Compound as CCR6 antagonist, and pharmaceutical composition and use thereof

Abstract

The present invention provides a compound represented by formula (I), or a racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof. The compound has good CCR6 antagonistic activity, and excellent pharmacokinetic and pharmacodynamic properties.

Description

Compounds as CCR6 antagonists, pharmaceutical compositions and uses thereof

[0001] This application requires the applicant to:

[0002] Priority benefit of the prior application, patent application number 202311457524.9, filed with the State Intellectual Property Office of China on November 3, 2023, entitled “Compounds as CCR6 Antagonists, Pharmaceutical Compositions and Uses Thereof”;

[0003] Priority benefit of the prior application, patent application number 202410716094.6, filed with the State Intellectual Property Office of China on June 4, 2024, entitled “Compounds as CCR6 Antagonists, Pharmaceutical Compositions and Uses Thereof”;

[0004] The entire contents of said prior application are incorporated into the present application by reference. Technical Field

[0005] The present invention relates to the field of medicine, and in particular to CCR6 antagonist compounds, pharmaceutical compositions and uses thereof. Background Art

[0006] Chemokines are a class of cytokines that control directional cell migration, and their function is mediated by chemokine receptors. Gene knockout, antibody blocking, and transgenic techniques have demonstrated that the chemokine system plays a crucial role in pathogen clearance, inflammatory responses, pathogen infection, cell and organ development, wound repair, tumor formation and metastasis, and transplant rejection. Chemokines exert their biological effects by interacting with G protein-coupled transmembrane receptors (i.e., chemokine receptors). Chemokine receptors, the natural ligands for chemokines, are a subfamily of seven transmembrane proteins on the cell surface. Chemokine receptors are divided into four families based on the type of chemokine they bind: CCRs, which bind to CC chemokines; CXCRs, which bind to CXC chemokines; CX3CR1, which binds to a single CX3C chemokine (CX3CL1); and XCR1, which binds to two XC chemokines (XCL1 and XCL2).

[0007] C-C chemokine receptor 6 (CCR6) is expressed on a variety of key immune cells, including immature dendritic cells, B cells, memory T cells (including all Th17 cells), neutrophils, and a subset of Tregs. CCR6 is the only known receptor for the chemokine CCL20, also known as macrophage inflammatory protein 3a (MIP-3a) and liver and activation-regulated chemokine (LARC). CCL20 is produced by synovial cells, colonic epithelial cells, various skin cells (such as keratinocytes and dermal fibroblasts), and alveolar epithelial cells. The ligand-receptor pair CCL20-CCR6 is responsible for the migration of immature dendritic cells and effector / memory T cells to the skin and mucosal surfaces under steady-state and inflammatory conditions, as well as in autoimmune diseases such as psoriasis and inflammatory bowel disease.

[0008] CCL20 is an inducible chemokine that is highly upregulated in the inflammatory lesions of various autoimmune diseases, including allergic lung inflammation, psoriasis, contact hypersensitivity, inflammatory bowel disease, Sjögren's syndrome, juvenile idiopathic arthritis, rheumatoid arthritis, and multiple sclerosis. Studies have shown that CCL20 and CCR6 play an important role in regulating the physiology of the colonic mucosa. In normal colonic mucosa, CCL20 is weakly expressed, but when stimulated by inflammation, CCL20 is significantly upregulated. Compared with normal mucosal tissue, the expression of CCL20 and CCR6 in colorectal cancer (CRC) liver metastasis is significantly upregulated and positively correlated with liver or lung metastasis.

[0009] Inflammatory bowel disease (IBD) is an idiopathic, chronic, and relapsing inflammatory disease of the intestine. Its pathogenesis is highly complex, influenced by the interplay of genetic, environmental, and microbial factors. Clinical manifestations include diarrhea, abdominal pain, and even bloody stools, accompanied by anemia, malnutrition, and fatigue, which severely impact patients' quality of life. Currently marketed medications for IBD primarily include glucocorticoids and monoclonal antibodies such as Remicade, Humira, and Vedolizumab, as well as the small molecule inhibitor Imurax. CCL20 / CCR6 may serve as a new therapeutic target for IBD patients.

[0010] Currently, there are no small molecule antagonists for CCR6 on the market, so the development of small molecule antagonists with good biological activity has positive significance for the treatment of the above diseases.

[0011] Summary of the Invention

[0012] The present invention provides a compound represented by the following formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof:

[0013] R 1is a 5-12 membered heteroaryl, a 3-8 membered heterocycloalkyl, a C 3-5 Cycloalkyl or C 6-8 wherein the 5-12 membered heteroaryl group is optionally substituted by 1, 2, 3 or 4 R 1-1 Substituted, the 3-8 membered heterocycloalkyl and the C 6-8 The cycloalkyl group is optionally substituted by 1, 2, 3 or 4 R 1-2 Substitute, the C 3-5 The cycloalkyl group is optionally substituted by 1, 2, 3 or 4 R 1-3 replace;

[0014] in,

[0015] When R 1 When it is a C5 cycloalkyl group, the C5 cycloalkyl group is substituted by 1, 2, 3 or 4 R 1-3 Replace; when R 1 When it is a C6 cycloalkyl group, the C6 cycloalkyl group is substituted by 1, 2, 3 or 4 R 1-2 replace;

[0016] Each R 1-1 The same or different, independently of each other, are halogen, CN, OH, -COOH, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-5 Cycloalkyl or C 1-6 Deuterated alkyl, the C 1-6 Alkyl and C 3-5 Cycloalkyl is optionally substituted by 1, 2, 3 or 4 groups independently selected from -OH, halogen and C 1-6 substituted by an alkyl substituent;

[0017] Each R 1-2 The same or different, independently of each other, are C 1-6 Alkyl, halogen, C 6-10 Aryl or 5-9 membered heteroaryl, wherein the C 1-6 Alkyl, C 6-10 Aryl and 5-9 membered heteroaryl are optionally substituted by 1, 2, 3 or 4 independently selected C 1-6 Alkyl and halogen substituents, or R on two adjacent carbon atoms 1-2 Together with the carbon atom to which it is attached, it forms a phenyl group;

[0018] Each R 1-3 The same or different, independently of each other, are C 1-6 Alkyl, halogen or 5-9 membered heteroaryl, wherein the C 1-6Alkyl and 5-9 membered heteroaryl are optionally substituted by 1, 2, 3 or 4 independently selected C 1-6 substituted by alkyl and halogen substituents;

[0019] R 2 -C(=O)NR a R b , 5-9 membered heteroaryl, -C(=O)R z 、C 1-6 Alkyl, halogen, cyano, 4-10 membered heterocycloalkyl, C 3-8 Cycloalkyl, -S(=O)2-C 1-6 Alkyl or -S(=NH)-C 1-6 Alkyl, the 5-9 membered heteroaryl, C 1-6 Alkyl, 4-10 membered heterocycloalkyl, C 3-8 Cycloalkyl, -S(=O)2-C 1-6 Alkyl and -S(=NH)-C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R 2-1 replace;

[0020] Each R 2-1 The same or different, independently of each other, are C 1-6 Alkyl, halogen, cyano, oxo (=O) or -OH, the C 1-6 Alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from -OH, halogen and oxo (=O);

[0021] R a and R b Each independently is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-8 membered heteroaryl, C 1-6 Alkoxy or C 1-6 Deuterated alkyl, or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4-10 membered heterocycloalkyl or 5-9 membered heteroaryl group containing one N heteroatom and optionally one or two additional heteroatoms selected from O, N and S; wherein said C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-8 membered heteroaryl, 4-10 membered heterocycloalkyl and 5-9 membered heteroaryl are optionally substituted by 1, 2, 3 or 4 R a-1 replace;

[0022] Each R a-1 The same or different, independently of each other, are H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, -OH, -N(C1-6 Alkyl)(C 1-6 alkyl) or oxo (=O);

[0023] R z C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R z-1 replace;

[0024] Each R z-1 The same or different, independently of each other, are C 1-6 Alkyl, halogen, oxo (=O), cyano, -OH or -N(C 1-3 Alkyl)(C 1-3 alkyl);

[0025] R 3 -OH, halogen, oxo (=O), cyano, C 1-6 Alkyl or C 1-6 Alkoxy.

[0026] According to an embodiment of the present invention, R 3 It is -OH or Cl.

[0027] According to an embodiment of the present invention, R 1 is 8-10 membered heteroaryl, 6 membered heterocycloalkyl, C 3-5 Cycloalkyl or C6 cycloalkyl; the 8-10 membered heteroaryl is optionally replaced by 1, 2, 3 or 4 R 1-1 Substituted; the 6-membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 R 1-2 Substituted; the C6 cycloalkyl is 1, 2, 3 or 4 R 1-2 Substitution; said C 3-5 The cycloalkyl group is optionally substituted by 1, 2, 3 or 4 R 1- 3 Replacement; wherein, when R 1 When it is a C5 cycloalkyl group, the C5 cycloalkyl group is substituted by 1, 2, 3 or 4 R 1-3 Replace, when R 1 When it is a C6 cycloalkyl group, the C6 cycloalkyl group is substituted by 1, 2, 3 or 4 R 1-2 replace.

[0028] According to an embodiment of the present invention, R 1 wherein the 5-12 membered heteroaryl group is an 8-10 membered heteroaryl group; preferably, the 5-12 membered heteroaryl group is selected from:

[0029] According to an embodiment of the present invention, R 1 wherein the 5-12 membered heteroaryl group is selected from:

[0030] According to an embodiment of the present invention, R 1 wherein the 3-8 membered heterocycloalkyl group is a 4-6 membered azacycloalkyl group or a 4-6 membered oxacycloalkyl group; preferably, the 3-8 membered heterocycloalkyl group is a 6 membered azacycloalkyl group; more preferably, the 3-8 membered heterocycloalkyl group is a 3-azabicyclo[3.1.0]hexyl group or a 2-azabicyclo[3.1.0]hexyl group, for example Preferably

[0031] According to an embodiment of the present invention, R 1 In the C 3-5 Cycloalkyl is selected from:

[0032] According to an embodiment of the present invention, R 1 In the C 6-8 The cycloalkyl group is a monocyclic or bicyclic cycloalkyl group; preferably, the C 6-8 Cycloalkyl is selected from cyclohexyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, cycloheptyl, bicyclo[2.2.1]heptyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[3.1.1]heptyl, cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and bicyclo[5.1.0]octyl, for example Preferably

[0033] According to an embodiment of the present invention, each R 1-1 The same or different, independently of each other, are halogen, CN, OH, -COOH, oxo (=O), C 1-6 Alkyl, C 2-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-5 Cycloalkyl or C 1-6 Deuterated alkyl, the C 1-6 Alkyl and C 3-5 Cycloalkyl is optionally substituted by 1, 2, 3 or 4 groups independently selected from -OH, halogen and C 1-6 substituted by an alkyl substituent.

[0034] According to an embodiment of the present invention, R 1-1Halogen, CN, OH, -COOH, oxo (=O), C 1-4 Alkyl or C 3-5 Cycloalkyl, the C 1-4 Alkyl and C 3-5 Cycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from -OH and halogen.

[0035] According to an embodiment of the present invention, R 1-2 C 1-3 Alkyl, halogen or C6 aryl, the C 1-3 Alkyl and C6 aryl are optionally substituted by 1, 2, 3 or 4 independently selected C 1-3 Alkyl and halogen substituents, or R on two adjacent carbon atoms 1-2 Together with the carbon atom to which it is attached, it forms a phenyl group.

[0036] According to an embodiment of the present invention, R 1-3 C 1-3 Alkyl or 5-6 membered heteroaryl, the C 1-3 Alkyl and 5-6 membered heteroaryl are optionally substituted by 1, 2, 3 or 4 independently selected C 1-3 substituted by alkyl and halogen substituents.

[0037] According to an embodiment of the present invention, R 1-1 is F, Cl, Br, CN, methyl, -CH2F, -CHF2, -CF3, CH2OH, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or cyclopropyl.

[0038] According to an embodiment of the present invention, R 1-2 is F, phenyl, or R on two adjacent carbon atoms 1-2 Together with the carbon atom to which it is attached, it forms a phenyl group.

[0039] According to an embodiment of the present invention, R 1-3 is methyl, ethyl, n-propyl, isopropyl, pyrazolyl or pyridinyl; the pyrazolyl and pyridinyl are optionally substituted by 1, 2 or 3 substituents independently selected from F and methyl.

[0040] According to an embodiment of the present invention, R 1-3 Methyl, ethyl, According to an embodiment of the present invention, R 1 for

[0041] According to an embodiment of the present invention, R 2 -C(=O)NR aR b , 5-6 membered heteroaryl, -C(=O)R z 、C 1-6 Alkyl, halogen, cyano, 4-6 membered heterocycloalkyl, C 3-4 Cycloalkyl, -S(=O)2-C 1-6 Alkyl or -S(=NH)-C 1-6 Alkyl, the 5-6 membered heteroaryl, C 1-6 Alkyl, 4-6 membered heterocycloalkyl, C 3-4 Cycloalkyl, -S(=O)2-C 1-6 Alkyl and -S(=NH)-C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R 2-1 Substituted, wherein the R a 、R b 、R z and R 2-1 Each independently has the definition described in any embodiment of the present application.

[0042] According to an embodiment of the present invention, R a and R b Each independently is H, C 1-4 Alkyl, C 3-5 Cycloalkyl, 6-membered heteroaryl or C 1-3 Alkoxy, or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4-8 membered heterocycloalkyl or 6-9 membered heteroaryl group containing one N heteroatom and optionally one or two additional heteroatoms selected from O, N and S, wherein the C 1-4 Alkyl, C 3-5 Cycloalkyl, 6-membered heteroaryl, 4-8-membered heterocycloalkyl and 6-9-membered heteroaryl are optionally substituted by 1, 2, 3 or 4 R a-1 Substituted, where R a-1 It has the definition described in any scheme of this application.

[0043] According to an embodiment of the present invention, R z C 1-4 Alkyl, C 3-5 Cycloalkyl, 5-9 membered heteroaryl or 4-8 membered heterocycloalkyl, wherein the C 3-5 Cycloalkyl, 5-9 membered heteroaryl and 4-8 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R z-1 Substituted, where R z-1 It has the definition described in any scheme of this application.

[0044] According to an embodiment of the present invention, R a H, C 1-4 Alkyl or C 3-5Cycloalkyl, the C 1-4 Alkyl and C 3-5 The cycloalkyl group is optionally substituted by 1, 2, 3 or 4 R a-1 replace.

[0045] According to an embodiment of the present invention, R b C 1-4 Alkyl, C 3-5 Cycloalkyl, 6-membered heteroaryl or C 1-3 Alkoxy, the C 1-4 Alkyl, C 3-5 Cycloalkyl and 6-membered heteroaryl are optionally substituted by 1, 2, 3 or 4 R a-1 replace.

[0046] According to an embodiment of the present invention, the R a For H, methyl, ethyl, or cyclopropyl.

[0047] According to an embodiment of the present invention, the R b is methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, pyridyl,

[0048] According to an embodiment of the present invention, the R a and R b together with the nitrogen atom to which it is attached, form a tetrahydropyrrolyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, diazabicyclo[3.2.1]octanyl, oxazaspiro[3.3]heptyl or isoindolinyl group; said tetrahydropyrrolyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, diazabicyclo[3.2.1]octanyl, oxazaspiro[3.3]heptyl and isoindolinyl group being optionally substituted by 1, 2, 3 or 4 R a-1 replace.

[0049] According to an embodiment of the present invention, R 2 wherein the 5-6 membered heteroaryl group is pyridyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl or isothiazolyl.

[0050] According to an embodiment of the present invention, R 2 wherein the 4-6 membered heterocycloalkyl group is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, tetrahydropyrrolyl or morpholinyl.

[0051] According to an embodiment of the present invention, R 2 In the C 3-4 Cycloalkyl is cyclopropyl.

[0052] According to an embodiment of the present invention, R zwherein the 5-9 membered heteroaryl group is isoindolinyl, pyridyl or isoxazolyl.

[0053] According to an embodiment of the present invention, R z wherein the 4-8 membered heterocycloalkyl group is tetrahydropyrrolyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, diazabicyclo[3.2.1]octanyl, oxazaspiro[3.3]heptyl or tetrahydropyranyl.

[0054] According to an embodiment of the present invention, R z In the C 3-5 Cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl.

[0055] According to an embodiment of the present invention, each R 2-1 are the same or different and are independently H, methyl, F, oxo (=O), cyano or

[0056] According to an embodiment of the present invention, each R a-1 The same or different, independently of one another, are H, methyl, ethyl, F, -N(CH3)(CH3), -CH2F, -CHF2, -CF3 or -OCH3.

[0057] According to an embodiment of the present invention, each R z-1 are the same or different and are independently H, methyl, ethyl, F, cyano or -N(CH3)(CH3).

[0058] According to an embodiment of the present invention, R 2 for

[0059] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by the following formula (Ia) or (Ib):

[0060] Among them, R 1 、R 2 、R 3 It has the definition described in any scheme of this application.

[0061] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (II), (II-a) or (II-b):

[0062] in,

[0063] Ring A, i.e. C 5-7 Cycloalkyl, 5-7 membered heterocycloalkyl or phenyl;

[0064] Ring B, i.e. is a 5-6 membered heteroaryl, a 5 membered heterocycloalkyl or a phenyl group;

[0065] X and Y are each independently C, CH or N;

[0066] R 1-1 and R 2 It has the definition described in any embodiment of the present application, and s is 0, 1, 2 or 3.

[0067] According to an embodiment of the present invention, the ring A, namely is cyclohexyl, cyclopentyl, cycloheptyl, tetrahydrofuranyl, phenyl, tetrahydropyrrolyl, piperidinyl or 4-azaspiro[2.4]heptanyl;

[0068] According to an embodiment of the present invention, the ring B, namely is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, phenyl, isothiazolyl, furanyl, tetrahydrofuranyl, thienyl or pyridyl.

[0069] According to an embodiment of the present invention, the for

[0070] According to an embodiment of the present invention, the Selected from:

[0071] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (III) or (IV):

[0072] Among them, ring A, ring B, X, Y, R 1-1 、R a 、R b and R z It has the definition described in any embodiment of the present application, and s is 0, 1, 2 or 3.

[0073] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by the following formula (I-1):

[0074] Among them, ring A, ring B, X, Y, R 1-1 and s have the definitions given in any scheme of this application.

[0075] According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown below:

[0076] According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown below:

[0077] According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown below:

[0078] The present invention also provides a method for preparing the compound represented by formula (I), comprising the following steps:

[0079] Compound 1 reacts with compound 2 to obtain a compound represented by formula (I);

[0080] Wherein, R1, R2 and R3 each independently have the definition described in any scheme of this application, R 0 C 1-6 alkyl.

[0081] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) of the present invention, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salts thereof.

[0082] In some embodiments, the pharmaceutical composition of the present invention further comprises a therapeutically effective amount of the compound of formula (I) of the present invention, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

[0083] The carrier in the pharmaceutical composition is "pharmaceutically acceptable" in that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and is not deleterious to the subject being treated. One or more pharmaceutical excipients can be used to deliver the active compound.

[0084] According to the present invention, the pharmaceutical composition of the present invention can be prepared into a dosage form suitable for administration by methods known in the art.

[0085] The present invention further provides the use of the compound represented by formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of drugs.

[0086] According to some embodiments, the medicament is a medicament for diagnosing, preventing and / or treating a disease or disorder mediated by the CCR6 receptor.

[0087] According to some embodiments, the drug is a CCR6 antagonist.

[0088] According to some embodiments, the disease or disorder is an allergic disease, psoriasis, contact hypersensitivity, Sjögren's syndrome, dry eyes, or multiple sclerosis.

[0089] According to some embodiments, the disease or disorder is rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, systemic onset rheumatoid arthritis, oligoarticular rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile idiopathic arthritis (JIA), juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, giant cell arteritis, or secondary osteoarthritis due to inflammatory disease.

[0090] According to some embodiments, the disease or disorder is inflammatory bowel disease (IBD), Crohn's disease, or ulcerative colitis.

[0091] The present invention also provides a method for diagnosing, preventing and / or treating a disease or condition mediated by the CCR6 receptor, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present invention alone, or optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0092] According to the present invention, the disease or disorder is an allergic disease, psoriasis, contact hypersensitivity, Sjögren's syndrome, dry eye or multiple sclerosis.

[0093] According to the present invention, the disease or condition is rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, systemic onset rheumatoid arthritis, oligoarticular rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile idiopathic arthritis (JIA), juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, giant cell arteritis or secondary osteoarthritis caused by inflammatory disease.

[0094] According to the present invention, the disease or disorder is inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis.

[0095] The compounds of the present invention may be used in combination with additional therapeutic agents. Beneficial effects

[0096] The present invention provides a class of CCR6 antagonist compounds represented by formula (I), which have good CCR6 antagonist activity, as well as excellent pharmacokinetic and pharmacodynamic properties.

[0097] Definitions and Explanations of Terms

[0098] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0099] The "room temperature" and "ambient temperature" described in this specification should be understood as the ambient temperature when the experiment is performed, for example, 10-35°C, preferably 25°C±5°C.

[0100] The term "overnight" as used herein refers to a reaction time of 10-16 hours, preferably 12 hours.

[0101] The term "optional" (or "optionally", "optionally") in the general formula definitions of this application means the case of being substituted by 0, 1 or more substituents, for example, "optionally substituted by 1, 2 or more R" means that it may not be substituted by R (unsubstituted) or may be optionally substituted by 1, 2 or more R.

[0102] The term "C n-m ” and “C n -C m ", where n and m are integers, represents a group containing n to m carbon atoms. Examples include C 1-6 、C 1-3 etc. The term is intended to specifically disclose each member within the scope, i.e., C n 、C n+1 、C n+2 ......C m-2 、C m-1 、C m For example, C 1-6 Intended to disclose C1, C2, C3, C4, C5 and C6. n-m " means the same as "C n -C m "same.

[0103] The term "n-membered," where n is an integer, generally describes a ring wherein the number of atoms forming the ring is n.

[0104] The term "nm-membered," where n and m are integers, describes a range in which the number of ring atoms is n to m. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, and pyridinyl is an example of a 6-membered heteroaryl ring.

[0105] Unless otherwise indicated, numerical ranges recited in this specification and claims are equivalent to reciting at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to reciting each integer value in the numerical range "1-10", namely, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0106] The term "C 1-6 "Alkyl" means a straight or branched saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. 1-6 Alkyl groups include C 1-3 Alkyl, C 1-4 Alkyl, C 3-4 Alkyl, C 4-6 Alkyl, C 2-6Alkyl, etc. Examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0107] The term "C 1-6 "Deuterated alkyl" means a C 1-6 Alkyl, the C 1-6 Deuterated alkyl groups include, for example, monodeuterated methyl, dideuterated methyl, trideuterated methyl, pentadeuterated ethyl, and 1,2-dideuterated ethyl.

[0108] The term "C 2-6 "Alkenyl" means a straight or branched hydrocarbon group having 2 to 6 carbon atoms and containing at least one carbon-carbon double bond. The alkenyl group includes, but is not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 3-butenyl or 2-pentenyl.

[0109] The term "C 2-6 "Alkynyl" refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. The alkynyl group includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-butynyl or 2-pentynyl.

