0[M+H] + .

[0191] Compounds 32, 39, 51, 95, 96, and 104 were prepared using the synthetic method of Example 7.

[0192] Example 8: Synthesis of Compound 59

[0193] Step 1: Synthesis of Intermediate 2-59

[0194] In a 50 mL single-necked flask, intermediate 4-2 (1.2 g, 4.27 mmol), 2-(2-bromoethoxy)tetrahydropyran (1.0 g, 4.7 mmol), and sodium carbonate (0.9 g, 8.54 mmol) were dissolved in DMF (15 mL) and reacted at 90°C for 2 h. The reaction was quenched by adding water (50 mL), extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and separated on silica gel flash chromatography (PE / EA = 1 / 4) to obtain intermediate 2-59 (640 mg, yield: 36.64%) as a yellow solid. LCMS (ESI) m / z = 410.2 [M+H] + .

[0195] Step 2: Synthesis of Intermediate 3-59

[0196] In a 25 mL single-necked vial, Intermediate 2-59 (600 mg, 1.46 mmol), 5-bromo-2-methyl-2H-indazole (462 mg, 2.20 mmol), (1R,2R)-dimethylcyclohexane-1,2-diamine (207 mg, 1.46 mmol), cuprous iodide (277 mg, 1.46 mmol), and potassium phosphate (403 mg, 2.92 mmol) were dissolved in DMSO (10 mL) and reacted at 110°C under nitrogen for 16 h. The reaction was quenched with water, extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the product was separated on silica gel flash chromatography (EA / PE = 9 / 1) to afford Intermediate 3-59 (600 mg, yield: 76.24%) as a yellow solid. LCMS (ESI) m / z = 540.2 [M+H] + .

[0197] Step 3: Synthesis of Intermediate 4-59

[0198] In a 50 mL single-necked flask, intermediate 3-59 (500 mg, 0.928 mmol) was dissolved in THF (20 mL), and NBS (173 mmol, 0.974 mmol) was added portionwise. The reaction was allowed to react at room temperature for 2 h. The reaction was quenched with saturated sodium thiosulfate solution, extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified on silica gel flash chromatography (EA / PE = 90 / 10) to afford intermediate 4-59 (400 mg, yield: 69.82%) as a light yellow solid. LCMS (ESI) m / z = 618.0 [M+H] + .

[0199] Step 4: Synthesis of Intermediate 5-59

[0200] Intermediate 4-59 (100 mg, 0.162 mmol), 4-chlorophenylboronic acid pinacol ester (77.1 mg, 0.324 mmol), Pd(dppf)Cl2 (11.8 mg, 0.016 mmol), potassium carbonate (44.7 mg, 0.324 mmol), and 1,4-dioxane / water = 5 / 1 (2 mL) were added sequentially to a 25 mL single-necked bottle and reacted at 100°C under nitrogen for 16 h. The reaction was quenched with water (10 mL), extracted with DCM, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified on silica gel flash chromatography (methanol / DCM = 2 / 98) to obtain Intermediate 5-59 (94 mg, yield: 89.40%) as a light yellow solid. LCMS (ESI) m / z = 650.1 [M+H] + .

[0201] Step 5: Synthesis of compound 59

[0202] In a 25 mL single-necked vial, intermediate 5-59 (80 mg, 0.123 mmol) was dissolved in a 4 M hydrogen chloride / 1,4-dioxane solution (2 mL) and allowed to react at room temperature for 4 h. The reaction was quenched with ice water (10 mL), and the pH of the reaction mixture was adjusted to 8-9 with aqueous ammonia. The mixture was extracted with DCM / methanol (10 / 1), washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and separated by prep-HPLC (ACN / water-0.1% NH3H2O). After lyophilization, the final product 59 (16.68 mg, yield: 31.17%) was obtained as a white solid. 1 H NMR (400MHz, DMSO) δ13.35(s,1H),8.55(s,1H),8.39(s,1H),7.70(s,1H),7.65(d,J=8.8Hz,1H),7.46-7.41(m,2H),7.39-7.34(m,2 H),7.11(d,J=8.8Hz,1H),4.84(t,J=5.2Hz,1H),4.41(s,2H),4.21(s,3H),3.64(dd,J=9.6,4.8Hz,2H).LCMS(ESI)m / z=436.0[M+H] + .

[0203] Example 9: Synthesis of Compound 67

[0204] Step 1: Synthesis of Intermediate 2-67

[0205] 4-Amino-5-imidazolecarboxamide 1-67 (10 g, 79 mmol), methanesulfonic acid (20 mL), and ethanol (100 mL) were added sequentially to a 200 mL reactor. After sealing, the system was placed at 120°C for 16 h. Aqueous ammonia was added to neutralize the reaction solution to a pH of 8-9. Extraction with methanol / DCM = 1:10 (50 mL x 5) was performed and the crude product was concentrated. Separation on silica gel flash chromatography (methanol / DCM = 20:80) afforded intermediate 2-67 (6.4 g, yield: 52.03%) as a white solid. LCMS (ESI) m / z = 156.0 [M+H] + .

[0206] Step 2: Synthesis of Intermediate 3-67

[0207] In a 250 mL three-necked flask, intermediate 2-67 (6.0 g, 38.7 mmol) and diisopropylethylamine (7.5 g, 58.1 mmol) were dissolved in THF (100 mL). 2-(Trimethylsilyl)ethoxymethyl chloride (9.6 g, 58.1 mmol) was slowly added dropwise. The mixture was allowed to react at room temperature for 2 h. The solvent was removed, the mixture was diluted with water, extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and separated on a silica gel flash chromatography column (EA / PE = 1 / 1) to obtain crude intermediate 3-67 (3.0 g, yield: 27.3%) as a colorless viscous oil. LCMS (ESI) m / z = 285.9 [M+H] + .

[0208] Step 3: Synthesis of Intermediate 4-67

[0209] In a 100 mL three-necked flask, the crude intermediate 3-67 (3.0 g, 10.5 mmol) and diethyl malonate (9.2 g, 57.7 mmol) were dissolved in ethanol (20 mL). Sodium ethoxide (20%) (17.8 g, 52.5 mmol) was added dropwise under an ice-water bath and the mixture was reacted at 95°C for 16 h. Most of the solvent was removed, ice water (100 mL) was added, and the mixture was extracted with EA, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and separated on silica gel flash chromatography (methanol / DCM = 15 / 85) to obtain intermediate 4-67 (3.2 g, yield: 86.3%) as a white solid. LCMS (ESI) m / z = 354.0 [M+H] + .

[0210] Step 4: Synthesis of Intermediate 5-67

[0211] In a 100 mL single-necked bottle, intermediate 4-67 (3.2 g, 9.1 mmol) was dissolved in 15% aqueous sodium hydroxide solution (30 mL) and reacted at 105°C for 5 h. The system was cooled to 0°C, the pH was adjusted to 5 with 4 M hydrochloric acid, and filtered to obtain intermediate 5-67 (1.5 g, yield: 58.68%) as a white solid. LCMS (ESI) m / z = 282.1 [M+H] + .

[0212] Step 5: Synthesis of Intermediate 6-67

[0213] In a 50 mL single-necked flask, intermediate 5-67 (1.0 g, 3.56 mmol) and potassium carbonate (982 mg, 7.12 mmol) were dissolved in DMF (5 mL). Ethyl iodide (833 mg, 5.34 mmol) was added dropwise and the mixture was allowed to react at 40°C for 16 h. The reaction was quenched with water (20 mL), extracted with EA, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and separated on a silica gel flash chromatography column (methanol / DCM = 7 / 93) to afford intermediate 6-67 (310 mg, yield: 28.18%). 1H NMR (400MHz, DMSO) δ11.72(s,1H),8.14(s,1H),5.71(s,1H),5.59(s,2H),4.21(q,J=6.8Hz,2H),3.59(t,J=7.8Hz,2H), 1.46(t,J=6.8Hz,3H),0.91(t,J=8.0Hz,2H),-0.00(s,9H).

[0214] Step 6: Synthesis of Intermediate 7-67

[0215] In a 100 mL single-necked vial, intermediate 6-67 (280 mg, 0.906 mmol), 5-bromo-2-methylindazole (285 mg, 1.35 mmol), (1R,2R)-dimethylcyclohexane-1,2-diamine (128.6 mg, 0.906 mmol), cuprous iodide (172 mg, 0.906 mmol), and potassium phosphate (384 mg, 1.81 mmol) were dissolved in DMSO (5 mL) and reacted at 110°C under nitrogen for 16 h. The reaction was quenched with water, extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the product was purified on silica gel flash chromatography (methanol / DCM = 6 / 94) to afford intermediate 7-67 (190 mg, yield: 47.77%) as a light yellow solid. LCMS (ESI) m / z = 440.1 [M+H] + .

