Dicyclic ring system MAT2A inhibitor and its use

Abstract

The present invention relates to a bicyclic ring system MAT2A inhibitor and its use. Specifically, the present invention discloses a bicyclic ring system compound represented by formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof. The compound represented by formula (I) has MAT2A enzyme inhibitory activity and can be used as a good MAT2A inhibitor in the manufacture of drugs for treating and / or preventing MTAP-related diseases, especially tumors. 【Chemical 1】 TIFF2025523100000088.tif30170

Description

Technical Field

[0001] The present invention claims the priority of a Chinese patent application with an application number of 202210828873.6 and an invention title of "Bicyclic MAT2A Inhibitor and Its Use", filed on July 13, 2022, and all of its contents are incorporated herein by reference in their entirety.

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

Background Art

[0003] Cancer treatment is a major challenge in the current world. For conventional common treatments such as chemotherapy and immunotherapy, the biggest problem is that the cell-killing effect causes significant side effects not only on cancer cells but also on normal cells and tissues. Therefore, the development of new treatment means that can better target cancer cells is eagerly desired.

[0004] Synthetic lethality is defined as the deletion of two or more genes leading to cell death, while the single deletion of any one of these genes has no effect. In recent years, a large number of studies have shown that due to the presence of multiple gene mutations in cancer cells, they are more sensitive to synthetic lethality treatment means. These tumor-specific gene mutations enable the inventors to kill cancer cells using appropriate targeted therapeutic drugs without adversely affecting normal cells.

[0005] Methionine adenosyltransferase 2A (MAT2A) is an enzyme that catalyzes the reaction of methionine (Met) and ATP to produce S-adenosyl-L-methionine (SAM). SAM is the main methyl group donor in the body and can regulate gene expression through methyl group transfer reactions to DNA, RNA, and proteins, and further has an important impact on cell differentiation, growth, and death. Arginine N-methyltransferase 5 (PRMT5) is a methyltransferase that uses SAM as a methyl group donor. SAM is very important for the activity of PRMT5, while 5’methylthioadenosine (MTA) can inhibit the activity of PRMT5. MTA is a product of the methionine salvage pathway and is maintained at a relatively low level by generating 5-methylthioribose-1-phosphate and adenine through the catalysis of methylthioadenosine phosphorylase (MTAP) in cells.

[0006] The MTAP gene is located on chromosome 9, which is deleted in cells of various cancer patients, including pancreatic cancer, esophageal cancer, bladder cancer, and lung cancer (cBioPortal database). Deletion of MTAP causes an abundance of MTA in cells, and further makes these cells more dependent on SAM yield and MAT2A activity than normal cells. Studies have shown that inhibiting the expression of MAT2A in cancer cells with MTAP deficiency can selectively inhibit cell activity compared to cancer cells with normal MTAP (Non-Patent Document 1). At the same time, reducing the expression of MAT2A can selectively inhibit tumor growth in a mouse xenograft tumor model of MTAP-deficient tumor cells (Non-Patent Document 2). These results indicate that MAT2A inhibitors can provide a novel and effective treatment method for cancer patients, especially those with tumors containing MTAP deficiency.

Prior Art Documents

Non - Patent Literature

[0007]

Non - Patent Literature 1

Non - Patent Literature 2

Summary of the Invention

[0008] The inventors surprisingly found that the compound of formula (I) of the present invention has an inhibitory effect on MAT2A enzyme activity and its inhibitory effect on tumor cell activity was verified by cell experiments. Therefore, the compound of formula (I) can function as a good MAT2A inhibitor.

[0009] One object of the present invention is to provide a bicyclic ring system compound represented by formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate, or isotope - labeled compound thereof.

Chemical Formula

[0010] Another object of the present invention is to provide a pharmaceutical composition comprising one or more selected from a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate, or isotope - labeled compound thereof, and at least one pharmaceutically acceptable carrier.

[0011] Another further object of the present invention is to provide the use of a compound represented by formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate, or isotope-labeled compound thereof in the manufacture of a drug that inhibits the activity of MAT2A.

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

[0013] To achieve the above object, a first aspect of the present invention provides a bicyclic ring system compound represented by formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate, or isotope-labeled compound thereof. [Chemical formula] (Wherein, R 1 is selected from halogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkylsulfonyl group, a C3-C7 cycloalkyl group, a 3-6 membered heterocycloalkyl group, a cyano group, a nitro group, a carboxyl group, -NR a R a2 , -NHCOR a , -OR a , -SR a and the C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C7 cycloalkyl group, 3-6 membered heterocycloalkyl group are optionally substituted with one or more substituents selected from D, halogen, R a , R a2 are each independently H, a C1-C 10 alkyl group, a C3-C 10 cycloalkyl group, a C6-C10 One or more substituents selected from an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 6-membered heterocycloalkyl group, and Group A substituted on a C1-C 10 alkyl group, a C3-C substituted with one or more substituents selected from Group A 10 selected from a cycloalkyl group, and the substituents in Group A are D, halogen, a C1-C3 alkoxy group, a hydroxy group, a C6-C 10 aryl group, a 5- to 10-membered heteroaryl group, a C3-C unsubstituted or substituted with one or more substituents selected from Group A2 10 cycloalkyl group, and the substituents in Group A2 include D, halogen, a hydroxyl group, a C1-C6 alkyl group, a C1-C 10 alkoxy group, R 2 、R 3 are each independently an unsubstituted or substituted C3-C 10 cycloalkyl group, an unsubstituted or substituted C6-C 10 aryl group, an unsubstituted or substituted 4- to 6-membered heterocycloalkyl group, an unsubstituted or substituted 5- to 10-membered heteroaryl group, where the substitution means being substituted with one or more substituents selected from Group B, and the substituents in Group B are halogen, cyano group (-CN), hydroxy group (-OH), oxo group (=O), mercapto group (-SH), amino group (-NH2), nitro group (-NO2), 4- to 6-membered heterocycloalkyl group, a C1-C4 alkyl group unsubstituted or substituted with one or more substituents selected from Group C, a C3-C7 cycloalkyl group unsubstituted or substituted with halogen, a C1-C4 alkoxy group unsubstituted or substituted with halogen, -COOH, -CONHR b 、-NHCOR b 、-NHSO2R b including, and the substituents in Group C include D, halogen, a hydroxyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, and a C1-C4 alkoxy group, R b is H, a C1-C4 alkyl group, a C3-C 10 cycloalkyl group, a C1-C 10 alkoxy group, a C6-C10 selected from aryl groups, said R b in the C1-C4 alkyl group, C3-C 10 cycloalkyl group, C1-C 10 alkoxy group, C6-C 10 aryl group is unsubstituted or substituted with one or more selected from halogen, hydroxy group, cyano group, Ring A is a 5-membered heteroaromatic ring, and at most one of X, Y, Z is CR 4 and the rest are each independently selected from N, NR 5 , O, S, R 4 R 5 are each independently selected from H, D, halogen, amino group, C1-C6 alkyl group, C3-C6 cycloalkyl group, or R 4 R 5 are each independently selected from H, D, halogen, amino group, C1-C6 alkyl group, C3-C6 cycloalkyl group, and the C1-C6 alkyl group, C3-C6 cycloalkyl group are unsubstituted or substituted with a hydroxy group.)

[0014] In some embodiments, R 1 is selected from C1-C6 alkyl group, C3-C7 cycloalkyl group, 3-6 membered heterocycloalkyl group, -OR a , NR a R a2 and the C1-C6 alkyl group, C3-C7 cycloalkyl group, 3-6 membered heterocycloalkyl group are unsubstituted or substituted with one or more substituents selected from D, halogen, and R a R a2 are each independently selected from H, C3-C7 cycloalkyl group, C1-C6 alkyl group unsubstituted or substituted with one or more substituents selected from Group A, and the substituents in Group A are D, halogen, C1-C3 alkoxy group, hydroxy group, C6-C 10 aryl group, 5-10 membered heteroaryl group, C3-C unsubstituted or substituted with one or more substituents selected from Group A2 10It contains a cycloalkyl group, and the substituents of the A2 group include D, halogen, hydroxyl group, C1-C6 alkyl group, and C1-C6 alkoxy group.

[0015] In some embodiments, R 1 is selected from a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a 3-6 membered heterocycloalkyl group, -OR a , -SR a , NR a R a2 and the C1-C6 alkyl group, C3-C7 cycloalkyl group, 3-6 membered heterocycloalkyl group are unsubstituted or substituted with one or more substituents selected from D and halogen, and R a , R a2 are each independently selected from H, a C3-C7 cycloalkyl group, and a C1-C6 alkyl group unsubstituted or substituted with one or more substituents selected from the A group, and the substituents of the A group include D, halogen, a C1-C3 alkoxy group, a hydroxyl group, a C6-C 10 aryl group, a 5-10 membered heteroaryl group, and a C3-C 10 cycloalkyl group unsubstituted or substituted with one or more substituents selected from the A2 group, and the substituents of the A2 group include D, halogen, hydroxyl group, C1-C6 alkyl group, and C1-C6 alkoxy group.

[0016] In some embodiments, R 2 , R 3 are each independently an unsubstituted or substituted C3-C 10 cycloalkyl group, an unsubstituted or substituted C6-C 10Selected from an aryl group, an unsubstituted or substituted 5- to 10-membered heteroaryl group, wherein the substitution means being substituted with one or more substituents selected from Group B, and the substituents in Group B are halogen, cyano group, hydroxy group, mercapto group, nitro group, amino group, oxo group, unsubstituted or substituted 4- to 6-membered heterocycloalkyl group, unsubstituted or C1-C4 alkyl group substituted with one or more substituents selected from Group C, unsubstituted or C3-C7 cycloalkyl group substituted with halogen, unsubstituted or C1-C4 alkoxy group substituted with halogen, and the substituents in Group C include D, halogen, hydroxy group, C3-C6 cycloalkyl group, 4- to 6-membered heterocycloalkyl group, C1-C4 alkoxy group. In particular, the 5- to 10-membered heteroaryl group is a benzo 5-membered heteroaryl group, a benzo 6-membered heteroaryl group, a 6-membered heteroaryl 5-membered heteroaryl group, a 6-membered heteroaryl 6-membered heteroaryl group, [Chemical formula] selected from

[0017] In some embodiments, R 1 is selected from a C2-C6 alkyl group, a C3-C6 cycloalkyl group, -OR a , NR a R a2 , wherein the C2-C6 alkyl group and the C3-C6 cycloalkyl group are unsubstituted or substituted with one or more substituents selected from D and halogen, and R a , R a2 are each independently selected from H, a C3-C6 cycloalkyl group, and a C2-C6 alkyl group unsubstituted or substituted with one or more substituents selected from Group A, and the substituents in Group A include D, halogen, methoxy group, hydroxy group, and C3-C6 cycloalkyl group.

[0018] In some embodiments, R 1 is selected from a C2-C6 alkyl group, a C3-C6 cycloalkyl group, -OR a , -SR a , NR a R a2selected from, wherein the C2-C6 alkyl group and C3-C6 cycloalkyl group are unsubstituted or substituted with one or more substituents selected from D and halogen, R a , R a2 are each independently selected from H, a C3-C6 cycloalkyl group, and a C2-C6 alkyl group which is unsubstituted or substituted with one or more substituents selected from Group A, and the substituents in Group A include D, halogen, a methoxy group, a hydroxy group, and a C3-C6 cycloalkyl group.

[0019] In some embodiments, R 2 and R 3 are each independently selected from an unsubstituted or substituted cyclohexyl group, an unsubstituted or substituted phenyl group, and an unsubstituted or substituted 5- to 10-membered heteroaryl group, and the 5- to 10-membered heteroaryl group is

Chemical formula

[0020] In some embodiments, R 2 and R 3 are each independently selected from an unsubstituted or substituted cyclohexyl group, an unsubstituted or substituted phenyl group, and an unsubstituted or substituted 5- to 10-membered heteroaryl group, and the 5- to 10-membered heteroaryl group is

Chemical formula

[0021] In some embodiments, R 5 are each independently H, D, a C1-C3 alkyl group or a C3-C6 cycloalkyl group, or R 5 are each independently H, D, a C1-C3 alkyl group or a C3-C6 cycloalkyl group, and the C1-C3 alkyl group and C3-C6 cycloalkyl group are unsubstituted or substituted with a hydroxy group.

[0022] In some embodiments, R 1 is selected from -OR a and NHR a .

[0023] In some embodiments, R 1 is selected from a C2-C6 alkyl group, -OR a and NHR a .

[0024] In some embodiments, R a is selected from a C3-C6 cycloalkyl group, a C2-C6 alkyl group unsubstituted or substituted with one or more substituents selected from Group A, and the substituents in Group A include D, halogen, methoxy group, hydroxy group, C3-C6 cycloalkyl group.

[0025] In some embodiments, R 2 and R 3 are each independently

Chem.

Chem.

[0026] In some embodiments, R 5 are each independently H or a methyl group.

[0027] In some embodiments, R 5 is, independently of each other, H, a methyl group or a hydroxyethyl group.

[0028] In some embodiments, R 1 is -OR a , NHR a selected from, and R a is selected from a C3-C6 cycloalkyl group, an unsubstituted C2-C4 alkyl group, a C2-C4 alkyl group substituted with a halogen, a C2-C4 alkyl group substituted with a cyclopropyl group, a C2-C4 alkyl group substituted with a methoxy group, and a C2-C4 alkyl group substituted with a hydroxy group.

[0029] In some embodiments, R 1 is selected from a C2-C6 alkyl group, -OR a , -SR a , NHR a selected from, and R a is selected from a C3-C6 cycloalkyl group, an unsubstituted C2-C4 alkyl group, a C2-C4 alkyl group substituted with a halogen, a C2-C4 alkyl group substituted with a cyclopropyl group, a C2-C4 alkyl group substituted with a methoxy group, and a C2-C4 alkyl group substituted with a hydroxy group.

[0030] In some embodiments, R 2 and R 3 are, independently of each other,

Chemical formula

[0031] In some embodiments, R 2 and R 3 are, independently of each other,

Chemical formula

[0032] In some embodiments, m is 1, 2, or 3, and R 6 and R 7 are each independently selected from H, halogen, cyano group, hydroxy group, mercapto group, nitro group, amino group, 4- to 6-membered heterocycloalkyl group, C1-C4 alkyl group unsubstituted or substituted with one or more substituents selected from group C, C3-C7 cycloalkyl group unsubstituted or substituted with halogen, and C1-C4 alkoxy group unsubstituted or substituted with halogen, and the substituents in group C include D, halogen, C3-C6 cycloalkyl group, hydroxy group, 4- to 6-membered heterocycloalkyl group, and C1-C4 alkoxy group.

[0033] In some embodiments, m is 1, 2, or 3, and R 6 and R 7 are each independently selected from H, halogen, cyano group, hydroxy group, mercapto group, nitro group, amino group,

Chemical formula

Chemical formula

[0034] In some embodiments, R 1 is selected from -OC2H5, -OCH2CF3, -NHCH3, -NHC2H5,

Chemical formula

[0035] In some embodiments, R 1is a propyl group, -OC2H5, -SC2H5, -OCH2CF3, -NHCH3, -NHC2H5,

Chem.