[0110] The term "oxo (=O)" refers to the replacement of hydrogen or lone electron pairs on non-oxygen atoms with oxygen, for example, After being oxygenated After being oxygenated

[0111] The term "C 3-8 "Cycloalkyl" means a monovalent or polyvalent cyclic alkane having 3 to 8 carbon atoms, including monocyclic, bicyclic or tricyclic alkanes, wherein the bicyclic and tricyclic alkanes include fused rings, bridged rings or spiro rings. 3-8 Cycloalkyl groups include C 4-8 Cycloalkyl, C 3-5 Cycloalkyl, C 6-8 Cycloalkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 5-7 Cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, etc. 3-8Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.2.0]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.1.0]octanyl.

[0112] The term "C 6-10 "Aryl" means a monovalent or polyvalent aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms, and the bicyclic and tricyclic hydrocarbon rings may be fused rings. Among them, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indenyl; or a ring having 10 carbon atoms ("C 10 Aryl "), such as naphthyl. When the C 6-10 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0113] The term "5-12 membered heteroaryl" refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic aromatic ring system having 5-12 ring atoms and whose ring atoms contain 1-5 (1, 2, 3, 4 or 5) heteroatoms independently selected from N, O and S, wherein the bicyclic and tricyclic aromatic ring systems may be fused rings or spiro rings, and the bicyclic and tricyclic aromatic ring systems contain at least one aromatic ring, which may be a phenyl (i.e., a benzo-fused ring, such as dihydrophenylfuran) or a heteroaryl. The number of heteroatoms in the 5-12 membered heteroaryl is preferably 1-3. The 5-12 membered heteroaryl includes a 5-8 membered heteroaryl, a 5-9 membered heteroaryl, a 5-10 membered heteroaryl, a 5-6 membered heteroaryl, a 6-9 membered heteroaryl, an 8-10 membered heteroaryl, a 6 membered heteroaryl, a 9 membered heteroaryl, and the like. Examples of heteroaryl groups include, but are not limited to, 5-membered rings such as oxazolyl, pyrazolyl, thienyl, thiazolyl, triazolyl, imidazolyl, and the like; and 6-membered rings such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like. The heterocyclic group may be bicyclic, including but not limited to: 5,5-membered rings, such as tetrahydrocyclopenta-pyrazolyl, etc.; 5,6-membered rings, such as tetrahydroindolyl, tetrahydropyrazolopyridinyl, tetrahydroimidazopyridinyl, tetrahydrobenzisoxazolyl, tetrahydrobenzoxazolyl, tetrahydrobenzothiazolyl, tetrahydrobenzisothiazolyl, tetrahydrobenzisothiazolyl, tetrahydrobenzimidazolyl, dihydrofuropyrazolyl, tetrahydrobenzofuranyl, dihydrobenzofuranyl, tetrahydrobenzothienyl, isoindolyl, tetrahydroindolizinyl, etc.; 6,6-membered rings, such as tetrahydroquinolinyl, tetrahydroisoquinolinyl; 5,7-membered rings, such as tetrahydrocyclohepta-thiazolyl, tetrahydrocyclohepta-furanyl, etc. The heterocyclic group may be tricyclic, for example, a fused ring or spiro ring formed by a bicyclic ring and a monocyclic ring, including but not limited to 6,7-dihydrospiro[cyclopropane-1,5-pyrrolo[1,2-c]imidazole]. When the 5-12 membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, a hydrogen atom attached to a carbon atom on the heteroaryl ring may be substituted, or a hydrogen atom attached to a heteroatom on the heteroaryl ring may be substituted.

[0114] The term "3-10 membered heterocycloalkyl" refers to a saturated ring or ring system having 3-10 ring atoms and containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S and N, wherein N and S may be optionally oxidized to various oxidation states to form nitrogen oxides, -S(=O)- or -S(=O)2-. The 3-10 membered heterocycloalkyl may be a 3-, 4-, 5-, 6- or 7-membered monocyclic ring, a 6-, 7-, 8-, 9- or 10-membered bicyclic ring or a 10-membered tricyclic ring system, wherein the bicyclic and tricyclic ring systems include fused rings, bridged rings or spiro rings. The 3-10 membered heterocycloalkyl includes 3-8 membered heterocycloalkyl, 4-10 membered heterocycloalkyl, 4-6 membered heterocycloalkyl, 4-8 membered heterocycloalkyl, 5-7 membered heterocycloalkyl, 6 membered heterocycloalkyl, etc. Examples of the heterocycloalkyl radical include, but are not limited to, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, morpholinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, diazabicyclo[3.2.1]octanyl, oxazaspiro[3.3]heptyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[3.1.0]hexanyl, 4-azaspiro[2.4]heptanyl, and the like.

[0115] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0116] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0117] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0118] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0119] "Halo" means substituted with one or more halogens.

[0120] The term "C 1-6 "Haloalkyl" refers to an alkyl group as defined above, substituted with one or more halogen groups as defined above. Such haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.

[0121] The term "alkoxy" refers to the group -OR X , where R X is an alkyl group as defined above, for example "C 1-6 "Alkoxy" refers to -OC 1-6 Alkyl, "C 2-6 "Alkoxy" refers to -OC 2-6Alkyl, the alkoxy includes but is not limited to methoxy, ethoxy, isopropoxy, tert-butoxy.

[0122] It will be appreciated by those skilled in the art that the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form internal salts.

[0123] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0124] Depending on their molecular structure, the compounds of the present invention may be chiral (having one or more stereocenters) and therefore may exist in various enantiomeric forms. These compounds may thus exist in racemic or optically active forms. The compounds of the present invention encompass isomers or mixtures thereof, racemates, in which each chiral carbon is in the R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriate N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, e.g., hexane / isopropanol / acetonitrile.

[0125] In some embodiments, the compounds of the present invention have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds with more than one chiral center, unless otherwise indicated, each chiral center in the compound can independently be (R) or (S).

[0126] Compounds described herein may also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the accompanying proton migration. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic ring system, such as 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms may be in equilibrium or spatially locked into one form by appropriate substitution. The present disclosure is intended to include all of these tautomers of the compounds.

[0127] The compounds described herein may also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0128] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0129] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0130] The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. DETAILED DESCRIPTION

[0131] The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included within the scope of protection intended by the present disclosure.

[0132] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0133] Method summary:

[0134] The chiral purity of the compounds of the present invention was tested using the following HPLC method:

[0135] HPLC method A: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 30% isopropanol / n-hexane, 0.8 mL / min, 30°C.

[0136] HPLC method B: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 30% ethanol / n-hexane, 0.8 mL / min, 30°C.

[0137] HPLC method C: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 20% ethanol / 0.05% diethylamine / n-hexane, 0.8 mL / min, 30°C.

[0138] HPLC method D: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 15% ethanol / n-hexane, 0.8 mL / min, 30°C.

[0139] HPLC method E: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 15% ethanol / 0.05% diethylamine / n-hexane, 0.8 mL / min, 30°C.

[0140] HPLC method F: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 20% isopropanol / 0.1% diethylamine / n-hexane, 0.8 mL / min, 30°C.

[0141] HPLC method G: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 10% ethanol / n-hexane, 0.8 mL / min, 30°C.

[0142] HPLC method H: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 20% ethanol / n-hexane, 0.8 mL / min, 30°C.

[0143] HPLC method I: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 20% ethanol / 0.1% trifluoroacetic acid / n-hexane, 0.8 mL / min, 30°C.

[0144] HPLC method J: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 25% ethanol / n-hexane, 0.8 mL / min, 30°C.

[0145] HPLC method K: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 35% isopropanol / 0.05% diethylamine / n-hexane, 0.8 mL / min, 30°C.

[0146] HPLC method L: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 25% ethanol / 0.1% diethylamine / n-hexane, 0.8 mL / min, 30°C.

[0147] HPLC method M: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 30% ethanol / 0.1% diethylamine / n-hexane, 0.8 mL / min, 30°C.

[0148] HPLC method N: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 25% isopropanol / 0.1% diethylamine / n-hexane, 0.8 mL / min, 30°C.

[0149] HPLC method O: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 20% isopropanol / n-hexane, 0.8 mL / min, 30°C.

[0150] HPLC method P: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 10% isopropanol / 10% ethanol / n-hexane, 0.8 mL / min, 30°C.

[0151] HPLC method Q: CHIRALPAK CHIRALPAK IC, 4.6*250 mm 5 μm, 10% isopropanol / 20% ethanol / n-hexane, 0.8 mL / min, 30°C.

[0152] HPLC method R: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 20% isopropanol / 0.1% diethylamine / n-hexane, 0.8 mL / min, 30°C.

[0153] HPLC method S: CHIRALPAK CHIRALPAK IC, 4.6*250mm 5um, 90% methanol / water, 1 mL / min, 30°C.

[0154] Nouns and representative reagents:

[0155] Unless otherwise specified, the nouns used in the following experimental descriptions represent the following reagents:

[0156] i-PrMgCl: isopropylmagnesium chloride; (Boc)2O: di-tert-butyl dicarbonate; B2Pin2: diboronic acid pinacol ester; DIAD: diisopropyl azodicarboxylate; DMF: N,N-dimethylformamide; DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; Et3N: triethylamine; EA: ethyl acetate; KOAc: potassium acetate; MeOH: methanol; MeCN: acetonitrile ; PPh3: triphenylphosphine; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; X-Phos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0157] Preparation Example

[0158] Example 1. Synthesis of 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydro-2H-indazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 001)

[0159] 1.1 Preparation of Compound 001-1

[0160] Weigh 001-a (10 g, 53.3 mmol) into dichloromethane (100 mL). Add oxalyl chloride (9 mL, 106.6 mmol) and two drops of N,N-dimethylformamide dropwise at 0°C. Warm to ambient temperature and continue stirring for 2 hours. Concentrate the reaction mixture under reduced pressure, dissolve the residue in dichloromethane (150 mL), add triethylamine (22.3 mL, 160 mmol) at 0°C, followed by a solution of dimethylamine in tetrahydrofuran (32 mL, 64 mmol, 2N), keeping the internal temperature below 5°C. After the addition is complete, warm to room temperature and continue stirring for 12 hours. Quench the reaction mixture with water (200 mL) and extract with dichloromethane (200 mL x 2). The organic phases were combined and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 001-1 (11 g).

[0161] 1.2 Preparation of Compound 001-2

[0162] Compound 001-1 (11 g, 51.25 mmol) was dissolved in 1,4-dioxane (300 mL). Tert-butyl carbamate (12 g, 102.5 mmol), cesium carbonate (33.4 g, 102.5 mmol), palladium acetate (1.15 g, 5.12 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (2.2 g, 5.12 mmol) were added. The mixture was stirred at 95°C under nitrogen for 16 hours. The reaction mixture was cooled to 20°C, filtered through a pad of celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound 001-2 (10 g).

[0163] 1.3 Preparation of Compound 001-3

[0164] Compound 001-2 (10 g, 34 mmol) was dissolved in dichloromethane (400 mL), and a solution of hydrogen chloride in 1,4-dioxane (52 mL, 4 M) was added, followed by stirring at 20°C for 4 hours. The reaction mixture was concentrated to afford compound 001-3 (10 g, crude product), which was used directly in the next step.

[0165] 1.4 Preparation of Compound 001-4

[0166] Compound 001-3 (10 g, 51.2 mmol) was dissolved in dichloromethane (50 mL), and tetrabutylammonium iodide (11.4 g, 30.7 mmol) was added. Under nitrogen, boron tribromide (154 mL, 154 mmol) was slowly added dropwise at 0°C. After the addition was complete, the mixture was warmed to room temperature and stirred overnight. Saturated aqueous sodium bicarbonate (200 mL) was then slowly added dropwise to quench the reaction mixture. The resulting mixture was extracted with dichloromethane (200 mL x 2). The organic phase was discarded, and the aqueous phase was concentrated to afford compound 001-4 (35 g, crude product), which was used directly in the next step.

[0167] 1.5 Preparation of Compound 001-5

[0168] 001-4 (35 g, 193.2 mmol) was weighed and dissolved in ethanol (150 mL), and 001-b (6.78 g, 38.64 mmol) and N,N-diisopropylethylamine (21.6 g, 165.5 mmol) were added. The reaction solution was stirred at 55 ° C overnight and then directly concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 001-5 (4.2 g).

[0169] 1.6 Preparation of Compound 001-6

[0170] At room temperature, 001-c (5 g, 30.6 mmol) and ethyl acetate (5 mL) were added to a reaction flask, followed by trimethyloxonium tetrafluoroborate (5.9 g, 39.8 mmol). The mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 001-6 (5 g). LC-MS: [M+H] + =178.05.

[0171] 1.7 Preparation of Compound 001-7

[0172] At room temperature, 001-6 (5 g, 28.2 mmol) was dissolved in methanol (60 mL). 10% wt palladium on carbon (1 g) and hydrazine hydrate (98%, 10 mL, 312.5 mmol) were added. The reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was filtered, and the filtrate was directly concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 001-7 (4.4 g). LC-MS: [M+H] + =148.15.

[0173] 1.8 Preparation of Compound 001-8

[0174] At room temperature, 001-7 (4.3 g, 29.2 mmol) was dissolved in sulfuric acid (44 mL, 818 mmol) and water (55 mL). A solution of sodium nitrite (2 g, 29.2 mmol) in water (30 mL) was added. The mixture was stirred at 0°C for 1 hour, then heated to 100°C and reacted for 40 minutes. Water (20 mL) was added to the reaction solution, which was extracted with ethyl acetate (50 mL x 3). The organic phase was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 001-8 (2.2 g). LC-MS: [M+H] + =149.10.

[0175] 1.9 Preparation of Compound 001-9

[0176] At room temperature, 001-8 (1.8 g, 12.2 mmol) and 10% wt palladium on carbon (400 mg) were dissolved in methanol (20 mL). The atmosphere was replaced with hydrogen three times, and the reaction mixture was stirred at 60°C and 5 Psi for 20 hours. The reaction mixture was filtered, and the filtrate was directly concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 001-9 (1.3 g). LC-MS: [M+H] + =151.1.

[0177] 1.10 Preparation of Compound 001-10

[0178] At room temperature, sodium hydride (0.7 g, 16 mmol, 60% wt dispersion in mineral oil) was dissolved in N,N-dimethylformamide (15 mL). Compound 001-9 (1.2 g, 8 mmol) was added and stirred for 1 hour. Iodomethane (4 mL, 64 mmol) was then added and allowed to react at room temperature for 3 hours. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL × 3) and washed with saturated brine (20 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to yield compound 001-10 (1.1 g). LC-MS: [M+H] + =179.10.

[0179] 1.11 Preparation of Compound 001-11

[0180] At room temperature, 001-10 (0.9 g, 5 mmol) and hydroxylamine hydrochloride (2.5 g, 35 mmol) were dissolved in pyridine (10 mL) and stirred at 45 ° C for 2 hours. The reaction solution was added with water (20 mL), extracted with ethyl acetate (50 mL × 3), washed with saturated brine (20 mL × 3), and the organic phase was concentrated under reduced pressure. Zinc powder (3.4 g, 50 mmol) was added to the residue, dissolved in methanol (10 mL), and 6M hydrochloric acid (20 mL) was slowly added. Stir at room temperature for 1 hour. The reaction solution was filtered, the methanol was concentrated, and the residue was added with water (20 mL). The pH was adjusted to alkaline with sodium carbonate aqueous solution, extracted with ethyl acetate (50 mL × 3), washed with saturated brine (20 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 001-11 (240 mg). LC-MS: [M-16] + =163.20.

[0181] 1.12 Preparation of Compound 001

[0182] At room temperature, 001-11 (70 mg, 390.5 μmol), 001-5 (100 mg, 327.6 μmol), and N,N-diisopropylethylamine (90 mg, 697 μmol) were dissolved in ethanol (2 mL) and stirred at 30°C for 2 hours. The reaction solution was purified by preparative HPLC (alkaline conditions) and freeze-dried to obtain compound 001 (97.4 mg). LC-MS: [M+H] + =439.05.

[0183] 1 H NMR (400MHz, DMSO-d6): δ8.87(s,1H),8.08(s,1H),7.47(s,1H),4.99(d,J=8.0Hz,1H),3.79(s,3H ), 3.73 (s, 1H), 3.17 (s, 3H), 3.04 (s, 3H), 1.65-1.58 (m, 3H), 0.94 (d, J = 32.0Hz, 6H), 3.73 (s, 1H).

[0184] Example 2: Synthesis of 4-((2-((5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 002)

[0185] 2.1 Preparation of Compound 002-1

[0186] 002-a (350 mg, 2.57 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (3 mL) was added. Sodium hydride (308 mg, 7.71 mmol, 60% wt dispersion in mineral oil) was added at 0°C and allowed to react for 0.5 hours. Iodomethane (1.1 g, 7.71 mmol) was added and the temperature was raised to 25°C for 1 hour. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 002-1 (300 mg, 71.4% yield).

[0187] 2.2 Preparation of Compound 002-2

[0188] Compound 002-1 (300 mg, 1.82 mmol) was dissolved in ethanol (2 mL). Hydroxylamine hydrochloride (844 mg, 5.10 mmol) and sodium acetate (356 mg, 5.10 mmol) were added and reacted at 40°C for 6 hours. The reaction mixture was quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 002-2 (320 mg, 97.8% yield).

[0189] 2.3 Preparation of Compound 002-3

[0190] Compound 002-2 (200 mg, 1.12 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum tetrahydride (84.7 mg, 2.23 mmol) was added. The mixture was reacted at 60°C for 12 hours. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 002-3 (160 mg, 54.4% yield).

[0191] 2.4 Preparation of Compound 002

[0192] Dissolve 002-3 (100 mg, 0.60 mmol) in ethanol (2 mL), add triethylamine (121 mg, 1.20 mmol) and 001-5 (184.7 mg, 0.6 mmol), and react at room temperature for 1 hour. The reaction mixture is purified by preparative HPLC to give compound 002 (29.8 mg, 11.6% yield). LC-MS: [M+H] + =425.1.

[0193] 1H NMR (400MHz, DMSO-d6): δ8.91(s,2H),8.04(d,J=4.0Hz,1H),7.92(s,1H),7.45(d,J=4.0Hz,1H),6.25(s,1H),5 .15(d,J=8.0Hz,1H),4.14-4.02(m,2H),3.11(s,3H),3.01(s,3H),1.97-1.93(m,2H),1.03(s,3H),0.90(s,3H).

[0194] Example 3, 4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydro-2H-indazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 003), (R)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydro-2H-indazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (S)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydro-2H-indazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 003A or 003B)

[0195] 3.1 Preparation of Compound 003-1

[0196] At room temperature, 003-a (10.0 g, 89.2 mmol) was added to N,N-dimethylformamide (100 mL). The reaction mixture was stirred at 90°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 003-1 (10.0 g, crude product). LC-MS: [M+H] + =168.15.

[0197] 3.2 Preparation of Compound 003-2

[0198] At room temperature, 003-1 (10.0 g, 59.9 mmol), hydrazine hydrochloride (4.07 g, 59.9 mmol), and sodium hydroxide (3.35 g, 83.8 mmol) were added to methanol (200 mL). The reaction solution was stirred at 70°C for 1 hour. Water (200 mL) was added to the reaction solution to dilute it, and then extracted with ethyl acetate (200 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure to obtain compound 003-2 (7.0 g, crude product). LC-MS: [M+H] + =137.15.

[0199] 3.3 Preparation of Compound 003-3

[0200] At room temperature, 003-2 (7.0 g, 51.5 mmol), iodomethane (11.0 g, 77.3 mmol), and potassium carbonate (14.2 g, 103.0 mmol) were added to acetonitrile (70 mL). The reaction solution was stirred at 70°C for 2 hours. Water (100 mL) was added to the reaction solution to dilute it, and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1 to 20 / 1) to give compound 003-3 (3.2 g, yield 41.4%). LC-MS: [M+H] + =151.15.

[0201] 3.4 Preparation of Compound 003

[0202] Synthesis of Compound 003: Refer to the synthesis method of Compound 002 in Example 2, except that 002-a is replaced with 003-3 to obtain Compound 003 (118 mg, yield 28.2%). LC-MS: [M+H] + =438.49.

[0203] 1 H NMR (600MHz, DMSO-d6): δ11.62(s,1H),9.65(s,1H),8.68(s,1H),8.04(t,J=18.0Hz,2H),7.63(s,1H),4.97–4.90(m,1H),3. 74(s,3H),3.09–3.02(s,6H),2.69–2.52(m,2H),1.77–1.67(m,1H),1.59(dt,J=13.6,6.8Hz,1H),0.97(s,3H),0.88(s,3H).

[0204] 3.5 Preparation of Compounds 003-A and 003-B

[0205] Compound 003 (60 mg, 0.14 mmol) was purified by supercritical fluid chromatography (basic conditions) to give 003A (20.9 mg) and 003B (19.0 mg). LC-MS: [M+H] + =438.49.

[0206] 003-A characterization data is as follows:

[0207] Chiral purity: 99.1%; T R =13.443 min, HPLC method D.

[0208] 1 H NMR (600MHz, DMSO-d6): δ8.69(s,1H),8.05(s,1H),7.92(s,1H),7.62(s,1H),4.93(d,J=9.2Hz,1H),3.74(s,3H),3.12(s, 3H), 3.02(s,3H),2.64–2.51(m,2H),1.71(dd,J=13.6,6.8Hz,1H),1.59(dd,J=13.6,6.8Hz,1H),0.96(s,3H),0.90(s,3H).

[0209] Characterization data for 003-B is as follows:

[0210] Chiral purity: 98.0%; T R =15.791 min, HPLC method D.

[0211] 1 H NMR (600MHz, DMSO-d6): δ8.71(s,1H),8.04(s,1H),7.91(s,1H),7.62(s,1H),4.93(d,J=9.2Hz,1H),3.74(s,3H ),3.13(s,3H),3.02(s,3H),2.62–2.51(m,2H),1.78–1.66(m,1H),1.64–1.54(m,1H),0.97(s,3H),0.90(s,3H).

[0212] Example 4. Synthesis of 4-((3,4-dioxo-2-((1,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 004)

[0213] 4.1 Preparation of Compound 004

[0214] Synthesis of Compound 004: Refer to the synthesis method of Compound 002 in Example 2, except that 002-a is replaced with 004-a to obtain Compound 004 (28.3 mg). LC-MS: [M+H] + =439.05.

[0215] 1H NMR (400MHz, DMSO-d6): δ11.59(s,1H),9.64(s,1H),8.68(s,1H),8.08-7.98(m,2H),7.35(d,J=4.0Hz,1H),4.91(d,J =9.6Hz,1H),3.69(s,3H),3.15(s,3H),3.03(s,3H),2.71–2.55(m,2H),1.77–1.59(m,2H),0.95(s,3H),0.91(s,3H).

[0216] Example 5. Synthesis of 4-((3,4-dioxo-2-((1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 005)

[0217] 5.1 Preparation of Compound 005-1

[0218] 005-a (8.0 g, 71.4 mmol) and p-toluenesulfonic acid monohydrate (1.4 g, 7.14 mmol) were dissolved in ethanol (50 mL) and toluene (50 mL). A water separator was installed and the mixture was reacted at 95°C under nitrogen for 5 hours. The reaction solution was directly concentrated under reduced pressure, then the pH was adjusted to neutral with saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with dichloromethane (150 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 005-1 (6.38 g, yield 63.82%).

[0219] 5.2 Preparation of Compound 005-2

[0220] 005-1 (6.4 g, 45.57 mmol) was dissolved in N,N-dimethylformamide (50 mL), followed by the addition of N,N-dimethylformamide dimethyl acetal (44.8 g, 376.80 mmol). The reaction system was heated to 130°C for 6 hours. The reaction solution was directly concentrated under reduced pressure without purification to obtain compound 005-2 (8.89 g, crude product).