[0216] Step 7: Synthesis of Intermediate 8-67

[0217] In a 25 mL single-necked flask, intermediate 7-67 (170 mg, 0.36 mmol) was dissolved in THF (3 mL). NBS (61.6 mg, 0.36 mmol) was added portionwise and allowed to react at room temperature for 1 h. The reaction was quenched with saturated sodium thiosulfate solution, extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified on silica gel flash chromatography (methanol / DCM = 5 / 95) to obtain intermediate 8-67 (120 mg, yield: 64.44%) as a light yellow solid. LCMS (ESI) m / z = 518.0 [M+H] + .

[0218] Step 8: Synthesis of Intermediate 9-67

[0219] Intermediate 8-67 (50 mg, 0.0967 mmol), 4-chlorophenylboronic acid pinacol ester (46 mg, 0.193 mmol), Pd(dppf)Cl2 (8.1 mg, 0.00967 mmol), potassium carbonate (26.6 mg, 0.193 mmol), and 1,4-dioxane / water (5 / 1) (2 mL) were placed sequentially in a 25 mL single-necked flask and reacted at 100°C under nitrogen for 16 h. The reaction was quenched with water, extracted with DCM, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by prep-TLC (methanol / DCM = 1 / 10) to afford Intermediate 9-67 (50 mg, yield: 94.18%) as a white solid. LCMS (ESI) m / z = 550.1 [M+H] + .

[0220] Step 9: Synthesis of compound 67

[0221] In a 50 mL single-necked vial, intermediate 9-67 (50 mg, 0.091 mmol) was dissolved in a 4 M hydrogen chloride / 1,4-dioxane solution (3 mL) and allowed to react at room temperature for 4 h. The reaction was quenched with ice water (10 mL) and the pH adjusted to 8-9 with aqueous ammonia. The mixture was extracted with DCM / methanol (10 / 1), washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and separated by prep-TLC (methanol / DCM = 1 / 10). After concentration and lyophilization, 67 (12.70 mg, 33.30% yield) was obtained as a white solid. 1 H NMR (400MHz, DMSO) δ13.06(s,1H),8.42(s,1H),7.92(s,1H),7.73(s,1H),7.67(d,J=8.4Hz,1 H),7.40(s,4H),7.14(d,J=8.4Hz,1H),4.21(s,5H),1.23(m,3H).LCMS(ESI)m / z=420.0[M+H] + .

[0222] Using the synthetic method of Example 9, compound 44 was prepared.

[0223] Example 10: Synthesis of Compound 61

[0224] Step 1: Synthesis of intermediate 2-61

[0225] Intermediate 2-3 (6.0 g, 19.4 mmol), 5-bromo-2-methyl-2H-indazole (8.2 g, 38.8 mmol), trans-N,N'-dimethylcyclohexanediamine (551 mg, 3.88 mmol), cuprous iodide (739 mg, 3.88 mmol), potassium phosphate (8.2 g, 38.8 mmol), and DMSO (80 ml) were placed in a 250 mL three-necked flask and heated to 120°C under N2 protection for overnight reaction. The reaction solution was concentrated to dryness, added with ice water, and extracted with 50 mL (methanol / DCM = 1 / 10). The organic layers were combined, washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel flash column (0-3% methanol / DCM) to obtain intermediate compound 2-61 (7.0 g, yield: 82.0%) as a white solid. 1 H NMR (400MHz, DMSO) δ8.47(d,J=3.2Hz,2H),7.75(d,J=9.6Hz,2H),7.15(dd,J1=8.8Hz,J2=1.6Hz,1H),5.81(s,1H),5.41(s,2H) ,4.36-4.22(m,5H),3.58(t,J=8.0Hz,2H),1.49(t,J=7.2Hz,3H),0.91-0.80(m,2H),-0.00(s,9H).LCMS(ESI)m / z=440.2[M+H] + .

[0226] Step 2: Synthesis of Intermediate 3-61

[0227] In a 25 mL single-necked flask, intermediate 2-61 (4.0 g, 9.1 mmol) was dissolved in THF (120 mL). NBS (1.46 g, 8.2 mmol) was added portionwise with stirring at room temperature. The mixture was allowed to react at room temperature for 2 h. The reaction solution was poured into ice water and extracted with EA (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified on a silica gel flash column (0-100% EA) to obtain intermediate 3-61 (3.5 g, yield: 74.2%) as a light yellow solid. LCMS (ESI) m / z = 518 [M+H] + .

[0228] Step 3: Synthesis of Intermediate 4-61

[0229] Intermediate 3-61 (100 mg, 0.19 mmol), cyclohexyl-1-en-1-ylboronic acid (49 mg, 0.38 mmol), Pd(dppf)Cl2 (30 mg, 0.04 mmol), potassium carbonate (53 mg, 0.38 mmol), and dioxane:water = 5:1 (5 mL) were added to a 50 mL single-necked flask and stirred at 100°C under N2 protection for 16 h. The reaction solution was filtered and concentrated, and the crude product was flash purified (DCM / MeOH = 98 / 2) to obtain Intermediate 4-61 (80 mg, yield: 79.2%) as a yellow solid. LCMS (ESI) m / z = 520.3 [M+H] + .

[0230] Step 4: Synthesis of Intermediate 5-61

[0231] Intermediate 4-61 (80 mg, 0.15 mmol), Pd / C (10 mg), and EtOH (3 ml) were placed sequentially in a 50 ml single-necked flask and stirred at room temperature under a hydrogen atmosphere for 72 h. The reaction solution was concentrated to afford crude intermediate 5-61 (70 mg, yield: 87.5%) as a yellow solid. LCMS (ESI) m / z = 522.2 [M+H] + .

[0232] Step 5: Synthesis of compound 61

[0233] In a 25 mL single-necked flask, intermediate 5-61 (120 mg, 0.13 mmol) was dissolved in 4 M HCl / 1,4-dioxane (5 mL) and allowed to react at room temperature for 3 h. The reaction mixture was poured into ice water and the pH was adjusted to 9-10 with aqueous ammonia. The mixture was extracted with DCM / methanol (10 / 1). The organic phase was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The product was purified by Prep-HPLC (H2O / ACN, 0.1% NH3.H2O) and freeze-dried to afford compound 61 (10 mg, 19.2% yield) as a white solid. 1H NMR (400MHz, DMSO) δ13.14(s,1H),8.38(s,2H),7.63(d,J=3.2Hz,2H),7.04(dd,J1=9.1Hz,J2=1.7Hz,1H),4.47(d,J=6.9Hz,2 H),4.21(s,3H),3.09(t,J=12.0Hz,1H),2.11-2.00(m,2H),1.74(d,J=12.3Hz,2H),1.66(d,J=11.1Hz,1H),1.47(d,J=11.9Hz, 2H),1.42(t,J=7.0Hz,3H),1.22(td,J=25.0,12.6Hz,3H).LCMS(ESI)m / z=392.0[M+H] + .

[0234] Example 11: Synthesis of Compound 63

[0235] Step 1: Synthesis of intermediate 2-63

[0236] 4-2 (1.05 g, 3.39 mmol), 2,2,2-trifluoroethane-1-amine (2 mL), and THF (5 mL) were added to a 50 mL reactor and heated to 110°C for 16 h. The reaction solution was concentrated, and the crude product was purified on a silica gel flash column (DCM / MeOH = 97 / 3) to afford intermediate 2-63 (175 mg, yield: 24.72%) as a yellow solid. LCMS (ESI) m / z = 363.10 [M+H] + .

[0237] Step 2: Synthesis of Intermediate 3-63

[0238] Intermediate 2-63 (175 mg, 0.48 mmol), 5-bromo-2-methylindazole (203 mg, 0.97 mmol), trans-N,N'-dimethylcyclohexanediamine (69 mg, 0.48 mmol), cuprous iodide (92 mg, 0.48 mmol), potassium phosphate (205 mg, 0.97 mmol), and DMSO (3 ml) were placed sequentially in a 25 mL single-necked flask. The mixture was reacted at 110°C under N2 protection for 16 h. The reaction solution was concentrated, and the crude product was purified on a silica gel flash column (DCM / MeOH = 97 / 3) to obtain Intermediate 3-63 (200 mg, yield: 84.03%) as a black solid. LCMS (ESI) m / z = 493.10 [M+H] + .