[0036] In some embodiments, R 2 is

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

[0037] In some embodiments, the compound of formula (I) is

Chemical formula

[0038] In some embodiments, the compound of formula (I) is

Chemical formula

[0039] In some embodiments, the compound represented by formula (I) is selected from the following structures.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

[0040] The second aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a racemate, an atropisomer, a polymorph, a solvate, and an isotope-labeled compound, and at least one pharmaceutically acceptable carrier. Optionally, the pharmaceutical composition may further comprise one or more other therapeutic agents.

[0041] In one embodiment of the present invention, the present invention provides a combination, particularly a drug combination, comprising a therapeutically effective amount of one or more selected from the group consisting of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a racemate, an atropisomer, a polymorph, a solvate, and an isotope-labeled compound, and one or more other therapeutic agents.

[0042] 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, either simultaneously or sequentially.

[0043] The third aspect of the present invention provides the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a racemate, an atropisomer, a polymorph, a solvate or an isotope-labeled compound, or the pharmaceutical composition, in the manufacture of a drug for inhibiting the activity of MAT2A.

[0044] In a fourth aspect of the present invention, there is provided the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a racemate, an atropisomer, a polymorph, a solvate or an isotope-labeled compound thereof, or the pharmaceutical composition, in the manufacture of a drug for treating and / or preventing MTAP-related diseases, particularly tumors.

[0045] Preferably, the tumors include MTAP-deleted tumors, MTAP-low-expressing tumors, MAT2A-abnormally-expressing tumors, and other MAT2A-dependent tumors.

[0046] Specifically, the tumors include breast cancer, lung cancer, glioblastoma, brain and spinal cord cancer, head and neck cancer, skin cancer, genital cancer, gastrointestinal cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, heart tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma, midline carcinoma, and cancer of unknown primary origin.

[0047] 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, pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, atropisomers, polymorphs, solvates, isotope-labeled compounds of the present invention, or the 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 which is one or more other therapeutic agents.

[0048] The present invention also provides a product or kit comprising one or more selected from the compounds of the present invention as defined above, pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, atropisomers, polymorphs, solvates, and isotopically labeled compounds of the present invention, or a pharmaceutical composition of the present invention. The kit may further include one or more other therapeutic agents for constituting a combined preparation to be used simultaneously, separately, or sequentially in anti-cancer therapy.

Embodiments for Carrying Out the Invention

[0049] Term Explanation 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 commonly understood by those skilled in the art.

[0050] In the context of the present invention (especially in the context of the claims), singular terms used shall be understood to include the plural meaning unless the context specifically indicates otherwise or is clearly inconsistent therewith.

[0051] A short horizontal line ("-") not between two letters or symbols represents the connecting site of a substituent. For example, -O(C1-C3 alkyl group) indicates that the group is connected to the rest of the molecule by an oxygen atom. However, when the connecting site of the substituent is obvious to those skilled in the art, for substituents such as halogen and hydroxy group, "-" may be omitted.

[0052] As used herein, "heteroatom" refers to a nitrogen (N), oxygen (O), or sulfur (S) atom, particularly nitrogen or oxygen, which may be either substituted or unsubstituted and includes their oxidized forms. Examples of heteroatoms include, but are not limited to, -O-, -N=, -NR-, -S-, -S(O)-, and -S(O)2-, where R is hydrogen, a C1-C4 alkyl group, or a nitrogen protecting group (e.g., benzyloxycarbonyl group, p-methoxybenzylcarbonyl group, tert-butoxycarbonyl group, acetyl group, benzoyl group, benzyl group, p-methoxy-benzyl group, p-methoxy-phenyl group, 3,4-dimethoxybenzyl group, etc.). A heteroatom having an unsaturated bond is considered to have sufficient hydrogen atoms to satisfy the bond, unless otherwise specified.

[0053] As used herein, "halogen" or "halogenated" refers to fluorine, chlorine, bromine, and iodine. Preferred halogens as substituents are fluorine and chlorine.

[0054] As used herein, the term "alkyl group" refers to a fully saturated, straight-chain or branched-chain 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 group" represents an alkyl group having 1-6 carbon atoms, "C1-C4 alkyl group" represents an alkyl group having 1-4 carbon atoms, and "C1-C3 alkyl group" represents an alkyl group having 1-3 carbon atoms, and so on by analogy. Representative examples of the alkyl group include, but are not limited to, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, 3-methylhexyl group, 2,2-dimethylpentyl group, 2,3-dimethylpentyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, etc. The term "alkyl group" applies to the definition whether it appears alone or as part of other groups such as halogenated alkyl groups and alkoxy groups.

[0055] As used herein, the term "alkenyl group" refers to a straight-chain or branched-chain 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 the alkenyl group include, but are not limited to, vinyl group, propenyl group, isopropenyl group, butenyl group, isobutenyl group, pentenyl group, isopentenyl group, hexenyl group, heptenyl group, octenyl group, etc.

[0056] As used herein, the term "alkynyl group" refers to a straight-chain or branched-chain monovalent hydrocarbon group containing at least one triple bond. The alkynyl group preferably contains 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms. The number preceding the alkynyl group represents the number of carbon atoms. Representative examples of the alkynyl group include, but are not limited to, ethynyl group, propynyl group, isopropynyl group, butynyl group, isobutynyl group, pentynyl group, isopentynyl group, hexynyl group, heptynyl group, octynyl group, etc.

[0057] As used herein, the term "alkoxy group" refers to an alkyl group as defined herein linked by an oxygen bridge, i.e., an alkyl-O- group, and the number preceding the alkoxy group represents the number of carbon atoms. For example, "C1-C6 alkoxy group" refers to an alkoxy group having 1 to 6 carbon atoms, i.e., -O~C 1-6 represents an alkyl group, and "C1-C4 alkoxy group" refers to an alkoxy group having 1 to 4 carbon atoms, i.e., -O~C 1-4 represents an alkyl group, and "C1-C3 alkoxy group" refers to an alkoxy group having 1 to 3 carbon atoms, i.e., -O~C 1-3 represents an alkyl group. Representative examples of the alkoxy group include, but are not limited to, methoxy group, ethoxy group, propoxy group, 2-propoxy group, butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group, etc.

[0058] As used herein, the term "cycloalkyl group" refers to a saturated or partially saturated non-aromatic carbocyclic ring, including mono-, di- or tricyclic, 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. The C3-C8 cycloalkyl group is intended to include cycloalkyl groups of C3, C4, C5, C6, C7 and C8, and the "C3-C6 cycloalkyl group" is intended to include cycloalkyl groups of C3, C4, C5 and C6. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclohexyl group and cyclohexenyl group. Exemplary bicyclic cycloalkyl groups include, but are not limited to, bornyl group, tetrahydronaphthyl group, decahydronaphthyl group, bicyclo[2.1.1]hexyl group, bicyclo[2.2.1]heptyl group, bicyclo[2.2.1]heptenyl group, 6,6-dimethylbicyclo[3.1.1]heptyl group, 2,6,6-trimethylbicyclo[3.1.1]heptyl group, bicyclo[2.2.2]octyl group, etc. Exemplary tricyclic cycloalkyl groups include, but are not limited to, adamantyl group, etc.

[0059] As used herein, the term "haloalkyl group" refers to an alkyl group as defined herein in which one or more of the hydrogen atoms, for example, 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, for example, 1, 2, or 3 hydrogen atoms are substituted with halogen, and when more than one hydrogen atom is substituted with halogen atoms, the halogen atoms may be the same or different from each other. For example, "C1-C4 haloalkyl group" is intended to include C1, C2, C3, and C4 haloalkyl groups, and "C1-C3 haloalkyl group" is intended to include C1, C2, and C3 haloalkyl groups. Examples of haloalkyl groups include, but are not limited to, fluoromethyl group, difluoromethyl group, trifluoromethyl group, trichloromethyl group, 1,1-difluoroethyl group, 1,1-difluoropropyl group, and 1,1,1-trifluoropropyl group. Examples of haloalkyl groups further include "fluoroalkyl group", which is intended to include an alkyl group as defined herein in which one or more hydrogen atoms are substituted with fluorine atoms. As used herein, the "haloalkyl group" is preferably one in which a maximum of three hydrogen atoms in the alkyl group are substituted with halogen.

[0060] As used herein, the term "haloalkoxy group" represents a haloalkyl group as defined above having a predetermined number of carbon atoms linked by an oxygen bridge, in which one or more of the hydrogen atoms, for example, 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, for example, 1, 2, or 3 hydrogen atoms are substituted with halogen. For example, "C1-C6 haloalkoxy group" or "C1-C6 haloalkoxy group" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-fluoroethoxy group, 2,2,2-trifluoroethoxy group. Examples of haloalkoxy groups further include "fluoroalkoxy group".

[0061] As used herein, an "aryl group" has 6 to 20, preferably 6 to 14, more preferably 6 to 12, and most preferably 6 to 10 ring carbon atoms, which are formed by the condensation of one ring or multiple rings. An aryl group having 6 to 10 ring carbon atoms, i.e., C6~C 10 The aryl group includes a monocyclic aryl group (e.g., phenyl group), or a condensed bicyclic system in which one ring is an aromatic ring and the other ring is an aromatic (e.g., in naphthalene, biphenyl group) or non-aromatic ring (e.g., in dihydroindene, tetrahydronaphthalene). Non-limiting examples of the aryl group include phenyl group, biphenyl group, naphthyl group, tetrahydronaphthyl group, indenyl group, dihydroindenyl group or anthracenyl group, etc.

[0062] As used herein, a "heteroaryl group" refers to an aromatic ring system having 5 to 14, preferably 5 to 10, more preferably 5 to 7 or 5 to 6 members, containing 1 to 4, preferably 1 to 3 ring heteroatoms selected from N, O or S, including monocyclic, bicyclic or condensed polycyclic rings, and the remaining ring atoms are carbon atoms. Examples of the heteroaryl group include, but are not limited to, pyrrolyl group, furanyl group, thienyl group, pyrazolyl group, imidazolyl group, triazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, pyridyl group, pyranyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group, oxazinyl group, oxazinyl group, quinolyl group, isoquinolyl group, cinnolinyl group, quinazolinyl group, quinoxalinyl group, benzoxazinyl group, 2H-chromenyl group, benzopyranyl group, benzothienyl group, indolyl group, indazolyl group, benzopyrazole group, benzimidazolyl group, imidazopyridyl group, benzoxazolyl group, benzothiazolyl group, 7-azaindolyl group, 6-azaindolyl group, 5-azaindolyl group, 4-azaindolyl group, 1H-benzo[d][1,2,3]triazolyl group, [1,2,4]triazolo[1,5-a]pyridyl group, [1,2,4]triazolo[4,3-a]pyridine, pyrazolo[1,5-a]pyridine, etc.

[0063] As used herein, "heterocycloalkyl group" refers to a group in which one or more ring carbons in the cycloalkyl group defined in the present application are substituted with a heteroatom selected from N, O, or S, and the heteroatom is, for example, -O-, -N=, -NR-, -S-, -S(=O)-, and -S(=O)2-, where R is hydrogen, C 1-4It is an alkyl group or a nitrogen protecting group (for example, benzyloxycarbonyl group, p-methoxybenzylcarbonyl group, tert-butoxycarbonyl group, acetyl group, benzoyl group, benzyl group, p-methoxy-benzyl group, p-methoxy-phenyl group, 3,4-dimethoxybenzyl group, etc.). Preferably, the heterocycloalkyl group is a monocyclic, bicyclic or tricyclic saturated and partially unsaturated non-aromatic ring having 3 to 20 ring atoms, for example, 3 to 12 ring atoms, for example, 3 to 8 ring atoms, for example, 3 to 6 ring atoms. More preferably, the heterocycloalkyl group is preferably a 4- to 12-membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 4- to 8-membered heterocycloalkyl group, more preferably a 4- to 7-membered, 4- to 6-membered or 5- to 6-membered heterocycloalkyl group, and the heteroatom is substituted or unsubstituted, for example, substituted with a C1-C4 alkyl group. For example, examples of the heterocycloalkyl group include, but are not limited to, oxiranyl group, aziridinyl group, azetidinyl group, oxetanyl group, azetidinyl group (pyrrolidinyl group), tetrahydrofuranyl group, tetrahydrothiophenyl group, tetrahydrothiophenyl 1,1-dioxide group, pyrazolidinyl group, imidazolidinyl group, oxazolidinyl group, thiazolidinyl group, isothiazolidinyl group, pyrrolidinyl-2-one group, imidazolidinyl group, piperidinyl group (hexahydropyridine), N-methylpiperidinyl group, tetrahydropyranyl group, oxazolidinyl group, 1,3-oxazolidinyl group, hexahydropyrimidinyl group, piperazinyl group, piperidone group (piperidinylone), 1,4-dioxa-8-aza-spiro[4.5]decane-8-yl group, morpholino group, thiomorpholino group, thiomorpholino-S-monooxide group (sulfanomorpholino), thiomorpholino-S,S-dioxide group (sulfonomorpholino), octahydropyrrolo[3,2-b]pyrrolyl group, etc.

[0064] As used herein, the term "oxo group" refers to an oxygen atom linked to other atoms by a double bond and can be represented as "=O". For terms, "-C(=O)" is a carbonyl group, "-S(=O)" is a sulfoxide group, and "-S(=O)2" is a sulfone group.

[0065] As used herein, "optional", "optionally" or "at will" means that the event described hereinafter may or may not occur, and the description includes the situation where the event occurs and the situation where the event does not occur. For example, "optionally substituted alkyl group" includes "unsubstituted alkyl group" and "substituted alkyl" as defined herein. "Optionally substituted with halogen" includes the case of "substituted with halogen" and the case of "not substituted with halogen", for example, substituted with 0 - 3 halogens. Those skilled in the art should understand that for any group containing one or more substituents, the group does not include substitution modes that are not spatially practical, not chemically accurate, synthetically impossible, and / or internally unstable.

[0066] As used herein, the terms "substituted", "substitution", or "substituted with" mean that one or more hydrogen atoms in a given atom or group are replaced with one or more substituents selected from a given group of substituents, provided that the normal valence of the given atom is not exceeded. When the substituent is oxo (i.e., =O), two hydrogen atoms of one atom are replaced with oxygen. There is no oxo substituent in the aromatic moiety. When a ring system (e.g., a carbocyclic or heterocyclic ring) is substituted with 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 of substituents and / or variables are permitted only if they result in a chemically correct and stable compound. A chemically correct and stable compound means that the compound is stable enough to be separated from the reaction mixture and its chemical structure determined, and then prepared into at least a formulation having an actual effect. For example, when a substituent is not explicitly listed, "substituted", "substitution", or "substituted with" as used herein means that one or more hydrogen atoms in a given atom or group are independently replaced with one or more, e.g., 1, 2, 3, or 4 substituents. When one atom or group is substituted with a plurality of substituents, the substituents may be the same or different.

[0067] Unless otherwise indicated, the term "compound of the present invention" or "compound of the invention" refers to one or more compounds of the present invention of formula (I) as defined herein or its sub-formulas such as formula (I-1), (I-2), (I-1-1), (I-2-1), (I-3-1), etc., or a pharmaceutically acceptable salt thereof, and all isomers such as stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, conformational isomers (including rotational isomers and atropisomers), tautomers, etc., internal addition products of isomers, prodrugs and compounds labeled with isotopes (including deuterium substitution), and moieties formed inherently therewith (e.g., polymorphs, solvates and / or hydrates). When there are moieties capable of forming salts, salts, especially pharmaceutically acceptable salts, are also included. The presence of tautomers or internal addition products of isomers can be confirmed by those skilled in the art using means such as NMR. The compounds of formula (I) of the present invention can readily form the tautomers and internal addition products of isomers described herein.