[0221] 5.3 Preparation of Compound 005-3

[0222] 005-2 (8.9 g, 45.57 mmol) was dissolved in methanol (200 mL), followed by the addition of methylhydrazine sulfate (19.80 g, 136.80 mmol) and acetic acid (15 mL, 262.25 mmol). The reaction was allowed to react at room temperature for 16 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford compound 005-3 (3.45 g, 50.47% yield).

[0223] 1 H NMR (400MHz, CDCl3): δ7.33 (s, 1H), 4.13 (s, 3H), 2.74 (t, J = 6.0 Hz, 2H), 2.54 (dd, J = 7.0, 5.8 Hz, 2H), 2.10 (dd, J = 9.6, 6.4 Hz, 2H).

[0224] 5.4 Preparation of Compound 005

[0225] Synthesis of Compound 005: Refer to the synthesis method of Compound 002 in Example 2, except that 002-a is replaced with 005-3 to obtain Compound 005 (33.9 mg). LC-MS: [M+H] + =439.00.

[0226] 1 H NMR (400MHz, DMSO-d6): δ7.67(d,J=4.8Hz,1H),7.21(s,1H),7.17(d,J=4.8Hz,1H),5.01(s,1H),3.63(s,3H), 2.87(s,3H),2.77(s,3H),2.44–2.30(m,2H),1.77–1.69(m,1H),1.43–1.36(m,1H),0.97(s,3H),0.89(s,3H).

[0227] Example 6. Synthesis of 3-hydroxy-N,N-dimethyl-4-((2-((2-methyl-4,5,6,7-tetrahydro-2H-indazol-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)picolinamide (Compound 006)

[0228] 6.1 Preparation of Compound 006-1

[0229] Compound 001-9 (80 mg, 0.53 mmol), hydroxylamine hydrochloride (0.23 g, 3.2 mmol), and sodium acetate (0.27 g, 3.3 mmol) were dissolved in ethanol (4 mL) at room temperature and stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was added with water (10 mL), extracted with ethyl acetate (10 mL × 3), and washed with saturated brine (10 mL). The organic phase was directly concentrated under reduced pressure. Zinc powder (0.32 g, 4.9 mmol) was added to the residue and dissolved in methanol (5 mL). 6M hydrochloric acid (1.7 mL) was slowly added at 0°C and stirred at room temperature for 1 hour. The reaction mixture was filtered, the methanol was concentrated, and the residue was added with water (10 mL). The pH was adjusted to alkaline with sodium carbonate solution, extracted with ethyl acetate (10 mL × 3), washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated under reduced pressure to obtain compound 006-1 (34 mg). LC-MS: [M+H-17] + =135.20.

[0230] 6.2 Preparation of Compound 006

[0231] At room temperature, 006-1 (34 mg, 230 μmol), 001-5 (75 mg, 250 μmol), and N,N-diisopropylethylamine (150 mg, 1.16 mmol) were dissolved in ethanol (2 mL) and stirred at 30°C for 1 hour. The reaction solution was purified by preparative HPLC (basic conditions) and freeze-dried to obtain compound 006 (19.7 mg). LC-MS: [M+H] + =411.00.

[0232] 1 H NMR (400MHz, DMSO-d6): δ9.04(s,1H),8.01(d,J=5.2Hz,1H),7.89(s,1H),7.45(s,1H),5.21(d,J=6.4Hz,1H), 3.78(s,3H),3.13(s,3H),3.02(s,3H),2.46(d,J=9.6Hz,2H),2.09(s,1H),1.80(s,2H),1.71(d,J=6.8Hz,1H).

[0233] Example 7. Synthesis of 4-((3,4-dioxo-2-((2,5,5-trimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 007)

[0234] 7.1 Preparation of Compound 007-1

[0235] 007-a (20.0 g, 142.8 mmol) was weighed into a reaction flask, and acetonitrile (100 mL) was added. Under nitrogen, iodine (43.4 g, 214.2 mmol) and cerium ammonium nitrate (76.0 g, 428.4 mmol) were added, and the mixture was stirred at 80°C for 4 hours. The reaction solution was cooled to room temperature and quenched with saturated sodium thiosulfate aqueous solution (100 mL). The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 007-1 (35 g, 92% yield). LC-MS: [M+H] + =266.85.

[0236] 7.2 Preparation of Compound 007-2

[0237] Dissolve 007-1 (20.0 g, 75.2 mmol) in N,N-dimethylacetamide (100 mL) and water (10 mL), then add methyl acrylate (9.6 g, 112 mmol), N-methyldicyclohexylamine (22.0 g, 112 mmol), and bis(tri-o-tolylphosphine)palladium dichloride (1.8 g, 2.2 mmol). Stir at 80°C under nitrogen for 4 hours. Cool the reaction mixture to room temperature, dilute with aqueous solution (100 mL), and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography to yield compound 007-2 (22.5 g, crude product). LC-MS: [M+H] + =225.05.

[0238] 7.3 Preparation of Compound 007-3

[0239] Dissolve 007-2 (22.0 g, 98.1 mmol) in ethyl acetate (50 mL), add wet palladium on carbon (2.0 g, 10% palladium content), replace the hydrogen atmosphere three times, and stir at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture is filtered through a pad of celite, and the filtrate is concentrated under reduced pressure to obtain compound 007-3 (15 g, yield 68%). LC-MS: [M+H] + =227.05.

[0240] 7.4 Preparation of Compound 007-4

[0241] Dissolve 007-3 (15 g, 66.3 mmol) in N,N-dimethylformamide (60 mL) and add potassium tert-butoxide (15 g, 133.0 mmol) at 0°C under nitrogen. After completion, warm to room temperature and continue stirring for 4 hours. Dilute the reaction mixture with aqueous solution (100 mL) and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography to yield compound 007-4 (15 g, crude product).

[0242] 7.5 Preparation of Compound 007-5

[0243] Dissolve 007-4 (15.0 g, 77.2 mmol) in dimethyl sulfoxide (50 mL) and water (5 mL), add lithium chloride (6.6 g, 155.0 mmol), and react at 100°C for 16 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 007-5 (1.5 g, yield 15%). LC-MS: [M+H] + =137.15.

[0244] 7.6 Preparation of Compound 007

[0245] Synthesis of Compound 007: Refer to the synthesis method of Compound 002 in Example 2, except that 002-a is replaced with 007-5 to obtain Compound 007 (42.7 mg, yield 33%). LC-MS: [M+H] + =425.00.

[0246] 1 H NMR (400MHz, DMSO-d6): δ8.85(d,J=8.0Hz,1H),7.97(d,J=8.0Hz,1H),7.80(d,J=4.0Hz,1H),7.36(s,1H),5.01(d, J=4.0Hz,1H),3.78(s,3H),2.97(d,J=20.0Hz,6H),2.47(s,1H),2.39(d,J=16.0Hz,1H),1.14(s,3H),1.03(s,3H).

[0247] Example 8. Synthesis of 3-hydroxy-N,N-dimethyl-4-((2-((2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)picolinamide (Compound 008)

[0248] 8.1 Preparation of Compound 008-1

[0249] Dissolve 007-5 (150 mg, 1.10 mmol) in ethanol (10 mL), add hydroxylamine hydrochloride (460 mg, 6.62 mmol) and sodium acetate (542 mg, 6.62 mmol), and stir at 80°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (10 mL) and extracted with dichloromethane / methanol = 10 / 1 (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 008-1 (120 mg). LC-MS: [M+H] + =152.10.

[0250] 8.2 Preparation of Compound 008-2

[0251] 008-1 (100 mg, 0.66 mmol) and zinc powder (260 mg, 3.97 mmol) were added to methanol (5 mL). Hydrochloric acid (0.64 mL, 3.97 mmol, 6N) was added dropwise at 0°C. After completion, the mixture was warmed to room temperature and stirred for 0.5 hours. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution to adjust the pH to 8. The mixture was diluted with water (10 mL) and extracted with dichloromethane / methanol = 10 / 1 (20 mL x 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 008-2 (100 mg, crude product). LC-MS: [M-NH2] + =121.15.

[0252] 8.3 Preparation of Compound 008-3

[0253] At room temperature, 008-2 (80 mg, 0.58 mmol), 001-5 (178 mg, 0.58 mmol), and N,N-diisopropylethylamine (226 mg, 1.75 mmol) were dissolved in ethanol (2 mL) and stirred at room temperature for 12 hours. The reaction solution was purified by preparative HPLC (alkaline conditions) and freeze-dried to obtain compound 008 (30.2 mg, 13% yield). LC-MS: [M+H] + =396.95.

[0254] 1H NMR (400MHz, DMSO-d6): δ10.52(s,1H),9.61(d,J=12.0Hz,1H),8.37(d,J=4.0Hz,1H),8.32(d,J=8.0Hz,1H),7.43(s,1H),5.50 –5.44(m,1H),3.82(s,3H),2.96(d,J=36.0Hz,6H),2.88-2.82(m,1H),2.77–2.70(m,1H),2.61–2.54(m,1H),2.33–2.25(m,1H).

[0255] Example 9. Synthesis of 4-((3,4-dioxo-2-((2,5,5-trimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 009A) and 4-((3,4-dioxo-2-((1,5,5-trimethyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 009B)

[0256] 9.1 Preparation of Compound 009-1

[0257] Dissolve 009-a (10.00 g, 102.00 mmol) in N,N-dimethylformamide dimethyl acetal (89.70 g, 752.77 mmol) and allow the reaction to proceed at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure, washed with n-hexane (100 mL x 2), and filtered to collect the solid to obtain compound 009-1 (15.10 g, crude product).

[0258] 9.2 Preparation of Compound 009-2

[0259] Dissolve 009-1 (13.00 g, 84.87 mmol) in methanol (128 mL), then add p-toluenesulfonylhydrazide (17.39 g, 93.35 mmol). Allow the reaction to proceed at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to yield compound 009-2 (23.10 g, 92.48% yield). LC-MS: [M+H] + =294.95.

[0260] 9.3 Preparation of Compound 009-3

[0261] At room temperature, 009-2 (11.50 g, 39.07 mmol) was dissolved in n-butanol (100 mL) and concentrated hydrochloric acid (46 mL, 12 M). The reaction mixture was stirred at 110°C for 1.5 hours. The reaction mixture was directly concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 009-3 (1.05 g, yield 22.00%). LC-MS: [M+H] + =123.10.

[0262] 9.4 Preparation of Compounds 009-4A and 009-4B

[0263] 009-3 (900 mg, 7.37 mmol) and potassium carbonate (2.04 g, 14.74 mmol) were dissolved in N,N-dimethylformamide (9 mL). The atmosphere was then replaced with nitrogen three times. Methyl iodide (1.26 g, 8.84 mmol) was added dropwise to the reaction mixture at room temperature. The reaction system was allowed to react at 50°C for 2 hours. The reaction mixture was poured into water (30 mL) for quenching and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield a mixture of 009-4A and 009-4B (1.54 g, 1:1 ratio, 76.74% yield). LC-MS: [M+H] + =137.10.

[0264] 9.5 Preparation of Compounds 009-5A and 009-5B

[0265] A mixture of 009-4A and 009-4B (1.50 g, 11.02 mmol) was dissolved in N,N-dimethylformamide (18 mL). The reaction mixture was cooled to 0°C and sodium hydride (2.20 g, 55.08 mmol) was slowly added. The mixture was then allowed to react at room temperature for 0.5 hours. The reaction mixture was cooled to 0°C again and iodomethane (3.4 mL, 55.08 mmol) was slowly added at 0°C. The reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride (30 mL) for quenching and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a mixture of compounds 009-5A and 009-5B, which was then purified by preparative HPLC to obtain compounds 009-5A (166 mg, yield 7.96%) and 009-5B (137 mg, yield 7.57%), respectively. LC-MS: [M+H] + =165.10.

[0266] The 009-5A NMR data are as follows:

[0267] 1 H NMR (400MHz, CDCl3) δ7.62 (s, 1H), 3.82 (s, 3H), 2.77 (s, 2H), 1.29 (d, J = 0.6Hz, 6H).

[0268] The 009-5B NMR data are as follows:

[0269] 1 H NMR (400MHz, CDCl3) δ7.59(s,1H),3.93(s,3H),2.81(s,2H),1.23(s,6H).

[0270] 9.6 Preparation of Compounds 009A and 009B

[0271] The synthesis of compounds 009A and 009B was carried out by referring to the synthesis method of compound 008 in Example 8, except that 007-5 in Example 8 was replaced with 009-5A and 009-5B to obtain compounds 009A (62.3 mg) and 009B (47.5 mg), respectively. LC-MS: [M+H] + =425.00.

[0272] 009A NMR data are as follows:

[0273] 1 H NMR (400MHz, DMSO-d6): δ11.57(s,1H),9.52(s,1H),8.68(s,1H),8.06(t,J=29.4Hz,2H),7.64–7.58(m,1H),4.97(d,J=9.2Hz,1 H), 3.80 (d, J = 10.6Hz, 3H), 3.15 (s, 3H), 3.02 (s, 3H), 2.59 (d, J = 15.4Hz, 1H), 2.44 (d, J = 15.5Hz, 1H), 1.13 (s, 3H), 1.07 (s, 3H).

[0274] 009B NMR data are as follows:

[0275] 1H NMR (400MHz, DMSO-d6): δ11.55(s,1H),9.53(s,1H),8.70(s,1H),8.05(d,J=4.8Hz,1H),7.99(s,1H),7.33(s,1H),4.93(d,J= 9.2Hz,1H),3.70(s,3H),3.14(s,3H),3.02(s,3H),2.65(d,J=15.8Hz,1H),2.56(d,J=15.8Hz,1H),1.19(s,3H),1.07(s,3H).

[0276] Example 10, 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 010), (S)-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (R)-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 010A or 010B) and (R)-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 010B or 010A)

[0277] 10.1 Preparation of Compound 010-1

[0278] 010-a (3.0 g, 21.40 mmol) was dissolved in diethyl ether (15 mL). Liquid bromine (1.1 mL, 21.40 mmol) was slowly added dropwise to the reaction flask at -10°C and reacted at this temperature for 0.5 hours. Water (15 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed sequentially with saturated aqueous sodium bicarbonate solution (15 mL × 3) and saturated aqueous sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 010-1 (2.9 g). LC-MS: [M+H] + =220.95.

[0279] 10.2 Preparation of Compounds 010-2 and 010-3

[0280] 010-1 (3.5 g, 15.75 mmol) was dissolved in pyridine (15 mL), and thioacetamide (1.8 g, 23.62 mmol) was added. The mixture was refluxed at 120°C under nitrogen for 5 hours. The reaction solution was concentrated under reduced pressure to remove pyridine. Dilute hydrochloric acid (5 mL, 1 M) and ethyl acetate (15 mL) were added to the residue, mixed well, and extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compounds 010-2 (260.9 mg) and 010-3 (158.0 mg). LC-MS: [M+H] + =196.05.

[0281] 10.3 Preparation of Compound 010

[0282] The synthesis of compound 010 was carried out by referring to the synthesis method of compound 008 in Example 8, except that 007-5 in Example 8 was replaced with 010-2 to obtain 010 (42.5 mg). 010 was further chirally resolved to obtain compounds 010A and 010B. LC-MS: [M+H] + =455.95.

[0283] Characterization data of 010A:

[0284] Chiral purity: 98.7%; T R =7.456 min, HPLC method H.

[0285] 1 H NMR (400MHz, DMSO-d6): δ8.87(s,2H),7.94(d,J=5.4Hz,1H),7.80(d,J=5.0Hz,1H),5.06(s,1H),2.97(d,J=19.2 Hz, 6H), 2.78–2.61 (m, 2H), 2.57 (s, 3H), 1.72 (dt, J = 13.4, 6.4Hz, 1H), 1.64–1.53 (m, 1H), 0.96 (d, J = 14.2Hz, 6H).

[0286] Characterization data of 010B:

[0287] Chiral purity: 96.7%; T R =9.107 min, HPLC method H.

[0288] 1H NMR (400MHz, DMSO-d6): δ8.89(s,2H),7.89(d,J=5.2Hz,1H),7.72(d,J=4.8Hz,1H),5.06(s,1H),2.93(d,J=5.0H z, 6H), 2.75–2.62 (m, 2H), 2.56 (s, 3H), 1.76–1.67 (m, 1H), 1.57 (dd, J = 13.4, 6.4Hz, 1H), 0.95 (d, J = 14.8Hz, 6H).

[0289] Example 11. Synthesis of 4-((3,4-dioxo-2-((2,4,4-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 011)

[0290] The synthesis of compound 011 was carried out by referring to the synthesis method of compound 002 in Example 2, except that 002-1 was replaced with 010-3 to obtain compound 011 (70.4 mg). LC-MS: [M+H] + =455.95.

[0291] 1 H NMR (400MHz, DMSO-d6): δ11.63(s,1H),9.59(s,1H),8.99(s,1H),7.99(t,J=12.4Hz,2H),5.33(dd,J=13.4,5.2Hz,1H),3.12(s,3H),3.01(s,3H) ),2.62(d,J=24.8Hz,3H),2.20(d,J=5.2Hz,1H),1.95–1.82(m,1H),1.80–1.72(m,1H),1.67(dd,J=11.2,8.2Hz,1H),1.28(s,3H),1.20(s,3H).

[0292] Example 12: Synthesis of 4-((2-((6,6-dimethyl-5,6,7,8-tetrahydroquinolin-5-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 012)

[0293] Synthesis of Compound 012: Refer to the synthesis method of Compound 002 in Example 2, except that 002-a is replaced with 012-a to obtain Compound 012 (27.5 mg). LC-MS: [M+H] + =436.05.

[0294] 1 H NMR (400MHz, DMSO-d6): δ8.76(d,J=7.6Hz,1H),8.43(d,J=3.4Hz,1H),8.06(d,J=5.4Hz,1H),7.93(s,1H),7.71(d,J=7.8Hz,1H),7.24(d d,J=7.8,4.7Hz,1H),5.06(d,J=9.4Hz,1H),3.06(d,J=43.4Hz,6H),2.90(dd,J=15.8,7.0Hz,2H),1.85–1.67(m,2H),1.07–0.79(m,6H).

[0295] Example 13. Synthesis of 4-((2-((7,7-dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 013)

[0296] Synthesis of Compound 013: Refer to the synthesis method of Compound 002 in Example 2, except that 002-a is replaced with 013-a to obtain Compound 013 (55.1 mg). LC-MS: [M+H] + =436.00.

[0297] 1 H NMR (400MHz, DMSO-d6): δ11.60(s,1H),9.69(s,1H),8.80(d,J=8.0Hz,1H),8.45(d,J=4.0Hz,1H),8.06(d,J=8.0Hz,1H),7.94(s,1H),7.62(d,J=8 .0Hz,1H),7.29(q,J=4.0,1H),5.08(d,J=12.0Hz,1H),3.14(s,3H),3.02 (s,3H),2.87-2.82(m,2H),1.78-1.65(m,2H),1.02(s,3H),0.95(s,3H).

[0298] Example 14. Synthesis of 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydro-2H-indazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 014A) and 4-((3,4-dioxo-2-((1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 014B)

[0299] 14.1 Preparation of Compound 014-1

[0300] Dissolve 014-a (4.0 g, 28.53 mmol) in N,N-dimethylformamide dimethyl acetal (8 mL) and react at 100°C for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain compound 014-1 (5.2 g, crude product). The crude product was used directly in the next reaction. LC-MS: [M+H] + =196.10.

[0301] 14.2 Preparation of Compound 014-2

[0302] 014-1 (5.0 g, 25.61 mmol) was dissolved in N,N-dimethylformamide (10 mL), and hydrazine hydrate (1.62 mL, 51.21 mmol) was added. The mixture was refluxed at 130°C for 5 hours. After cooling to room temperature, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 014-2 (1.7 g). LC-MS: [M+H] + =165.10.

[0303] 14.3 Preparation of Compounds 014-3A and 014-3B

[0304] 014-2 (1.6 g, 9.44 mmol) was dissolved in ethanol (10 mL), and anhydrous potassium carbonate (3.9 g, 28.32 mmol) and iodomethane (0.88 mL, 14.16 mmol) were added. The mixture was reacted at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a mixture of 014-3A and 014-3B (1.2 g). The mixture was separated by high-performance liquid chromatography to obtain 014-3A (617.0 mg) and 014-3B (463.0 mg). LC-MS: [M+H] + =179.10.

[0305] 14.4 Preparation of Compounds 014A and 014B

[0306] The synthesis of compounds 014A and 014B was carried out by referring to the synthesis method of compound 008 in Example 8, except that 007-5 in Example 8 was replaced with 014-3A and 014-3B, respectively, to obtain compounds 014A (33.9 mg) and 014B (63.3 mg). LC-MS: [M+H] + =439.15.

[0307] 014A's NMR data:

[0308] 1 H NMR (400MHz, DMSO-d6): δ8.83(s,1H),7.90(d,J=5.2Hz,1H),7.68(d,J=4.6Hz,1H),7.54(s,1H),5.12(s,1H),3.70(s,3H ),2.93(d,J=12.6Hz,6H),2.31(s,2H),1.85(dd,J=12.8,5.8Hz,1H),1.46–1.33(m,1H),1.05(s,3H),0.90–0.79(m,3H).

[0309] 014B's NMR data:

[0310] 1 H NMR (400MHz, DMSO-d6): δ8.72(s,1H),7.94(d,J=5.4Hz,1H),7.77(d,J=5.2Hz,1H),7.34(s,1H),5.10(s,1H),3.64(s,3H) ,2.94(d,J=19.6Hz,6H),2.38(d,J=9.0Hz,2H),1.84(dd,J=12.8,5.6Hz,1H),1.41–1.29(m,1H),1.07(s,3H),0.91(s,3H).

[0311] Example 15. Synthesis of 4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydro-2H-indazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide (Compound 015)

[0312] 15.1 Preparation of Compound 015-1

[0313] Weigh 001-a (2.0 g, 10.66 mmol) into a reaction flask, add dichloromethane (20 mL), and add oxalyl chloride (2.0 g, 16.0 mmol) and 5 drops of N,N-dimethylformamide dropwise at 0°C. After the addition is complete, warm to room temperature and stir for 2 hours. The reaction solution is directly concentrated under reduced pressure, and the residue is added to dichloromethane (20 mL). Triethylamine (3.24 g, 32.0 mmol) and N-isopropylmethylamine (1.2 g, 16.0 mmol) are added sequentially at 0°C. After the addition is complete, warm to room temperature and stir for 12 hours. Dilute the reaction system with water (20 mL) and extract with dichloromethane (20 mL x 2). Combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 015-1 (2.5 g, yield: 96%).

[0314] 15.2 Preparation of Compound 015-5

[0315] Synthesis of Compound 015-5 Refer to the synthesis method of Compound 001-5 in Example 1, except that 001-1 is replaced with 015-1 to obtain Compound 015-5 (330 mg, yield 21%).

[0316] 15.3 Preparation of Compound 015

[0317] 015-5 (150 mg, 0.45 mmol) was weighed into a reaction flask, and 003-6 (81 mg, 0.45 mmol), ethanol (5 mL), and N,N-diisopropylethylamine (175 mg, 1.35 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by preparative HPLC and freeze-dried to obtain compound 015 (77.2 mg, 36.7% yield). LC-MS: [M+H] + =467.05.