[0239] Step 3: Synthesis of Intermediate 4-63

[0240] In a 25 mL single-necked vial, intermediate 3-63 (200 mg, 0.41 mmol) was dissolved in THF (5 mL). After the solution cleared, NBS (72 mg, 0.41 mmol) was added portionwise and allowed to react at room temperature for 2 h. The reaction mixture was poured into a saturated sodium sulfite solution and extracted with DCM. The organic phase was concentrated and the crude product was purified on a silica gel flash column (DCM / MeOH = 96 / 4) to obtain intermediate 4-63 (100 mg, yield: 43.10%) as a yellow solid. LCMS (ESI) m / z = 571.00 [M+H] + .

[0241] Step 4: Synthesis of Intermediate 5-63

[0242] Intermediate 4-63 (100 mg, 0.18 mmol), 4-chlorophenylboronic acid pinacol ester (83 mg, 0.35 mmol), Pd(dppf)Cl2 (14 mg, 0.02 mmol), potassium carbonate (48 mg, 0.35 mmol), 1,4-dioxane (3 ml), and water (0.6 ml) were placed sequentially in a 25 mL single-necked flask. The mixture was reacted at 110°C under N2 protection for 16 h. The reaction solution was filtered, the filtrate collected, and concentrated to obtain the crude product, which was purified on a silica gel flash column (0-3% methanol / DCM) to obtain 5-63 as a yellow solid (40 mg, yield: 37.74%). LCMS (ESI) m / z = 603.15 [M+H] + .

[0243] Step 5: Synthesis of compound 63

[0244] In a 25 mL single-necked flask, intermediate 5-63 (40 mg, 0.07 mmol) was dissolved in TBAF tetrahydrofuran solution (6 mL) and refluxed at 60°C for 2 h. The reaction solution was concentrated, EA was added, and the TBAF was washed with water to remove it. The organic phase was concentrated, and the crude product was purified by prep-TLC (DCM / MeOH = 12 / 1) and freeze-dried to give the final product, compound 63 (7.25 mg, yield: 23.39%), as a white solid. 1 H NMR (400MHz, DMSO) δ13.18(s,1H),8.52(s,1H),8.37(s,1H),7.66(s,1H),7.61(d,J= 8.9Hz,1H),7.47(d,J=8.5Hz,2H),7.25(d,J=8.5Hz,2H),7.09(dd,J=9.1,1.7Hz,1H), 5.98(t,J=7.5Hz,1H),4.20(s,3H),4.17-4.05(m,2H).LCMS(ESI)m / z=473.05[M+H] + .

[0245] Compounds 105-108, 123, and 129 were prepared using the synthetic method of Example 11.

[0246] Example 12: Synthesis of Compound 64

[0247] Step 1: Synthesis of Intermediate 2-64

[0248] In a 50 mL reaction vessel, 4-2 (1.0 g, 3.55 mmol) was dissolved in ethylamine in tetrahydrofuran (12 mL) and reacted at 110°C for 16 h. Water was added to the reaction solution, which was extracted with EA. The organic phase was concentrated, and the crude product was purified on a silica gel flash column (DCM / MeOH = 40 / 1) to afford intermediate 2-64 (550 mg, 50.0% yield) as a white solid. 1 H NMR (400MHz, DMSO) δ10.64(s,1H),8.21(s,1H),6.90(t,J=5.0Hz,1H),5.44(s,2H),4.89(s,1H),3.6 4-3.50(m,2H),3.16(dd,J=7.1,5.2Hz,2H),1.24(t,J=7.2Hz,3H),0.94-0.83(m,2H),-0.00(s,9H).

[0249] Step 2: Synthesis of Intermediate 3-64

[0250] Intermediate 2-64 (550 mg, 1.78 mmol), 5-bromo-2-methylindazole (753 mg, 3.57 mmol), trans-N,N'-dimethylcyclohexanediamine (254 mg, 1.78 mmol), cuprous iodide (340 mg, 1.78 mmol), potassium phosphate (757 mg, 3.57 mmol), and DMSO (4 ml) were placed sequentially in a 25 mL single-necked flask. The mixture was reacted at 110°C under N2 protection for 16 h. The reaction solution was concentrated, and the crude product was purified on a silica gel flash column (DCM / MeOH = 97 / 3) to obtain Intermediate 3-64 (800 mg, yield: 100%) as a black solid. LCMS (ESI) m / z = 439.10 [M+H] + .

[0251] Step 3: Synthesis of Intermediate 4-64

[0252] In a 50 mL single-necked flask, intermediate 3-64 (800 mg, 1.82 mmol) was dissolved in THF (10 mL). After the solution was clear, NBS (292 mg, 1.64 mmol) was added portionwise and allowed to react at room temperature for 2 h. The reaction mixture was poured into a saturated sodium sulfite solution and extracted with DCM. The organic phase was concentrated and the crude product was purified on a silica gel flash column (DCM / MeOH = 96 / 4) to obtain intermediate 4-64 (700 mg, yield: 74.23%) as a yellow solid. LCMS (ESI) m / z = 518.05 [M+H] + .

[0253] Step 4: Synthesis of Intermediate 5-64

[0254] Intermediate 4-64 (350 mg, 0.68 mmol), 4-chlorophenylboronic acid pinacol ester (323 mg, 1.35 mmol), Pd(dppf)Cl2 (56 mg, 0.07 mmol), potassium carbonate (189 mg, 1.35 mmol), 1,4-dioxane (5 ml), and water (1 ml) were placed sequentially in a 25 mL single-necked flask. The mixture was reacted at 100°C under N2 protection for 16 h. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product, which was purified on a silica gel flash column (DCM / MeOH = 97 / 3) to obtain intermediate 5-64 (260 mg, yield: 70.08%) as a yellow solid. 1 H NMR (400MHz, DMSO) δ8.68(s,1H),8.41(s,1H),7.76-7.56(m,2H),7.49(dd,J=8.8,2.1Hz,2H),7.40-7.24(m,2H),7.11(dd,J=9.0,2.0Hz,1 H),5.80(t,J=6.2Hz,1H),5.43(s,2H),4.25(s,3H),3.76-3.52(m,2H),1.17(t,J=7.0Hz,3H),0.93-0.84(m,2H),0.06(s,2H),0.01(s,9H).

[0255] Step 5: Synthesis of Intermediate 6-64

[0256] Intermediate 5-64 (109 mg, 0.20 mmol) and DMF (5 mL) were added to a 25 mL three-necked flask. The mixture was cooled to 0°C under N2 protection, and NaH (24 mg, 0.60 mmol) was added. The mixture was stirred for approximately 10 min, and CH3I (56 mg, 0.40 mmol) was added and stirred for a further 20 min. The reaction mixture was quenched with water, extracted with EA, and the organic phase was concentrated to afford crude intermediate 6-64 (109 mg, purity: 83%, yield: 80.78%) as a gray solid. LCMS (ESI) m / z = 562.95 [M+H] +.

[0257] Step 6: Synthesis of Compound 64

[0258] In a 25 mL single-necked vial, intermediate 9 (109 mg, 0.19 mmol) was dissolved in HCl / 1,4-dioxane solution (10 mL) and allowed to react at room temperature for 2 h. The reaction mixture was poured into ice water and the pH was adjusted to 9-10 with aqueous ammonia. The mixture was extracted with DCM / methanol (10 / 1). The organic phase was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified on silica gel flash chromatography (DCM / MeOH = 97 / 3) and freeze-dried to afford compound 64 (14.95 mg, yield: 16.65%) as a white solid. 1 H NMR (400MHz, DMSO) δ13.11(s,1H),8.36(s,1H),8.32(s,1H),7.68-7.56(m,2H),7.41-7.34(m,2H),7.33-7.27(m,2H),7.07 (dd,J=9.1,1.5Hz,1H),4.19(s,3H),3.16(q,J=6.6Hz,2H),2.71(s,3H),1.00(t,J=7.0Hz,3H).LCMS(ESI)m / z=433.10[M+H] + .