[0068] One of ordinary skill in the art will recognize that the compounds of the present invention may contain chiral centers, and thus different isomeric forms may exist. As used herein, the term "isomers" refers to various compounds having the same molecular formula but different arrangements and configurations of atoms.

[0069] 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 ordinary RS system is used to specify a single stereoisomer having a known relative and absolute configuration at two chiral centers (e.g., (1S,2S)), and a single stereoisomer having a known relative configuration but an unknown absolute configuration is designated with an asterisk (e.g., (1R * ,2R *)) is attached, and a racemate having two characters (for example, (1RS,2RS) is a racemic mixture of (1R,2R) and (1S,2S), and (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. Based on Cahn-Ingold-Prelog, the R-S system indicates absolute stereochemistry. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon site can be explained by R or S. A resolved compound with an unknown absolute configuration can be designated as (+) or (-) based on the direction (clockwise or counterclockwise) of the rotation of plane-polarized light at the sodium D-line wavelength. Alternatively, a resolved compound can be defined by the respective retention times of the corresponding enantiomers / diastereomers by chiral HPLC.

[0070] Some of the compounds described herein contain one or more asymmetric centers or axes and can therefore generate enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- in terms of absolute stereochemistry.

[0071] When a compound contains a double bond or other features that impart a certain amount of structural rigidity to the molecule, geometric isomers can be generated. When a compound contains a double bond, the substituents may be in the E or Z conformation. When a compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group can have a cis or trans configuration.

[0072] Conformational isomers are isomers that differ by the rotation of one or more valence bonds. Rotational isomers are conformational isomers that differ by the rotation of only a single valence bond.

[0073] "Atropisomers" refer to structural isomers based on axial or planar chirality that arise due to restricted rotation in a molecule.

[0074] Unless otherwise indicated, the compounds of the invention are intended to include all such possible isomers, including racemic mixtures, optically active forms, and mixtures of intermediates. The optically active (R)- and (S)-isomers may be prepared using chiral synthetic intermediates or chiral reagents, or may be resolved using conventional techniques.

[0075] The compounds of the invention can be separated into optically active forms or racemic forms. The use of 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 invention and the intermediates thus produced are considered part of the invention. When producing products that are enantiomers or diastereomers, they can be separated by conventional methods such as chromatography or stepwise crystallization.

[0076] Depending on the method conditions, the final products of the invention are obtained in free (neutral) or salt form. The free and salt forms of these final products are within the scope of the invention. If desired, one form of the compound can be converted to the other form. The free base or acid may be converted to a salt, the salt may be converted to the free compound or another salt, and mixtures of the structurally isomeric compounds of the invention can be separated into individual isomers.

[0077] As used herein, "pharmaceutically acceptable salts" refers to salts that retain the biological effects and properties of the compounds of the present invention, and such salts are not desirable biologically or otherwise. Non-limiting examples of such salts include addition salts of inorganic or organic bases or acids that are non-toxic to the compounds of the present invention. In many cases, due to the presence of amino groups and / or carboxyl groups or groups similar thereto, the compounds of the present invention can form acid salts and / or alkali salts. Inorganic acids and organic acids can form pharmaceutically acceptable acid addition salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. 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, etc. Inorganic and organic bases can form pharmaceutically acceptable base addition salts. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., and particularly preferably ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary amines, secondary amines, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc., and particularly preferably isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds (basic or acidic moieties) 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., hydroxides, carbonates, bicarbonates 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 usually carried out in water or an organic solvent or a mixed solvent of both.Generally, when performing, non-aqueous media such as ethers, ethyl acetate groups, ethanol, isopropanol or acetonitrile are preferred. For other suitable salts, see Remington’s Pharmaceutical Sciences, 20th Edition, Mack Publishing Company, Easton, Pa., (1985), which is incorporated herein by reference.

[0078] As used herein, "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweetening agents, flavoring agents, dyes, the like substances and combinations thereof, and are known to those skilled in the art (see, e.g., Remington’s Pharmaceutical Sciences, 18th Edition, Mack Printing Company, 1990, pp. 1289-1329, which is incorporated herein by reference). Any conventional carrier can be considered for use in a therapeutic or pharmaceutical composition only if it can coexist with the active ingredient.

[0079] Any formula provided herein is also intended to represent both the unlabeled form and the isotopically labeled form of a compound. An isotopically labeled compound has a structure represented by a formula provided herein except that one or more atoms are replaced with an atom 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, e.g., 2 H (i.e., D), 3 H (i.e., T), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P,35 S, 36 Cl, 125 and I. The present invention includes compounds labeled with different isotopes as defined herein, for example, 3 H, 13 C and 14 C, etc., which contain radioactive isotopes. Compounds labeled with such isotopes can be used for metabolic studies (using 14 C), kinetic studies (e.g., using 2 H or 3 H), and detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution measurements, or can be used for radiation therapy of individuals. In particular, 18 compounds labeled with F are particularly promising for PET or SPECT studies. The compounds of the present invention labeled with isotopes can usually be prepared by carrying out the procedures in the flow described below or in the Examples and Preparation Examples and using readily available reagents labeled with isotopes instead of reagents not labeled with isotopes.

[0080] Also, substitution with heavier isotopes, particularly deuterium (i.e., 2 H or D), can provide several therapeutic benefits due to greater metabolic stability, such as an extended half-life in the body, a reduced dose requirement, or an improved therapeutic index. It can be understood that deuterium in the context can be regarded as a substituent of the compounds of the present invention. The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotope enrichment factor. The "isotope enrichment factor" indicates the ratio of the isotopic abundance ratio of a specified isotope to its natural abundance ratio.

[0081] As used herein, a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound of the invention that elicits a biological or medical response in an individual, ameliorates symptoms, delays the progression of a disease or prevents the disease. A "therapeutically effective amount" can be determined by an attending physician or veterinarian in practice, and varies depending on factors such as the compound, the condition of the disease being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, and the judgment of the attending physician or veterinarian in practice.

[0082] As used herein, "individual" refers to an animal. Preferably, the animal is a mammal. An individual 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 individual is a human.

[0083] As used herein, "inhibit" refers to the reduction or inhibition of a particular patient, symptom, disorder or disease, or a significant decrease in biological activity or process baseline activity.

[0084] As used herein, in one embodiment, the term "treating" any disease or disorder refers to ameliorating the disease or disorder (i.e., inhibiting or alleviating the progression of the disease or at least one of its clinical symptoms). In another embodiment, "treating" refers to ameliorating at least one physical parameter that may not be perceptible to the patient. In another embodiment, "treating" refers to modulating the disease or disorder physically (e.g., stable and perceptible symptoms), physiologically (e.g., stable physical parameters), or in both of the above aspects.

[0085] As used herein, "prevent" refers to administering one or more drug substances, particularly a compound of the invention and / or a pharmaceutically acceptable salt thereof, to an individual having a predisposition to the disease, to prevent the individual from contracting the disease.

[0086] Generally, the term "about" is used herein to adjust a given numerical value by more than 20% higher or lower, e.g., 10%, e.g., 5%.

[0087] Technical and scientific terms not specifically defined herein have the meanings that are commonly understood by those skilled in the art.

[0088] Example The following examples illustrate the present invention and are not intended to limit the scope of the present invention in any way. The beneficial effects of the combinations of the present invention may also be determined by other test models known to those skilled in the art.

[0089] In the present invention, the origin and trade names of the reagents and devices used are specified when they first appear, and the same reagents used thereafter are the same as those specified for the first time, unless otherwise specified. Usually, reagents that are not annotated are purchased from the Sinopharm Chemical Reagent Co., Ltd.

[0090] Meanings of abbreviations: DIPEA: N,N - diisopropylethylamine, SEMCl: 2 - (trimethylsilyl)oxymethyl chloride, TBAF: tetrabutylammonium fluoride, NBS: N - bromosuccinimide, Tf: trifluoromethanesulfonyl, FA: formic acid, BSA: bovine serum albumin, Brij35: polyoxyethylene lauryl ether, Pd(dppf)Cl2: 1,1’ - bis(diphenylphosphino)ferrocene dichloropalladium, NBS: N - bromosuccinimide, PE: petroleum ether, EA: ethyl acetate.

[0091] Example 1: Synthesis of Compound 1

Chemical formula

[0092] Step 1: Synthesis of Intermediate 2-1 In a 100 mL one-neck flask, 5-aminopyrazole 1-1 (8.3 g, 100 mmol) was dissolved in glacial acetic acid (AcOH) (80 mL), and methyl propionate (8.4 g, 100 mmol) was added while stirring at room temperature. The mixture was refluxed and reacted overnight. The reaction solution was concentrated to dryness, ethyl acetate (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] + .

[0093] Step 2: Synthesis of Intermediate 3-1 In a 100 mL one-neck flask, intermediate 2-1 (3.8 g, 28.1 mmol) was dissolved in acetic acid (72.0 mL), and liquid bromine (18.0 g, 112.5 mmol) was added while stirring at room temperature. The mixture was reacted for 3 hours until the reaction was complete. It was filtered, and the filter cake was collected. The filter cake was washed twice with petroleum ether (PE) to obtain intermediate 3-1 (4.0 g, yield: 66.7%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO) δ 12.14 (s, 1H), 9.82 (s, 2H), 8.29 (s, 1H), 8.03 (s, 1H).

[0094] Step 3: Synthesis of Intermediate 4-1 In a 100 mL one-neck flask, intermediate 3-1 (2.14 g, 100 mmol) and DIPEA (2.84 g, 220 mmol) were dissolved in tetrahydrofuran (THF) (50 mL). While stirring at room temperature, SEMCl (2.0 g, 120 mmol) was added dropwise, and the mixture was reacted for 16 h. The reaction solution was poured into water and extracted with ethyl acetate (EA) (100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by silica gel flash column chromatography (0 - 30% PE / EA) to obtain intermediate 4-1 (0.8 g, yield: 23.3%) as a wax-like solid. LCMS (ESI) m / z = 346.0 [M+H] + .

[0095] Step 4: Synthesis of Intermediate 5-1 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 sequentially added to a 50 mL one-neck flask and stirred at 110 °C for 16 h under N2 protection. The reaction solution was filtered, and the filtrate was concentrated and then purified by silica gel flash column (0 - 50% PE / EA) to obtain 800 mg of the crude product of intermediate 5-1 as a white solid. 400 mg was taken and 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] + 。

[0096] Step 5: Synthesis of Intermediate 6-1 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 sequentially added to a 50 mL one-neck flask and stirred at 110 °C for 16 h under nitrogen gas protection. The reaction solution was concentrated to dryness and purified by 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] + 。

[0097] Step 6: Synthesis of Compound 1 Intermediate 6-1 (21 mg, 0.057 mmol) and TBAF tetrahydrofuran solution (5 ml, 5 mmol) were sequentially added to a 25 mL one-neck flask and stirred at 60 °C for 16 h under N2 protection. The reaction solution was concentrated to dryness and prepared by prep-TLC (DCM / THF = 1 / 1) to obtain compound 1 (3 mg, yield: 19.4%) as a white solid. 11H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 8.77 (s, 1H), 8.46 (s, 1H), 8.14 (s, 1H), 7.85 (s, 1H), 7.81 (d, J = 9.4 Hz, 1H), 7.75 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 7.8 Hz, 2H), 4.20 (s, 3H), 3.79 (s, 3H). LCMS (ESI) m / z = 372.2 [M+H] + 。

[0098] Example 2: Synthesis of Compound 2

Chemical Structure

[0099] Step 1: Synthesis of Intermediate 2-2 In a 100 mL single-neck flask, 3-amino-4-ethoxycarbonylpyrazole (40 g, 258 mmol) was dissolved in THF (500 mL), the temperature was lowered to 0 °C, DIPEA (40 g, 310 mmol) was added, and the mixture was stirred for 15 min. SEMCl (51.5 g, 310 mmol) was added dropwise to the reaction solution. After the addition was complete, the mixture was stirred at room temperature for 12 h. The reaction solution was poured into a 1 L ice-water mixture and extracted with EA. The organic phases were combined, washed once with water (200 mL / time) and saturated brine (200 mL / time) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then purified by silica gel flash column (EA / PE = 1 / 2) to obtain Intermediate 2-2 (55 g, yield: 74.8%) as a pale yellow oily liquid. LCMS (ESI) m / z = 286.2 [M+H] + 。

[0100] Step 2: Synthesis of Intermediate 3-2 In a 500 mL one-necked flask, intermediate 2-2 (54 g, 189.5 mmol) was dissolved in ethanol (250 mL), and diethyl malonate (113.6 g, 709.5 mmol) was added while stirring at room temperature. After the addition was complete, 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 under reduced pressure until dry, 200 mL of ice water was added, and it was extracted with methanol / DCM (1 / 10). The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by silica gel column (DCM / MeOH = 30 / 1) to obtain intermediate 3-2 (50 g, yield: 75.9%) as a pale yellow solid. LCMS (ESI) m / z = 354.2 [M+H] + 。

[0101] Step 3: Synthesis of Intermediate 4-2 In a 500 mL one-necked flask, intermediate 3-2 (50 g, 141 mmol) was dissolved in a 15% aqueous sodium hydroxide solution (350 mL), and the temperature was raised to 105 °C and reacted for 15 hours. The reaction solution was cooled to 0 °C in an ice water bath, the pH was adjusted to about 5 with 4 M dilute hydrochloric acid, filtered to obtain a white solid, and purified by silica gel flash column (DCM / MeOH = 10:1) to obtain intermediate 4-2 (30.8 g, yield: 77.4%) as a white solid. LCMS (ESI) m / z = 282.1 [M+H] + 。

[0102] Step 4: Synthesis of Intermediate 5-2 In a 100 mL single-necked flask, the 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, and then N-phenylbis(trifluoromethylsulfonyl)imide (46.9 g, 131.4 mmol) was added in one batch. The reaction was carried out at room temperature for 16 hours. The reaction mixture was poured into 1 L of ice water and extracted with EA. The organic phases were combined, washed once with water and once with saturated brine (100 mL each time), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Then it was purified by silica gel flash column chromatography (PE / EA = 2:1) to obtain the intermediate 5-2 (10.1 g, yield: 22.3%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 12.41 (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).

[0103] Step 5: Synthesis of Intermediate 6-2 In a 25 mL single-necked flask, the 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 further ethylamine tetrahydrofuran solution (13.3 ml, 26.6 mmol, 2 M) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction mixture 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 brine (50 mL each time), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Then it was purified by silica gel flash column chromatography (DCM / MeOH = 40 / 1) to obtain the intermediate 6-2 (1.1 g, yield: 29.5%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 8.21 (s, 1H), 6.90 (t, J = 5.2 Hz, 1H), 5.43 (d, J = 4.0 Hz, 2H), 4.88 (d, J = 5.6 Hz, 1H), 3.57 (t, J = 8.2 Hz, 2H), 3.15 (d, J = 4.4 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 8.0 Hz, 2H), 0.02 (s, 9H).