[0318] 1 H NMR (400MHz, DMSO-d6): δ8.71(s,1H),7.96(d,J=32.0Hz,2H),7.62(s,1H),4.94(d,J=8.0Hz,1H), 4.44(d,J=256.0Hz,1H), 3.75(s,3H),2.86(s,3H),2.63-2.53(m,2H),1.75-1.69(m,1H),1.62-1.55(m,1H),1.13(s,6H),0.96(s,3H),0.90(s,3H).

[0319] Example 16. Synthesis of 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]oxazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 016)

[0320] 16.1 Preparation of Compound 016-1

[0321] At room temperature, 010-a (2.0 g, 14.3 mmol) and acetic acid amine (1.32 g, 17.1 mmol) were added to toluene (20 mL). The reaction solution was stirred at 115°C for 3 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (10 mL) was added to the residue. After stirring at room temperature for 30 minutes, the mixture was filtered, the filter cake was recovered, and dried to obtain compound 016-1 (1.16 g, yield 58.4%). LC-MS: [M+H] + =140.15.

[0322] 16.2 Preparation of Compound 016-2

[0323] Compound 016-1 (1.06 g, 7.62 mmol) and pyridine (1.2 g, 15.2 mmol) were added to tetrahydrofuran (30 mL). The temperature was then lowered to 0°C, and acetyl chloride (1.2 g, 15.2 mmol) was added to the reaction mixture. The temperature was raised to 60°C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-20 / 1) to afford compound 016-2 (1.35 g, 97.8% yield). LC-MS: [M+H] + =182.1.

[0324] 16.3 Preparation of Compound 016-3

[0325] Dissolve 016-2 (1.25 g, 6.9 mmol) in N,N-dimethylformamide (12 mL), cool to 0°C, and add N-bromosuccinimide (1.23 g, 6.9 mmol) in portions. Stir at room temperature for 1 hour. Dilute the reaction mixture with water (20 mL) and extract with ethyl acetate (15 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 016-3 (1.56 g, yield 86.9%). LC-MS: [M+H] + =260.0.

[0326] 16.4 Preparation of Compound 016-4

[0327] Compound 016-3 (1.47 g, 5.65 mmol), N,N-dimethylglycine (349 mg, 3.39 mmol), cesium carbonate (3.87 g, 11.9 mmol), and cuprous iodide (215 mg, 1.13 mmol) were added to 1,4-dioxane (15 mL). The reaction mixture was stirred at 90°C under nitrogen for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 016-4 (480 mg, 47.4% yield). LC-MS: [M+H] + =180.10.

[0328] 16.5 Preparation of Compound 016-5

[0329] 016-4 (360 mg, 1.58 mmol), tert-butylsulfenamide (440 mg, 6.03 mmol), and tetraethyl titanate (1.37 g, 6.03 mmol) were added to toluene (8.0 mL) and stirred at 100°C overnight. The reaction was cooled to room temperature and quenched with water. The mixture was filtered, and the filtrate was extracted with ethyl acetate (15 mL x 3) and washed with saturated sodium chloride (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 2 / 1) to obtain compound 016-5 (0.45 g, yield 79.3%). LC-MS: [M+H] + =283.10.

[0330] 16.6 Preparation of Compound 016-6

[0331] Dissolve 016-5 (0.4 g, 1.42 mmol) in methanol (8.0 mL) and add sodium borohydride (69.6 mg, 1.84 mmol) in portions at room temperature. The reaction mixture is heated to 40°C and stirred for 1 hour. The reaction mixture is then cooled to 0°C and quenched with water (0.5 mL). The reaction mixture is then concentrated under reduced pressure to obtain compound 016-6 (450 mg, crude product). LC-MS: [M+H] + =285.10.

[0332] 16.7 Preparation of Compound 016-7

[0333] Dissolve 016-6 (0.4 g, 1.41 mmol) in 1,4-dioxane (3.0 mL) and add a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M). Stir the reaction mixture at room temperature for 1 hour. Concentrate the reaction mixture under reduced pressure to obtain compound 016-7 (260 mg, crude product). LC-MS: [M-NH2] + =164.15.

[0334] 16.8 Preparation of Compound 016

[0335] 016-7 (80.0 mg, 443 μmol), 001-5 (130 mg, 443 μmol), and N,N-diisopropylethylamine (286 mg, 2.2 mmol) were dissolved in ethanol (3.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 016 (26.9 mg, yield 13.8%). LC-MS: [M+H] + =440.10.

[0336] 1 H NMR (400MHz, DMSO-d6): δ8.79(s,1H),7.98(d,J=5.2Hz,1H),7.85(s,1H),4.94(s,1H),3.02(d,J=24.8Hz ,6H),2.43(dd,J=14.8,6.8Hz,2H),2.37(s,3H),1.76–1.64(m,1H),1.54(d,J=13.2Hz,1H),0.97(s,6H).

[0337] Example 17. Synthesis of (4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]oxazol-4-yl)amino)cyclobut-1-en-1-yl)amino-3-hydroxy-N,N-dimethylpicolinamide (Compound 017)

[0338] 17.1 Preparation of Compound 017-1

[0339] Dissolve 010-a (2.00 g, 14.27 mmol) in acetonitrile (80 mL), add 4-methylsulfonyl azide (5.20 mL, 17.12 mmol) and triethylamine (2.18 mL, 15.69 mmol), and incubate the reaction at 20°C for 2 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford compound 017-1 (2.51 g, 95.28% yield). LC-MS: [M+H] + =167.15.

[0340] 17.2 Preparation of Compound 017-2

[0341] 017-1 (550 mg, 3.31 mmol) was dissolved in acetonitrile (12 mL), and dimerized rhodium acetate (44 mg, 0.09 mmol) was added. The atmosphere was then replaced with nitrogen three times, and the reaction mixture was allowed to react at 60°C for 16 hours. The reaction mixture was directly concentrated under reduced pressure, diluted with water (30 mL), and extracted with dichloromethane (30 mL × 3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 017-2 (210 mg, yield 32.93%). LC-MS: [M+H] + =180.10.

[0342] 17.3 Preparation of Compound 017

[0343] Synthesis of Compound 017: Refer to the synthesis method of Compound 016 in Example 16, except that 016-4 is replaced with 017-2 to obtain Compound 017 (85.1 mg). LC-MS: [M+H] + =440.10.

[0344] 1 H NMR (400MHz, DMSO-d6): δ8.85(s,1H),8.03(d,J=5.2Hz,1H),7.95(s,1H),5.09(dd,J=13.0,5.4Hz,1H),3.15(s,3H ),3.03(s,3H),2.38(s,3H),2.23–2.15(m,1H),1.85–1.73(m,2H),1.69(d,J=9.0Hz,1H),1.27(s,3H),1.21(s,3H).

[0345] Example 18, 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 018), (S)-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (R)-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 018A or 018B)

[0346] 18.1 Preparation of Compound 018-1

[0347] Weigh ammonium cerium nitrate (18.91 g, 35.67 mmol) in methanol (20 mL), add dropwise a methanol solution (10 mL) of 018-a (2.0 g, 17.84 mmol) at -35 ° C, and then slowly add 2-(trimethylsilyloxy)propylene (5.81 g, 44.59 mmol). The mixture is reacted at -35 ° C for 1 hour, and sodium thiosulfate aqueous solution is added to quench the reaction. The mixture is extracted with ethyl acetate (25 mL × 3), and the organic phase is washed with saturated sodium chloride aqueous solution (35 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain compound 018-1 (1.8 g, crude product), which is directly used in the next reaction.

[0348] 18.2 Preparation of Compound 018-2

[0349] 018-1 (1.8 g, crude product) was dissolved in toluene (15 mL), and a polymer of vinylbenzenesulfonic acid and divinylbenzene (2.24 g, 7.13 mmol) was added. The mixture was refluxed at 110°C for 20 minutes, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 018-2 (1.0 g). LC-MS: [M+H] + =151.15.

[0350] 18.3 Preparation of Compound 018

[0351] Synthesis of Compound 018: Refer to the synthesis method of Compound 002 in Example 2, except that 002-a is replaced with 018-2 to obtain Compound 018 (17.2 mg). LC-MS: [M+H] + =439.15.

[0352] 1 H NMR (400MHz, DMSO-d6): 9.63(s,1H),8.78(s,1H),8.06(s,1H),7.99(s,1H),6.00(s,1H),4.87(d,J=8.0Hz,1H ), 3.16 (s, 3H), 3.04 (s, 3H), 2.45–2.27 (m, 2H), 2.24 (s, 3H), 1.61 (m, 1H), 1.50 (m, 1H), 0.96 (d, J = 4.0Hz, 6H).

[0353] 18.4 Preparation of Compounds 018A and 018B

[0354] 018 was further subjected to chiral separation to give compounds 018A and 018B.

[0355] Characterization data of 018A:

[0356] Chiral purity: 98.4%; T R =6.469 min, HPLC method S.

[0357] 1 H NMR (400MHz, DMSO-d6): δ8.76(d,J=12.0Hz,1H),8.04(d,J=4.0Hz,1H),7.93(s,1H),5.97(s,1H),4.86(d,J=8.0Hz,1H) ,3.11(s,3H),3.01(s,3H),2.45–2.28(m,2H),2.22(s,3H),1.63–1.55(m,1H),1.50-1.44(m,1H),0.95(d,J=3.2Hz,6H).

[0358] Characterization data of 018B:

[0359] Chiral purity: 96.0%; T R =7.741 min, HPLC method S.

[0360] 1 H NMR (400MHz, DMSO-d6): δ8.74(d,J=12.0Hz,1H),8.02(d,J=4.0Hz,1H),7.91(s,1H),5.97(s,1H),4.85(d,J=8.0Hz,1H) ,3.08(s,3H),2.99(s,3H),2.44–2.29(m,2H),2.22(s,3H),1.62–1.55(m,1H),1.48–1.44(m,1H),0.95(d,J=4.0Hz,6H).

[0361] Example 19, 4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzofuran-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 019), (R)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzofuran-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (S)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzofuran-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 019A or 019B)

[0362] 19.1 Preparation of Compound 019-1

[0363] 003-a (10.092 g, 90 mmol) was dissolved in a potassium hydroxide aqueous solution (3.25 M, 36 mL, 117 mmol), cooled to 0°C, 3-bromopropyne (10.1 mL, 117 mmol) was added, and the mixture was reacted at 40°C for 4 hours. The pH was adjusted to 3 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 019-1 (7.448 g, crude product), which was used directly in the next step.

[0364] 19.2 Preparation of Compound 019-2

[0365] Dissolve 019-1 (7.448 g, 49.6 mmol) in 1,2-dichloroethane (124 mL), add p-toluenesulfonic acid monohydrate (943 mg, 4.96 mmol), and reflux in an oil bath at 110°C for 2 hours. Cool to room temperature, and concentrate the reaction mixture under reduced pressure. Add saturated aqueous sodium bicarbonate (10 mL) to the residue, stir for 10 minutes, and then dilute with water (300 mL). Extract with ethyl acetate (150 mL x 3). The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 019-2 (7.708 g, 51.3 mmol). LC-MS: [M+H] + =151.10.

[0366] 19.3 Preparation of Compound 019-3

[0367] The nitrogen atmosphere in the three-necked flask was replaced, diisopropylamine (4.2 mL, 30 mmol) and tetrahydrofuran (13.2 mL) were added, and the temperature was lowered to -78°C. n-Butyl lithium (2.5 M, 12.6 mL, 31.5 mmol) was added, and the mixture was stirred for 30 minutes, and then returned to room temperature to obtain a freshly prepared lithium diisopropylamide solution with a concentration of 1 M.

[0368] The atmosphere in the three-necked flask was replaced with nitrogen, and 019-2 (1.48 g, 9.865 mmol) and tetrahydrofuran (20 mL) were added. The temperature was lowered to -78°C, and freshly prepared lithium diisopropylamide solution (27.6 mL, 27.6 mmol, 1 M) was added. After stirring for 30 minutes, iodomethane (3.7 mL, 59.2 mmol) was added. The mixture was brought to room temperature and stirred for 2 hours. Saturated aqueous ammonium chloride (200 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain compound 019-3 (1.321 g, 8 mmol). LC-MS: [M+H] + =165.15.

[0369] 19.4 Preparation of Compound 019-4

[0370] Synthesis of Compound 019-4: Refer to the synthesis method of Compound 019-3 in Example 19, except that 019-2 is replaced with 019-3 to obtain Compound 019-4 (909 mg, 5.1 mmol). LC-MS: [M+H] + =179.10.

[0371] 19.5 Preparation of Compound 019-5

[0372] 019-4 (909 mg, 5.1 mmol) and (S)-tert-butylsulfonimide (3.708 g, 30.6 mmol) were dissolved in toluene (5.1 mL). The atmosphere was replaced with nitrogen, and tetraethyl titanate (6.42 mL, 30.6 mmol) was added. The mixture was refluxed for 2 hours and cooled to room temperature. Saturated aqueous ammonium chloride (80 mL) and ethyl acetate (40 mL) were added to the reaction solution, which was filtered. The filtrate was extracted with ethyl acetate (60 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain compound 019-5 (428 mg, 1.52 mmol). LC-MS: [M+H] + =282.05.

[0373] 19.6 Preparation of Compound 019-6

[0374] 019-5 (428 mg, 1.52 mmol) was dissolved in tetrahydrofuran (7 mL), the atmosphere was replaced with nitrogen, and tetraethyl titanate (6.42 mL, 30.6 mmol) was added to the reaction mixture. The temperature was lowered to -50°C, and sodium borohydride (260 mg, 6.84 mmol) was added. The mixture was returned to room temperature and stirred for 2 hours. The temperature was lowered to -78°C, and methanol (10 mL) was slowly added to quench the mixture. When no more bubbles escaped, the mixture was warmed to room temperature. Saturated aqueous ammonium chloride (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate (40 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 2) to obtain compound 019-6 (298 mg, 1.05 mmol). LC-MS: [M+H] + =284.10.

[0375] 19.7 Preparation of Compound 019-7

[0376] Dissolve 019-6 (298 mg, 1.05 mmol) in 1,4-dioxane (3 mL), add a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M), and stir at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure to obtain 019-7. LC-MS: [M-NH2] + =163.15.

[0377] 19.8 Preparation of Compounds 019A and 019B

[0378] To 019-7, ethanol (4 mL), N,N-diisopropylethylamine (549 μL, 3.15 mmol), and 001-5 (321 mg, 1.05 mmol) were added sequentially and allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to afford compound 019, which was then subjected to chiral separation to afford 019A (101.4 mg, 231.25 μmol) and 019B (7.0 mg, 15.96 μmol). LC-MS: [M+H]+ = 439.10.

[0379] 019A characterization data are as follows:

[0380] Chiral purity: 96.7%; T R =13.724 min, HPLC method G.

[0381] 1H NMR (400MHz, DMSO-d6): δ8.65(d,J=9.6Hz,1H),8.05(d,J=5.2Hz,1H),7.92(d,J=4.4Hz,1H),6.03(s,1H),4.77(d,J =9.2Hz,1H),3.12(s,3H),3.02(s,3H),2.21(s,3H),1.75-1.68(m,2H),1.62-1.55(m,2H),0.96(s,3H),0.92(s,3H).

[0382] 019B characterization data are as follows:

[0383] Chiral purity: 100%; T R =15.558 min, HPLC method G.

[0384] 1 H NMR (400MHz, DMSO-d6): δ9.74(s,1H),8.69(d,J=9.6Hz,1H),8.11(d,J=5.6Hz,1H),8.00(d,J=5.2Hz,1H),6.04(s,1H),4.7 8(d,J=9.6Hz,1H),3.12(s,3H),3.04(s,3H),2.21(s,3H),1.76-1.69(m,2H),1.63-1.57(m,2H),0.96(s,3H),0.92(s,3H).

[0385] Example 20, 4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 020), (R)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (S)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 020A or 020B) and (S)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 020B or 020A)

[0386] 20.1 Preparation of Compound 020-1

[0387] 018-a (3.0 g, 26.76 mmol) was weighed into a reaction flask, ethanol (15 mL) was added, and a solution of liquid bromine (4.3 g, 26.76 mmol) in ethanol (5 mL) was slowly added dropwise to the reaction flask at 0°C. After completion, the reaction was allowed to react at room temperature for 2 hours, and water (30 mL) was added to the reaction solution for dilution. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed sequentially with saturated aqueous sodium bicarbonate solution (30 mL × 3) and saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 020-1 (2.5 g, yield 49%).

[0388] 20.2 Preparation of Compound 020-2

[0389] 020-1 (2.0 g, 10.47 mmol) was weighed into a reaction flask, and ethanol (20 mL) and thioacetamide (787 mg, 10.47 mmol) were added. The reaction was refluxed at 90°C for 12 hours, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 020-2 (0.9 g, yield 51%). LC-MS: [M+H] + =168.10.

[0390] 20.3 Preparation of Compound 020

[0391] Synthesis of Compound 020: Refer to the synthesis method of Compound 002 in Example 2, except that 002-a is replaced with 020-2 to obtain Compound 020 (26.7 mg, yield 11.5%). LC-MS: [M+H] + =456.10. 020 was further chirally resolved to give 020A and 020B.

[0392] 1 H NMR(400MHz,dmso)δ10.65(d,J=792.0Hz,1H),8.81(s,1H),8.05(d,J=4.0Hz,1H),7.95(s,1H),4.98(d,J=8.0Hz,1H),3.13(s,3 H),3.02(s,3H),2.87–2.78(m,1H),2.77–2.68(m,1H),2.59(s,3H),1.80–1.69(m,1H),1.69–1.59(m,1H),0.97(d,J=8.0Hz,6H).

[0393] Characterization data of 020A:

[0394] LC-MS: [M+H] + =456.05. Chiral purity: 97.4%; T R: 14.503 min, HPLC method V.

[0395] 1 H NMR (400MHz, DMSO-d6): δ10.62(d,J=808Hz,1H),8.80(s,1H),8.03(t,J=4.0Hz,2H),4.99(d,J=12.0Hz,1H),3.15(s,3H),3 .03(s,3H),2.90–2.78(m,1H),2.78–2.69(m,1H),2.59(s,3H),1.77-1.70(m,1H),1.69–1.57(m,1H),0.97(d,J=8.0Hz,6H).

[0396] Characterization data of 020B:

[0397] LC-MS: [M+H] + =456.05. Chiral purity: 98.1%; T R : 10.954 min, HPLC method V.

[0398] 1 H NMR (400MHz, DMSO-d6): δ10.64(d,J=824Hz,1H),8.79(s,1H),8.04(t,J=4.0Hz,2H),4.99(d,J=12.0Hz,1H),3.15(s,3H),3 .03(s,3H),2.86-2.80(m,1H),2.76-2.67(m,1H),2.59(s,3H),1.77-1.70(m,1H),1.68–1.62(m,1H),0.97(d,J=8.0Hz,6H).

[0399] Example 21. Synthesis of 4-((3,4-dioxo-2-((4,6,6-trimethyl-5,6,7,8-tetrahydroquinolin-5-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 021)

[0400] 21.1 Preparation of Compound 021-1

[0401] Dissolve 021-a (1.712 g, 15 mmol) in toluene (30 mL), add crotonaldehyde (1.48 mL, 18 mmol) and palladium on carbon (4.8 g, 4.5 mmol, 10% wt), replace nitrogen three times, and reflux at 110°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1 / 3) to obtain compound 021-1 (640 mg, 3.97 mmol). LC-MS: [M+H] + =162.15.

[0402] 21.2 Preparation of Compound 021-2

[0403] Compound 021-1 (640 mg, 3.97 mmol) was dissolved in N,N-dimethylformamide (20 mL), the atmosphere was purged with nitrogen three times, and the temperature was lowered to 0°C. Sodium hydride (365 mg, 9.13 mmol, 60% wt dispersion in mineral oil) was added and stirred for 30 minutes. Methyl iodide (0.52 mL, 8.34 mmol) was then added and the mixture was brought to room temperature and allowed to react for 2 hours. Saturated aqueous ammonium chloride (20 mL) was then added and stirred for 20 minutes. The mixture was then diluted with water (200 mL) and extracted with ethyl acetate (80 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to yield compound 021-2 (586 mg, 3.1 mmol). LC-MS: [M+H] + =190.10.

[0404] 21.3 Preparation of Compound 021-3

[0405] Dissolve 021-2 (586 mg, 3.1 mmol) in methanol (15 mL), cool to 0°C, add sodium borohydride (353 mg, 9.3 mmol), stir for 20 minutes, then return to room temperature and continue stirring for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (100 mL) and extracted with dichloromethane (40 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 16 / 1) to obtain compound 021-3 (511 mg, 2.67 mmol). LC-MS: [M+H] + =192.15.

[0406] 21.4 Preparation of Compound 021-4

[0407] Dissolve 021-3 (511 mg, 2.67 mmol) and triethylamine (0.93 mL, 6.68 mmol) in N,N-dimethylformamide (10 mL). After cooling to 0°C, add methanesulfonyl chloride (310 μL, 4 mmol) and stir at this temperature for 40 minutes. Add sodium azide (520 mg, 8 mmol) to the system, transfer to a 60°C oil bath, and continue stirring for 4 hours. Dilute with water (150 mL) and extract with ethyl acetate (50 mL x 3). The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 021-4 (303 mg, 1.4 mmol). LC-MS: [M+H] + =217.15.

[0408] 21.5 Preparation of Compound 021-5

[0409] Dissolve 021-4 (281 mg, 1.3 mmol) in methanol (30 mL) and add wet palladium on carbon (138 mg, 0.13 mmol, 10% wt). Replace the hydrogen atmosphere three times and stir at room temperature for 4 hours. The reaction mixture is filtered through celite, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane / methanol = 8 / 1) to obtain compound 021-5 (102 mg, 0.54 mmol). LC-MS: [M+H] + =191.15.

[0410] 21.6 Preparation of Compound 021

[0411] Dissolve 021-5 (102 mg, 0.536 mmol), N,N-diisopropylethylamine (117 μL, 0.672 mmol), and 001-5 (133 mg, 0.436 mmol) in ethanol (2.5 mL) and react at 40°C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 021 (72.2 mg, 0.16 mmol). LC-MS: [M+H] + =450.10.

[0412] 1H NMR (600MHz, DMSO-d6): δ8.69(bs,1H),8.29(d,J=4.8Hz,1H),7.85(d,J=4.8Hz,1H),7.48(s,1H),7.07(d,J=4.8Hz,1H),5.05(s,1 H),2.90(s,3H),2.89(s,3H),2.87-2.82(m,2H),2.23(s,3H),1.88-1.83(m,1H),1.48(d,J=10.4Hz,1H),1.01(s,3H),0.87(s,3H).

[0413] Example 22: Synthesis of 4-((3,4-dioxo-2-((2,6,6-trimethyl-5,6,7,8-tetrahydroquinolin-5-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 022)

[0414] 22.1 Preparation of Compound 022-1

[0415] 022-a (600.0 mg, 3.3 mmol) was dissolved in 1,4-dioxane and water (10 mL, 10 / 1), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (80.0 mg, 0.09 mmol), trimethylcyclotriboroxine (622.06 mg, 4.96 mmol) and anhydrous potassium carbonate (1.37 g, 9.91 mmol) were added in sequence. The nitrogen atmosphere was replaced three times, and the mixture was reacted at 100°C overnight. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 022-1 (410.0 mg). LC-MS: [M+H] + =162.10.