[0259] Example 13: Synthesis of Compound 112

[0260] Step 1: Synthesis of intermediate 2-112

[0261] In a 100 mL single-necked bottle, 4-2 (9.0 g, 32.0 mmol), N-phenylbis(trifluoromethanesulfonimide) (13.7 g, 38.4 mmol), and TEA (9.7 g, 96 mmol) were dissolved in DMF (50 mL). The reaction was allowed to react at room temperature under nitrogen for 16 h. The reaction was quenched with ice water (50 mL), extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified on silica gel flash chromatography (PE / EA = 2 / 1) to obtain intermediate 2-112 (2.6 g, yield 19.66%) as a white solid. LCMS (ESI) m / z = 414.0 [M+H] + .

[0262] Step 2: Synthesis of intermediate 3-112

[0263] In a 100 mL single-necked flask, intermediate 2-112 (500 mg, 1.2 mmol), potassium n-propyltrifluoroborate (259 mg, 2.4 mmol), Pd(dppf)Cl2 (101 mg, 0.12 mmol), and potassium phosphate (770 mg, 3.6 mmol) were added sequentially. A toluene / water mixture (10 mL, 10 / 1) was added and the mixture was reacted at 90°C under nitrogen for 16 h. The reaction was quenched with water (20 mL), extracted with DCM, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified on silica gel flash chromatography (DCM / methanol = 98 / 2) to afford intermediate 3-112 (180 mg, yield: 48.45%) as a white solid. LCMS (ESI) m / z = 308.0 [M+H] + .

[0264] Step 3: Synthesis of intermediate 4-112

[0265] To a 100 mL single-necked flask, intermediate 3-112 (160 mg, 0.52 mmol), 5-bromo-2-methylindazole (163 mg, 0.78 mmol), (1R,2R)-dimethylcyclohexane-1,2-diamine (73.8 mg, 0.52 mmol), cuprous iodide (99 mg, 0.52 mmol), and potassium phosphate (220 mg, 1.04 mmol) were added sequentially. Dimethyl sulfoxide (4 mL) was added, and the mixture was reacted at 110°C under nitrogen for 16 h. The reaction was quenched with water (20 mL), extracted with EA (30 mL / times), washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified on silica gel flash chromatography (methanol / DCM = 3 / 97) to afford intermediate 4-112 (160 mg, yield: 70.41%) as a black solid. LCMS (ESI) m / z = 438.1 [M+H] +.

[0266] Step 4: Synthesis of intermediate 5-112

[0267] In a 100 mL three-necked flask, intermediate 4-112 (140 mg, 0.32 mmol) was dissolved in THF (4 mL). NBS (62.7 mmol, 0.35 mmol) was added portionwise under nitrogen and allowed to react at room temperature for 2 h. The reaction was quenched with saturated sodium thiosulfate solution (10 mL), extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified on silica gel flash chromatography (PE / EA = 65 / 35) to obtain intermediate 5-112 (120 mg, yield: 72.81%) as a colorless, sticky solid. LCMS (ESI) m / z = 516.1 [M+H] + .

[0268] Step 5: Synthesis of intermediate 6-112

[0269] Intermediate 5-112 (100 mg, 0.19 mmol), 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (92 mg, 0.39 mmol), Pd(dppf)Cl2 (16 mg, 0.019 mmol), potassium carbonate (53 mg, 0.39 mmol), and 1,4-dioxane / water (5 / 1) (2 mL) were added sequentially to a 25 mL single-necked bottle and reacted at 100°C under nitrogen for 16 h. The reaction was quenched with water, extracted with DCM, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified on silica gel flash chromatography (methanol / DCM = 3 / 97) to afford Intermediate 6-112 (120 mg, yield: 94.15%) as a white solid. LCMS (ESI) m / z = 548.1 [M+H] + .

[0270] Step 6: Synthesis of compound 112

[0271] Intermediate 6-112 (110 mg, 0.20 mmol) was added to a 25 mL single-necked vial. Under nitrogen, a 4 M solution of 1,4-dioxane hydrochloride (4 mL) was added and allowed to react at room temperature for 4 h. The reaction was quenched with ice water (10 mL) and the pH adjusted to 8-9 with aqueous ammonia. The mixture was extracted with DCM / methanol (10 / 1), washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by prep-HPLC (water / acetonitrile, 0.1% NH3H2O) to afford the final product 112 (41.73 mg, 50.03% yield) as a white solid. 1H NMR (400MHz, DMSO) δ13.14(s,1H),8.38(d,J=5.6Hz,2H),7.73(s,1H),7.65(d,J=9.2Hz,1H),7.46(d,J=8.4Hz,2H),7.27(d,J=8.4H z,2H),7.14(dd,J=9.2,2.0Hz,1H),4.20(s,3H),2.53(m,2H),1.64-1.51(m,2H),0.84(t,J=7.2Hz,3H).LCMS(ESI)m / z=418.1[M+H] + .

[0272] Example 14: Synthesis of Compound 122

[0273] In a 50 mL single-necked flask, compound 13 (110 mg, 0.26 mmol), cesium carbonate (169 mg, 0.52 mmol), and 2-bromo-1-ol (40 mg, 0.31 mmol) were dissolved in DMF (3 mL) and reacted at 80°C for 3 h. The reaction solution was filtered and purified by Prep-HPLC (H2O / ACN, 0.1% FA). After freeze-drying, compound 122 (21 mg, yield: 17.4%) was obtained as a white solid. 1 H NMR (400MHz, DMSO) δ8.54(s,1H),8.39(s,1H),7.69(d,J=1.3Hz,1H),7.66(d,J=9.1Hz,1H),7.38(s,4H),7.10(dd,J=9.1,1.9Hz,1H),4.92( s,1H),4.43(q,J=6.9Hz,2H),4.20(s,3H),4.12(t,J=5.3Hz,2H),3.67(t,J=5.1Hz,2H),1.25(t,J=7.0Hz,3H).LCMS(ESI)m / z=464.05[M+H] + .

[0274] Compounds 134, 136, 138, and 140 were prepared using the synthetic method of Example 14.

[0275] Example 15: Synthesis of Compounds 109 and 121

[0276] In a 25 mL single-necked flask, compound 84 (120 mg, 0.28 mmol) was dissolved in 5 mL of DMF. NaH (18 mg, 0.42 mmol) was added under ice-cooling. After stirring for 10 min, iodomethane (48 mg, 0.34 mmol) was added and stirring continued for 1 h. The reaction solution was poured into water and extracted with EA. The organic phase was washed with water and saturated brine, and concentrated to obtain the crude product. The crude product was purified by prep-HPLC (water / acetonitrile, 0.1% FA) and freeze-dried to afford compound 109 (34.96 mg, yield: 36.9%) as a white solid and compound 121 (16.86 mg, yield: 17.8%) as a white solid.

[0277] Compound 109: 1 H NMR (400MHz, DMSO) δ8.68(s,1H),8.60(s,1H),8.23(dd,J=8.8,0.8Hz,1H),7.41-7.35(m,4H),7.25(d,J=8. 9Hz,1H),4.45(q,J=7.2Hz,2H),4.26(s,3H),3.83(s,3H),1.26(t,J=7.2Hz,3H).LCMS(ESI)m / z=435.1[M+H] + .

[0278] Compound 121: 1 H NMR (400MHz, DMSO) δ8.79(s,1H),8.33(d,J=8.8Hz,1H),8.19(s,1H),7.51(d,J=8.8Hz,1H),7.41-7.35(m ,4H),4.51(q,J=6.8Hz,2H),4.28(s,3H),2.97(s,3H),1.26(t,J=6.8Hz,3H).LCMS(ESI)m / z=435.1[M+H] + .

[0279] Example 16: Synthesis of Compound 130

[0280] Step 1: Synthesis of Intermediate 2-130

[0281] Compound 3-61 (3.0 g, 5.8 mmol), 4-chlorophenylboronic acid pinacol ester (2.8 g, 11.6 mmol), Pd(dppf)Cl2 (0.47 g, 0.58 mmol), potassium carbonate (1.6 g, 11.6 mmol), 1,4-dioxane (45 mL), and water (9 mL) were placed sequentially in a 100 mL single-necked flask. The mixture was reacted at 110°C overnight under nitrogen protection. The reaction mixture was filtered, the filter cake rinsed with DCM, and the filtrates were combined and concentrated to obtain the crude product. The product was purified on a silica gel flash column (0-2% methanol / DCM) to obtain intermediate 2-130 (3.0 g, yield: 94.1%) as a light yellow solid. LCMS (ESI) m / z = 550.1 [M+H] + .