[0104] Step 6: Synthesis of Intermediate 7-2 In a 25 mL single-necked flask, intermediate 6-2 (1.1 g, 3.57 mmol) was dissolved in THF (15 mL), NBS (634 mg, 3.57 mmol) was added, and the reaction was carried out 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 (20 mL / time) and once with saturated brine (20 mL / time), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel flash column chromatography (DCM / MeOH = 25 / 1) to obtain intermediate 7-2 (1.1 g, yield: 79.6%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 11.31 (s, 1H), 8.62 (s, 1H), 6.36 (t, J = 6.0 Hz, 1H), 5.48 (s, 2H), 3.67 - 3.55 (m, 4H), 1.27 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 8.0 Hz, 2H), 0.01 (s, 9H).

[0105] Step 7: Synthesis of Intermediate 8-2 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 successively added to a 50 mL single-necked flask, and the temperature was raised to 100 °C under N2 protection 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. 11H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 8.49 (s, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 5.45 (s, 2H), 5.21 (t, J = 6.0 Hz, 1H), 3.80 (s, 3H), 3.60 (dd, J = 10.8, 5.3 Hz, 2H), 3.33 - 3.28 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H), 0.92 - 0.87 (m, 2H), 0.01 (s, 9H).

[0106] Step 8: Synthesis of Intermediate 9-2 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), DMSO (25 ml) were sequentially added to a 50 mL one-necked flask, and the temperature was raised to 130 °C under N2 protection and stirred for 16 h. The reaction solution was poured into ice water, extracted with DCM / methanol (10 / 1), the organic layers were combined, washed with water and saturated brine once each (25 mL / time), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to obtain a crude product, and purified by 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] + 。

[0107] Step 9: Synthesis of Compound 2 In a 25 mL one-necked flask, Intermediate 9-2 (100 mg, 1.83 mmol) was dissolved in 4M HCl / 1,4-dioxane solution (15 mL) and reacted at room temperature for 2 h. The reaction solution was poured into ice water, and the pH was adjusted to neutral with aqueous sodium bicarbonate solution. Extracted with DCM / methanol (10 / 1), the organic phases were combined, washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, then purified by prep-HPLC (H2O / CAN, 0.1% FA), and freeze-dried to obtain Compound 2 (31.77 mg, yield: 41.8%) as a white solid.1 1H NMR (400 MHz, DMSO) δ 13.03 (s, 1H), 8.35 (s, 2H), 7.60 (d, J = 13.2 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 7.07 (dd, J = 9.2, 2.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 5.27 (s, 1H), 4.19 (s, 3H), 3.77 (s, 3H), 3.36 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H). LCMS (ESI) m / z = 415.2 [M+H] + 。

[0108] Compounds 5, 6, 7, 9, 10, 11, and 16 were prepared by the synthesis method of Example 2.

Table 2

[0109] Example 3: Synthesis of Compound 4

Chem.

[0110] Step 1: Synthesis of Intermediate 2-4 In a 25 mL autoclave, 4-2 (2.5 g, 8.9 mmol) was dissolved in a THF solution of methylamine (25 mL, 2 M), and the temperature was raised to 100 °C and reacted overnight. The reaction solution was directly concentrated to obtain a crude product, which was purified by silica gel flash column (0 - 2% methanol / DCM) to obtain Intermediate 2-4 (1.0 g, yield: 38.3%) as a white solid. 1 1H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 8.14 (s, 1H), 7.05 (d, J = 4.8 Hz, 1H), 5.44 (s, 2H), 4.86 (s, 1H), 3.61 - 3.54 (m, 2H), 2.78 (d, J = 4.8 Hz, 3H), 0.93 - 0.85 (m, 2H), -0.00 (s, 9H).

[0111] Step 2: Synthesis of Intermediate 3-4 In a 25 mL single-neck flask, intermediate 2-4 (1.0 g, 3.4 mmol) was dissolved in THF (15 mL), NBS (604 mg, 3.4 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated to dryness to obtain a 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] + .

[0112] Step 3: Synthesis of Intermediate 4-4 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 successively placed in a 50 mL single-neck flask, and the mixture was stirred at 90 °C for 16 h under N2 protection. The reaction solution was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel flash column chromatography (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] + .

[0113] Step 4: Synthesis of Intermediate 5-4 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 successively placed in a 10 mL microwave tube, and the mixture was subjected to microwave reaction at 110 °C for 3 h under nitrogen gas protection. 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 to obtain a crude product, which was purified by silica gel flash column chromatography (0 - 2% methanol / DCM) to obtain intermediate 5-4 (75 mg, yield: 75.5%) as a white solid. LCMS (ESI) m / z = 531.3 [M+H]+ 。

[0114] Step 5: Synthesis of Compound 4 In a 25 mL single-necked flask, the intermediate 5-4 (75 mg, 0.14 mmol) was dissolved in a 4 mol / L hydrogen chloride dioxane solution (5 mL) and stirred at room temperature for 2 h. The reaction solution was poured into 10 mL of water, and the pH was adjusted to neutral with an aqueous sodium bicarbonate solution. It was extracted with 50 mL of DCM / methanol (10 / 1), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to dryness, purified by prep-HPLC (water / acetonitrile, 0.1% NH₃·H₂O), and freeze-dried to obtain Compound 4 (6.83 mg, yield: 12.1%) as a white solid. 1 ¹H NMR (400 MHz, DMSO) δ 13.02 (s, 1H), 8.36 (s, 2H), 7.61 (d, J = 12.0 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.06 (dd, J₁ = 9.2 Hz, J₂ = 2.0 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 5.61 (s, 1H), 4.19 (s, 3H), 3.77 (s, 3H), 2.99 (d, J = 4.4 Hz, 3H). LCMS (ESI) m / z = 401.1 [M + H] + 。

[0115] Example 4: Synthesis of Compound 3

Chemical formula

[0116] Step 1: Synthesis of Intermediate 2-3 In a 25 mL single-necked flask, 4-2 (2.0 g, 7.1 mmol) was dissolved in DMF (25 mL), and sodium bicarbonate (1.2 g, 14.2 mmol) and iodoethane (EtI) (1.66 g, 10.7 mmol) were added. The reaction was carried out at 45 °C overnight. The reaction mixture was poured into ice water and extracted with EA (100 mL). The combined organic layers were washed once with water and once with saturated brine, 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 - 80% EA / PE) to obtain intermediate 2-3 (0.2 g, yield: 9.1%) as a white solid. 1 HNMR (400 MHz, DMSO) δ 11.37 (s, 1H), 8.30 (s, 1H), 5.52 (s, 1H), 5.44 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 3.62 - 3.55 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H), 0.91 - 0.85 (m, 2H), 0.00 (s, 9H).

[0117] Step 2: Synthesis of Intermediate 3-3 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 mixture was poured into water and extracted 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 to obtain a crude product, which was purified by silica gel flash column (0 - 4% methanol / DCM) to obtain intermediate 3-3 (205 mg, yield: 82.3%) as a white solid. 1 HNMR (400 MHz, DMSO) δ 12.01 (s, 1H), 8.77 (s, 1H), 5.49 (s, 2H), 4.63 (q, J = 7.2 Hz, 2H), 3.67 - 3.59 (m, 2H), 1.44 (t, J = 7.2 Hz, 3H), 0.94 - 0.85 (m, 2H), 0.02 - 0.04 (m, 9H).

[0118] Step 3: Synthesis of Intermediate 4-3 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 successively added to a 50 mL one-necked flask. The temperature was raised to 100 °C under N2 protection and stirred for 16 h. The reaction solution was filtered, the filtrate was collected, concentrated under reduced pressure to obtain a crude product, and purified by 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 (400 MHz, DMSO) 11.62 (s, 1H), 8.61 (s, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.47 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 3.65 - 3.57 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H), 0.93 - 0.86 (m, 2H), -0.00 (s, 9H). LCMS (ESI) m / z = 416.2 [M + H] + 。

[0119] Step 4: Synthesis of Intermediate 5-3 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 successively added to a 20 mL microwave tube. The microwave reaction was carried out at 110 °C for 3 h under nitrogen gas protection. 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, the filtrate was concentrated, and purified by silica gel flash column (0 - 3% methanol / DCM) to obtain Intermediate 5-3 (100 mg, yield: 58.8%) as a white solid. LCMS (ESI) m / z = 546.2 [M + H] + 。

[0120] Step 5: Synthesis of Compound 3 In a 25 mL single-neck flask, intermediate 5-3 (100 mg, 0.183 mmol) was dissolved in a 4 mol / L hydrogen chloride dioxane solution (5 mL), and the mixture was stirred at room temperature for 2 h. The reaction solution was poured into 10 mL of water, and the pH was adjusted to neutral with an aqueous sodium hydrogen carbonate solution. It was extracted with 50 mL of DCM / methanol (10 / 1), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to dryness, purified by prep-HPLC (water / acetonitrile, 0.1% FA), and freeze-dried to obtain 3 (9.0 mg, yield: 11.84%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 13.29 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 7.76 - 7.57 (m, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.10 (dd, J1 = 9.2 Hz, J2 = 2.0 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 4.40 (q, J = 6.8 Hz, 2H), 4.21 (s, 3H), 3.76 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). LCMS (ESI) m / z = 416.1 [M + H] + 。

[0121] 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, 142 were prepared by the synthesis method of Example 4.

Table 3 - 1

Table 3 - 2

Table 3 - 3

Table 3 - 4

Table 3 - 5

Table 3-6

Table 3-7

Table 3-8

Table 3-9

[0122] Trifluoroacetate Salt of Compound 35: By the synthesis method of Example 4, replace 4-methoxyphenylboronic acid pinacol ester in Step 3 with 4-chlorophenylboronic acid pinacol ester, replace 5-bromo-2-methyl-2H-indazole in Step 4 with 1-(azacyclobuten-3-yl)-6-iodo-1H-benzo-[d]imidazole, and replace the mobile phase FA purified by prep-HPLC in Step 5 with trifluoroacetic acid to obtain the trifluoroacetate salt of Compound 35. 1 H 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] + 。

[0123] Example 5: Synthesis of Compound 12

Chemical formula

[0124] Step 1: Synthesis of Intermediate 2-12 In a 25 mL single-neck flask, 4-2 (2.0 g, 7.1 mmol) and potassium carbonate (1.96 g, 14.2 mmol) were dissolved in DMF (25 mL). A solution of 2,2,2,2-tetrafluoroethyl trifluoromethanesulfonate (3.3 g, 14.2 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 6 h. The reaction solution was poured into water and extracted with EA (100 mL). The combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. After purification by silica gel flash column (0 - 60% EA), intermediate 2-12 (0.6 g, yield: 51.9%) was obtained as a white solid. 1 HNMR (400 MHz, DMSO) δ 11.53 (s, 1H), 8.35 (s, 1H), 5.70 (s, 1H), 5.41 (s, 2H), 4.91 (q, J = 8.8 Hz, 2H), 3.54 (t, J = 8.0 Hz, 2H), 0.83 (t, J = 8.0 Hz, 2H), 0.05 (s, 9H). LCMS (ESI) m / z = 363.9 [M + H] + 。

[0125] Step 2: Synthesis of Intermediate 3-12 In a 25 mL single-neck 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 the mixture was stirred at room temperature for 2 h. The reaction solution was slowly added dropwise to ice water to precipitate a large amount of solid, which was then suction filtered. The filter cake was purified by silica gel flash column (0 - 4% methanol / DCM), and intermediate 3-12 (600 mg, yield: 93.7%) was obtained as a white solid. 1 HNMR (400 MHz, DMSO) δ 12.23 (s, 1H), 8.76 (s, 1H), 5.50 (s, 2H), 5.26 (q, J = 8.5 Hz, 2H), 3.68 - 3.57 (m, 2H), 0.89 (dd, J1 = 10.6 Hz, J2 = 5.6 Hz, 2H), 0.00 (s, 9H). LCMS (ESI) m / z = 441.9 [M + H] + 。

[0126] Step 3: Synthesis of Intermediate 4-12 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 successively placed in a 50 mL one-neck flask and stirred at 100 °C for 16 h under N2 protection. After filtration and concentration of the filtrate, it was purified by silica gel flash column (0 - 3% methanol / DCM), and Intermediate 4-12 (95 mg, yield: 47.5%) was obtained as a white solid. LCMS (ESI) m / z = 470.0 [M+H] + .

[0127] Step 4: Synthesis of Intermediate 5-12 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 successively placed in a 20 mL microwave tube and subjected to a microwave reaction at 110 °C for 3 h under nitrogen gas protection. 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 collected and purified by silica gel flash column (0 - 3% methanol / DCM), and Intermediate 5-12 (80 mg, yield: 65.8%) was obtained as a white solid. LCMS (ESI) m / z = 600.2 [M+H] + .

[0128] Step 5: Synthesis of Compound 12 In a 25 mL single-neck flask, the intermediate 5-12 (80 mg, 0.133 mmol) was dissolved in 4 M hydrogen chloride and 1,4-dioxane (6 mL), and stirred at room temperature for 4 h. The reaction solution was poured into water, and the pH was adjusted to neutral with an aqueous sodium hydrogen carbonate solution. It was extracted with 50 mL of DCM / methanol (10 / 1), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, concentrated under reduced pressure to dryness, passed through prep-HPLC (water / acetonitrile, 0.1% FA), and freeze-dried to obtain compound 12 (31.53 mg, yield: 50.4%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 13.38 (s, 1H), 8.51 (s, 1H), 8.41 (s, 1H), 7.72 (s, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.11 (dd, J1 = 9.2 Hz, J2 = 2.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 4.98 (q, J = 8.8 Hz, 2H), 4.21 (s, 3H), 3.77 (s, 3H). LCMS (ESI) m / z = 470.1 [M+H] + 。

[0129] Compounds 27 - 29, 46 - 47, 49, 52 - 54, 89, 93, 99 were prepared by the synthesis method of Example 5.

Table 4-1

Table 4-2

Table 4-3

[0130] Example 6: Synthesis of Compound 31 and Compound 45

Chem.