[0416] 22.2 Preparation of Compound 022-2

[0417] 022-1 (410.0 mg, 2.54 mmol) was dissolved in N,N-dimethylformamide (10 mL), and the nitrogen atmosphere was replaced three times. Sodium hydride (223.8 mg, 5.6 mmol, 60% wt dispersed in mineral oil) was slowly added at 0°C. The reaction was continued at 0°C for 1 hour. Methyl iodide (794.21 mg, 5.6 mmol) was added, and the mixture was allowed to warm to room temperature and react for 3 hours. The reaction solution was quenched with water and extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 022-2 (406.0 mg). LC-MS: [M+H]+ =190.10.

[0418] 22.3 Preparation of Compound 022-3

[0419] 022-2 (300 mg, 1.59 mmol) was dissolved in ethanol (10 mL), and sodium acetate (780 mg, 9.51 mmol) and hydroxylamine hydrochloride (661 mg, 9.51 mmol) were added. The mixture was allowed to react at 80°C overnight. The reaction solution was concentrated under reduced pressure to remove the solvent. Water (10 mL) was added to the residue, and extraction was performed with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 022-3 (200.0 mg). LC-MS: [M+H] + =205.10.

[0420] 22.4 Preparation of Compound 022-4

[0421] Dissolve 022-3 (200 mg, 0.98 mmol) in methanol (10 mL), add 10% wt wet palladium on carbon (100 mg), replace the hydrogen atmosphere three times, and react at 60°C under a hydrogen balloon atmosphere for 3 hours. The reaction solution is filtered to remove the palladium on carbon, and the filtrate is concentrated under reduced pressure to obtain compound 022-4 (140.0 mg, crude product). LC-MS: [M+H] + =191.15.

[0422] 22.5 Preparation of Compound 022

[0423] 022-4 (140 mg, crude product) was dissolved in ethanol (5 mL), and N,N-diisopropylethylamine (285 mg, 2.21 mmol) and 001-5 (112 mg, 0.37 mmol) were added. The mixture was reacted at 40°C for 2 hours. The reaction solution was purified by preparative HPLC to obtain compound 022 (112.2 mg). LC-MS: [M+H] + =450.10.

[0424] 1H NMR (400MHz, DMSO-d6): δ8.72(d,J=9.6Hz,1H),8.04(d,J=5.4Hz,1H),7.89(d,J=5.2Hz,1H),7.56(d,J=8.0Hz,1H),7.08(d,J=8.0Hz,1H),5.00(d,J=9 .2Hz,1H),3.03(d,J=39.8Hz,6H),2.81(tt,J=18.4,9.0Hz,2H),2.40(s,3H ),1.86–1.73(m,1H),1.67(dt,J=13.8,7.0Hz,1H),0.94(d,J=22.8Hz,6H).

[0425] Example 23. Synthesis of 4-((2-((1-(1,4-dimethyl-1H-pyrazol-3-yl)cyclopentyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 023)

[0426] 23.1 Preparation of Compound 023-1

[0427] At room temperature, 023-a (10.0 g, 121 mmol) was dissolved in N,N-dimethylformamide (50 mL), and N-iodosuccinimide (22.4 g, 121 mmol) was added. The mixture was allowed to react at room temperature for 4 hours. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 023-1 (12.0 g, yield 47.4%). LC-MS: [M+H] + =208.9.

[0428] 23.2 Preparation of Compound 023-2

[0429] At room temperature, sodium hydride (2.9 g, 72.50 mmol, 60% wt dispersion in mineral oil) was added to tetrahydrofuran (100 mL). 023-1 (11.6 g, 55.70 mmol) was slowly added at 0°C. The mixture was stirred at 0°C for 1 hour, followed by the addition of iodomethane (8.7 g, 61.27 mmol). The temperature was raised to room temperature and the reaction continued for 3 hours. The reaction solution was slowly poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 023-2 (3.4 g, 27.6% yield).

[0430] 23.3 Preparation of Compound 023-3

[0431] At room temperature, 023-b (2 g, 23.8 mmol), tert-butylsulfenamide (2.9 g, 23.8 mmol), tetraethyl titanate (13.6 g, 59.5 mmol), and tetrahydrofuran (40 mL) were added to a reaction flask. The atmosphere was purged with nitrogen three times and the reaction was carried out at 50°C for 1 hour. The reaction solution was poured into saturated brine (20 mL). A large amount of solid precipitated and was filtered through a pad of celite. The filter cake was rinsed with ethyl acetate, and the filtrate was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 023-3 (1.0 g, crude product).

[0432] 23.4 Preparation of Compound 023-4

[0433] At room temperature, 023-2 (888 mg, 4.0 mmol) and anhydrous dichloromethane (6 mL) were added to the reaction flask, replaced with nitrogen three times, and n-butyllithium hexane solution (2.5 mL, 4.0 mmol, 1.6 M) was added at -78 ° C. After stirring for 10 minutes, 023-3 (300 mg, 1.6 mmol) was added. The system was warmed to room temperature and continued to stir for 1 hour. The reaction solution was quenched with aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 023-4 (30 mg, crude product). LC-MS: [M+H] + =284.05.

[0434] 23.5 Preparation of Compound 023-5

[0435] At room temperature, 023-4 (36 mg, 0.13 mmol) was dissolved in a mixture of 1,4-dioxane (1 mL, 4 M) and dichloromethane (1 mL) in hydrogen chloride and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain compound 023-5 (30 mg). LC-MS: [M-NH2] + =163.15.

[0436] 23.6 Preparation of Compound 023

[0437] At room temperature, 023-5 (20 mg, 110 μmol), 001-5 (33 mg, 110 μmol), and N,N-diisopropylethylamine (42 mg, 330 μmol) were dissolved in ethanol (2 mL) and stirred at 30°C for 0.5 hours. The reaction mixture was purified by preparative HPLC (basic conditions) and freeze-dried to give compound 023 (4.2 mg). LC-MS: [M+H] + =439.05.

[0438] 1 H NMR (400MHz, DMSO-d6): δ8.98(s,1H),7.90-7.80(m,1H),7.32-7.30(m,1H),3. 67(s,3H),3.14(s,3H),3.04(s,3H),2.27-2.25(m,3H),2.12–1.98(m,1H),1.75 -1.72(m,4H),1.22(s,3H).

[0439] Example 24. Synthesis of 4-((2-((1-ethylcyclopentyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 024)

[0440] 24.1 Preparation of Compound 024-1

[0441] 024-a (1.0 g, 8.92 mmol) was dissolved in a reaction flask with ethanol (5 mL). Thionyl chloride (0.53 g, 4.45 mmol) was added dropwise at 0°C and allowed to react at room temperature for 2 hours. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 024-1 (1.02 g, yield: 81.6%).

[0442] 24.2 Preparation of Compound 024-2

[0443] Tetrahydrofuran (10 mL) and diisopropylamine (541 mg, 5.35 mmol) were placed in a three-necked flask. The atmosphere in the flask was replaced with nitrogen. n-Butyllithium solution (3.4 mL, 5.44 mmol, 1.6 M) was slowly added at -78°C, and the mixture was slowly warmed to room temperature and allowed to react for 1 hour. Compound 024-1 (500 mg, 3.56 mmol) was then added at -78°C. After reacting at -78°C for 1 hour, iodoethane (829 mg, 5.35 mmol) was added dropwise. The mixture was slowly warmed to room temperature and allowed to react for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated aqueous sodium chloride (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford compound 024-2 (480 mg, yield: 79.99%).

[0444] 24.3 Preparation of Compound 024-3

[0445] 024-2 (450 mg, 2.67 mmol) was dissolved in methanol (4 mL), and aqueous sodium hydroxide solution (2 mL, 2 M) was added. The mixture was refluxed at 80°C for 4 hours. The methanol was removed by concentration under reduced pressure, and the residue was diluted with water (4 mL). The mixture was extracted with diethyl ether (10 mL x 3), and the aqueous phase was retained. The aqueous phase was adjusted to pH 3-4 with dilute hydrochloric acid (1 M) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford compound 024-3 (480 mg, crude product), which was used directly in the next step.

[0446] 24.4 Preparation of Compound 024-4

[0447] Compound 024-3 (380 mg) was placed in a reaction flask and dissolved in 1,4-dioxane (10 mL). Benzyl alcohol (451 mg, 4.17 mmol), N,N-diisopropylethylamine (1.08 g, 8.35 mmol), and diphenylphosphoryl azide (919 mg, 3.34 mmol) were then added sequentially. The mixture was refluxed at 80°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 19 / 1) to afford compound 024-4 (100 mg).

[0448] 24.5 Preparation of Compound 024-5 Hydrochloride

[0449] 024-4 (100 mg, 0.4 mmol) was dissolved in methanol (5 mL), and wet palladium on carbon (10 mg, 10% palladium content) was added. The mixture was replaced with hydrogen three times and reacted under a hydrogen atmosphere at room temperature for 1 hour. The palladium on carbon was removed by filtration, and a solution of hydrogen chloride in ethyl acetate (1 mL, 1 M) was added to the filtrate. The mixture was stirred and mixed thoroughly, and then concentrated under reduced pressure to obtain 024-5 hydrochloride (135 mg).

[0450] 24.6 Preparation of Compound 024

[0451] 024-5 hydrochloride (135 mg, 0.90 mmol) was placed in a reaction flask and dissolved in ethanol (5 mL). N,N-diisopropylethylamine (158 mg, 1.22 mmol) and 001-5 (99.24 mg, 0.31 mmol) were added and reacted at room temperature for 1 hour. The reaction solution was directly concentrated, and the residue was purified by preparative HPLC to obtain compound 024 (4.8 mg). LC-MS: [M+H] + =373.05.

[0452] 1 H NMR (400MHz, DMSO-d6): δ9.71(s,1H),8.60(s,2H),7.99(s,2H),3.15(s,3H),3.04(s,3H),1.94 (s, 2H), 1.80 (d, J = 7.4Hz, 2H), 1.68 (d, J = 7.8Hz, 5H), 1.20–1.10 (m, 1H), 0.84 (t, J = 7.4Hz, 3H).

[0453] Example 25. Synthesis of 4-((2-((1-(1,4-dimethyl-1H-pyrazol-3-yl)cyclobutyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 025)

[0454] 25.1 Preparation of Compound 025

[0455] Synthesis of Compound 025: Refer to the synthesis method of Compound 023 in Example 23, except that 023-b is replaced with 025-a to obtain Compound 025 (10.3 mg). LC-MS: [M+H] + =425.10.

[0456] 1H NMR (400MHz, DMSO-d6): δ11.63(s,1H),9.81-9.58(m,1H),9.07(s,1H),7.97(s,2H),7.49(s,1H),3. 77(s,3H),3.15(s,3H),3.03(s,3H),2.72-2.67(m,4H),1.99(s,3H),1.90(s,1H),1.76–1.55(m,1H).

[0457] Example 26. Synthesis of 4-((2-((1-(1,4-dimethyl-1H-pyrazol-3-yl)cyclopropyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 026)

[0458] 26.1 Preparation of Compound 026-1

[0459] 023-2 (1.0 g, 4.50 mmol) and cuprous cyanide (806 mg, 9.00 mmol) were weighed into a reaction flask. The atmosphere was purged with nitrogen three times, and dimethyl sulfoxide (12 mL) was added. The reaction was allowed to react at 150°C for 3 hours. The reaction mixture was poured into an aqueous solution (40 mL) for quenching and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 026-1 (340 mg, 62.50% yield).

[0460] 26.2 Preparation of Compound 026-2

[0461] 026-1 (340 mg, 2.81 mmol) was dissolved in ultra-dry tetrahydrofuran (8 mL) and the atmosphere was replaced with nitrogen three times. Tetraisopropoxytitanium (0.86 mL, 5.62 mmol) was added, followed by the dropwise addition of ethylmagnesium bromide (7.0 mL, 7.00 mmol) at -78°C. After completion of the addition, the mixture was allowed to warm to room temperature and react for 2 hours. Boron trifluoride etherate (0.75 mL, 5.62 mmol) was added dropwise at 0°C. After completion of the addition, the mixture was allowed to warm to room temperature and react for 1 hour. The reaction mixture was poured into water (20 mL) for quenching and extracted with ethyl acetate (30 mL x 2). The aqueous phase was adjusted to pH 3 with 2N hydrochloric acid solution and stirred for 0.25 hours. Aqueous sodium hydroxide solution (6N) was then added dropwise to adjust the pH to 10. The mixture was then extracted with dichloromethane / methanol (10 / 1). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 026-2 (220 mg, yield 51.88%). LC-MS: [M+H] + =152.15.

[0462] 26.3 Preparation of Compound 026

[0463] 026-2 (200 mg, 1.32 mmol) was dissolved in ethanol (2 mL), and 001-5 (200 mg, 0.66 mmol) and N,N-diisopropylethylamine (322 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by preparative HPLC (alkaline conditions) and freeze-dried to obtain compound 026 (44.7 mg). LC-MS: [M+H] + =411.00.

[0464] 1 H NMR (400MHz, DMSO-d6): δ11.53(s,1H),10.35(s,1H),9.67(s,1H),7.98(s,1H),7.62–7.23(m,2H),3.72(d, J=34.4Hz, 3H), 3.18 (d, J=26.4Hz, 3H), 3.04 (s, 3H), 2.04 (d, J= 30.2Hz, 3H), 1.22 (dd, J= 39.8, 27.0Hz, 4H).

[0465] Example 27. Synthesis of 4-((2-((1-(6-fluoro-3-methylpyridin-2-yl)cyclopentyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 027)

[0466] 27.1 Preparation of Compound 027-1

[0467] 027-a (0.5 g, 2.67 mmol) was weighed into a reaction flask and a pyridine hydrofluoride solution (4 mL, 70 wt%) was added at 0°C, followed by sodium nitrite (0.37 g, 5.35 mmol) and stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 7-8 by adding a saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 027-1 (0.4 g, yield 79%). LC-MS: [M+H] + =189.95.

[0468] 27.2 Preparation of Compound 027-2

[0469] 027-1 (237 mg, 1.25 mmol) was dissolved in tetrahydrofuran (7 mL), replaced with nitrogen three times, and n-butyl lithium (0.95 mL, 1.51 mmol) was added dropwise to the reaction solution at -78 ° C. and reacted at this temperature for 0.5 hours. Subsequently, a solution of 023-3 (234 mg, 1.25 mmol) in tetrahydrofuran (0.5 mL) was added dropwise to the above reaction solution and reacted at -78 ° C for 1 hour. The reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL) for quenching, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL). After drying over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 027-2 (51 mg, yield 13.71%). LC-MS: [M+H] + =299.05.

[0470] 27.3 Preparation of Compound 027-3

[0471] At room temperature, 027-2 (51 mg, 0.17 mmol) was dissolved in a solution of hydrogen chloride in ethanol (3 mL, 1 M) and stirred at room temperature for 0.5 hours. The reaction solution was directly concentrated under reduced pressure to obtain compound 027-3 (45 mg, crude product). LC-MS: [M+H] + =195.10.

[0472] 27.4 Preparation of Compound 027

[0473] 027-3 (45 mg, 0.23 mmol) was dissolved in ethanol (2 mL), and 001-5 (70 mg, 0.23 mmol) and N,N-diisopropylethylamine (148 mg, 1.15 mmol) were added. The mixture was stirred at 80°C for 5 hours. The reaction mixture was separated and purified by HPLC preparative chromatography (basic conditions) and freeze-dried to obtain compound 027 (5.7 mg). LC-MS: [M+H] + =454.00.

[0474] 1 H NMR (400MHz, DMSO-d6): δ11.74(s,1H),9.68(s,1H),9.17(s,1H),7.98(d,J=10.6Hz,2H),7.70(t,J=8.2Hz,1H),6.9 5(dd,J=8.2,3.8Hz,1H),3.18(s,3H),3.05(s,3H),2.46(s,2H),2.34(s,3H),2.29–2.16(m,2H),1.90–1.70(m,4H).

[0475] Example 28. Synthesis of N-cyclopropyl-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methylpicolinamide (Compound 028)

[0476] 28.1 Preparation of Compound 028-1

[0477] Compound 001-a (3.0 g, 15.99 mmol) was weighed into a reaction flask, and tetrahydrofuran (20 mL), tert-butyl alcohol (10 mL), di-tert-butyl dicarbonate (7.0 g, 31.99 mmol), and 4-dimethylaminopyridine (585.7 mg, 4.7 mmol) were added. The mixture was allowed to react at 25°C for 4 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 028-1 (3.2 g, 84.2% yield).

[0478] 28.2 Preparation of Compound 028-2

[0479] 028-1 (2.5 g, 10.26 mmol) was weighed and dissolved in tetrahydrofuran (50 mL). 028-a (4.3 g, 30.78 mmol), sodium carbonate (1.6 g, 15.39 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (250 mg, 10 wt%), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (250 mg, 10 wt%) were added in sequence. The mixture was reacted at 80°C under nitrogen for 4 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 028-2 (1.2 g, yield 34.2%). LCMS: [M+H] + =349.1.

[0480] 28.3 Preparation of Compound 028-3

[0481] Dissolve 028-2 (319 mg, 0.92 mmol), 010-5 (600 mg, 3.06 mmol), and N,N-diisopropylethylamine (1.19 g, 9.17 mmol) in ethanol (5 mL) and stir at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain compound 028-3 (650 mg). LC-MS: [M+H] + =499.10.

[0482] 28.4 Preparation of Compound 028-4

[0483] Dissolve 028-3 (650 mg, 1.3 mmol) in trifluoroacetic acid and dichloromethane (1 / 1, 5 mL), react at room temperature for 6 hours, and concentrate the reaction solution under reduced pressure to obtain compound 028-4 (900 mg, crude product). LC-MS: [M+H] + =443.10.

[0484] 28.5 Preparation of Compound 028-5

[0485] 028-4 (250 mg, 0.46 mmol) was dissolved in dichloromethane (2 mL), and triethylamine (187 mg, 1.85 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (264 mg, 0.69 mmol), and 028-b (33 mg, 0.46 mmol) were added in sequence. The mixture was reacted at room temperature for 1 hour. Water (10 mL) was then added to the reaction solution, which was then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 028-5 (170 mg). LC-MS: [M+H] + =496.15.

[0486] 28.6 Preparation of Compound 028

[0487] At room temperature, 028-5 (170 mg, 0.34 mmol) was dissolved in dichloromethane (1 mL), cooled to 0°C in an ice-water bath, and then a dichloromethane solution of boron tribromide (1 M, 1.7 mL, 1.72 mmol) was added. After the addition, the mixture was allowed to react at room temperature for 5 hours. The reaction solution was quenched with methanol (5 mL) and purified by preparative HPLC (acidic conditions) and then by preparative HPLC (alkaline conditions). The mixture was freeze-dried to obtain compound 028 (30.1 mg). LC-MS: [M+H] + =482.15.

[0488] 1H NMR (400MHz, DMSO-d6): δ10.45(s,1H),9.62(s,1H),8.84(s,1H),8.01(s,2H),5.11(d,J=9.6Hz,1H),3.01(s,3H),2.89(s,1H),2 .78–2.64(m,2H),2.62(d,J=10.4Hz,3H),1.77(dt,J=6.0,5.2Hz,1H),1.72–1.62(m,1H),1.01(s,3H),0.99(s,3H),0.47(s,4H).

[0489] Example 29. Synthesis of N,N-dicyclopropyl-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxypicolinamide (Compound 029)

[0490] 29.1 Preparation of Compound 029-1

[0491] 028-4 (250 mg, 0.46 mmol) was dissolved in dichloromethane (2 mL), and triethylamine (187 mg, 1.85 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (264 mg, 0.69 mmol), and 029-a (45 mg, 0.46 mmol) were added in sequence. The mixture was allowed to react at room temperature for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 029-1 (110 mg). LC-MS: [M+H] + =522.15.

[0492] 29.2 Preparation of Compound 029 Hydrochloride

[0493] At room temperature, 029-1 (110 mg, 0.21 mmol) was dissolved in dichloromethane (1 mL), cooled to 0°C in an ice-water bath, and then a dichloromethane solution of boron tribromide (1 mL, 1.05 mmol, 1 M) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was quenched with methanol (2 mL), purified by HPLC (acidic conditions), and freeze-dried to obtain compound 029 hydrochloride (16.3 mg). LC-MS: [M+H] + =508.15.

[0494] 1H NMR (400MHz, DMSO-d6): δ10.62(s,1H),9.46(d,J=9.7Hz,1H),8.39(d,J=6.5Hz,1H),8.31(d,J=6.5Hz,1H),5.11(d,J=9.6Hz,1H),2.82–2.65(m,4 H),2.62(s,3H),1.85(dt,J=13.2,6.4Hz,1H),1.71–1.62(m,1H),1.01(s ,6H),0.99–0.88(m,2H),0.83(d,J=16.7Hz,2H),0.60(d,J=23.2Hz,4H).

[0495] 29.3 Preparation of Compound 029

[0496] The resulting 029 hydrochloride was freed with a saturated sodium bicarbonate aqueous solution, adjusted to pH 8-9, and extracted with ethyl acetate (5 mL x 3). The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and freeze-dried to obtain compound 029. LC-MS: [M+H] + =508.15.

[0497] Example 30. Synthesis of N-cyclobutyl-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methylpicolinamide (Compound 030)

[0498] 30.1 Preparation of Compound 030

[0499] Synthesis of Compound 030: Refer to the synthesis method of Compound 028 in Example 28, except that 028-b is replaced with 030-a to obtain Compound 030 (47.0 mg). LC-MS: [M+H] + =496.15.

[0500] 1 H NMR (400MHz, DMSO-d6): δ9.60(s,1H),8.81(s,1H),7.99(s,2H),5.09(d,J=12.0Hz,2H),4.38(s,1H),2.99(s,3H),2.80–2.63(m,2H),2 .58(s,3H),2.30–2.14(m,2H),2.05–1.85(m,2H),1.81–1.70(m,1H),1.68–1.61(m,1H),1.50(d,J=52.0Hz,2H),0.98(d,J=8.0Hz,6H).

[0501] Example 31. Synthesis of 3-((2-(3,3-difluoropyrrolidine-1-carbonyl)-3-hydroxypyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 031)

[0502] 31.1 Preparation of Compound 031-1

[0503] At room temperature, 028-4 (124 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine was added to adjust the pH to 10. A solution of 1-propylphosphoric anhydride in ethyl acetate (267 mg, 0.42 mmol, 50% ethyl acetate solution) was added and the mixture was reacted for 10 minutes. The reaction mixture was added to a solution of 031-a (48 mg, 0.34 mmol) and N,N-diisopropylethylamine in N,N-dimethylformamide (1 mL) and the mixture was reacted for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 031-1 (130 mg, yield 87.2%). LC-MS: [M+H] + =532.10.

[0504] 31.1 Preparation of Compound 031

[0505] At room temperature, 031-1 (100 mg, 0.19 mmol) was dissolved in dichloromethane (1 mL), and a dichloromethane solution of boron tribromide (0.57 mL, 1 M) was added. The mixture was allowed to react at room temperature for 16 hours. Methanol (2 mL) was added to the reaction solution to quench the reaction, which was then diluted with water (5 mL) and extracted with dichloromethane (5 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (0.1% hydrochloric acid conditions) and freeze-dried to obtain compound 031 (10.2 mg, yield 10%). LC-MS: [M+H] + =518.15.