[0282] Step 2: Synthesis of Intermediate 3-130

[0283] Intermediate 2-130 (550 mg, 1.0 mmol), sodium ethanethiolate (84 mg, 10 mmol), and 1,4-dioxane (25 mL) were placed sequentially in a 50 mL three-necked flask and reacted at 70°C under N2 protection for 16 h. The reaction solution was poured into water (50 mL) and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. This was purified by silica gel column chromatography (0-2% methanol / DCM) to obtain Intermediate 3-130 (350 mg, yield: 61.8%) as a light yellow solid. LCMS (ESI) m / z = 566.2 [M+H] + .

[0284] Step 3: Synthesis of Compound 130

[0285] In a 50 mL three-necked flask, intermediate 3-130 (350 mg, 0.62 mmol) was dissolved in 4 M HCl / 1,4-dioxane (16 mL) and allowed to react at room temperature for 4 h. The reaction solution was poured into ice water (50 mL), and the pH was adjusted to 9-10 with aqueous ammonia. Stirring was continued at room temperature for 1 h, and the mixture was extracted with EA. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by prep-HPLC (water / acetonitrile, 0.1% NH3H2O) to afford product 130 (33.90 mg, yield: 12.7%) as a white solid. 1HNMR (400MHz, DMSO) δ13.25(s,1H),8.40(s,2H),7.75(s,1H),7.66(d,J=9.2Hz,1H),7.47-7.41(m,2H),7.34-7.26(m,2H) ,7.15(dd,J1=9.2Hz,J2=2.0Hz,1H),4.20(s,3H),2.99(q,J=7.2Hz,2H),1.12(t,J=7.2Hz,3H).LCMS(ESI)m / z=436.1[M+H] + .

[0286] Example 17: Synthesis of Compound 55

[0287] Step 1: Synthesis of Intermediate 2-55

[0288] In a 250 mL single-necked flask, ethyl 4-nitropyrazole-5-carboxylate 1-55 (10 g, 54.05 mmol) was dissolved in ethanol (100 mL). 1 g of wet palladium on carbon was added and stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated to dryness to afford intermediate 2-55 (8.7 g, yield >100%, including solvent) as a purple solid. 1 H NMR (400MHz, DMSO) δ12.80 (s, 1H), 7.09 (s, 1H), 4.78 (s, 2H), 4.25 (q, J = 7.1Hz, 2H), 1.29 (t, J = 7.1Hz, 3H).

[0289] Step 2: Synthesis of Intermediate 3-55

[0290] In a 500 mL single-necked flask, intermediate 2-55 (8.66 g, 55.9 mmol) was dissolved in THF (200 mL) and cooled to 0°C in an ice bath. DIPEA (14.42 g, 111.8 mmol) was added, followed by the dropwise addition of SEMCl (10.27 g, 61.49 mmol). The mixture was stirred overnight at room temperature. An additional amount of SEMCl (5 g, 30 mmol) was added, and stirring continued at room temperature for 16 h. The reaction mixture was poured into water, extracted with EA, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 16.3 g of crude intermediate 3-55 as a light yellow oil, which was used directly in the next step without purification. LCMS (ESI) m / z = 285.9 [M+H] + .

[0291] Step 3: Synthesis of Intermediate 4-55

[0292] In a 500 mL single-necked flask, intermediate 3-55 (16.16 g, 56.7 mmol) was dissolved in ethanol (250 mL). Diethyl malonate (54.4 g, 340 mmol) and a 20% sodium ethoxide solution in ethanol (115.7 g, 340 mmol) were added, and the mixture was refluxed at 85°C for 18 h. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with EA, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 8 g of crude intermediate 4-55 as a yellow oil, which was used directly in the next step without purification. LCMS (ESI) m / z = 354.1 [M+H] + .

[0293] Step 4: Synthesis of Intermediate 5-55

[0294] In a 250 mL single-necked flask, intermediate 4-55 (7.5 g, 21.22 mmol) was added to a 15% NaOH solution, heated to 105°C, and refluxed for 6 h. The reaction solution was adjusted to pH 4 with 2 M hydrochloric acid. A solid precipitated and was filtered to afford intermediate 5-55 (6.1 g, yield: 95.31%) as a yellow solid. LCMS (ESI) m / z = 282.10 [M+H] + .

[0295] Step 5: Synthesis of Intermediate 6-55

[0296] In a 100 mL single-necked flask, intermediate 5-55 (3.3 g, 11.73 mmol) was dissolved in DMF (60 mL). Na2CO3 (2.49 g, 23.45 mmol) was added, and iodoethane (3.66 g, 23.45 mmol) was added dropwise. After completion of the addition, the temperature was raised to 40°C and stirred for 3 h. The reaction solution was poured into water and extracted with EA. The organic phase was washed with water and saturated brine, dried, filtered, and the filtrate was concentrated to obtain the crude product. Purification on silica gel flash chromatography (DCM / MeOH = 96 / 4) afforded intermediate 6-55 (1 g, yield: 27.55%) as a white solid. LCMS (ESI) m / z = 310.15 [M+H] + .

[0297] Step 6: Synthesis of Intermediate 7-55

[0298] To a 100 mL single-necked flask, 6-55 (1.05 g, 3.39 mmol), 5-bromo-2-methylindazole (1.43 g, 6.79 mmol), trans-N,N'-dimethylcyclohexanediamine (483 mg, 3.39 mmol), cuprous iodide (646 mg, 6.79 mmol), potassium phosphate (1.44 g, 3.39 mmol), and DMSO (12 ml) were added. The mixture was reacted at 110°C under N2 protection for 16 h. The reaction solution was concentrated, and the crude product was purified on a silica gel flash column (DCM / MeOH = 96 / 4) to obtain intermediate 7-55 (1.2 g, yield: 80.54%) as a black oil. LCMS (ESI) m / z = 440.15 [M+H] + .

[0299] Step 7: Synthesis of Intermediate 8-55

[0300] In a 25 mL single-necked flask, intermediate 7-55 (1.2 g, 2.72 mmol) was dissolved in THF. After the solution was clear, NBS (437 mg, 2.46 mmol) was added portionwise and allowed to react at room temperature for 10 h. The reaction mixture was poured into an aqueous sodium sulfite solution and extracted with DCM. The organic phase was concentrated and purified on a silica gel flash column (DCM / MeOH = 97 / 3) to obtain intermediate 8-55 (400 mg, yield: 28.5%) as a yellow solid. LCMS (ESI) m / z = 518.05 [M+H] + .

[0301] Step 8: Synthesis of Intermediate 9-55

[0302] Intermediate 8-55 (250 mg, 0.48 mmol), 4-chlorophenylboronic acid pinacol ester (230 mg, 0.96 mmol), Pd(dppf)Cl2 (39 mg, 0.05 mmol), potassium carbonate (133 mg, 0.96 mmol), 1,4-dioxane (5 ml), and water (1 ml) were placed sequentially in a 50 mL single-necked flask. The mixture was reacted at 100°C under nitrogen for 16 h. The mixture was filtered, the filtrate was concentrated, and purified on a silica gel flash column (0-3% methanol / DCM) to obtain Intermediate 9-55 (150 mg, yield: 56.60%) as a yellow solid. LCMS (ESI) m / z = 550.10 [M+H] + .

[0303] Step 9: Synthesis of Compound 55

[0304] In a 25 mL single-necked vial, intermediate 9-55 (150 mg, 0.27 mmol) was dissolved in TBAF (10 mL) and the mixture was heated to 60°C and refluxed for 1 h. The reaction solution was concentrated, the TBAF was washed with water, and the mixture was extracted with EA. The organic phase was concentrated and purified by Prep-HPLC (water / acetonitrile, 0.1% FA). After freeze-drying, compound 55 (77.75 mg, yield: 68.2%) was obtained as a white solid. 1 H NMR (400MHz, DMSO) δ13.71(s,1H),8.43(s,1H),7.79(d,J=1.3Hz,1H),7.70(d,J=9.1Hz,1H),7.47-7.34(m,5 H),7.18(dd,J=9.1,2.0Hz,1H),4.81(s,2H),4.21(s,3H),1.25(t,J=7.0Hz,3H).LCMS(ESI)m / z=420.05[M+H] + .