[0131] Compound 31: 1 H NMR (400 MHz, DMSO) δ 8.49 (s, 1H), 8.14 (s, 1H), 7.86 (d, J = 1.3 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.26 (t, J = 76.0 Hz, 1H), 7.24 (dd, J = 9.0, 2.0 Hz, 1H), 7.13 (d, J = 8.7 Hz, 2H), 4.46 (q, J = 7.0 Hz, 2H), 4.22 (s, 3H), 3.05 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H). LCMS (ESI) m / z = 466.0 [M+H] + 。

[0132] Compound 45: 1 H NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 8.40 (s, 1H), 7.68 (d, J = 1.4 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H), 7.26 (t, J = 76.0 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 1.9 Hz, 1H), 4.42 (d, J = 7.0 Hz, 2H), 4.20 (s, 3H), 3.83 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H). LCMS (ESI) m / z = 466.0 [M+H] + 。

[0133] Example 7: Synthesis of Compound 50

Chemical Structure

[0134] Step 1: Synthesis of Intermediate 2-50 In a 250 mL single-neck 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 temperature was raised to 90 °C and stirred for 3 h. After completion of the reaction, the reaction solution was poured into water to precipitate a solid, which was collected by suction filtration to obtain a crude product. The crude product was purified by 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] + 。

[0135] Step 2: Synthesis of Intermediate 3-50 In a 50 mL single-neck 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 in one portion at room temperature, and the reaction was carried out 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 a crude product. The crude product was purified by silica gel Flash column (0 - 100% EA) to obtain intermediate 3-50 (1.35 g, yield: 73.6%) as a pale yellow solid. LCMS (ESI) m / z = 414.0 [M+H] + 。

[0136] Step 3: Synthesis of Intermediate 4-50 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 successively placed in a 100 mL single-neck flask, and the temperature was raised to 100 °C under N2 protection and reacted 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 pale yellow solid. LCMS (ESI) m / z = 446.1 [M+H] + 。

[0137] Step 4: Synthesis of Intermediate 5-50 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 sequentially added to a 50 mL one-neck flask. The temperature was raised to 130 °C under N2 protection and reacted overnight. The reaction solution was concentrated to dryness to obtain a crude product, which was purified by 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] + 。

[0138] Step 5: Synthesis of Compound 50 In a 50 mL one-neck flask, Intermediate 5-50 (420 mg, 0.73 mmol) was dissolved in 4 M hydrochloric acid / 1,4-dioxane (10 mL) and reacted at room temperature for 4 h. The reaction solution was poured into water, and the pH was adjusted to alkaline with aqueous ammonia solution. It was 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 under reduced pressure to dryness and purified by prep-HPLC (water / acetonitrile, 0.1% NH3·H2O). After lyophilization, the final product Compound 50 (164.39 mg, yield: 50.5%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO) δ 13.33 (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 = 8.9 Hz, 1H), 4.28 (d, J = 6.6 Hz, 2H), 4.20 (s, 3H), 1.18 - 1.04 (m, 1H), 0.50 (d, J = 7.3 Hz, 2H), 0.29 (d, J = 4.0 Hz, 2H). LCMS (ESI) m / z = 446.0 [M+H] + 。

[0139] Compounds 32, 39, 51, 95, 96, and 104 were produced by the synthesis method of Example 7.

Table 5

[0140] Example 8: Synthesis of Compound 59

Chem.

[0141] Step 1: Synthesis of Intermediate 2-59 In a 50 mL single-neck 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 the mixture was reacted at 90 °C for 2 h. Water (50 mL) was added to quench the reaction, and the mixture was extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated to obtain a crude product, which was separated by silica gel Flash (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] + 。

[0142] Step 2: Synthesis of Intermediate 3-59 In a 25 mL single-neck flask, 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 the mixture was reacted at 110 °C for 16 h under the protection of nitrogen gas. Water was added to quench the reaction, and the mixture was extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by silica gel Flash (EA / PE = 9 / 1) to obtain intermediate 3-59 (600 mg, yield: 76.24%) as a yellow solid. LCMS (ESI) m / z = 540.2 [M+H]+ .

[0143] Step 3: Synthesis of Intermediate 4-59 In a 50 mL single-neck flask, the intermediate 3-59 (500 mg, 0.928 mmol) was dissolved in THF (20 mL), then NBS (173 mmol, 0.974 mmol) was added in one portion, and the reaction was carried out at room temperature for 2 h. A saturated sodium thiosulfate solution was added to quench the reaction, and the mixture was extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, a crude product was obtained and purified by silica gel Flash (EA / PE = 90 / 10) to obtain the intermediate 4-59 (400 mg, yield: 69.82%) as a pale yellow solid. LCMS (ESI) m / z = 618.0 [M+H] + .

[0144] Step 4: Synthesis of Intermediate 5-59 The 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 sequentially placed in a 25 mL single-neck flask and reacted at 100 °C for 16 h under the protection of nitrogen gas. Water (10 mL) was added to quench the reaction, and the mixture was extracted with DCM, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, a crude product was obtained and purified by silica gel Flash (methanol / DCM = 2 / 98) to obtain the intermediate 5-59 (94 mg, yield: 89.40%) as a pale yellow solid. LCMS (ESI) m / z = 650.1 [M+H] + .

[0145] Step 5: Synthesis of Compound 59 In a 25 mL single-necked flask, the intermediate 5-59 (80 mg, 0.123 mmol) was dissolved in hydrogen chloride / 1,4-dioxane solution (4 M, 2 mL), and the reaction was carried out at room temperature for 4 h. Ice water (10 mL) was added to quench the reaction, the pH of the reaction solution was adjusted to 8-9 with aqueous ammonia, extracted with DCM / methanol = 10 / 1, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated to obtain a crude product, separated by prep-HPLC (ACN / water - 0.1% NH₃·H₂O), and lyophilized to obtain the final product, compound 59 (16.68 mg, yield: 31.17%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 13.35 (s, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 7.70 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.39 - 7.34 (m, 2H), 7.11 (d, J = 8.8 Hz, 1H), 4.84 (t, J = 5.2 Hz, 1H), 4.41 (s, 2H), 4.21 (s, 3H), 3.64 (dd, J = 9.6, 4.8 Hz, 2H). LCMS (ESI) m / z = 436.0 [M + H] + 。

[0146] Example 9: Synthesis of Compound 67

Chemical Structure

[0147] Step 1: Synthesis of Intermediate 2-67 4-Amino-5-imidazoleformamide 1-67 (10 g, 79 mmol), methanesulfonic acid (20 mL) and ethanol (100 mL) were sequentially added to a 200 mL reaction kettle. After sealing, the system was reacted at 120 °C for 16 h. Aqueous ammonia was added to neutralize the pH of the reaction solution to 8-9, extracted with methanol / DCM = 1 / 10 (50 mL × 5), concentrated to obtain a crude product, and separated by silica gel Flash (methanol / DCM = 20 / 80) to obtain the intermediate 2-67 (6.4 g, yield: 52.03%) as a white solid. LCMS (ESI) m / z = 156.0 [M + H] + 。

[0148] Step 2: Synthesis of Intermediate 3-67 In a 250 mL three-necked flask, the intermediate 2-67 (6.0 g, 38.7 mmol) and diisopropylethylamine (7.5 g, 58.1 mmol) were dissolved in THF (100 mL), and 2-(trimethylsilyl)oxymethyl chloride (9.6 g, 58.1 mmol) was slowly added dropwise. After the addition was completed, the reaction was carried out at room temperature for 2 h. The solvent was removed, water was added for dilution, extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated to obtain a crude product, which was separated by silica gel Flash (EA / PE = 1 / 1) to obtain a crude product of intermediate 3-67 (3.0 g, yield: 27.3%) as a colorless viscous oil. LCMS (ESI) m / z = 285.9 [M+H] + 。

[0149] Step 3: Synthesis of Intermediate 4-67 In a 100 mL three-necked flask, the crude product of 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 in an ice-water bath. After the addition was completed, the reaction was carried out at 95 °C for 16 h. Most of the solvent was removed, ice water (100 mL) was added, extracted with EA, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. It was concentrated to obtain a crude product, which was separated by silica gel Flash (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] + 。

[0150] Step 4: Synthesis of Intermediate 5-67 In a 100 mL single-necked flask, the intermediate 4-67 (3.2 g, 9.1 mmol) was dissolved in a 15% aqueous sodium hydroxide solution (30 mL), and the reaction was carried out at 105 °C for 5 h. The system was cooled to 0 °C, adjusted to pH = 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] + 。

[0151] Step 5: Synthesis of Intermediate 6-67 In a 50 mL single-neck flask, the intermediate 5-67 (1.0 g, 3.56 mmol) and potassium carbonate (982 mg, 7.12 mmol) were dissolved in DMF (5 mL). Iodoethane (833 mg, 5.34 mmol) was added dropwise. After the addition was completed, the reaction was carried out at 40 °C for 16 h. Water (20 mL) was added to quench the reaction, and the mixture was extracted with EA, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated to obtain a crude product, which was separated by silica gel flash (methanol / DCM = 7 / 93) to obtain the intermediate 6-67 (310 mg, yield: 28.18%). 1 H NMR (400 MHz, DMSO) δ 11.72 (s, 1H), 8.14 (s, 1H), 5.71 (s, 1H), 5.59 (s, 2H), 4.21 (q, J = 6.8 Hz, 2H), 3.59 (t, J = 7.8 Hz, 2H), 1.46 (t, J = 6.8 Hz, 3H), 0.91 (t, J = 8.0 Hz, 2H), 0.00 (s, 9H).

[0152] Step 6: Synthesis of Intermediate 7-67 In a 100 mL single-neck flask, the 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 the reaction was carried out at 110 °C for 16 h under the protection of nitrogen gas. Water was added to quench the reaction, and the mixture was extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, it was purified by silica gel flash (methanol / DCM = 6 / 94) to obtain the intermediate 7-67 (190 mg, yield: 47.77%) as a pale yellow solid. LCMS (ESI) m / z = 440.1 [M+H] + 。

[0153] Step 7: Synthesis of Intermediate 8-67 In a 25 mL single-neck flask, the intermediate 7-67 (170 mg, 0.36 mmol) was dissolved in THF (3 mL), and NBS (61.6 mg, 0.36 mmol) was added thereto in one batch. The reaction was carried out at room temperature for 1 h. A saturated sodium thiosulfate solution was added to quench the reaction, and the mixture was extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated to obtain a crude product, which was purified by silica gel Flash (methanol / DCM = 5 / 95) to obtain the intermediate 8-67 (120 mg, yield: 64.44%) as a pale yellow solid. LCMS (ESI) m / z = 518.0 [M+H] + 。

[0154] Step 8: Synthesis of Intermediate 9-67 The 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 sequentially placed in a 25 mL single-neck flask and reacted at 100 °C for 16 h under the protection of nitrogen gas. Water was added to quench the reaction, and the mixture was extracted with DCM, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated to obtain a crude product, which was purified by prep-TLC (methanol / DCM = 1 / 10) to obtain the intermediate 9-67 (50 mg, yield: 94.18%) as a white solid. LCMS (ESI) m / z = 550.1 [M+H] + 。

[0155] Step 9: Synthesis of Compound 67 In a 50 mL single-neck flask, the intermediate 9-67 (50 mg, 0.091 mmol) was dissolved in a hydrogen chloride / 1,4-dioxane solution (4 M, 3 mL), and reacted at room temperature for 4 h. Ice water (10 mL) was added to quench the reaction, and the pH of the reaction solution was adjusted to 8-9 with aqueous ammonia. It was extracted with DCM / methanol = 10 / 1, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated to obtain a crude product, separated by prep-TLC (methanol / DCM = 1 / 10), concentrated and freeze-dried to obtain compound 67 (12.70 mg, yield 33.30%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 13.06 (s, 1H), 8.42 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.40 (s, 4H), 7.14 (d, J = 8.4 Hz, 1H), 4.21 (s, 5H), 1.23 (m, 3H). LCMS (ESI) m / z = 420.0 [M+H] + 。

[0156] Compound 44 was prepared by the synthesis method of Example 9.

Table 6

[0157] Example 10: Synthesis of Compound 61

Chem.

[0158] Step 1: Synthesis of Intermediate 2-61 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 successively added to a 250 mL three-necked flask. The temperature was raised to 120 °C under N2 protection and reacted overnight. The reaction solution was concentrated to dryness, ice water was added, and it was extracted with 50 mL (methanol / DCM = 1 / 10). The organic layers were combined, washed successively with water and saturated brine, 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 (400 MHz, DMSO) δ 8.47 (d, J = 3.2 Hz, 2H), 7.75 (d, J = 9.6 Hz, 2H), 7.15 (dd, J1 = 8.8 Hz, J2 = 1.6 Hz, 1H), 5.81 (s, 1H), 5.41 (s, 2H), 4.36 - 4.22 (m, 5H), 3.58 (t, J = 8.0 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H), 0.91 - 0.80 (m, 2H), -0.00 (s, 9H). LCMS (ESI) m / z = 440.2 [M + H] + 。

[0159] Step 2: Synthesis of Intermediate 3-61 In a 25 mL single-necked flask, Intermediate 2-61 (4.0 g, 9.1 mmol) was dissolved in THF (120 mL). While stirring at room temperature, NBS (1.46 g, 8.2 mmol) was added in one portion, and the reaction was carried out 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 a crude product, which was purified by silica gel Flash column (0 - 100% EA) to obtain Intermediate 3-61 (3.5 g, yield: 74.2%) as a pale yellow solid. LCMS (ESI) m / z = 518 [M + H] + 。

[0160] Step 3: Synthesis of Intermediate 4-61 Intermediate 3-61 (100 mg, 0.19 mmol), cyclohex-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 placed in a 50 mL one-neck flask and stirred at 100 °C for 16 h under N2 protection. The reaction solution was filtered, concentrated to obtain a crude product, and purified by silica gel Flash (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] + .

[0161] Step 4: Synthesis of Intermediate 5-61 Intermediate 4-61 (80 mg, 0.15 mmol), Pd / C (10 mg), and EtOH (3 ml) were successively placed in a 50 ml one-neck flask and stirred at room temperature for 72 h in a hydrogen gas atmosphere. The reaction solution was concentrated to obtain a crude product of Intermediate 5-61 (70 mg, yield: 87.5%) as a yellow solid. LCMS (ESI) m / z = 522.2 [M+H] + .

[0162] Step 5: Synthesis of Compound 61 In a 25 mL one-neck flask, Intermediate 5-61 (120 mg, 0.13 mmol) was dissolved in a 4M HCl / 1,4-dioxane solution (5 mL) and reacted at room temperature for 3 h. The reaction solution was poured into ice water and the pH was adjusted to 9-10 with aqueous ammonia solution. Extracted with DCM / methanol (10 / 1), the organic phase was washed once with water and saturated brine respectively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to dryness, purified by Prep-HPLC (H2O / ACN, 0.1% NH3.H2O), and freeze-dried to obtain Compound 61 (10 mg, yield: 19.2%) as a white solid. 11H NMR (400 MHz, DMSO) δ 13.14 (s, 1H), 8.38 (s, 2H), 7.63 (d, J = 3.2 Hz, 2H), 7.04 (dd, J1 = 9.1 Hz, J2 = 1.7 Hz, 1H), 4.47 (d, J = 6.9 Hz, 2H), 4.21 (s, 3H), 3.09 (t, J = 12.0 Hz, 1H), 2.11 - 2.00 (m, 2H), 1.74 (d, J = 12.3 Hz, 2H), 1.66 (d, J = 11.1 Hz, 1H), 1.47 (d, J = 11.9 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H), 1.22 (td, J = 25.0, 12.6 Hz, 3H). LCMS (ESI) m / z = 392.0 [M + H] + 。

[0163] Example 11: Synthesis of Compound 63

Chemical Structure

[0164] Step 1: Synthesis of Intermediate 2-63 4 - 2 (1.05 g, 3.39 mmol), 2,2,2 - trifluoroethan - 1 - amine (2 mL) and THF (5 mL) were placed in a 50 mL reaction kettle, heated to 110 °C and reacted for 16 h. After concentrating the reaction solution, the crude product was purified by silica gel Flash column (DCM / MeOH = 97 / 3) to obtain Intermediate 2 - 63 (175 mg, yield: 24.72%) as a yellow solid. LCMS (ESI) m / z = 363.10 [M + H] + 。

[0165] Step 2: Synthesis of Intermediate 3-63 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 sequentially added to a 25 mL single-neck flask and reacted at 110 °C for 16 h under N2 protection. The reaction solution was concentrated, and the crude product was purified by 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] + .

[0166] Step 3: Synthesis of Intermediate 4-63 In a 25 mL single-neck flask, Intermediate 3-63 (200 mg, 0.41 mmol) was dissolved in THF (5 mL). After dissolution, NBS (72 mg, 0.41 mmol) was added in one portion, and the reaction was carried out at room temperature for 2 h. The reaction solution was poured into a saturated sodium sulfite solution and extracted with DCM. The organic phase was concentrated, and the crude product was purified by 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] + .