[0506] 1H NMR (400MHz, DMSO-d6): δ9.71(s,1H),8.84(s,1H),8.12(d,J=11.6Hz,3H),5.10(d,J =9.6Hz,1H),4.51(d,J=12.8Hz,2H),4.31(s,1H),4.01(t,J=13.2Hz,1H),3.83(t,J=7 .2Hz,2H),3.29(s,2H),2.81–2.73(m,1H),2.69(d,J=9.6Hz,2H),2.61(s,4H),1.78(m ,2H),1.73–1.63(m,2H),1.23(s,2H),1.19(d,J=12.0Hz,2H),1.00(d,J=10.4Hz,9H).

[0507] Example 32. Synthesis of 3-((2-(3-fluoroazetidine-1-carbonyl)-3-hydroxypyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 032)

[0508] 32.1 Preparation of Compound 032-1

[0509] At room temperature, 028-4 (200 mg, 0.45 mmol), 032-a (62 mg, 0.54 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (256 mg, 0.67 mmol), and N,N-diisopropylethylamine (290 mg, 2.25 mmol) were added to N,N-dimethylformamide (4 mL) and stirred at room temperature for 1 hour. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (system dichloromethane / methanol = 20 / 1) to obtain compound 032-1 (500 mg, yield 148%). LC-MS: [M+H] + =500.10.

[0510] 32.2 Preparation of Compound 032

[0511] 032-1 (400 mg, 0.80 mmol) was directly added to a dichloromethane solution of boron tribromide (8 mL, 1 M) and allowed to react at room temperature for 2 hours. The reaction solution was directly concentrated, and the residue was quenched with water (10 mL). The pH was adjusted to 7 with saturated sodium bicarbonate, and finally extracted with dichloromethane / methanol = 10 / 1 (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by high-performance liquid chromatography (0.1% ammonia solution) and lyophilized to obtain compound 032 (113.2 mg, yield 23.34%). LC-MS [M+H] + =486.10.

[0512] 1 H NMR (600MHz, DMSO-d6): δ13.53(s,1H),9.70(s,1H),8.81(s,1H),8.25–7. 95(m,2H),5.46(d,J=57.6Hz,1H),5.14–4.98(m,2H),4.80–4.68(m,1H),4. 55–4.44(m,1H),4.25–4.13(m,1H),2.80–2.73(m,1H),2.71–2.64(m,1H), 2.60(s,3H),1.80–1.73(m,1H),1.71–1.62(m,1H),1.00(d,J=16.2Hz,6H).

[0513] Example 33. Synthesis of 3-((2-(3,3-difluoroazetidine-1-carbonyl)-3-hydroxypyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 033)

[0514] 33.1 Preparation of Compound 033

[0515] Synthesis of Compound 033: Refer to the synthesis method of Compound 032 in Example 32, except that 032-a is replaced with 033-a to obtain Compound 033 (5.6 mg, yield 4.11%). LC-MS [M+H] + =504.10.

[0516] 1H NMR (400MHz, DMSO-d6): δ13.10(s,1H),9.72(s,1H),8.81(d,J=9.1Hz,1H),8.13(d,J=5.4Hz,1H),8.06(s,1H),5.10( t,J=11.0Hz,3H),4.58(t,J=12.4Hz,2H),2.81–2.63(m,2H),2.60(s,3H),1.80–1.62(m,2H),0.99(d,J=10.8Hz,6H).

[0517] Example 34. Synthesis of 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpicolinamide (Compound 034)

[0518] 34.1 Preparation of Compound 034

[0519] Synthesis of Compound 034: Refer to the synthesis method of Compound 032 in Example 32, except that 032-a is replaced with 034-a to obtain Compound 034 (88.2 mg, yield 36.2%). LC-MS [M+H] + =470.10.

[0520] 1 H NMR (400MHz, DMSO-d6): δ9.68(s,1H),8.86(s,1H),8.03–7.96(m,2H),5.10(d,J=9.6Hz,1H),3.33(s,3H),3.12(s,1H),3.00(s,1H), 2.77–2.70(m,1H),2.69–2.63(m,1H),2.60(s,3H),1.80–1.74(m,1H),1.71–1.61(m,1H),1.14–1.13(m,3H),0.99(d,J=17.6Hz,6H).

[0521] Example 35. Synthesis of 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methyl-N-(2,2,2-trifluoroethyl)picolinamide (Compound 035)

[0522] 35.1 Preparation of Compound 035

[0523] Synthesis of Compound 035: Refer to the synthesis method of Compound 031 in Example 31, except that 031-a is replaced with 035-a to obtain Compound 035 (32 mg, yield 13%). LC-MS: [M+H] + =524.10.

[0524] 1 H NMR (600MHz, DMSO-d6): δ9.68(s,1H),8.88(s,2H),8.07(d,J=27.2Hz,4H),5.10(d,J=9.2Hz,2H),4.82(s,1H),4.38(q,J=9.2Hz,2H),3.12(d ,J=32.0Hz,6H),2.75(m,2H),2.70–2.64(m,2H),2.60(s,6H),2.50(s, 17H),1.82–1.73(m,2H),1.70–1.64(m,2H),1.01(s,6H),0.98(s,7H).

[0525] Example 36. Synthesis of 3-((3-hydroxy-2-(4-methylisothiazol-5-yl)pyridin-4-yl)amino-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 036)

[0526] 36.1 Preparation of Compound 036-1

[0527] 001-a (3.00 g, 15.99 mmol) was dissolved in N,N-dimethylformamide (33 mL). The reaction mixture was cooled to 0°C. N,N-diisopropylethylamine (8.40 mL, 47.97 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (7.30 g, 19.19 mmol), and dimethylhydroxylamine hydrochloride (1.73 g, 17.59 mmol) were then added sequentially to the reaction mixture. The mixture was allowed to return to room temperature and allowed to react for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 036-1 (2.83 g, 69.05% yield). LC-MS: [M+H] + =231.00.

[0528] 36.2 Preparation of Compound 036-2

[0529] 036-1 (2.00 g, 8.67 mmol) was dissolved in ultra-dry tetrahydrofuran (28 mL) and replaced with nitrogen three times. The reaction solution was then cooled to 0°C and ethylmagnesium bromide (10.50 mL, 10.50 mmol) was added dropwise to the reaction solution. The reaction was then allowed to react at room temperature for 3 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution (30 mL) for quenching and then extracted with ethyl acetate (40 mL × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 036-2 (957 mg, yield 49.76%). LC-MS: [M+H] + =200.00.

[0530] 36.3 Preparation of Compound 036-3

[0531] Dissolve 036-2 (758 mg, 3.80 mmol) in N,N-dimethylformamide dimethyl acetal (8 mL), replace the atmosphere with nitrogen three times, and heat the reaction system to 100°C for 16 hours. The reaction solution was directly concentrated under reduced pressure without post-treatment to obtain compound 036-3 (800 mg, crude product). LC-MS: [M+H] + =255.05.

[0532] 36.4 Preparation of Compound 036-4

[0533] 036-3 (750 mg, 2.94 mmol) was dissolved in ethanol (8 mL) at room temperature, followed by the addition of hydroxylamine hydrochloride (307 mg, 4.42 mmol). The mixture was heated to 80°C and reacted for 0.5 hours. The reaction solution was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 036-4 (110 mg, 14.97% yield).

[0534] 36.5 Preparation of Compound 036-5

[0535] 036-4 (110 mg, 0.48 mmol) was dissolved in ultra-dry tetrahydrofuran (3 mL). Compound 028-a (270 mg, 1.47 mmol), sodium carbonate (77.8 mg, 0.73 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (39.7 mg, 0.05 mmol), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (21.2 mg, 0.05 mmol) were then added to the reaction solution. The atmosphere was then purged with nitrogen three times and the reaction mixture was allowed to react at 80°C for 16 hours. The reaction solution was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 036-5 (195 mg, 84.65% yield). LC-MS: [M+H] + =329.95.

[0536] 36.6 Preparation of Compound 036-6

[0537] 036-5 (130 mg, 0.39 mmol) was dissolved in ethanol (12 mL), followed by the addition of 010-5 (154 mg, 0.78 mmol) and N,N-diisopropylethylamine (252 mg, 1.95 mmol). The mixture was stirred at 40°C for 16 hours. The reaction mixture was directly concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 036-6 (160 mg, yield 67.61%). LC-MS: [M+H] + =480.15.

[0538] 36.7 Preparation of Compound 036

[0539] 036-6 (80 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL). Boron tribromide (1.60 mL, 1.60 mmol) was slowly added dropwise at 0°C. After completion of the addition, the mixture was allowed to react at room temperature for 16 hours. The reaction solution was poured into methanol (5 mL) for quenching and concentrated under reduced pressure. The residue was purified by preparative HPLC (alkaline conditions) and freeze-dried to obtain compound 036 (24.5 mg, 99.0% purity). LC-MS: [M+H] + =466.10.

[0540] 1H NMR (400MHz, DMSO-d6): δ9.77(s,2H),8.97(s,1H),8.55(s,1H),8.11(s,1H),5.12(d,J=9.6Hz,1H),2.78–2.67(m, 2H), 2.61 (s, 3H), 2.14 (s, 3H), 1.78 (dd, J = 13.8, 7.0Hz, 1H), 1.68 (dd, J = 13.4, 6.6Hz, 1H), 1.01 (d, J = 10.4Hz, 6H).

[0541] Example 37. Synthesis of 3-((3-hydroxy-2-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-4-yl)amino)-4-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)amino)cyclobut-3-ene-1,2-dione (Compound 037)

[0542] 37.1 Preparation of Compound 037-1

[0543] 001-a (2.0 g, 10.66 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (20 mL) and potassium carbonate (2.2 g, 15.92 mmol) were added. Methyl iodide (2.3 g, 16 mmol) was then slowly added and stirred at room temperature for 2 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain compound 037-1 (2.15 g, yield 100%).

[0544] 37.2 Preparation of Compound 037-2

[0545] Weigh 037-1 (2.0 g, 9.92 mmol) into a reaction flask, add methanol (20 mL) and hydrazine hydrate (2.5 g, 49.60 mmol), and stir at 70°C for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove methanol. Ether (30 mL) was added, stirred at room temperature for 30 minutes, filtered, and the filter cake was vacuum dried to obtain 037-2 (3.2 g, crude product). LC-MS: [M+H] + =202.00.

[0546] 37.3 Preparation of Compound 037-3

[0547] 037-2 (2.2 g, 10.91 mmol) was weighed into a reaction flask, and N,N-dimethylformamide dimethyl acetal (20 mL) was added. The mixture was stirred at 100°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 037-3 (2.2 g, yield 78.5%).

[0548] 37.4 Preparation of Compound 037-4

[0549] 037-3 (2.0 g, 7.8 mmol) was weighed into a reaction flask, and methylamine hydrochloride (2.64 g, 39.0 mmol), acetonitrile (10 mL), and glacial acetic acid (2 mL) were added. The mixture was stirred at 90°C for 16 hours. The reaction solution was cooled to 20°C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to obtain compound 037-4 (1.5 g, yield 85.7%). LC-MS: [M+H] + =225.00.

[0550] 37.5 Preparation of Compound 037-5

[0551] 037-4 (1.2 g, 5.40 mmol) was weighed into a reaction flask and 1,4-dioxane (20 mL), tert-butyl carbamate (960 mg, 8.02 mmol), cesium carbonate (3.5 g, 10.70 mmol), palladium acetate (120 mg, 0.54 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (254 mg, 0.54 mmol) were added. The mixture was stirred at 100°C under nitrogen for 16 hours. The reaction solution was cooled to 20°C and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 1 / 3) to obtain compound 037-5 (1.2 g, yield 76%). LC-MS: [M+H] + =306.05.

[0552] 37.6 Preparation of Compound 037-6

[0553] 037-5 (1.2 g, 4.0 mmol) was dissolved in dichloromethane (10 mL). A solution of hydrogen chloride in 1,4-dioxane (5 mL, 4 M) was added, and the mixture was stirred at 20°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to afford compound 037-6 (0.5 g, 62% yield).

[0554] 37.7 Preparation of Compound 037-7

[0555] 037-6 (200 mg, 0.97 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (5 mL) was added. Sodium hydride (60 mg, 1.46 mmol) was slowly added at 0°C under nitrogen protection. The reaction was allowed to react at 0°C for 0.5 hours. 001-b (160 mg, 0.97 mmol) was then added dropwise to the reaction solution. After the addition was complete, the temperature was raised to room temperature and stirred for 2 hours. Water (10 mL) was added at 0°C to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 037-7 (0.2 g, 62.5% yield).

[0556] 37.8 Preparation of Compound 037-8

[0557] 037-7 (150 mg, 0.455 mmol) was weighed into a reaction flask, and 020-4 (89.4 mg, 0.455 mmol), ethanol (3 mL), and N,N-diisopropylethylamine (177 mg, 1.37 mmol) were added. The mixture was stirred at 55°C for 12 hours and concentrated under reduced pressure to obtain a residue which was purified by silica gel column chromatography to obtain compound 037-8 (120 mg, 55% yield). LC-MS: [M+H] + =480.15.

[0558] 37.9 Preparation of Compound 037

[0559] 037-8 (120 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL) under nitrogen protection. Boron tribromide (1.5 mL, 1.5 mmol) was slowly added dropwise at 0°C, maintaining the temperature at 0°C. After the addition was complete, the reaction was allowed to react at room temperature overnight. Methanol (10 mL) was then slowly added dropwise to quench the reaction. The mixture was concentrated and purified by preparative HPLC (basic conditions) to obtain compound 037 (45.1 mg, 38.7% yield). LC-MS: [M+H] + =466.10.

[0560] 1 H NMR (400MHz, DMSO-d6): δ9.82(s,1H),8.85(d,J=8.0Hz,1H),8.78(s,1H),8.18(d,J=8.0Hz,1H),8.13(d,J=8.0Hz,1H),5.12(d,J=12. 0Hz,1H),4.15(s,3H),2.84-2.73(m,1H),2.72-2.69(m,1H),2.61(s,3H),1.82-1.76(m,1H),1.72–1.65(m,1H),1.02(d,J=8.0Hz,6H).

[0561] Example 38. Synthesis of 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methyl-N-(1-(trifluoromethyl)cyclopropyl)picolinamide (Compound 038)

[0562] 38.1 Preparation of Compound 038

[0563] Synthesis of Compound 038: Refer to the synthesis method of Compound 032 in Example 32, except that 032-a is replaced with 038-a to obtain Compound 038 (5.0 mg, yield 8.2%). LC-MS: [M+H] + =550.1.

[0564] 1 H NMR (400MHz, DMSO-d6): δ7.63(s,1H),7.16(d,J=4.0Hz,1H),5.08(s,1H),2.89(s,3H),2.72-2.56( m,2H),2.48(s,3H),2.33-2.26(m,2H),1.77-1.73(m,2H),1.61-1.58(m,2H),0.96(d,J=8.0Hz,3H).

[0565] Example 39. Synthesis of 3-chloro-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-N,N-dimethylpicolinamide (Compound 039)

[0566] 39.1 Preparation of Compound 039-1

[0567] At room temperature, 2,2,6,6-tetramethylpiperidine (4.71 g, 33.4 mmol) and anhydrous ether (35 mL) were added to the reaction flask, and the atmosphere was replaced with nitrogen three times. In an ice-water bath, a solution of n-butyllithium in n-hexane (13.4 mL, 33.4 mmol) was slowly added dropwise. After the addition was complete, the mixture was reacted at 0°C for 30 minutes, then the temperature was further lowered to -78°C, 039-a (dissolved in 10 mL of anhydrous ether) was added, and the mixture was reacted at -78°C for 2 hours. At this time, dry ice was slowly added to the reaction flask. It was observed that the system gradually became turbid. The temperature was slowly raised to room temperature and the reaction was continued for 1 hour. The reaction mixture was quenched by adding saturated aqueous ammonium chloride (40 mL) and extracted with ethyl acetate (30 mL × 2). The aqueous phase was adjusted to pH = 2 with 1 M dilute hydrochloric acid and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (60 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 039-1 (2.5 g). LC-MS: [M+H] + =191.95.

[0568] 39.2 Preparation of Compound 039-2

[0569] At room temperature, 039-1 (2.5 g, 13.08 mmol) and dichloromethane (50 mL) were added to a reaction flask, and a drop of N,N-dimethylformamide was added. The temperature was lowered to 0°C, and oxalyl chloride (3.32 g, 26.16 mmol) was slowly added dropwise. After the addition was complete, the temperature was slowly raised to room temperature and the reaction was carried out for 0.5 hours. The reaction solution was concentrated, and dichloromethane (50 mL) was added again to dissolve it. The temperature was lowered to 0°C, and triethylamine (3.96 g, 39.24 mmol) and a tetrahydrofuran solution of dimethylamine (7.8 mL, 15.7 mmol, 2 M) were added. The temperature was slowly raised to room temperature and the reaction was carried out for 1 hour. After dilution with 50 mL of water, the mixture was extracted with dichloromethane (30 mL x 2). The combined organic phases were washed with saturated brine (60 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 1 / 2) to obtain compound 039-2 (2.2 g). LC-MS: [M+H] + =219.00.

[0570] 39.3 Preparation of Compound 039-3

[0571] At room temperature, 039-2 (1.9 g, 8.71 mmol), tert-butyl carbamate (1.52 g, 13.0 mmol), cesium carbonate (7.4 g, 21.77 mmol), tris(dibenzylideneacetone)dipalladium (797 mg, 0.87 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (503 mg, 0.87 mmol), and 1,4-dioxane (30 mL) were added to a reaction flask, replaced with nitrogen three times, and reacted at 95 ° C for 15 hours. After the reaction solution was cooled to room temperature, it was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (70 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 1 / 2) to obtain compound 039-3 (1.6 g). LC-MS: [M+H] + =300.05.

[0572] 39.4 Preparation of Compound 039-4

[0573] At room temperature, 039-3 (1.5 g, 5.0 mmol) was added to a reaction flask, followed by dichloromethane (15 mL). A solution of hydrogen chloride in 1,4-dioxane (15 mL, 4 M) was added dropwise. The reaction was continued at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with 30 mL of water, and the pH was adjusted to 9 by adding saturated aqueous sodium carbonate. The mixture was extracted with a mixed solvent (dichloromethane / methanol = 10 / 1) (20 mL × 3). The organic phases were combined, washed with saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 60 / 1 to 20 / 1) to obtain compound 039-4 (310 mg). The aqueous phase was freeze-dried, slurried with dichloromethane, and filtered to obtain compound 039-4 (300 mg). LC-MS: [M+H] + =200.05.

[0574] 39.5 Preparation of Compound 039-5

[0575] At room temperature, 039-4 (260 mg, 1.30 mmol) was added to a reaction flask, and N,N-dimethylformamide (1 mL) was added to dissolve the mixture. The temperature was lowered to 0°C, and sodium hydride (60 mg, 6.5 mmol, 60% wt dispersed in mineral oil) was added. The mixture was reacted at 0°C for 1 hour. 001-b (265 mg, 1.56 mmol) was added, and the temperature was slowly raised to room temperature for 1 hour. The reaction solution was quenched by adding water at 0°C and directly purified by wet column chromatography (petroleum ether / ethyl acetate = 1 / 1 to dichloromethane / methanol = 20 / 1) to obtain compound 039-5 (50 mg, crude product, containing N,N-dimethylformamide). LC-MS: [M+H] + =324.00.

[0576] 39.6 Preparation of Compound 039 Hydrochloride

[0577] At room temperature, 039-5 (50 mg, crude product) was added to a reaction flask, along with 010-5 (36 mg, 0.19 mmol), anhydrous ethanol (1.5 mL), and N,N-diisopropylethylamine (82 mg, 0.64 mmol). The mixture was heated to 60°C and reacted for 36 hours. The reaction solution was directly purified by preparative HPLC (0.1% hydrochloric acid) and freeze-dried to obtain compound 039 hydrochloride (3.1 mg). LC-MS: [M+H] + =474.05.

[0578] 1 H NMR (400MHz, DMSO-d6): δ10.05(d,J=9.6Hz,1H),9.44(d,J=9.6Hz,1H),8.40(d,J=5.6Hz,1H),7.83(m,1H),5.12(d,J=9 .6Hz,1H),3.01(s,3H),2.76(s,3H),2.75–2.66(m,2H),2.63(s,3H),1.91–1.82(m,1H),1.71–1.62(m,1H),1.01(s,6H).

[0579] 39.6 Preparation of Compound 039

[0580] The resulting 039 hydrochloride was freed by saturated sodium bicarbonate aqueous solution, adjusted to pH 8-9, extracted with ethyl acetate (5 mL x 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and freeze-dried to obtain compound 039. LC-MS: [M+H] + =474.05.

[0581] Example 40: Synthesis of 4-((2-((5-chloro-2,3-dihydrobenzofuran-4-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 040)

[0582] 40.1 Preparation of Compound 040-1

[0583] Dissolve 040-a (1 g, 7.4 mmol) in dichloromethane (10 mL) and slowly add N-chlorosuccinimide (1.1 g, 8.14 mmol). Allow to react at room temperature for 2 hours. Concentrate the reaction mixture under reduced pressure, and purify the residue by silica gel column chromatography to obtain compound 040-1 (150 mg). LC-MS: [M+H] + =170.05.

[0584] 40.2 Preparation of Compound 040

[0585] Dissolve 040-1 (100 mg, 0.59 mmol) in ethanol (1 mL), add N,N-diisopropylethylamine (152 mg, 1.18 mmol) and 001-5 (180 mg, 0.59 mmol), and react at room temperature for 1 hour. The reaction solution is purified by high-performance liquid chromatography (alkaline conditions) and freeze-dried to obtain compound 040 (90.7 mg). LC-MS: [M+H] + =429.00.

[0586] 1 H NMR (400MHz, DMSO-d6): δ7.62 (s, 2H), 7.31 (s, 1H), 7.14 (d, J = 8.8 Hz, 1H), 4.58 (t, J = 8.0 Hz, 2H), 3.24 (t, J = 8.4 Hz, 2H), 2.84 (s, 6H).

[0587] Example 41, 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methyl-N-propylpicolinamide (Compound 041), (R)-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methyl-N-propylpicolinamide (S)-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methyl-N-propylpicolinamide (Compound 041A or 041B) and (S)-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methyl-N-propylpicolinamide (Compound 041B or 041A)

[0588] 41.1 Preparation of Compound 041-1

[0589] 001-a (1.49 g, 9.92 mmol) was dissolved in N,N-dimethylformamide (15 mL), and triethylamine (2.40 g, 23.76 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (4.53 g, 11.91 mmol) and N-methyl-n-propylamine (0.87 g, 11.91 mmol) were added. The reaction was carried out at room temperature for 1 hour. Water (20 mL) and dichloromethane (25 mL) were added, and the mixture was extracted. The organic phase was separated, and the aqueous phase was washed with dichloromethane (20 mL×3). The organic phases were combined and washed with saturated sodium chloride aqueous solution (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 041-1 (1.9 g, yield 98.56%). LC-MS: [M+H] + =243.05.

[0590] 41.2 Preparation of Compound 041-2

[0591] 041-1 (1.7 g, 7.00 mmol) was dissolved in 1,4-dioxane (30 mL), and tert-butyl carbamate (1.64 mg, 14.00 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.33 g, 0.70 mmol), palladium acetate (0.16 g, 0.70 mmol), and cesium carbonate (6.84 g, 21.0 mmol) were added. The nitrogen atmosphere was replaced three times, and the mixture was reacted at 100°C for 4 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 041-2 (1.6 g, yield 70.63%). LC-MS: [M+H] + =324.10.