[0305] Example 18: Synthesis of Compound 56

[0306] In a 25 mL single-necked vial, compound 55 (50 mg, 0.12 mmol) was dissolved in acetone (3 mL), and CsCO (78 mg, 0.24 mmol) was added, followed by CHI (34 mg, 0.24 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was filtered, concentrated, and purified by Prep-HPLC (water / acetonitrile, 0.1% TFA). After freeze-drying, compound 56 (13.40 mg, yield: 25.8%) was obtained as a white solid. 1 H NMR (400MHz, DMSO) δ8.43(s,1H),7.79(d,J=1.2Hz,1H),7.71(d,J=9.1Hz,1H),7.46(s,1H),7.43-7.36(m,4H),7.17(dd ,J=9.1,2.0Hz,1H),4.78(q,J=7.0Hz,2H),4.21(s,3H),3.94(s,3H),1.25(t,J=7.0Hz,3H).LCMS(ESI)m / z=434.05[M+H] + .

[0307] Example 19: Synthesis of Compound 100

[0308] Step 1: Synthesis of Intermediate 2-100

[0309] Ethyl 4-nitropyrazole-5-carboxylate 1-55 (5.0 g, 27.0 mmol) was dissolved in 50 mL of DCM in a 100 mL single-necked flask. Me3OBF4 (6.0 g, 40.5 mmol) was slowly added and allowed to react at room temperature for 3 h. The reaction solution was concentrated, and the crude product was purified on a silica gel flash column (0-1% methanol / DCM) to afford intermediate 2-100 (2.5 g, 47% yield) as a light yellow liquid. LCMS (ESI) m / z = 200.1 [M+H] + .

[0310] Step 2: Synthesis of Intermediate 3-100

[0311] In a 50 mL single-necked flask, intermediate 2-100 (2.5 g, 12.56 mmol) was dissolved in 30 mL of ethanol, and Pd / C (0.5 g) was added. The mixture was allowed to react overnight at room temperature under a hydrogen atmosphere. The Pd / C was filtered off with Celite, and the filtrate was concentrated to afford intermediate 3-100 (2.2 g, yield: 103%) as a yellow liquid. LCMS (ESI) m / z = 170.1 [M+H] + .

[0312] Step 3: Synthesis of Intermediate 4-100

[0313] In a 250 mL single-necked flask, intermediate 3-100 (2.2 g, 13.0 mmol) was dissolved in 100 mL of ethanol. Diethyl malonate (6.25 g, 39.0 mmol) and NaOEt (20% in EtOH, 4.42 g, 39.0 mmol) were added sequentially. The mixture was heated to 80°C and allowed to react overnight. The reaction solution was concentrated, dissolved in EA (20 mL), and 50 mL of HCl (dioxane) was added. The mixture was stirred for 1 h, and the solid was collected by filtration to obtain intermediate 4-100 (3.0 g, yield: 97%) as a yellow solid. LCMS (ESI) m / z = 238.2 [M+H] + .

[0314] Step 4: Synthesis of Intermediate 5-100

[0315] In a 100 mL single-necked bottle, intermediate 4-100 was dissolved in 30 mL of 15% aqueous NaOH solution and heated to 100°C for overnight reaction. The mixture was diluted with water and the pH was adjusted to 3-4 with dilute hydrochloric acid. A white solid precipitated and was collected by filtration to afford intermediate 5-100 (1.2 g, yield: 57%) as a white solid. LCMS (ESI) m / z = 166.2 [M+H] + .

[0316] Step 5: Synthesis of Intermediate 6-100

[0317] In a 100 mL single-necked flask, intermediate 5-100 (1.0 g, 6.1 mmol) was dissolved in 20 mL of DMF. Na2CO3 (1.9 g, 18.2 mmol) and EtI (0.94 g, 9.1 mmol) were added and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with EA. The organic phase was washed with water and saturated brine and concentrated. The crude product was purified on a silica gel flash column (0-2% methanol / DCM) to obtain intermediate 6-100 (300 mg, yield: 26%) as a white solid. LCMS (ESI) m / z = 194.2 [M+H] + .

[0318] Step 6: Synthesis of Intermediate 7-100

[0319] Intermediate 6-100 (300 mg, 1.55 mmol), 5-bromo-2-methyl-2H-indazole (492 mg, 2.33 mmol), trans-N,N'-dimethylcyclohexanediamine (220 mg, 1.55 mmol), cuprous iodide (295 mg, 1.55 mmol), potassium phosphate (660 mg, 3.10 mmol), and DMSO (10 ml) were placed sequentially in a 50 mL single-necked flask and reacted overnight at 110°C under N2 protection. The reaction solution was concentrated to dryness, and the crude product was purified on a silica gel flash column (0-3% methanol / DCM) to obtain Intermediate 7-100 (300 mg, yield: 60%) as a light yellow solid. LCMS (ESI) m / z = 324.0 [M+H] + .

[0320] Step 7: Synthesis of Intermediate 8-100

[0321] The reaction was carried out in a 25 mL single-necked vial. Intermediate 7-100 (300 mg, 0.99 mmol) was dissolved in 10 mL of DCM, and NBS (211 mg, 1.19 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated to dryness and purified on a silica gel flash column (0-3% methanol / DCM) to obtain Intermediate 8-100 (300 mg, yield: 73%) as a yellow solid. LCMS (ESI) m / z = 402.0 [M+H] + .

[0322] Step 8: Synthesis of Compound 100

[0323] Intermediate 8-100 (80 mg, 0.2 mmol), 4-chlorophenylboronic acid pinacol ester (95 mg, 0.4 mmol), Pd(dppf)Cl2 (29 mg, 0.02 mmol), potassium carbonate (55 mg, 0.4 mmol), 1,4-dioxane (5 mL), and water (1 mL) were placed sequentially in a 25 mL single-necked flask. The mixture was reacted at 100°C under nitrogen for 16 h. The reaction solution was concentrated, and the crude product was purified on a silica gel flash column (0-2% methanol / DCM) to obtain a crude product. The product was then purified by prep-HPLC (water / acetonitrile, 0.1% FA) and freeze-dried to obtain compound 100 (16.26 mg, yield: 19%) as a white solid. 1 H NMR (400MHz, DMSO) δ8.44(s,1H),7.79(d,J=1.6Hz,1H),7.72(d,J=9.2Hz,1H),7.53-7.44(m,4H),7.17(dd,J=9.2,2.0H z,1H),7.06(s,1H),4.21(s,3H),4.14(s,3H),3.69(q,J=7.2Hz,2H),1.15(t,J=7.2Hz,3H).LCMS(ESI)m / z=434.2[M+H] + .

[0324] Test Example 1: Biochemical Test

[0325] Principle: MAT2A catalyzes the conversion of L-methionine and ATP into SAM, inorganic phosphate, and inorganic diphosphate. By adding a colorimetric reagent to the enzymatic reaction system, the inorganic phosphate content in the sample can be quantitatively determined, thereby characterizing the enzymatic activity of MAT2A.

[0326] Test materials: Tris(Life science#0497); BSA(Sigma#); MAT2A his-tag(BPS#71401-1); 384-well plate (Corning#3765); L-methionine(Admas#1100469); ATP(Sigma#A7699); MgCl2(Sigma#M8266); KCl(Sigma#7447-40-7); Brij35(Sigma#B4184); EDTA(Sigma#E1644)

[0327] Test method:

[0328] 1. Prepare 1xAssay buffer (buffer composition: Tris, KCl, MgCl2, BSA, Brij35, and EDTA; solvent: ultrapure water). Use 1xAssay buffer to prepare MAT2A his-tag enzyme solution (1.3 μL MAT2A enzyme and 998.7 μL 1xAssay buffer per 1000 μL) and substrate mixture solution (5 μL ATP, 1.3 μL L-methionine, and 993.7 μL 1xAssay buffer per 1000 μL).

[0329] 2. Preparation of compound concentration gradient: The test compound is tested with a starting concentration of 10 μM, and 10 isotropic concentrations are set according to 3-fold dilution. Specifically, first, a series of 10 solutions with different concentrations are gradiently diluted in a 384-well plate (so that the final detection concentration of the compound is 10, 3.33, 1.11, 0.37, 0.123, 0.041, 0.0137, 0.0046, 0.0015, and 0.0005 μM). Then, 250 nL of the above series of solutions are transferred to the 384-well reaction plate using the acoustic pipetting system Echo550 for later use. 250 nL of 100% DMSO is added to the negative control wells and the positive control wells respectively. Repeat the test.

[0330] 3. Add 15 μL of MAT2A his-tag enzyme solution to the compound wells and positive control wells respectively; add 15 μL of 1xAssay buffer to the negative control wells.