[0167] Step 4: Synthesis of Intermediate 5-63 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 sequentially added to a 25 mL single-neck flask and reacted at 110 °C for 16 h under N2 protection. The reaction solution was filtered, the filtrate was collected, concentrated to obtain a crude product, and purified by silica gel Flash column (0 - 3% methanol / DCM) to obtain yellow solid Intermediate 5-63 (40 mg, yield: 37.74%). LCMS (ESI) m / z = 603.15 [M+H] + .

[0168] Step 5: Synthesis of Compound 63 In a 25 mL single-neck flask, the intermediate 5-63 (40 mg, 0.07 mmol) was dissolved in a TBAF tetrahydrofuran solution (6 mL), and refluxed at 60 °C for 2 h. The reaction solution was concentrated, EA was added, washed with water to remove TBAF, the organic phase was concentrated, the crude product was purified by prep-TLC (DCM / MeOH = 12 / 1), and after lyophilization, the final product, compound 63 (7.25 mg, yield: 23.39%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO) δ 13.18 (s, 1H), 8.52 (s, 1H), 8.37 (s, 1H), 7.66 (s, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.09 (dd, J = 9.1, 1.7 Hz, 1H), 5.98 (t, J = 7.5 Hz, 1H), 4.20 (s, 3H), 4.17 - 4.05 (m, 2H). LCMS (ESI) m / z = 473.05 [M + H] + 。

[0169] Compounds 105 - 108, 123, and 129 were prepared by the synthesis method of Example 11.

Table 7

[0170] Example 12: Synthesis of Compound 64

Chemical Structure

[0171] Step 1: Synthesis of Intermediate 2-64 In a 50 mL reaction kettle, 4-2 (1.0 g, 3.55 mmol) was dissolved in a tetrahydrofuran solution of ethylamine (12 mL), and reacted at 110 °C for 16 h. Water was added to the reaction solution, extracted with EA, the organic phase was concentrated, and the crude product was purified by silica gel Flash column (DCM / MeOH = 40 / 1) to obtain the intermediate 2-64 (550 mg, yield: 50.0%) as a white solid.1 1H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 8.21 (s, 1H), 6.90 (t, J = 5.0 Hz, 1H), 5.44 (s, 2H), 4.89 (s, 1H), 3.64 - 3.50 (m, 2H), 3.16 (dd, J = 7.1, 5.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H), 0.94 - 0.83 (m, 2H), -0.00 (s, 9H).

[0172] Step 2: Synthesis of Intermediate 3-64 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), DMSO (4 ml) were sequentially added to a 25 mL one - neck flask and reacted at 110 °C for 16 h under N2 protection. The reaction solution was concentrated, and the crude product was purified by 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] + 。

[0173] Step 3: Synthesis of Intermediate 4-64 In a 50 mL one - neck flask, Intermediate 3 - 64 (800 mg, 1.82 mmol) was dissolved in THF (10 mL). After dissolution, NBS (292 mg, 1.64 mmol) was added in one portion, and the reaction was carried out at room temperature for 2 h. The reaction solution was poured into a saturated sodium sulfite solution and extracted with DCM. The organic phase was concentrated, and the crude product was purified by 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] + 。

[0174] Step 4: Synthesis of Intermediate 5-64 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 sequentially added to a 25 mL single-neck flask, and the reaction was carried out at 100 °C for 16 h under N2 protection. The reaction solution was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by 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 (400 MHz, DMSO) δ 8.68 (s, 1H), 8.41 (s, 1H), 7.76 - 7.56 (m, 2H), 7.49 (dd, J = 8.8, 2.1 Hz, 2H), 7.40 - 7.24 (m, 2H), 7.11 (dd, J = 9.0, 2.0 Hz, 1H), 5.80 (t, J = 6.2 Hz, 1H), 5.43 (s, 2H), 4.25 (s, 3H), 3.76 - 3.52 (m, 2H), 1.17 (t, J = 7.0 Hz, 3H), 0.93 - 0.84 (m, 2H), 0.06 (s, 2H), 0.01 (s, 9H).

[0175] Step 5: Synthesis of Intermediate 6-64 Intermediate 5-64 (109 mg, 0.20 mmol) and the solvent DMF (5 mL) were added to a 25 mL three-neck flask, cooled to 0 °C under N2 protection, NaH (24 mg, 0.60 mmol) was added, and the mixture was stirred for about 10 min. Then, CH3I (56 mg, 0.40 mmol) was added and stirring was continued for 20 min. Water was added to the reaction solution to quench it, and it was extracted with EA. The organic phase was concentrated to obtain a crude product of Intermediate 6-64 (109 mg, purity: yield: 83% 80.78%) as a gray solid. LCMS (ESI) m / z = 562.95 [M + H] + 。

[0176] Step 6: Synthesis of Compound 64 In a 25 mL single-necked flask, intermediate 9 (109 mg, 0.19 mmol) was dissolved in an HCl / 1,4-dioxane solution (10 mL) and reacted at room temperature for 2 h. The reaction solution was poured into ice water, and the pH was adjusted to 9-10 with aqueous ammonia solution. It was extracted with DCM / methanol (10 / 1), the organic phase was washed once with water and saturated brine respectively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the crude product was purified by silica gel Flash (DCM / MeOH = 97 / 3), and after lyophilization, compound 64 (14.95 mg, yield: 16.65%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO) δ 13.11 (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, 1.5 Hz, 1H), 4.19 (s, 3H), 3.16 (q, J = 6.6 Hz, 2H), 2.71 (s, 3H), 1.00 (t, J = 7.0 Hz, 3H). LCMS (ESI) m / z = 433.10 [M + H] +

[0177] Example 13: Synthesis of Compound 112

Chemical Structure

[0178] Step 1: Synthesis of Intermediate 2-112 In a 100 mL single-necked flask, 4-2 (9.0 g, 32.0 mmol), N-phenylbis(trifluoromethanesulfonylimide) (13.7 g, 38.4 mmol), and TEA (9.7 g, 96 mmol) were dissolved in DMF (50 mL). The reaction was carried out at room temperature for 16 h under the protection of nitrogen gas. Ice water (50 mL) was added to quench the reaction, extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, a crude product was obtained and purified by silica gel Flash (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] + 。

[0179] Step 2: Synthesis of Intermediate 3-112 In a 100 mL single-neck 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 in sequence. A toluene / water mixed solvent (10 mL, 10 / 1) was added, and the reaction was carried out at 90 °C for 16 h under the protection of nitrogen gas. Water (20 mL) was added to quench the reaction, and the mixture was extracted with DCM, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, a crude product was obtained and purified by silica gel Flash (DCM / methanol = 98 / 2) to obtain the product intermediate 3-112 (180 mg, yield: 48.45%) as a white solid. LCMS (ESI) m / z = 308.0 [M+H] + 。

[0180] Step 3: Synthesis of Intermediate 4-112 In a 100 mL single-neck 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 in sequence. Dimethyl sulfoxide (4 mL) was added, and the reaction was carried out at 110 °C for 16 h under the protection of nitrogen gas. Water (20 mL) was added to quench the reaction, and the mixture was extracted with EA (30 mL / time), washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, a crude product was obtained and separated and purified by silica gel Flash (methanol / DCM = 3 / 97) to obtain intermediate 4-112 (160 mg, yield: 70.41%) as a black solid. LCMS (ESI) m / z = 438.1 [M+H] + 。

[0181] Step 4: Synthesis of Intermediate 5-112 In a 100 mL three-necked flask, the intermediate 4-112 (140 mg, 0.32 mmol) was dissolved in THF (4 mL). Under the protection of nitrogen gas, NBS (62.7 mmol, 0.35 mmol) was added thereto in one batch, and the reaction was carried out at room temperature for 2 h. A saturated sodium thiosulfate solution was added to quench the reaction (10 mL), and the mixture was extracted with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated to obtain a crude product, which was purified by silica gel Flash (PE / EA = 65 / 35), and the product intermediate 5-112 (120 mg, yield: 72.81%) was obtained as a colorless viscous solid. LCMS (ESI) m / z = 516.1 [M+H] + 。

[0182] Step 5: Synthesis of Intermediate 6-112 The 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 sequentially placed in a 25 mL one-necked flask, and the reaction was carried out at 100 °C for 16 h under the protection of nitrogen gas. Water was added to quench the reaction, and the mixture was extracted with DCM, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated, and the crude product was purified by silica gel Flash (methanol / DCM = 3 / 97), and the intermediate 6-112 (120 mg, yield: 94.15%) was obtained as a white solid. LCMS (ESI) m / z = 548.1 [M+H] + 。

[0183] Step 6: Synthesis of Compound 112 Intermediate 6-112 (110 mg, 0.20 mmol) was placed in a 25 mL one-necked flask, and hydrochloric acid-1,4-dioxane solution (4 M, 4 mL) was added under the protection of nitrogen gas, and the reaction was carried out at room temperature for 4 h. Ice water (10 mL) was added to quench the reaction, the reaction solution was adjusted to pH = 8 - 9 with aqueous ammonia, extracted with DCM / methanol = 10 / 1, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated to obtain a crude product, which was separated and purified by prep-HPLC (water / acetonitrile, 0.1% NH₃H₂O), and the final product, compound 112 (41.73 mg, yield: 50.03%), was obtained as a white solid. 1 ¹H NMR (400 MHz, DMSO) δ 13.14 (s, 1H), 8.38 (d, J = 5.6 Hz, 2H), 7.73 (s, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.14 (dd, J = 9.2, 2.0 Hz, 1H), 4.20 (s, 3H), 2.53 (m, 2H), 1.64 - 1.51 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H). LCMS (ESI) m / z = 418.1 [M + H] + 。

[0184] Example 14: Synthesis of Compound 122

Chemical formula

[0185] In a 50 mL one-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 the reaction was carried out at 80 °C for 3 h. After filtering the reaction solution, it was purified by Prep-HPLC (H₂O / ACN, 0.1% FA), and after lyophilization, compound 122 (21 mg, yield: 17.4%) was obtained as a white solid. 11H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.39 (s, 1H), 7.69 (d, J = 1.3 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.38 (s, 4H), 7.10 (dd, J = 9.1, 1.9 Hz, 1H), 4.92 (s, 1H), 4.43 (q, J = 6.9 Hz, 2H), 4.20 (s, 3H), 4.12 (t, J = 5.3 Hz, 2H), 3.67 (t, J = 5.1 Hz, 2H), 1.25 (t, J = 7.0 Hz, 3H). LCMS (ESI) m / z = 464.05 [M + H] + 。

[0186] Compounds 134, 136, 138, and 140 were prepared by the synthetic method of Example 14.

Table 8

[0187] Example 15: Synthesis of Compounds 109 and 121

Chem.

[0188] 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 in an ice bath, and after stirring for 10 min, iodomethane (48 mg, 0.34 mmol) was added, and stirring was 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, concentrated to obtain a crude product, purified by prep-HPLC (water / acetonitrile, 0.1% FA), and freeze-dried to obtain 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.

[0189] Compound 109: 11H NMR (400 MHz, DMSO) δ 8.68 (s, 1H), 8.60 (s, 1H), 8.23 (dd, J = 8.8, 0.8 Hz, 1H), 7.41 - 7.35 (m, 4H), 7.25 (d, J = 8.9 Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 4.26 (s, 3H), 3.83 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H). LCMS (ESI) m / z = 435.1 [M+H] + 。

[0190] Compound 121: 1 1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.19 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.41 - 7.35 (m, 4H), 4.51 (q, J = 6.8 Hz, 2H), 4.28 (s, 3H), 2.97 (s, 3H), 1.26 (t, J = 6.8 Hz, 3H). LCMS (ESI) m / z = 435.1 [M+H] + 。

[0191] Example 16: Synthesis of Compound 130

Chemical Structure

[0192] Step 1: Synthesis of Intermediate 2-130 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 sequentially added to a 100 mL single-neck flask. The mixture was reacted overnight at 110 °C under N2 protection. The reaction solution was filtered, and the filter cake was washed with DCM. The filtrates were combined and concentrated to obtain a crude product, which was purified by silica gel Flash column (0 - 2% methanol / DCM) to obtain Intermediate 2 - 130 (3.0 g, yield: 94.1%) as a pale yellow solid. LCMS (ESI) m / z = 550.1 [M+H] + 。

[0193] Step 2: Synthesis of Intermediate 3-130 Intermediate 2-130 (550 mg, 1.0 mmol), sodium ethanethiolate (84 mg, 10 mmol), and 1,4-dioxane (25 mL) were successively placed into a 50 mL three-necked flask, and reacted at 70 °C for 16 h under N2 protection. The reaction solution was poured into water (50 mL), extracted with EA, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to obtain a crude product, and purified by silica gel column chromatography (0 - 2% methanol / DCM) to obtain Intermediate 3-130 (350 mg, yield: 61.8%) as a pale yellow solid. LCMS (ESI) m / z = 566.2 [M+H] + 。

[0194] Step 3: Synthesis of Compound 130 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 reacted at room temperature for 4 h. The reaction solution was poured into ice water (50 mL), the pH was adjusted to 9 - 10 with aqueous ammonia, stirred at room temperature for 1 h, extracted with EA, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to obtain a crude product, and purified by prep-HPLC (water / acetonitrile, 0.1% NH3H2O) to obtain the final product, Compound 130 (33.90 mg, yield: 12.7%) as a white solid. 1 HNMR (400 MHz, DMSO) δ 13.25 (s, 1H), 8.40 (s, 2H), 7.75 (s, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.34 - 7.26 (m, 2H), 7.15 (dd, J1 = 9.2 Hz, J2 = 2.0 Hz, 1H), 4.20 (s, 3H), 2.99 (q, J = 7.2 Hz, 2H), 1.12 (t, J = 7.2 Hz, 3H). LCMS (ESI) m / z = 436.1 [M+H] + 。

[0195] Example 17: Synthesis of Compound 55

Chemical formula

[0196] Step 1: Synthesis of Intermediate 2-55 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 carbon was added, and the mixture was stirred at room temperature overnight in a hydrogen gas atmosphere. The reaction solution was filtered, and the filtrate was concentrated to dryness to obtain intermediate 2-55 (8.7 g, yield > 100%, including solvent) as a purple solid. 1 H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 7.09 (s, 1H), 4.78 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H).