[0592] 41.3 Preparation of Compound 041-3

[0593] Dissolve 041-2 (1.6 g, 4.95 mmol) in a solution of hydrogen chloride in 1,4-dioxane (15 mL, 2.0 M) and react at room temperature for 3 hours. Concentrate under reduced pressure to remove the solvent to obtain compound 041-3 (1.2 g, crude product). The crude product was used directly in the next reaction without purification. LC-MS: [M+H] + =224.05.

[0594] 41.4 Preparation of Compound 041

[0595] Synthesis of Compound 041: Refer to the synthesis method of Compound 001 in Example 1, replace 001-3 with 041-3, and 001-11 with 010-5 to obtain Compound 041 (140 mg). LC-MS: [M+H] + =484.15.

[0596] 41.4 Preparation of Compounds 041A and 041B

[0597] 041 (140 mg, 0.29 mmol) was subjected to chiral separation to give 041A (9.1 mg) and 041B (11.1 mg).

[0598] HPLC method: CHIRALPAK CHIRALPAK AD-H, 4.6*250mm 5μm, 20% ethanol / n-hexane, 0.8mL / min, 30℃;

[0599] 041A:

[0600] Chiral purity: 96.8%, T R =8.486min;

[0601] 1H NMR (400MHz, DMSO-d6) δ8.88(s,1H),7.99(d,J=5.2Hz,1H),7.88(s,1H),5.10(s,1H),3.41(d,J=7.6Hz,3H),2.99(s,2H),2. 76–2.64(m,2H),2.60(s,3H),1.82–1.71(m,1H),1.70–1.63(m,1H),1.57(s,2H),0.99(d,J=11.6Hz,6H),0.91-0.70(m,3H).

[0602] 041B:

[0603] Chiral purity: 99.5%, T R =6.464min;

[0604] 1 H NMR (400MHz, DMSO-d6) δ8.89(s,1H),7.99(d,J=5.2Hz,1H),7.88(s,1H),5.10(s,1H),3.41(d,J=6.4Hz,3H),2.99(s,2H),2.69(dt,J=1 6.4,7.6Hz,2H),2.60(s,3H),1.77(dt,J=13.6,6.6Hz,1H),1.69–1.62(m,1H),1.56(s,2H),0.99(d,J=11.6Hz,6H),0.91–0.71(m,3H).

[0605] Example 42: Synthesis of 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide (Compound 042)

[0606] 42.1 Preparation of Compound 042

[0607] 015-5 (90 mg, 0.27 mmol) was dissolved in ethanol (2 mL), and 010-5 (53 mg, 0.27 mmol) and N,N-diisopropylethylamine (174 mg, 1.35 mmol) were added. The mixture was stirred at 50°C for 16 hours. After purification by high-performance liquid chromatography (basic conditions), the mixture was freeze-dried to obtain compound 042 (47.7 mg). LC-MS: [M+H] + =484.05.

[0608] Example 43. Synthesis of 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-N,N-diethyl-3-hydroxypicolinamide (Compound 043)

[0609] 43.1 Preparation of Compound 043-1

[0610] 028-4 (200.0 mg, crude product) was dissolved in N,N-dimethylformamide (5 mL), and triethylamine (137.21 mg, 1.36 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (257.79 mg, 0.67 mmol), and diethylamine (49.59 mg, 0.67 mmol) were added. The mixture was reacted at room temperature for 2 hours. Water (10 mL) and ethyl acetate (10 mL) were added for extraction. The organic phase was separated, and the aqueous phase was washed with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 043-1 (70.0 mg). LC-MS: [M+H] + =498.10.

[0611] 43.2 Preparation of Compound 043

[0612] 043-1 (70.0 mg, 0.14 mmol) was dissolved in dichloromethane (1 mL), and the nitrogen atmosphere was replaced three times. A dichloromethane solution of boron tribromide (5 mL, 1.0 M) was slowly added at 0°C, and the reaction was allowed to react at room temperature overnight. Methanol solution was slowly added dropwise at 0°C to quench the reaction. The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative HPLC to give compound 043 (24.0 mg). LC-MS: [M+H] + =484.05.

[0613] 1 H NMR (400MHz, DMSO-d6) δ8.86(s,1H),8.00(d,J=8.0Hz,1H),7.94(s,1H),5.08(d,J=12.0Hz,1H),3.59–3.40(m,4H),2.68(d dd,J=24.0,16.0,12.0Hz,2H),2.58(s,3H),1.88–1.64(m,1H),1.64(m,1H),1.12(d,J=8.0Hz,6H),0.97(d,J=12.0Hz,6H).

[0614] Example 44. Synthesis of N-(tert-butyl)-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methylpicolinamide (Compound 044)

[0615] 44.1 Preparation of Compound 044-1

[0616] 028-4 (180.0 mg, crude product) was dissolved in N,N-dimethylformamide (5 mL), and triethylamine (123.49 mg, 1.22 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (232.01 mg, 0.61 mmol), and N-methyl-tert-butylamine (42.55 mg, 0.49 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. Water (10 mL) and ethyl acetate (10 mL) were added, the organic phase was separated, and the aqueous phase was washed with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 044-1 (60.0 mg). LC-MS: [M+H] + =512.10.

[0617] 44.2 Preparation of Compound 044

[0618] 044-1 (60.0 mg, 0.12 mmol) was dissolved in dichloromethane (1 mL), and the nitrogen atmosphere was replaced three times. A dichloromethane solution of boron tribromide (5 mL, 1.0 M) was slowly added at 0°C and allowed to react overnight at room temperature. Methanol was slowly added dropwise at 0°C to quench the reaction, followed by the addition of aqueous sodium bicarbonate solution to adjust the pH to 8-9. The product was concentrated under reduced pressure, and the residue was purified by preparative HPLC to yield compound 044 (24.8 mg). LC-MS: [M+H] + =498.20.

[0619] 1 H NMR(400MHz,DMSO-d6)δ7.55(s,1H),7.21(d,J=4.0Hz,1H),5.06(s,1H),2.68(s,3H),2.65–2 .60(m,2H),2.55(s,3H),1.89–1.78(m,1H),1.55(m,1H),1.37(s,9H),0.96(d,J=8.0Hz,6H).

[0620] Example 45. Synthesis of 3-((2-(azetidine-1-carbonyl)-3-hydroxypyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 045)

[0621] Synthesis of Compound 045: Refer to the synthesis method of Compound 028 in Example 28, replacing 028-b with 045-a to obtain Compound 045 (25.5 mg). LC-MS: [M+H] + =468.00.

[0622] 1 H NMR (400MHz, DMSO-d6) δ7.79(s,1H),7.58(s,1H),5.09(s,1H),4.41(s,2H),4.00(t,J=8.0Hz,2H),2.82–2.60( m,2H),2.56(s,3H),2.34–2.12(m,2H),1.79(dt,J=16.0,8.0Hz,1H),1.64–1.53(m,1H),0.97(d,J=8.5Hz,6H).

[0623] Example 46. Synthesis of 3-((3-hydroxy-2-(pyrrolidine-1-carbonyl)pyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 046)

[0624] Synthesis of Compound 046: Refer to the synthesis method of Compound 028 in Example 28, replacing 028-b with 046-a to obtain Compound 046 (18.9 mg). LC-MS: [M+H] + =482.0.

[0625] 1H NMR (400MHz, DMSO-d6) δ9.66(s,1H),8.81(d,J=8.0Hz,1H),8.08(d,J=4.0Hz,1H),8.05(s,1H),5.08(d,J=12.0Hz,2H),4.03(s,2H),3.57(dd,J=12 .0,4.0Hz,2H),2.70(ddd,J=24.0,16.0,12.0Hz,2H),2.58(s,3H),1.97–1 .85(m,2H),1.82(m,2H),1.75(m,1H),1.66(m,1H),0.98(d,J=8.0Hz,6H).

[0626] Example 47. Synthesis of 3-((3-hydroxy-2-(piperidine-1-carbonyl)pyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 047)

[0627] Synthesis of Compound 047: Refer to the synthesis method of Compound 028 in Example 28, replacing 028-b with 047-a to obtain Compound 047 (35.0 mg). LC-MS: [M+H] + =496.05.

[0628] 1 H NMR(400MHz,DMSO-d6)δ8.88(s,1H),7.95(d,J=4.0Hz,1H),7.83(s,1H),5.07(s,1H),3.48(m,4H ),2.79-2.59(m,2H),2.57(s,3H),1.86–1.66(m,1H),1.66–1.45(m,7H),0.96(d,J=16.0Hz,6H).

[0629] Example 48. Synthesis of 4-((3,4-dioxo-2-((2,7,7-trimethyl-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-8-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 048)

[0630] 48.1 Preparation of Compound 048-1

[0631] At room temperature, 048-a (12.00 g, 108.94 mmol) was dissolved in methanol (120 mL), cooled to 0°C, and hydrogen peroxide (33.72 mL, 435.75 mmol) and 10% aqueous sodium hydroxide solution (16.8 mL) were slowly added. The mixture was allowed to react at 0°C for 1 hour, then returned to room temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous sodium chloride solution (60 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with aqueous sodium sulfite solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20) to give compound 048-1 (10.50 g, yield 76.40%). LC-MS: [M+H] + =127.10.

[0632] 48.2 Preparation of Compound 048-2

[0633] At room temperature, 048-1 (10.50 g, 83.23 mmol) was dissolved in pyridine (110 mL), and thioacetamide (9.38 g, 124.85 mmol) was added. The reaction solution was reacted at 110°C for 16 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain compound 048-2 (6.70 g, yield 43.92%). LC-MS: [M+H] + =184.05.

[0634] 48.3 Preparation of Compound 048-3

[0635] 048-2 (6.70 g, 36.56 mmol) was dissolved in dichloromethane (100 mL), cooled to 0°C, and Dess-Martin periodinane (20.15 g, 47.52 mmol) was added. The mixture was reacted at 0°C for 1 hour, and then returned to room temperature for 0.5 hours. The reaction solution was slowly poured into an aqueous sodium bisulfite solution (50 mL, 10%) and stirred for ten minutes. A saturated aqueous sodium bicarbonate solution (30 mL) was slowly added to adjust the pH to neutral. The mixture was extracted with dichloromethane (100 mL × 3), the organic phases were combined and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compound 048-3 (1.3 g, yield 19.62%). LC-MS: [M+H] + =182.00.

[0636] 48.4 Preparation of Compound 048-4

[0637] Potassium tert-butoxide (1.49 g, 13.24 mmol) was dissolved in tert-butanol (11 mL), the atmosphere was replaced with nitrogen three times, the reaction mixture was cooled to 0°C, and stirred for 0.25 hours. 048-3 (600 mg, 3.31 mmol) was dissolved in tert-butanol (1 mL) and slowly added dropwise to the reaction mixture, stirring for 1 hour. Iodomethane (2.82 g, 19.86 mmol) was then added, and the mixture was stirred at 0°C for 0.5 hours. The mixture was then allowed to warm to room temperature and react for 1.5 hours. The reaction mixture was poured into water (30 mL) to quench the reaction, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 048-4 (415 mg, 59.90% yield). LC-MS: [M+H] + =210.10.

[0638] 48.5 Preparation of Compound 048-5

[0639] At room temperature, 048-4 (150 mg, 0.72 mmol) was dissolved in ethanol (3 mL), and then hydroxylamine hydrochloride (298 mg, 4.30 mmol) and sodium acetate (353 mg, 4.30 mmol) were added. The temperature was raised to 80°C and the reaction was allowed to react for 16 hours. Water (10 mL) was added to quench the reaction, and then extracted with dichloromethane (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 048-5 (200 mg, crude product). LC-MS: [M+H] + =225.10.

[0640] 48.6 Preparation of Compound 048-6

[0641] 048-5 (200 mg, 0.89 mmol) and zinc powder (583 mg, 8.92 mmol) were dissolved in a mixture of methanol (7.2 mL) and hydrochloric acid (4.8 mL, 4N) at room temperature and allowed to react for 0.5 h. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 048-6 (115 mg, crude product).

[0642] 48.7 Preparation of Compound 048

[0643] 048-6 (50 mg, 0.24 mmol) was dissolved in ethanol (2 mL), and 001-5 (58 mg, 0.19 mmol) and N,N-diisopropylethylamine (155 mg, 1.20 mmol) were added. The mixture was stirred at 60°C for 16 hours. After purification by HPLC preparative chromatography (basic conditions), the product was freeze-dried to give compound 048 (45.9 mg). LC-MS: [M+H] + =470.05.

[0644] 1 H NMR (400MHz, DMSO-d6) δ7.62(s,1H),7.32(s,1H),5.26(s,1H),2.89(s,3H),2.83(d,J=12.0Hz,2H),2.78 (s,3H),2.49(s,3H),1.94(d,J=10.6Hz,1H),1.61(s,2H),1.52(d,J=13.2Hz,1H),0.92(d,J=8.4Hz,6H).

[0645] Example 49. Synthesis of 3-((3-hydroxy-2-(4-methylisoxazol-5-yl)pyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 049)

[0646] 49.1 Preparation of Compound 049-1

[0647] 036-5 (200 mg, 0.61 mmol) was weighed into a reaction flask, and ethanol (4 mL), 018-5 (110 mg, 0.61 mmol), and N,N-diisopropylethylamine (240 mg, 1.83 mmol) were added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 049-1 (250 mg, 89% yield). LC-MS: [M+H] + =463.10.

[0648] 49.2 Preparation of Compound 049-2

[0649] 049-1 (200 mg, 0.43 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (3 mL) and lithium chloride (360 mg, 8.6 mmol) were added. The mixture was reacted at 120°C for 12 hours. The reaction solution was purified by preparative HPLC (alkaline conditions) and freeze-dried to obtain compound 049 (105.5 mg, 52.04% yield). LC-MS: [M+H] + =449.10.

[0650] 1 H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.27(s,2H),5.92(s,1H),4.99(s,1H),2.36-2.38(m,2 H),2.21(s,3H),1.82(s,3H),1.78–1.73(m,1H),1.40-1.35(m,1H),0.97(d,J=12.0Hz,6H).

[0651] Example 50, 4-((3,4-dioxo-2-((3,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 050), (R)-4-((3,4-dioxo-2-((3,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (S)-4-((3,4-dioxo-2-((3,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 050A or 050B)

[0652] 50.1 Preparation of Compound 050-1

[0653] Solid sodium bicarbonate (17.53 g, 208.69 mmol) was weighed into water (150 mL), and chloroacetaldehyde aqueous solution (37.80 g, 192.6 mmol, 40% wt) was slowly added at 0°C, followed by the slow addition of 018-a (18.0 g, 160.53 mmol). After reacting at room temperature for 18 hours, ethyl acetate (100 mL) was added to the reaction solution, followed by adjusting the pH to 1-2 by adding 10% aqueous sulfuric acid solution. The reaction was continued at room temperature for 2 hours, and solid sodium bicarbonate was added to adjust the pH to 8-9. Ethyl acetate (100 mL) was added for extraction, and the organic phase was separated. The aqueous phase was washed with ethyl acetate (100 mL × 3), and the organic phases were combined and washed with saturated sodium chloride aqueous solution (400 mL × 3). The product was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 050-1 (7.2 g, yield 33%).

[0654] 50.2 Preparation of Compound 050-2

[0655] 050-1 (6.7 g, 49.21 mmol) was dissolved in N,N-dimethylformamide (80 mL), and the nitrogen atmosphere was replaced three times. Sodium hydride (5.90 g, 147.63 mmol, 60% wt.) was slowly added at 0°C and reacted for 1 hour. Methyl iodide (27.94 g, 196.84 mmol) was slowly added and reacted at room temperature for 2.5 hours. The reaction was quenched by slowly adding ice water and extracted with ethyl acetate (100 mL). The aqueous phase was washed with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (400 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 050-2 (4.5 g, yield 55%). LC-MS: [M+H] + =165.10.

[0656] 50.3 Preparation of a mixture of compounds 050-3A and 050-3B

[0657] 050-2 (5.3 g, 32.28 mmol) was dissolved in a mixture of glacial acetic acid and dichloromethane (20 mL, 1 / 1). Bromine (1.65 mL, 32.28 mmol) was slowly added dropwise at 0°C and allowed to react at room temperature for 18 hours. Aqueous sodium thiosulfate solution was then slowly added dropwise to quench the reaction. Dichloromethane (30 mL) was added for extraction. The aqueous phase was washed with dichloromethane (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to obtain a mixture of 050-3A and 050-3B (3.2 g). LC-MS: [M+H] + =243.00.

[0658] 50.4 Preparation of a mixture of compounds 018-3 and 050-4

[0659] A mixture of 050-3A and 050-3B (3.2 g) was dissolved in 1,4-dioxane (15 mL), and trimethylboroxane (7.52 mL, 26.33 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.07 g, 1.32 mmol), and potassium carbonate (5.46 g, 39.49 mmol) were added. The nitrogen atmosphere was replaced three times, and the mixture was reacted at 100°C for 3 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain a mixture of 018-3 and 050-4 (1.6 g). LC-MS: [M+H] + =179.10.

[0660] 50.5 Preparation of a mixture of compounds 018-4 and 050-5

[0661] A mixture of 018-3 and 050-4 (1.6 g) was dissolved in ethanol (30 mL), and hydroxylamine hydrochloride (3.73 g, 53.86 mmol) and sodium acetate (4.42 g, 53.86 mmol) were added. The mixture was refluxed at 80°C for 12 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a mixture of 018-4 and 050-5 (1.7 g). LC-MS: [M+H] + =194.10.

[0662] 50.6 Preparation of a mixture of compounds 018-5 and 050-6

[0663] A mixture of 018-4 and 050-5 (1.7 g) was dissolved in methanol (15 mL). Nickel chloride (462.72 mg, 3.57 mmol) was added at 0°C, followed by the slow addition of sodium borohydride (1.17 g, 31.05 mmol). The mixture was refluxed at 80°C for 1 hour and concentrated under reduced pressure to remove most of the solvent. Ice water (20 mL) and ethyl acetate (20 mL) were added to the residue for extraction. The organic phase was separated, and the aqueous phase was washed with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a mixture of 018-5 and 050-6 (1.0 g, crude product). The crude product was used directly in the next reaction without purification. LC-MS: [M+H] + =163.15.

[0664] 50.7 Preparation of Compounds 018 and 050

[0665] A mixture of 018-5 and 050-6 (520.0 mg, crude product) was dissolved in ethanol (8 mL), and N,N-diisopropylethylamine (1.12 g, 8.70 mmol) and 001-5 (885.57 mg, 2.90 mmol) were added. The mixture was reacted at 60°C for 12 hours. The reaction solution was purified by preparative HPLC to obtain a mixture of 018 and 050. Further chiral separation afforded compounds 018A (75.20 mg), 018B (91.50 mg), 050A (43.8 mg), and 050B (35.6 mg). LC-MS: [M+H] + =439.10.

[0666] HPLC method: CHIRALPAK CHIRALPAK AD-H, 4.6*250mm 5μm, 15% ethanol / n-hexane, 0.8mL / min, 30℃;

[0667] Characterization data for 018A and 018B are shown in Example 18;

[0668] 050A:

[0669] Chiral purity: 96.5%, T R =6.817min;

[0670] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),7.99(d,J=4.0Hz,1H),7.86(s,1H),7.34(s,1H),4.85(d,J=8.0Hz,1H),3.0 1(d,J=36.0Hz,6H),2.31(dt,J=16.0,8.0Hz,2H),1.88(s,3H),1.58(m,1H),1.49(m,1H),0.94(d,J=4.0Hz,6H).

[0671] 050B:

[0672] Chiral purity: 100%, T R =7.997min;

[0673] 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.00(d,J=8.0Hz,1H),7.88(s,1H),7.35(s,1H),4.85(d,J=8.0Hz,1H ),3.02(d,J=36.0Hz,6H),2.32–2.22(m,2H),1.88(s,3H),1.59(m,1H),1.50(m,1H),0.94(d,J=4.0Hz,6H).

[0674] Example 51, 3-hydroxy-N,N-dimethyl-4-((2-((2-methyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)picolinamide (Compound 051), (R)-3-hydroxy-N,N-dimethyl-4-((2-((2-methyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)picolinamide Synthesis of (S)-3-hydroxy-N,N-dimethyl-4-((2-((2-methyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)picolinamide (Compound 051A or 051B) and (S)-3-hydroxy-N,N-dimethyl-4-((2-((2-methyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)picolinamide (Compound 051B or 051A)

[0675] 51.1 Preparation of Compound 051-1

[0676] 018-2 (0.2 g, 1.33 mmol) was weighed into a reaction flask, and methanol (10 mL) was added. Under nitrogen protection, ammonium acetate (1.03 g, 13.32 mmol) and sodium cyanoborohydride (418.5 mg, 6.66 mmol) were added. The reaction was allowed to react at 80°C for 12 hours. Aqueous sodium bicarbonate solution (15 mL) was slowly added to adjust the pH to 8-9. The mixture was extracted with ethyl acetate (60 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 051-1 (100 mg, yield 49.6%). LC-MS: [M-NH2] + =135.2.

[0677] 51.2 Preparation of Compound 051

[0678] 001-5 (101 mg, 0.331 mmol) was weighed into a reaction flask, and ethanol (3 mL), 051-1 (50 mg, 0.331 mmol), and N,N-diisopropylethylamine (128.1 mg, 0.992 mmol) were added. The mixture was stirred at room temperature for 2 hours. The resulting mixture was purified by preparative HPLC (basic conditions) to obtain compound 051 (74.4 mg, 54.8% yield). LC-MS: [M+H] + =411.11.

[0679] 51.3 Preparation of Compounds 051A and 051B

[0680] 051 was further chirally resolved to give compounds 051A (7 mg, yield 11.45%) and 051B (11.6 mg, yield 18.63%).

[0681] HPLC method: CHIRALPAK AD-H, 4.6*250mm 5μm, 20% ethanol / n-hexane, 0.8mL / min, 30℃;

[0682] Characterization data of 051A:

[0683] Chiral purity: 100%, T R =12.587min;

[0684] 1H NMR (400MHz, DMSO-d6) δ8.99(d,J=8.0Hz,1H),7.99(d,J=4.0Hz,1H),7.85(s,1H),5.96(s,1H),5.19(s,1H),3.0 5(s,3H),2.98(s,3H),2.43–2.28(m,2H),2.21(s,3H),2.06–2.00(m,1H),1.98–1.84(m,1H),1.73-1.72(m,2H).

[0685] Characterization data of 051B:

[0686] Chiral purity: 85.5%, T R =8.511min;

[0687] 1 H NMR(400MHz, DMSO-d6)δ8.99(d,J=8.0Hz,1H),8.15(d,J=4.0Hz,1H),7.90(s,1H),5.98(s,1H),5.21-5.19(m,1H), 3.09(s,3H),3.00(s,3H),2.44–2.31(m,2H),2.29(s,3H),2.09–2.03(m,1H),2.01–1.85(m,1H),1.75-1.72(m,2H).

[0688] Example 52: Synthesis of 4-(2-((2-(tert-butyl)-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino-3-hydroxy-N,N-dimethylpicolinamide (Compound 052)

[0689] 52.1 Preparation of Compound 052-1

[0690] 050-2 (1.5 g, 9.14 mmol) was weighed into a reaction flask and dissolved in chlorobenzene (20 mL). Ferrous chloride (0.12 g, 0.91 mmol), p-valeraldehyde (3.94 g, 45.7 mmol), and di-tert-butyl peroxide (4.01 g, 27.42 mmol) were then added and reacted at 120°C for 12 hours. The reaction solution was concentrated under reduced pressure to remove most of the solvent. Water (100 mL) was then added, and the resulting mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (280 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to yield compound 052-1 (1.5 g). LC-MS: [M+H]+ =221.05.