[0331] 4. Centrifuge the 384-well plate at 1000 rpm for 60 seconds, shake to mix, and incubate for 15 minutes. Add 10 μL of the substrate mixture solution to each experimental well of the 384-well plate to initiate the reaction.

[0332] 5. Centrifuge the 384-well reaction plate at 1000 rpm for 60 seconds, shake to mix, and incubate for 150 minutes.

[0333] 6. Terminate the reaction by adding 50 μL of Biomol Enzyme Stop Solution to all wells of the 384-well reaction plate. Centrifuge at 1000 rpm for 60 seconds and incubate for 15 minutes. Read the OD620 value and process the data.

[0334] Data analysis: Calculate the compound inhibition rate (%) and obtain the IC of the test compound by fitting 50Compound inhibition rate calculation method: Compound inhibition rate (%) = (OD620_max - OD620_sample) / (OD620_max - OD620_min) x 100, where: OD620_sample is the absorbance value of the sample well; OD620_min is the absorbance value of the positive control well, indicating the reading of the well with no enzyme activity; OD620_max is the absorbance value of the negative control well, indicating the reading of the well with no compound inhibition.

[0335] Test results: Under the conditions of this test, the inhibitory effect of the test compound on MAT2A enzyme activity can be expressed as the IC value of the inhibition of the level of phosphate production during the enzymatic reaction. 50 The MAT2A inhibitory activity of the tested compounds is shown in Table 1. The results show that the compounds of the present invention have significant MAT2A enzyme inhibitory effects, compared with the structurally similar compound 1 as a control.

[0336] Table 1. Inhibitory effect on MAT2A enzyme activity

[0337] Test Example 2: Human pancreatic cancer KP-4 cell activity inhibition test

[0338] Principle: After incubating the MAT2A inhibitor to be tested with KP-4 cells for a period of time, a cell activity measurement method based on ATP content is used to characterize the effect of the test compound on cell activity.

[0339] Experimental Materials: KP-4 cells (JCRB#JCRB0182); IMDM (Gibco#12440061); Fetal bovine serum (EXCELL#FND500); Penicillin-Streptomycin (Gibco#15140-122); 0.25% Typsin-EDTA (Gibco#25200-072); DMSO (Sigma#D2650); 96-well plates (Corning#3610); CellTiter-Glo (Promega#G7571)

[0340] Test method:

[0341] 1. KP-4 cells were cultured in IMDM containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C and 5% CO2 in a cell culture incubator. Cells in the logarithmic growth phase were used for subsequent experiments.

[0342] 2. Cells in the logarithmic growth phase were seeded in a 96-well plate at a density of 500 cells per well and cultured overnight in a cell culture incubator at 37°C and 5% CO2.

[0343] 3. Dissolve the compound in DMSO and dilute it with culture medium to 10 different concentrations (approximately 10,000, 3333.3, 1111.1, 370, 123, 41.2, 13.7, 4.6, 1.5, and 0.5 nM). Add the compound to the cell plate and continue culturing at 37°C, 5% CO2 for 5 days.

[0344] 4. Add CellTiter-Glo reagent and detect cell activity using a microplate reader.

[0345] Data analysis: Calculate the compound inhibition rate (%) and obtain the IC of the test compound by fitting 50 Compound inhibition rate calculation method: Compound inhibition rate (%) = (Signal_max - Signal_sample) / (Signal_max - Signal_min) × 100, where: Signal_sample is the reading of the sample well, indicating the cell activity in the compound-inhibited well; Signal_min is the reading of the positive control well, indicating the background activity in the absence of cells; Signal_max is the reading of the negative control well, indicating the cell activity in the absence of compound-inhibited wells.

[0346] Test results: Under the conditions of this test, the IC of the test compound on KP-4 cell activity inhibition is 50 The values ​​are shown in Table 2. The results showed that compared with compound 1, the typical compound of the present invention has significant anti-tumor activity.

[0347] Table 2. Human pancreatic cancer KP-4 cell activity inhibition test

[0348] Test Example 3: In vivo antitumor efficacy study of compound 13

[0349] Compound 13 and AG-270 (a MAT2A inhibitor, ) in vivo antitumor efficacy.

[0350] Female CB-17 SCID mice were purchased from Beijing Weitong Lihua Laboratory Animal Co., Ltd. Tumor cell culture and subcutaneous inoculation: Human B-cell lymphoma DOHH-2 cells (DSMZ) were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum and 1% bispecific antibody in a 37°C 5% CO2 incubator. When the cell count reached the required level, the cells were harvested, counted, and 0.2 mL (10 × 10 6DOHH-2 cells (with Matrigel, volume ratio of 1:1) were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached 100-150 mm 3 The mice were randomly divided into groups of 5 at 4 hr. The drug-treated group (Compound 13 or Compound AG-270) was orally administered twice a day (dosages are shown in Table 3), and the negative control group was orally administered with the same volume of blank solvent every day.

[0351] Experimental indicators and data analysis

[0352] The experimental indicator is to examine whether tumor growth is inhibited, delayed, or cured. Tumor diameter is measured twice a week with a vernier caliper. The formula for calculating tumor volume is: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively.

[0353] The tumor inhibition efficacy of the compounds was evaluated by TGI (%) or relative tumor proliferation rate T / C (%).

[0354] TGI (%) reflects the rate of tumor growth inhibition. Calculation of TGI (%): TGI (%) = [(1 - (mean tumor volume at the end of treatment in the treatment group - mean tumor volume at the start of treatment in the treatment group)) / (mean tumor volume at the end of treatment in the negative control group - mean tumor volume at the start of treatment in the negative control group)] × 100%.

[0355] Relative tumor growth rate (T / C%): Calculated as follows: T / C% = TRTV / CRTV × 100% (TRTV: RTV of the treatment group; CRTV: RTV of the negative control group). Relative tumor volume (RTV) was calculated as RTV = Vt / V0, where V0 is the mean tumor volume measured at the time of group dosing (i.e., d0), and Vt is the mean tumor volume at a single measurement. TRTV and CRTV data were collected on the same day.

[0356] Experimental results: The TGI and T / C calculated based on the tumor volume growth curve of each group are shown in Table 3. The results show that compound 13 of the present invention exhibits dose-related in vivo efficacy.

[0357] Table 3. Evaluation of the antitumor efficacy of compound 13 on the human B cell lymphoma DOHH-2 xenograft tumor model

Claims

1. A dicyclic compound represented by formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof, in, R 1 Selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylsulfonyl, C3-C7 cycloalkyl, 3-6 membered heterocycloalkyl, cyano, nitro, carboxyl, -NR a R a2 、-NHCOR a 、-OR a 、-SR a , the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3-6 membered heterocycloalkyl is unsubstituted or optionally substituted with one or more substituents selected from D and halogen; R a 、R a2 Each independently selected from H, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-6 membered heterocycloalkyl, C1-C 10 Alkyl, C3-C substituted by one or more substituents selected from Group A 10 Cycloalkyl; Group A substituents include: D, halogen, C1-C3 alkoxy, hydroxyl, C6-C 10 Aryl, 5-10 membered heteroaryl, unsubstituted or substituted with one or more substituents selected from Group A2 C3-C 10 Cycloalkyl; the A2 group substituents include: D, halogen, hydroxyl, C1-C6 alkyl, C1-C 10 alkoxy; R 2 、R 3 Each independently selected from unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C6-C 10 Aryl, unsubstituted or substituted 4-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl; wherein the substitution refers to substitution by one or more substituents selected from Group B, and Group B substituents include: halogen, cyano (-CN), hydroxyl (-OH), oxo (=O), mercapto (-SH), amino (-NH2), nitro (-NO2), 4-6 membered heterocycloalkyl, C1-C4 alkyl unsubstituted or substituted by one or more substituents selected from Group C, C3-C7 cycloalkyl unsubstituted or halogen-substituted, C1-C4 alkoxy unsubstituted or halogen-substituted, -COOH, -CONHR b 、-NHCOR b 、-NHSO2R b ; Group C substituents include: D, halogen, hydroxy, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, C1-C4 alkoxy; R b Selected from H, C1-C4 alkyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C6-C 10 Aryl, wherein the R b C1-C4 alkyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C6-C 10 Aryl is unsubstituted or substituted by one or more substituted groups selected from halogen, hydroxyl, and cyano; Ring A is a five-membered heteroaromatic ring, wherein at most one of X, Y, and Z is CR 4 , the rest are independently selected from N, NR 5 ,O,S; R 4 、R 5 Each is independently selected from H, D, halogen, amino, C1-C6 alkyl, C3-C6 cycloalkyl, and the C1-C6 alkyl and C3-C6 cycloalkyl are unsubstituted or substituted with hydroxyl.