[0197] Step 2: Synthesis of Intermediate 3-55 In a 500 mL single-necked flask, intermediate 2-55 (8.66 g, 55.9 mmol) was dissolved in THF (200 mL), cooled to 0 °C in an ice bath, DIPEA (14.42 g, 111.8 mmol) was added, and then SEMCl (10.27 g, 61.49 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight, SEMCl (5 g, 30 mmol) was added, and after the addition was complete, the mixture was stirred at room temperature for 16 h. The reaction solution was poured into water, extracted with EA, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 16.3 g of the crude product of intermediate 3-55 as a pale yellow oil, which did not need to be purified and was directly used in the next step. LCMS (ESI) m / z = 285.9 [M + H] + 。

[0198] Step 3: Synthesis of Intermediate 4-55 In a 500 mL single-neck flask, intermediate 3-55 (16.16 g, 56.7 mmol) was dissolved in ethanol (250 mL), diethyl malonate (54.4 g, 340 mmol) and an ethanol solution of 20% sodium ethoxide (115.7 g, 340 mmol) were added. After the addition was completed, the mixture was refluxed at 85 °C for 18 h. The reaction solution was concentrated under reduced pressure, water was added, extracted with EA, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 8 g of a crude product of intermediate 4-55 as a yellow oil, which did not need to be purified and was directly used in the next step. LCMS (ESI) m / z = 354.1 [M+H] + 。

[0199] Step 4: Synthesis of Intermediate 5-55 In a 250 mL single-neck flask, intermediate 4-55 (7.5 g, 21.22 mmol) was added to a 15% NaOH solution, the temperature was raised to 105 °C, and the mixture was refluxed for 6 h. The pH of the reaction solution was adjusted to about 4 with 2 M hydrochloric acid, a solid was precipitated, filtered, and intermediate 5-55 (6.1 g, yield: 95.31%) was obtained as a yellow solid. LCMS (ESI) m / z = 282.10 [M+H] + 。

[0200] Step 5: Synthesis of Intermediate 6-55 In a 100 mL single-neck 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, iodoethane (3.66 g, 23.45 mmol) was added dropwise. After the addition was completed, the temperature was raised to 40 °C and stirred for 3 h. The reaction solution was poured into water, extracted with EA, the organic phase was washed with water and then with saturated brine, dried, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel Flash (DCM / MeOH = 96 / 4) to obtain intermediate 6-55 (1 g, yield: 27.55%) as a white solid. LCMS (ESI) m / z = 310.15 [M+H] + 。

[0201] Step 6: Synthesis of Intermediate 7-55 To a 100 mL single-necked flask, intermediate 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 reaction was carried out at 110 °C for 16 h under N2 protection. The reaction solution was concentrated, and the crude product was purified by silica gel Flash column (DCM / MeOH = 96 / 4) to obtain intermediate 7-55 (1.2 g, yield: 80.54%) as a black oily substance. LCMS (ESI) m / z = 440.15 [M+H] + 。

[0202] Step 7: Synthesis of Intermediate 8-55 In a 25 mL single-necked flask, intermediate 7-55 (1.2 g, 2.72 mmol) was dissolved in THF. After dissolution, NBS (437 mg, 2.46 mmol) was added in one batch, and the reaction was carried out at room temperature for 10 h. The reaction solution was poured into an aqueous sodium sulfite solution and extracted with DCM. The organic phase was concentrated and purified by 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] + 。

[0203] Step 8: Synthesis of Intermediate 9-55 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 sequentially added to a 50 mL single-necked flask. The reaction was carried out at 100 °C for 16 h under N2 protection. It was filtered, the filtrate was concentrated, and purified by 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] + 。

[0204] Step 9: Synthesis of Compound 55 In a 25 mL single-neck flask, intermediate 9-55 (150 mg, 0.27 mmol) was dissolved in TBAF (10 mL), heated to 60 °C, and refluxed for 1 h. The reaction solution was concentrated, TBAF was removed with water, extracted with EA, the organic phase was concentrated, purified by Prep-HPLC (water / acetonitrile, 0.1% FA), and freeze-dried to obtain compound 55 (77.75 mg, yield: 68.2%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 13.71 (s, 1H), 8.43 (s, 1H), 7.79 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.47 - 7.34 (m, 5H), 7.18 (dd, J = 9.1, 2.0 Hz, 1H), 4.81 (s, 2H), 4.21 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H). LCMS (ESI) m / z = 420.05 [M + H] + 。

[0205] Example 18: Synthesis of Compound 56

Chemical formula

[0206] In a 25 mL single-neck flask, compound 55 (50 mg, 0.12 mmol) was dissolved in acetone (3 mL), Cs2CO3 (78 mg, 0.24 mmol) was added, then CH3I (34 mg, 0.24 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was filtered, concentrated, purified by Prep-HPLC (water / acetonitrile, 0.1% TFA), and freeze-dried to obtain compound 56 (13.40 mg, yield: 25.8%) as a white solid. 11H NMR (400 MHz, DMSO) δ 8.43 (s, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.71 (d, J = 9.1 Hz, 1H), 7.46 (s, 1H), 7.43 - 7.36 (m, 4H), 7.17 (dd, J = 9.1, 2.0 Hz, 1H), 4.78 (q, J = 7.0 Hz, 2H), 4.21 (s, 3H), 3.94 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H). LCMS (ESI) m / z = 434.05 [M + H] + 。

[0207] Example 19: Synthesis of Compound 100

Chemical Structure

[0208] Step 1: Synthesis of Intermediate 2-100 Ethyl 4-nitropyrazole-5-carboxylate 1-55 (5.0 g, 27.0 mmol) was dissolved in 50 mL of DCM in a 100 mL one-neck flask, and Me3OBF4 (6.0 g, 40.5 mmol) was slowly added, and the reaction was carried out at room temperature for 3 h. The reaction solution was concentrated, and the crude product was purified by silica gel Flash column (0 - 1% methanol / DCM) to obtain Intermediate 2-100 (2.5 g, yield: 47%) as a pale yellow liquid. LCMS (ESI) m / z = 200.1 [M + H] + 。

[0209] Step 2: Synthesis of Intermediate 3-100 In a 50 mL one-neck flask, Intermediate 2-100 (2.5 g, 12.56 mmol) was dissolved in 30 mL of ethanol, Pd / C (0.5 g) was added, and the reaction was carried out at room temperature overnight in a hydrogen gas atmosphere. Pd / C was filtered off with celite, and the filtrate was concentrated to obtain Intermediate 3-100 (2.2 g, yield: 103%) as a yellow liquid. LCMS (ESI) m / z = 170.1 [M + H] + 。

[0210] Step 3: Synthesis of Intermediate 4-100 In a 250 mL single-neck flask, the intermediate 3-100 (2.2 g, 13.0 mmol) was dissolved in 100 mL of ethanol, and diethyl malonate (6.25 g, 39.0 mmol) and NaOEt (20% EtOH, 4.42 g, 39.0 mmol) were added in sequence. The temperature was raised to 80 °C and reacted overnight. After concentrating the reaction solution, it was dissolved in EA (20 mL), 50 mL of HCl (dioxane) was added, stirred for 1 h, filtered, and the solid was collected to obtain the intermediate 4-100 (3.0 g, yield: 97%) as a yellow solid. LCMS (ESI) m / z = 238.2 [M+H] + 。

[0211] Step 4: Synthesis of Intermediate 5-100 In a 100 mL single-neck flask, the intermediate 4-100 was dissolved in 30 mL of 15% aqueous NaOH solution, the temperature was raised to 100 °C and reacted overnight. Water was added for dilution, the pH was adjusted to 3-4 with dilute hydrochloric acid, a white solid was precipitated, filtered, and the white solid was collected to obtain the intermediate 5-100 (1.2 g, yield: 57%) as a white solid. LCMS (ESI) m / z = 166.2 [M+H] + 。

[0212] Step 5: Synthesis of Intermediate 6-100 In a 100 mL single-neck flask, the 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 solution was poured into water, extracted with EA, the organic phase was washed with water and saturated brine, concentrated, and the crude product was purified by silica gel Flash column (0-2% methanol / DCM) to obtain the intermediate 6-100 (300 mg, yield: 26%) as a white solid. LCMS (ESI) m / z = 194.2 [M+H] + 。

[0213] Step 6: Synthesis of Intermediate 7-100 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), DMSO (10 ml) were successively added to a 50 mL single-neck flask and reacted at 110 °C overnight under N2 protection. The reaction solution was concentrated to dryness, and the crude product was purified by silica gel Flash column (0 - 3% methanol / DCM) to obtain Intermediate 7-100 (300 mg, yield: 60%) as a pale yellow solid. LCMS (ESI) m / z = 324.0 [M+H] + .

[0214] Step 7: Synthesis of Intermediate 8-100 The reaction was carried out in a 25 mL single-neck flask. Intermediate 7-100 (300 mg, 0.99 mmol) was dissolved in 10 mL of DCM, NBS (211 mg, 1.19 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated to dryness and purified by 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] + .

[0215] Step 8: Synthesis of Compound 100 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), water (1 ml) were successively added to a 25 mL single-neck flask and reacted at 100 °C for 16 h under N2 protection. The reaction solution was concentrated, and the crude product was purified by silica gel Flash column (0 - 2% methanol / DCM) to obtain a crude product, which 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. 11H NMR (400 MHz, DMSO) δ 8.44 (s, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.53 - 7.44 (m, 4H), 7.17 (dd, J = 9.2, 2.0 Hz, 1H), 7.06 (s, 1H), 4.21 (s, 3H), 4.14 (s, 3H), 3.69 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H). LCMS (ESI) m / z = 434.2 [M + H] + 。

[0216] Test Example 1, Biochemical Test Test Principle: MAT2A can convert L-methionine and ATP into SAM, inorganic phosphate, and inorganic diphosphate using them as catalysts. By adding a chromogenic agent to the enzyme reaction system, the content of inorganic phosphate in the sample can be quantitatively detected, and further the enzyme activity of MAT2A can be characterized.

[0217] 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)

[0218] Test Method: 1. 1x Assay buffer (buffer composition: Tris, KCl, MgCl2, BSA, Brij35, and EDTA, solvent is ultrapure water) was prepared. Using 1x Assay buffer, an MAT2A his-tag enzyme solution (containing 1.3 μL of MAT2A enzyme and 998.7 μL of 1x Assay buffer per 1000 μL) and a substrate mixed solution (containing 5 μL of ATP, 1.3 μL of L-methionine, and 993.7 μL of 1x Assay buffer per 1000 μL) were prepared respectively.

[0219] 2. Preparation of Compound Concentration Gradient For the test on the test compound, the starting concentration was 10 μM, and 10 equi - ratio concentrations were set according to 3 - fold dilution. Specifically, first, a series of solutions with 10 different concentrations (the final detection concentrations of the compound were 10, 3.33, 1.11, 0.37, 0.123, 0.041, 0.0137, 0.0046, 0.0015, and 0.0005 μM) were serially diluted in a 384 - well plate. Next, 250 nL of each of the above - mentioned series of solutions was transferred to a 384 - well reaction plate using an acoustic droplet ejection system Echo550 to make preparations. 250 nL of 100% DMSO was added to the negative control well and the positive control well respectively. Duplicate well tests were conducted.

[0220] 3. 15 μL of MAT2A his - tag enzyme solution was added to each of the compound well and the positive control well, and 15 μL of 1x Assay buffer was added to the negative control well.

[0221] 4. The reaction plate of the above - mentioned 384 - well plate was centrifuged at 1000 rpm for 60 seconds, shaken to mix uniformly, and then incubated for 15 minutes. 10 μL of substrate mixed solution was added to each of all the experimental wells of the 384 - well reaction plate to start the reaction.

[0222] 5. The reaction plate of the above - mentioned 384 - well plate was centrifuged at 1000 rpm for 60 seconds, shaken to mix uniformly, and then incubated for 150 minutes.

[0223] 6. 50 μL of enzyme reaction stop solution Biomol was added to all the experimental wells of the 384 - well reaction plate to stop the reaction. After centrifuging at 1000 rpm for 60 seconds, it was incubated for 15 minutes. OD620 was read and the data was processed.

[0224] Data Analysis: Calculate the compound inhibition rate (%), fit it to obtain the IC of the test compound 50was obtained. Calculation method of compound inhibition rate: Compound inhibition rate (%) = (OD620_max - OD620_sample) / (OD620_max - OD620_min) × 100, where OD620_sample is the absorbance value of the sample well, OD620_min is the absorbance value of the positive control well, representing the reading of the well without enzyme activity, and OD620_max is the absorbance value of the negative control well, representing the reading of the well without compound inhibition.

[0225] Test results: Under the test conditions, the inhibitory effect of the compound to be measured on MAT2A enzyme activity can be represented by the IC value of the inhibition of the phosphate generation level in the enzyme reaction process. The MAT2A inhibitory activity of the compound to be measured is specifically shown in Table 9. From the results, taking Compound 1 with a similar structure as a control, it was shown that the compound of the present invention has a significant MAT2A enzyme inhibitory effect. 50 value. The MAT2A inhibitory activity of the compound to be measured is specifically shown in Table 9. From the results, taking Compound 1 with a similar structure as a control, it was shown that the compound of the present invention has a significant MAT2A enzyme inhibitory effect.

[0226] Table 9. Inhibitory effect on MAT2A enzyme activity

Table 9

[0227] Test Example 2, Human Pancreatic Cancer KP-4 Cell Activity Inhibition Test Test principle: After incubating the MAT2A inhibitor to be measured and KP-4 cells together for a certain period of time, the method for measuring cell activity based on the ATP content was used to characterize the effect of the compound to be measured on cell activity.

[0228] Test 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 plate (Corning#3610), CellTiter-Glo (Promega#G7571)

[0229] Test method: 1. KP-4 cells were cultured in IMDM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin in a cell incubator at 37°C and 5% CO2, and the cells in the logarithmic growth phase were used for subsequent tests.

[0230] 2. The cells in the logarithmic growth phase were inoculated into a 96-well plate at a seeding density of 500 cells per well and cultured overnight in a cell incubator at 37°C and 5% CO2.

[0231] 3. The compound was dissolved in DMSO and diluted to 10 different concentrations (about 10000, 3333.3, 1111.1, 370, 123, 41.2, 13.7, 4.6, 1.5 and 0.5 nM) with the medium, and then added to the cell plate and continuously cultured at 37°C and 5% CO2 for 5 days.

[0232] 4. CellTiter-Glo reagent was added, and cell viability was detected using a microplate reader.

[0233] Data analysis: Calculate the compound inhibition rate (%), fit to obtain the IC of the test compound 50was obtained. Calculation method of compound inhibition rate: Compound inhibition rate (%) = (Signal_max - Signal_sample) / (Signal_max - Signal_min) × 100, where Signal_sample is the reading number of the sample well, representing the cell activity of the compound inhibition well, Signal_min is the reading number of the positive control well, representing no cell background activity, and Signal_max is the reading number of the negative control well, representing no cell activity in the compound inhibition well.

[0234] Test results: Under the test conditions, the IC of the inhibition of the compound to be measured against KP-4 cell activity 50 value is shown in Table 10. From the results, it was shown that the typical compounds of the present invention have significant antitumor activity compared with Compound 1.

[0235] Table 10. Inhibitory test of human pancreatic cancer KP-4 cell activity

Table 10

[0236] Test Example 3, Study on the in vivo antitumor efficacy of Compound 13 Using a subcutaneous xenograft tumor model of human B cell lymphoma DOHH-2 cells, the in vivo antitumor efficacy of Compound 13 and AG-270 (MAT2A inhibitor,

Chemical formula

[0237] The female CB-17 SCID mice used were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Tumor cell culture and subcutaneous inoculation: Human B cell lymphoma DOHH-2 cells (DSMZ) were cultured in vitro in RPMI-1640 medium containing 10% fetal bovine serum and 1% double antibody, and cultured in an incubator at 37°C and 5% CO2. When the number of cells meets the requirements, the cells are collected, counted, and 0.2 mL (10×10 6(xxx) DOHH-2 cells (with Matrigel added, volume ratio 1:1) were subcutaneously inoculated into the right back of each mouse, and when the average tumor volume reached 100 - 150 mm 3 they were randomly grouped (5 mice in each group). The treatment groups (Compound 13 or Compound AG-270) were administered intragastrically twice a day (see Table 11 for dosage), and the negative control group was administered the same volume of blank solvent intragastrically every day.