2. The bicyclic compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof, characterized in that: R 1 Selected from C1-C6 alkyl, C3-C7 cycloalkyl, 3-6 membered heterocycloalkyl, -OR a 、-SR a NR a R a2 The C1-C6 alkyl, C3-C7 cycloalkyl, 3-6 membered heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from D and halogen; R a 、R a2 Each independently selected from H, C3-C7 cycloalkyl, C1-C6 unsubstituted or substituted by one or more substituents selected from Group A Alkyl, the substituents of group A include: D, halogen, C1-C3 alkoxy, hydroxyl, C6-C 10 Aryl, 5-10 membered heteroaryl, unsubstituted or substituted with one or more substituents selected from Group A2 C3-C 10 Cycloalkyl; the substituents of group A2 include: D, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy; R 2 、R 3 Each independently selected from unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C6-C 10 Aryl, unsubstituted or substituted 5-10 membered heteroaryl, the substitution refers to substitution by one or more substituents selected from Group B; the substituents of Group B include: halogen, cyano, hydroxyl, mercapto, nitro, amino, oxo, unsubstituted or substituted 4-6 membered heterocycloalkyl, C1-C4 alkyl unsubstituted or substituted by one or more substituents selected from Group C, unsubstituted or halogen-substituted C3-C7 cycloalkyl, unsubstituted or halogen-substituted C1-C4 alkoxy; the substituents of Group C include: D, halogen, hydroxyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, C1-C4 alkoxy; in particular, the 5-10 membered heteroaryl is selected from benzo 5 membered heteroaryl, benzo 6 membered heteroaryl, 6 membered heteroaryl and 5 membered heteroaryl, 6 membered heteroaryl and 6 membered heteroaryl, 3. The bicyclic compound according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof, characterized in that: R 1 Selected from C2-C6 alkyl, C3-C6 cycloalkyl, -OR a 、-SR a NR a R a2 The C2-C6 alkyl group and the C3-C6 cycloalkyl group are unsubstituted or substituted by one or more substituents selected from D and halogen; R a 、R a2 Each is independently selected from H, C3-C6 cycloalkyl, C2-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, wherein the substituents in Group A include: D, halogen, methoxy, hydroxyl, C3-C6 cycloalkyl; R 2 and R 3 Each is independently selected from an unsubstituted or substituted cyclohexyl group, an unsubstituted or substituted phenyl group, and an unsubstituted or substituted 5-10 membered heteroaryl group, wherein the 5-10 membered heteroaryl group is selected from the following structures: The substitution in the unsubstituted or substituted phenyl group, or the unsubstituted or substituted 5-10 membered heteroaryl group refers to substitution by one or more substituents selected from Group B, wherein the substituents in Group B include: halogen, cyano, hydroxyl, mercapto, nitro, amino, 4-6 membered heterocycloalkyl, C1-C4 alkyl group which is unsubstituted or substituted by one or more substituents selected from Group C, C3-C7 cycloalkyl group which is unsubstituted or halogen substituted, and C1-C4 alkoxy group which is unsubstituted or halogen substituted; and the substituents in Group C include: D, halogen, C3-C6 cycloalkyl group, hydroxyl group, 4-6 membered heterocycloalkyl group, and C1-C4 alkoxy group. R 5 Each occurrence is independently H, D, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl or C3-C6 cycloalkyl is unsubstituted or substituted with hydroxy.

4. The bicyclic compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof, characterized in that: R 1 Selected from C2-C6 alkyl, -OR a 、NHR a ; R a C3-C6 cycloalkyl, unsubstituted or substituted by one or more substituents selected from Group A C2-C6 alkyl; Group A substituents include: D, halogen, methoxy, hydroxy, C3-C6 cycloalkyl; R 2 and R 3 Each independently selected from: Among them, (R 7 ) m Indicates that there are m identical or different R7 substituents on the ring; m is 1, 2 or 3; R 6 and each R 7 Each is independently selected from: H, halogen, cyano, hydroxyl, mercapto, nitro, amino, 4-6 membered heterocycloalkyl, C1-C4 alkyl unsubstituted or substituted by one or more substituents selected from Group C, C3-C7 cycloalkyl unsubstituted or halogen substituted, C1-C4 alkoxy unsubstituted or halogen substituted; Group C substituents include: D, halogen, C3-C6 cycloalkyl, hydroxyl, 4-6 membered heterocycloalkyl, C1-C4 alkoxy; preferably, m is 1 or 2; R 6 and each R 7 Each is independently selected from: H, halogen, cyano, hydroxyl, mercapto, nitro, amino, 4-6 membered heterocycloalkyl, C1-C2 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, cyclopropyl which is unsubstituted or halogen substituted, C1-C2 alkoxy which is unsubstituted or halogen substituted; the substituents of Group C include: D, halogen, C3-C6 cycloalkyl, hydroxyl, 4-6 membered heterocycloalkyl, C1-C4 alkoxy; R 5 is independently at each occurrence H, methyl or hydroxyethyl.

5. The bicyclic compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof, characterized in that: R 1 Selected from C2-C6 alkyl, -OR a 、-SR a 、NHR a ; R a Selected from C3-C6 cycloalkyl, unsubstituted C2-C4 alkyl, halogen-substituted C2-C4 alkyl, cyclopropyl-substituted C2-C4 alkyl, methoxy-substituted C2-C4 alkyl, hydroxy-substituted C2-C4 alkyl; R 2 and R 3 Each independently selected from: Wherein, m is 1, 2 or 3; R 6 and R 7 Each is independently selected from: H, halogen, cyano, hydroxyl, mercapto, nitro, amino, 4-6 membered heterocycloalkyl, C1-C4 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C3-C7 cycloalkyl which is unsubstituted or halogen substituted, C1-C4 alkoxy which is unsubstituted or halogen substituted; Group C substituents include: D, halogen, C3-C6 cycloalkyl, hydroxyl, 4-6 membered heterocycloalkyl, C1-C4 alkoxy; Preferably, R 6 and R 7 Each independently selected from: H, halogen, cyano, hydroxyl, thiol, nitro, amino, C1-C3 alkyl, unsubstituted or substituted by one or more substituents selected from Group C, unsubstituted or halogen Substituted cyclopropyl, unsubstituted or halogen-substituted C1-C2 alkoxy; C group substituents include: D, halogen, C3-C6 cycloalkyl, hydroxyl, methoxy, Preferably, R 1 Selected from propyl, -OC2H5, -SC2H5, -OCH2CF3, -NHCH3, -NHC2H5, R 2 Selected from Wherein, m is 1, 2 or 3; R 8 and R 9 are each independently selected from H, halogen, CN, methoxy, methyl substituted by one or more halogens, methoxy substituted by one or more halogens, cyclopropyl; preferably, R 2 Selected from Among them, R 8 and R 9 Each is independently selected from H, halogen, cyano, methoxy, methyl substituted by one or more halogens, methoxy substituted by one or more halogens, cyclopropyl; R 3 Selected from Wherein, m is 1, 2 or 3; R 10 and R 11 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyano, methoxy, hydroxy-substituted ethyl, methoxy-substituted ethyl, cyclopropyl, 6. The bicyclic compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof, characterized in that: The dicyclic compound is selected from the following structures: Preferably, the dicyclic compound is selected from the following structures: Among them, R 1 、R 2 、R 3 、R 5 The definition is the same as that of the corresponding claims.

7. The bicyclic compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof, characterized in that: The dicyclic compound is selected from the following structures:

8. A pharmaceutical composition comprising a therapeutically effective dose of one or more of the bicyclic compounds according to any one of claims 1 to 7, and pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, atropisomers, polymorphs, solvates, and isotope-labeled compounds thereof, at least one pharmaceutically acceptable carrier, and optionally, one or more other therapeutic agents.

9. Use of the bicyclic compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, an enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for inhibiting MAT2A activity.

10. Use of the bicyclic compound according to any one of claims 1 to 7 or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing MTAP-related diseases, particularly tumors; Preferably, the tumor comprises: MTAP-deficient tumors; Tumors with low MTAP expression; Tumors with abnormal expression of MAT2A; other MAT2A-dependent tumors; More preferably, the tumor comprises breast cancer, lung cancer, glioblastoma, brain and spinal cancer, head and neck cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma, midline tract cancer and unknown primary cancer.

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