[0238] Experimental indicators and data analysis The experimental indicators were to investigate whether tumor growth was inhibited, delayed, or cured. The tumor diameter was measured twice a week with calipers. The formula for calculating tumor volume was V = 0.5a × b 2 where a and b represent the major axis and minor axis of the tumor respectively.

[0239] The tumor inhibitory effect of the compound was evaluated by TGI (%) or relative tumor growth rate T / C (%).

[0240] TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [(1 - (average tumor volume at the end of treatment in the treatment group - average tumor volume at the start of treatment in the treatment group)) / (average tumor volume at the end of treatment in the negative control group - average tumor volume at the start of treatment in the negative control group)] × 100%.

[0241] Relative tumor growth rate T / C (%): Calculation formula: T / C% = TRTV / CRTV × 100% (TRTV: RTV of the treatment group, CRTV: RTV of the negative control group). The calculation formula for relative tumor volume (RTV) is RTV = Vt / V0, where V0 is the average tumor volume measured at the time of grouping and dosing (i.e., d0), Vt is the average tumor volume at a certain measurement time, and TRTV and CRTV were taken from data on the same day.

[0242] Experimental results: The TGI and T / C of each group calculated based on the tumor volume increase curve were as shown in Table 11, and from the results, Compound 13 of the present invention showed dose-dependent in vivo efficacy.

[0243] Table 11. Evaluation of the antitumor efficacy of Compound 13 against a human B-cell lymphoma DOHH-2 xenograft tumor model [Table 11]

Claims

1. A bicyclic ring system compound represented by formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof. 【Chemical 1】 (wherein R １ is selected from halogen, C １ to C ６ alkyl group, C ２ to C ６ alkenyl group, C ２ to C ６ alkynyl group, C １ to C ６ alkylsulfonyl group, C ３ to C ７ cycloalkyl group, 3- to 6-membered heterocycloalkyl group, cyano group, nitro group, carboxyl group, -NR ａ R ａ２ , -NHCOR ａ , -OR ａ , -SR ａ and is optionally substituted with one or more substituents selected from unsubstituted or D, halogen, and the C １ to C ６ alkyl group, C ２ to C ６ alkenyl group, C ２ to C ６ alkynyl group, C ３ to C ７ cycloalkyl group, 3- to 6-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from unsubstituted or D, halogen, R ａ and R ａ２ are each independently H, C １ to C １０ alkyl group, C ３ to C １０ cycloalkyl group, C ６ to C １０ aryl group, 5- to 10-membered heteroaryl group, 3- to 6-membered heterocycloalkyl group, one or more substituents selected from Group A-substituted C １ to C １０ alkyl group, one or more substituents selected from Group A-substituted C ３ to C １０ cycloalkyl group, the substituents of Group A are D, halogen, C １ to C ３ alkoxy group, hydroxy group, C ６ to C １０ aryl group, 5- to 10-membered heteroaryl group, unsubstituted or one or more substituents selected from Group A2-substituted C ３ to C １０ cycloalkyl group, the substituents of Group A2 include D, halogen, hydroxyl group, C １ to C ６ alkyl group, C １ to C １０ alkoxy group, and R ２ 、R ３ is, independently of each other, unsubstituted or substituted C ３ - C １０ cycloalkyl group, unsubstituted or substituted C ６ - C １０ aryl group, unsubstituted or substituted 4-6 membered heterocycloalkyl group, unsubstituted or substituted 5-10 membered heteroaryl group, and the said substitution means being substituted with one or more substituents selected from Group B, and the substituents of Group B are halogen, cyano group (-CN), hydroxy group (-OH), oxo group (=O), mercapto group (-SH), amino group (-NH ２ ), nitro group (-NO ２ ), 4-6 membered heterocycloalkyl group, C １ - C ４ alkyl group which is unsubstituted or substituted with one or more substituents selected from Group C, unsubstituted or halogen-substituted C ３ - C ７ cycloalkyl group, unsubstituted or halogen-substituted C １ - C ４ alkoxy group, -COOH, -CONHR ｂ , -NHCOR ｂ , -NHSO ２ R ｂ and the substituents of Group C include D, halogen, hydroxyl group, C ３ - C ６ cycloalkyl group, 4-6 membered heterocycloalkyl group, C １ - C ４ alkoxy group, R ｂ is selected from H, C １ to C ４ alkyl group, C ３ to C １０ cycloalkyl group, C １ to C １０ alkoxy group, C ６ to C １０ aryl group, and the C ｂ in the said R １ to C ４ alkyl group, C ３ to C １０ cycloalkyl group, C １ to C １０ alkoxy group, C ６ to C １０ aryl group is unsubstituted or substituted with one or more selected from halogen, hydroxy group, cyano group, Ring A is a 5-membered heteroaromatic ring, and at most one of X, Y, and Z is CR ４ wherein the remainder are each independently selected from N, NR ５ , O, and S R ４ 、R ５ each independently represents H, D, a halogen, an amino group, C １ to C ６ alkyl group, C ３ to C ６ cycloalkyl group, and the C １ to C ６ alkyl group, C ３ to C ６ cycloalkyl group is unsubstituted or substituted with a hydroxy group.)

2. R １ is selected from C １ to C ６ alkyl group, C ３ to C ７ cycloalkyl group, 3- to 6-membered heterocycloalkyl group, -OR ａ -SR ａ NR ａ R ａ２ and the C １ to C ６ alkyl group, C ３ to C ７ cycloalkyl group, 3- to 6-membered heterocycloalkyl group are unsubstituted or substituted with one or more substituents selected from D and halogen, and R ａ , R ａ２ are each independently selected from H, C ３ to C ７ cycloalkyl group, C １ to C ６ alkyl group which is unsubstituted or substituted with one or more substituents selected from group A, and the substituents in group A are D, halogen, C １ to C ３ alkoxy group, hydroxy group, C ６ to C １０ aryl group, 5- to 10-membered heteroaryl group, C ３ to C １０ cycloalkyl group which is unsubstituted or substituted with one or more substituents selected from group A2, and the substituents in group A2 include D, halogen, hydroxyl group, C １ to C ６ alkyl group, C １ to C ６ alkoxy group, R ２ and R ３ are each independently an unsubstituted or substituted C ３ -C １０ cycloalkyl group, an unsubstituted or substituted C ６ -C １０ aryl group, an unsubstituted or substituted 5- to 10-membered heteroaryl group, where the substitution means being substituted with one or more substituents selected from Group B, and the substituents in Group B are halogen, cyano group, hydroxy group, mercapto group, nitro group, amino group, oxo group, an unsubstituted or substituted 4- to 6-membered heterocycloalkyl group, an unsubstituted C １ -C ４ alkyl group substituted with one or more substituents selected from Group C, an unsubstituted or halogen-substituted C ３ -C ７ cycloalkyl group, an unsubstituted or halogen-substituted C １ -C ４ alkoxy group, and the substituents in Group C include D, halogen, hydroxy group, C ３ -C ６ cycloalkyl group, 4- to 6-membered heterocycloalkyl group, C １ -C ４ alkoxy group, and in particular, the 5- to 10-membered heteroaryl group is a benzo 5-membered heteroaryl group, a benzo 6-membered heteroaryl group, a 6-membered heteroaryl 5-membered heteroaryl group, a 6-membered heteroaryl 6-membered heteroaryl group 【Chemical 2】 The bicyclic ring system compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof, selected from

3. R １ is selected from C ２ to C ６ alkyl groups, C ３ to C ６ cycloalkyl groups, -OR ａ , -SR ａ , NR ａ R ａ２ and is selected from the group consisting of, wherein the C ２ to C ６ alkyl groups, C ３ to C ６ cycloalkyl groups are unsubstituted or substituted with one or more substituents selected from D and halogen, and R ａ , R ａ２ are each independently selected from H, C ３ to C ６ cycloalkyl groups, C ２ to C ６ alkyl groups which are unsubstituted or substituted with one or more substituents selected from Group A, and the substituents in Group A include D, halogen, methoxy group, hydroxy group, C ３ to C ６ cycloalkyl groups, R ２ and R ３ are each independently selected from an unsubstituted or substituted cyclohexyl group, an unsubstituted or substituted phenyl group, and an unsubstituted or substituted 5- to 10-membered heteroaryl group, and the 5- to 10-membered heteroaryl group is 【Chemical 3】 selected from the structure, the substitution in the unsubstituted or substituted phenyl group, unsubstituted or substituted 5- to 10-membered heteroaryl group means being substituted with one or more substituents selected from Group B, and the substituents in Group B are halogen, cyano group, hydroxy group, mercapto group, nitro group, amino group, 4- to 6-membered heterocycloalkyl group, C which is unsubstituted or substituted with one or more substituents selected from Group C １ -C ４ alkyl group, C which is unsubstituted or substituted with halogen ３ -C ７ cycloalkyl group, C which is unsubstituted or substituted with halogen １ -C ４ including an alkoxy group, and the substituents in Group C are D, halogen, C ３ -C ６ cycloalkyl group, hydroxy group, 4- to 6-membered heterocycloalkyl group, C １ -C ４ including an alkoxy group R ５ is, independently of each other, H, D, C １ to C ３ alkyl group or C ３ to C ６ cycloalkyl group, and the C １ to Calkyl group, C ３ ３ to C ６ cycloalkyl group is unsubstituted or substituted with a hydroxy group, the bicyclic condensed ring system compound according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof.

4. R １ is selected from C ２ to C ６ alkyl group, -OR ａ , NHR ａ and R ａ is selected from C ３ to C ６ cycloalkyl group, C ２ to C ６ alkyl group which is unsubstituted or substituted with one or more substituents selected from Group A, and the substituents in Group A include D, halogen, methoxy group, hydroxy group, C ３ to C ６ cycloalkyl group, R ２ and R ３ are each independently 【Chemical Formula 4】 selected from Here, (R ７ ) ｍ indicates that there are m identical or different R ７ substituents on the ring, m is 1, 2, or 3, and R ６ and R ７ are each independently H, halogen, cyano group, hydroxy group, mercapto group, nitro group, amino group, 4- to 6-membered heterocycloalkyl group, C １ to C ４ alkyl group which is unsubstituted or substituted with one or more substituents selected from group C, C ３ to C ７ cycloalkyl group which is unsubstituted or substituted with halogen, C １ to C ４ alkoxy group which is unsubstituted or substituted with halogen, and the substituents in group C include D, halogen, C ３ to C ６ cycloalkyl group, hydroxy group, 4- to 6-membered heterocycloalkyl group, C １ to C ４ alkoxy group. Preferably, m is 1 or 2, and R ６ and R ７ are each independently H, halogen, cyano group, hydroxy group, mercapto group, nitro group, amino group, 4- to 6-membered heterocycloalkyl group, C １ to C ２ alkyl group which is unsubstituted or substituted with one or more substituents selected from group C, cyclopropyl group which is unsubstituted or substituted with halogen, C １ to C ２ alkoxy group which is unsubstituted or substituted with halogen, and the substituents in group C include D, halogen, C ３ to C ６ cycloalkyl group, hydroxy group, 4- to 6-membered heterocycloalkyl group, C １ to C ４ alkoxy group, and R ５ is, independently of one another, H, a methyl group or a hydroxyethyl group, a bicyclic ring system 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.

5. R １ is selected from C ２ to C ６ alkyl group, -OR ａ -SR ａ NHR ａ and R ａ is selected from C ３ to C ６ cycloalkyl group, unsubstituted C ２ to C ４ alkyl group, C alkyl group substituted with halogen ２ to C ４ alkyl group, C alkyl group substituted with cyclopropyl group ２ to C ４ alkyl group, C alkyl group substituted with methoxy group ２ to C ４ alkyl group, C alkyl group substituted with hydroxy group ２ to C ４ alkyl group, R ２ and R ３ are each independently 【Chemical Formula 5】 selected from Here, m is 1, 2, or 3, and R ６ and R ７ are each independently H, a halogen, a cyano group, a hydroxy group, a mercapto group, a nitro group, an amino group, a 4- to 6-membered heterocycloalkyl group, a C １ to C ４ alkyl group which is unsubstituted or substituted with one or more substituents selected from group C, a C ３ to C ７ cycloalkyl group which is unsubstituted or substituted with a halogen, a C １ to C ４ alkoxy group which is unsubstituted or substituted with a halogen, and the substituents in group C include D, a halogen, a C ３ to C ６ cycloalkyl group, a hydroxy group, a 4- to 6-membered heterocycloalkyl group, a C １ to C ４ alkoxy group, Preferably, R ６ and R ７ are each independently H, halogen, cyano group, hydroxy group, mercapto group, nitro group, amino group, ​ C substituted with no substitution or one or more substituents selected from Group C １ -C ３ alkyl group, cyclopropyl group substituted with no substitution or halogen, C substituted with no substitution or halogen １ -C ２ selected from alkoxy groups, and the substituents in Group C are D, halogen, C ３ -C ６ cycloalkyl group, hydroxy group, methoxy group 【Chemical Formula 7】 comprising Preferably, R １ is a propyl group, -OC ２ H ５ -, -SC ２ H ５ -, -OCH ２ CF ３ -, -NHCH ３ -, -NHC ２ H ５ , 【Chemical 8】 selected from R ２ is [Chemical Formula 9] selected from, m is 1, 2 or 3, R ８ and R ９ are each independently selected from H, halogen, CN, a methoxy group, a methyl group substituted with one or more halogens, a methoxy group substituted with one or more halogens, a cyclopropyl group, and preferably, R ２ is 【Chemical 10】 selected from, R ８ and R ９ are each independently selected from H, halogen, cyano group, methoxy group, methyl group substituted with one or more halogens, methoxy group substituted with one or more halogens, cyclopropyl group R ３ is 【Chemical 11】 selected from, m is 1, 2 or 3, R １０ and R １１ are each independently hydrogen, a methyl group, an ethyl group, an isopropyl group, a cyano group, a methoxy group, an ethyl group substituted with a hydroxy group, an ethyl group substituted with a methoxy group, a cyclopropyl group, 【Chemical 12】 selected from, the bicyclic ring system 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.

6. The bicyclic ring system compound is 【Chemical 13】 selected from the structures Preferably, 【Chemical 14】 selected from the structures Here, R １ , R ２ , R ３ , R ５ is defined as the same as the corresponding claim, a bicyclic ring system 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.

7. The bicyclic ring system compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof, wherein the bicyclic ring system compound is selected from the following structures. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】

8. A pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the bicyclic ring system compounds according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate, isotope-labeled compound thereof, at least one pharmaceutically acceptable carrier, and optionally one or more other therapeutic agents.

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

10. Use of a bicyclic ring system compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotope-labeled compound thereof, or a pharmaceutical composition according to claim 8, in the manufacture of a medicament for treating and / or preventing MTAP-related diseases, especially tumors, Preferably, the tumor includes MTAP-deleted tumors, MTAP-low-expressing tumors, MAT2A-abnormally-expressing tumors, and other MAT2A-dependent tumors, More preferably, breast cancer, lung cancer, glioblastoma, brain and spinal cord cancer, head and neck cancer, skin cancer, genital system cancer, gastrointestinal system cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, heart tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma, midline cancer and cancer of unknown primary origin.

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