[0691] 52.2 Preparation of Compound 052-2

[0692] 052-1 (300 mg, 1.36 mmol) was weighed into a reaction flask, and tert-butylsulfenamide (1.65 g, 13.60 mmol) and tetraethyl titanate (5 mL) were added. The mixture was stirred at 110°C for 48 hours. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 052-2 (300 mg). LC-MS: [M+H] + =324.10.

[0693] 52.3 Preparation of Compound 052-3

[0694] 052-2 (50 mg, 0.15 mmol) was weighed into a reaction flask and dissolved in tetrahydrofuran (2 mL). Sodium borohydride (5.62 mg, 0.15 mmol) was slowly added at 0°C and the temperature was raised to 25°C with stirring for 2 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 052-3 (25 mg). LC-MS: [M+H] + =326.10.

[0695] 52.4 Preparation of Compound 052-4

[0696] 052-3 (25 mg, 0.077 mmol) was weighed into a reaction flask and dissolved in dichloromethane (2 mL). A 4 M solution of hydrogen chloride in 1,4-dioxane (28 mg, 0.77 mmol) was then added and allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to afford compound 052-4 (18 mg, crude product), which was used directly in the next reaction. LC-MS: [M-16] + =205.10.

[0697] 52.5 Preparation of Compound 052

[0698] 052-4 (12 mg, 0.054 mmol) was weighed into a reaction flask, and 001-5 (19.78 mg, 0.065 mmol), N,N-diisopropylethylamine (21 mg, 0.16 mmol), and ethanol (3 mL) were added. The mixture was stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (basic conditions) to obtain compound 052 (1.5 mg). LC-MS: [M+H] + =481.20.

[0699] 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),9.54(s,1H),8.73(d,J=9.6Hz,1H),8.00(d,J=12.4Hz,2H),5.93(s,1H),4.80(d,J=9. 6Hz,1H),3.12(s,3H),2.99(s,3H),2.37–2.23(m,2H),1.60–1.55(m,1H),1.44(d,J=13.6Hz,1H),1.16(s,9H),0.92(s,6H).

[0700] Example 53, 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpicolinamide (Compound 053), (S)-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpicolinamide Synthesis of (R)-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpicolinamide (Compound 053A or 053B)

[0701] 53.1 Preparation of Compound 053-1

[0702] Dissolve 001-a (3.00 g, 15.99 mmol) in dichloromethane (60 mL). The reaction mixture was cooled to 0°C. N,N-dimethylformamide (0.5 mL) and oxalyl chloride (4.05 g, 31.98 mmol) were added dropwise to the reaction mixture. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure without post-treatment to obtain compound 053-1 (3.20 g, crude product).

[0703] 53.2 Preparation of Compound 053-2

[0704] 053-1 (3.20 g, 15.53 mmol) was dissolved in dichloromethane (60 mL). N-ethylmethylamine (1.10 g, 18.64 mmol) and triethylamine (6.67 mL, 46.60 mmol) were added sequentially to the reaction mixture and allowed to react at room temperature for 2 hours. The reaction mixture was poured into water (50 mL) for quenching and then extracted with dichloromethane (60 mL × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 053-2 (2.74 g, yield: 69.43%). LC-MS: [M+H] + =229.05.

[0705] 53.3 Preparation of Compound 053

[0706] Synthesis of Compound 053: Refer to the synthesis method of Compound 001 in Example 1, replace 001-1 with 053-2, and 001-11 with 018-5 to obtain Compound 053 (16.2 mg). LC-MS: [M+H] + =453.20.

[0707] 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),7.89(d,J=4.0Hz,1H),7.69(s,1H),5.90(s,1H),4.81(s,1H),3.37(d,J=8.0Hz,1H) ,3.27(s,1H),2.87(s,3H),2.38–2.22(m,2H),2.17(s,3H),1.53(m,1H),1.37(m,1H),1.02(t,J=8.0Hz,3H),0.91(s,6H).

[0708] 53.4 Preparation of Compounds 053A and 053B

[0709] Compound 053 was further chirally resolved to give compounds 053A (35.0 mg) and 053B (40.9 mg).

[0710] HPLC method: CHIRALPAK AD-H, 4.6*250mm 5μm, 15% ethanol / n-hexane, 0.8mL / min, 30℃;

[0711] 053A:

[0712] Chiral purity: 96.8%, T R :6.866min;

[0713] 1 H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.04(s,1H),7.96(s,1H),5.99(s,1H),4.87(d,1H),3.51(s,2H),3.0 6(d,3H),2.32-2.41(m,2H),2.23(s,3H),1.58-1.64(m,1H),1.50(d,1H),1.13(t,3H),0.95-0.96(d,6H).

[0714] 053B:

[0715] Chiral purity: 99.0%, T R :8.363min;

[0716] 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.04(d,1H),7.95(s,1H),5.94(s,1H),4.86(d,1H),3.51(t,2H),3.06( d,3H),2.32-2.44(m,2H),2.23(s,3H),1.57-1.64(m,1H),1.46-1.51(m,1H),1.13(t,3H),0.95-0.96(d,6H).

[0717] Example 54, N-cyclopropyl-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methylpicolinamide (Compound 054), (S)-N-cyclopropyl-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methylpicolinamide Synthesis of (R)-N-cyclopropyl-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methylpicolinamide (Compound 054A or 054B) and (R)-N-cyclopropyl-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methylpicolinamide (Compound 054B or 054A)

[0718] 54.1 Preparation of Compound 054-1

[0719] 001-a (2.00 g, 10.66 mmol) was dissolved in N,N-dimethylformamide (15 mL), and triethylamine (1.30 g, 42.64 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.10 g, 15.99 mmol) were added. Finally, N-methylcyclopropaneamine hydrochloride (1.14 g, 15.99 mmol) was added and allowed to react at room temperature for 1 hour. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 054-1 (2.0 g). LC-MS: [M+H] + =241.05.

[0720] 54.2 Preparation of Compound 054

[0721] Synthesis of Compound 054: Refer to the synthesis method of Compound 001 in Example 1, replace 001-1 with 054-1, and replace 001-11 with 018-5 to obtain Compound 054 (49.5 mg). LC-MS: [M+H] + =465.20.

[0722] 1 H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.74(d,1H),8.00(s,2H),6.00(s,1H),4.88(d,1H),3.00(s,3H),2.87 (s,1H),2.35-2.43(m,2H),2.23(s,3H),1.62-1-1.63(m,1H),1.49-1.53(m,1H),0.97(d,6H),0.47(s,4H).

[0723] 54.3 Preparation of Compounds 054A and 054B

[0724] The 054 racemate was separated by chiral column to obtain two isomers 054A (5.1 mg) and 054B (10.8 mg).

[0725] 054A:

[0726] Chiral purity: 98.9%, T R : 9.664min;

[0727] 1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.00(s,2H),7.89(s,1H),5.98(s,1H),4.86(d,1H),2.98(s,3H),2.8 8(s,1H),2.35-2.42(m,2H),2.23(s,3H),1.57-1.64(m,1H),1.46-1.51(m,1H),0.95(d,6H),0.46(s,4H).

[0728] HPLC method: CHIRALPAK AD-H, 4.6*250mm 5μm, 15% ethanol / n-hexane, 0.8mL / min, 30℃;

[0729] 054B:

[0730] Chiral purity: 97.4%, T R :6.892min;

[0731] 1 H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.72(d,1H),7.89(s,1H),8.01(s,1H),6.00(s,1H),4.88(d,1H),3.01(s,3 H),2.87(s,1H),2.34-2.39(m,2H),2.23(s,3H),1.60-1.64(m,1H),1.49-1.53(m,1H),0.97(d,6H),0.46(s,4H).

[0732] Example 55, Compound 4-((2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 055), (R)-4-((2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (S)-4-((2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 055A or 055B) and Synthesis of (S)-4-((2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 055B or 055A)

[0733] 55.1 Preparation of Compound 055-1

[0734] 050-2 (100.0 mg, 0.61 mmol) was dissolved in methanol (0.5 mL), and sodium cyanoborohydride (574.06 mg, 9.13 mmol) and ammonium acetate (938.87 mg, 12.18 mmol) were added. The mixture was refluxed at 80°C overnight. The reaction solution was concentrated under reduced pressure to remove the solvent. The residue was extracted with water (10 mL) and ethyl acetate (10 mL). The organic phase was separated, and the aqueous phase was washed with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (25 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 055-1 (115.0 mg, crude product). The crude product was used directly in the next reaction. LC-MS: [M-NH2] + =149.10.

[0735] 55.2 Preparation of Compound 055

[0736] 055-1 (90.0 mg, crude product) was dissolved in ethanol (5 mL), and N,N-diisopropylethylamine (211.19 mg, 1.63 mmol) and 001-5 (133.03 mg, 0.43 mmol) were added. The reaction was allowed to react overnight at room temperature. The reaction solution was purified by HPLC preparative chromatography to give compound 055 (52.3 mg). LC-MS: [M+H] + =425.05.

[0737] 1 H NMR (400MHz, DMSO-d6) δ8.72(s,1H),7.97(d,J=4.0Hz,1H),7.84(d,J=8.0Hz,1H),7.56(d,J=12.0Hz,1H),6.34(d ,J=12.0Hz,1H),4.90(s,1H),2.98(d,J=28.0Hz,6H),2.39(m,2H),1.52(d,J=28.0Hz,2H),0.93(d,J=12.0Hz,6H).

[0738] 55.3 Preparation of Compounds 055A and 055B

[0739] 055 was further chirally resolved to give compounds 055A (8.2 mg) and 055B (6.9 mg).

[0740] HPLC method: CHIRALPAK AD-H, 4.6*250mm 5μm, 15% ethanol / n-hexane, 0.8mL / min, 30℃;

[0741] 055A:

[0742] Chiral purity: 98.7%, T R:11.959min;

[0743] 1 H NMR (400MHz, DMSO-d6) δ8.73(s,1H),7.87(d,J=4.0Hz,1H),7.60(s,1H),7.55(d,J=12.0Hz,1H ),6.32(s,1H),4.90(s,1H),2.89(s,6H),2.38(m,2H),1.61(m,1H),1.41(m,1H),0.94(s,6H).

[0744] 055B:

[0745] Chiral purity: 87.2%, T R : 9.514min;

[0746] 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),7.97(d,J=4.0Hz,1H),7.80(s,1H),7.59(s,1H),6.36(s,1H),4.92(d ,J=8.0Hz,1H),3.00(d,J=24.0Hz,6H),2.45–2.31(m,2H),1.61(m,1H),1.49(m,1H),0.96(d,J=4.0Hz,6H).

[0747] Example 56. Synthesis of 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide (Compound 056)

[0748] Synthesis of Compound 056: Refer to the synthesis method of Compound 015 in Example 15, replacing 003-6 with 018-5 to obtain Compound 056 (51.1 mg). LC-MS: [M+H] + =467.25.

[0749] 1H NMR (400MHz, DMSO-d6) δ8.76(s,1H),8.01(s,2H),5.99(s,1H),4.87(d,J=9.6Hz,1H),4.45(d,J=254.0Hz,1H),2.86(s,3H),2 .45–2.31(m,2H),2.23(s,3H),1.67–1.58(m,1H),1.49(dt,J=13.2,4.8Hz,1H),1.12(d,J=5.2Hz,6H),0.96(d,J=5.2Hz,6H).

[0750] Example 57, 4-((2-((2-ethyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 057), (S)-4-((2-((2-ethyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (R)-4-((2-((2-ethyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 057A or 057B) and (R)-4-((2-((2-ethyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 057B or 057A)

[0751] 57.1 Preparation of Compound 057-1

[0752] Sodium bicarbonate (17.53 g, 208.69 mmol) was weighed into a reaction flask, and water (300 mL) was added. The temperature was lowered to 0°C, and chloroacetaldehyde (37.8 g, 192.6 mmol, 40% aqueous solution) was slowly added. 018-a (18.0 g, 160.53 mmol) was added, and the mixture was warmed to room temperature and stirred overnight. Ethyl acetate (100 mL) was added, and the pH was adjusted to 1 by adding 10% aqueous sulfuric acid (100 mL). The mixture was stirred at room temperature for 2 hours. The mixture was extracted with dichloromethane (300 mL x 3), and the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain compound 057-1 (15 g, yield 68.6%). LC-MS: [M+H] + =137.00.

[0753] 57.2 Preparation of Compound 057-2

[0754] 057-1 (15.0 g, 110.17 mmol) was weighed into a reaction flask, and ethanol (100 mL) was added. Sodium borohydride (4.17 g, 110.7 mmol) was slowly added at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0°C and quenched by the addition of saturated aqueous ammonium chloride (80 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 057-2 (10 g, 65.7% yield).

[0755] 57.3 Preparation of Compound 057-3

[0756] 057-2 (10 g, 72.36 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (80 mL) and imidazole (9.86 g, 144.76 mmol) were added. The temperature was lowered to 0°C, and tert-butyldimethylsilyl chloride (16.36 g, 108.54 mmol) was added in batches. The mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 057-3 (13 g, yield 71.2%).

[0757] 57.4 Preparation of Compound 057-4

[0758] 057-3 (1.10 g, 4.36 mmol) was dissolved in tetrahydrofuran (15 mL), the atmosphere was purged with nitrogen three times, and the mixture was cooled to -78°C. n-Butyllithium (0.84 g, 13.08 mmol) was slowly added. The mixture was allowed to react at 0°C for 1 hour. The temperature was then lowered to -78°C, and iodoethane (2.04 g, 13.08 mmol) was slowly added. The mixture was allowed to return to room temperature and react for 6 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution. Ethyl acetate (20 mL) was added, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 1) to afford compound 057-4 (0.90 g).

[0759] 57.5 Preparation of Compound 057-5

[0760] Dissolve 057-4 (0.90 g, 3.21 mmol) in tetrahydrofuran (5 mL), slowly add tetrabutylammonium fluoride (1.68 g, 6.42 mmol) dropwise, and react at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to obtain compound 057-5 (0.54 g).

[0761] 57.6 Preparation of Compound 057-6

[0762] Dissolve 057-5 (450 mg, 2.71 mmol) in dichloromethane (10 mL), add manganese dioxide (3.53 g, 40.65 mmol), and react at room temperature for 24 hours. The reaction solution is filtered through celite, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 057-6 (310 mg).

[0763] 57.7 Preparation of Compound 057-7

[0764] 057-6 (250 mg, 1.52 mmol) was dissolved in ultra-dry N,N-dimethylformamide (5 mL). The nitrogen atmosphere was replaced three times. After cooling to 0°C, sodium hydride (180 mg, 4.56 mmol) was slowly added. After stirring for 40 minutes, iodomethane (860 mg, 6.08 mmol) was slowly added and allowed to react at room temperature for 18 hours. Saturated aqueous ammonium chloride was slowly added dropwise in an ice-water bath to quench the reaction. Ethyl acetate (10 mL) was added, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to yield compound 057-7 (280 mg).

[0765] 57.8 Preparation of Compound 057

[0766] Synthesis of Compound 057: Refer to the synthesis method of Compound 016 in Example 16, replacing 016-4 with 057-7 to obtain Compound 057 (51.4 mg). LC-MS: [M+H] + =453.15.

[0767] 1H NMR(400MHz,DMSO-d6)δ7.80(d,1H),7.37(d,1H),5.95(s,1H),4.87(s,1H),2.96(s,3H),2.93(s,3H), 2.52-2.58(m,2H),2.34-2.38(m,2H),1.59-1.62(m,1H),1.41-1.44(m,1H),1.12(t,3H),0.94(d,6H).

[0768] 57.9 Preparation of Compounds 057A and 057B

[0769] Compound 057 (320 mg) was purified by chiral separation to give 057A (71.8 mg) and 057B (77.1 mg).

[0770] HPLC method: CHIRALPAK IC, 4.6*250mm 5μm, 85% methanol / 0.1% trifluoroacetic acid-water, 1.0 mL / min, 30°C;

[0771] 057A:

[0772] Chiral purity: 99.6%, T R =13.286min;

[0773] 1 H NMR(400MHz,DMSO-d6)δ7.66(d,1H),7.14(d,1H),5.97(s,1H),4.88(s,1H),2.89(s,3H),2 .79(s,3H),2.57(m,2H),2.39(s,2H),1.68(d,2H),1.43(d,1H),1.13(t,3H),0.95(s,6H).

[0774] 057B:

[0775] Chiral purity: 100%, T R =9.806min;

[0776] 1 H NMR(400MHz,DMSO-d6)δ7.66(d,1H),7.14(d,1H),5.97(s,1H),4.88(s,1H),2.89(s,3H),2 .79(s,3H),2.57(m,2H),2.36(m,2H),1.69(m,1H),1.43(d,1H),1.13(t,3H),0.94(s,6H).

[0777] Example 58. Synthesis of 4-((2-((6,6-dimethyl-2-(trifluoromethyl)-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 058)

[0778] 58.1 Preparation of Compound 058-1

[0779] 050-2 (300.0 mg, 1.83 mmol) was dissolved in 1,2-dichloroethane (10 mL), and cuprous iodide (695.90 mg, 3.65 mmol) and 1-(trifluoromethyl)-1,2-benzidoxyl-3(1H)-one (866.04 mg, 2.74 mmol) were added. The mixture was reacted at 60°C for 12 hours and filtered. Saturated aqueous sodium bicarbonate solution (15 mL) and dichloromethane (10 mL) were added to the filtrate. The organic phase was separated, and the aqueous phase was washed with dichloromethane (10 mL × 3). The organic phases were combined and washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 058-1 (70.0 mg, yield 16.5%). LC-MS: [M+H] + =233.05.

[0780] 58.2 Preparation of Compound 058-2

[0781] 058-1 (70.0 mg, 0.30 mmol) was dissolved in methanol (1.5 mL), and sodium cyanoborohydride (189.44 mg, 3.01 mmol) and ammonium acetate (356.13 mg, 6.03 mmol) were added. The reaction mixture was refluxed at 80°C overnight. The solvent was removed by concentration under reduced pressure. Water (10 mL) and ethyl acetate (10 mL) were added to the residue for extraction. The organic phase was separated, and the aqueous phase was washed with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 058-2 (70.0 mg, crude product), which was used directly in the next reaction. LC-MS: [M+H] + =217.05.

[0782] 58.3 Preparation of Compound 058

[0783] 058-2 (70.0 mg, crude product) was dissolved in ethanol (5 mL), and N,N-diisopropylethylamine (116.37 mg, 0.90 mmol) and 001-5 (73.30 mg, 0.24 mmol) were added. The mixture was reacted at 60°C overnight. The reaction solution was purified by preparative HPLC to obtain compound 058 (17.8 mg). LC-MS: [M+H] + =493.00.

[0784] 1 H NMR(400MHz, DMSO-d6)δ8.83(s,1H),8.02(d,J=8.0Hz,1H),7.93(s,1H),7.17(s,1H),4.99(d,J=4.0Hz,1H), 3.06(d,J=40.0Hz,6H),2.61–2.49(m,1H),2.41(m,1H),1.63(qd,J=16.0,8.0Hz,2H),0.97(d,J=8.0Hz,6H).

[0785] Example 59. Synthesis of 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methyl-N-(2,2,2-trifluoroethyl)picolinamide (Compound 059)

[0786] 59.1 Preparation of Compound 059-1

[0787] 001-a (3 g, 15.99 mmol) was weighed into a reaction flask, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.16 g, 31.98 mmol) and N,N-diisopropylethylamine (8.27 g, 63.96 mmol) were added. After stirring for 0.5 hour, methyl(2,2,2-trifluoroethyl)amine (2.17 g, 19.19 mmol) was added. Stir at 25°C for 2 hours. Dilute with water (100 mL) and extract with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (180 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 059-1 (3.5 g). LC-MS: [M+H] + =282.90.

[0788] 59.2 Preparation of Compound 059

[0789] Synthesis of Compound 059: Refer to the synthesis method of Compound 001 in Example 1, replace 001-1 with 059-1, and replace 001-11 with 018-5 to obtain Compound 059 (13.1 mg). LC-MS: [M+H] + =507.10.

[0790] 1 H NMR (400MHz, DMSO-d6) δ10.10(s,1H),9.02(d,J=10.0Hz,1H),8.15(dd,J=38.4, 14.0Hz,2H),6.00(s,1H),4.87(d,J=9.6Hz,1H),4.63(s,1H),4.37(d,J=9.6Hz, 1H),3.11(d,J=30.4Hz,3H),2.40(ddd,J=24.4,15.2,7.2Hz,2H),2.23(s,3H),1 .66(dd,J=14.4,6.1Hz,1H), 1.50(dt,J=14.4,5.0Hz,1H), 0.95(t,J=9.6Hz,6H).

[0791] Example 60, 4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpicolinamide (Compound 060), (S)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpicolinamide Synthesis of (R)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpicolinamide (Compound 060A or 060B) and (R)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpicolinamide (Compound 060B or 060A)

[0792] 60.1 Preparation of Compound 060

[0793] Synthesis of Compound 060: Refer to the synthesis method of Compound 001 in Example 1, replacing 018-5 with 020-4 to obtain Compound 060 (66.4 mg). LC-MS: [M+H] + =470.05.

[0794] 1H NMR (400MHz, DMSO-d6) δ8.80(s,1H),8.05(d,J=5.0Hz,1H),7.95(s,1H),4.98(d,J=9.8Hz,1H),3.51(s,2H),3.06(d,J=51.6Hz,3H),2.82(dd,J= 12.0,5.4Hz,1H),2.76–2.68(m,1H),2.59(s,3H),1.78–1.69(m,1H),1. 65(dd,J=12.6,6.4Hz,1H), 1.13(t,J=6.8Hz,3H), 0.97(d,J=7.6Hz,6H).

[0795] 60.2 Preparation of Compounds 060A and 060B

[0796] Compound 060 was further chirally resolved to give 060A (12.1 mg) and 060B (14.5 mg).

[0797] HPLC method: CHIRALPAK CHIRALPAK AD-H, 4.6*250mm 5μm, 20% isopropanol / n-hexane, 0.8mL / min, 30℃;

[0798] 060A:

[0799] Chiral purity: 99.4%, T R :10.566min;

[0800] 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),7.97(d,J=5.0Hz,1H),7.81(s,1H),4.95(d,J=9.4Hz,1H),3.48(d,J=10.0Hz,2H),2 .94(d,J=16.4Hz,3H),2.71(d,J=9.8Hz,2H),2.56(s,3H),1.67(s,1H),1.59(s,1H),1.08(t,J=7.0Hz,3H),0.95(s,6H).

[0801] 060B:

[0802] Chiral purity: 95.4%, T R :7.268min;

[0803] 1H NMR (400MHz, DMSO-d6) δ8.79(s,1H),7.99(d,J=5.0Hz,1H),7.85(s,1H),4.96(d,J=9.6Hz,1H),3.49(s,2H),2.97(d,J=25. 8Hz, 3H), 2.81–2.66 (m, 2H), 2.57 (s, 3H), 1.69 (d, J = 7.0Hz, 1H), 1.59 (d, J = 12.8Hz, 1H), 1.09 (t, J = 6.8Hz, 3H), 0.96 (s, 6H).

[0804] Example 61. Synthesis of 3-((2-(4,4-difluoropiperidine-1-carbonyl)-3-hydroxypyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 061)

[0805] Synthesis of Compound 061: Refer to the synthesis method of Compound 031 in Example 31, replacing 031-a with 061-a to obtain Compound 061 (29.3 mg). LC-MS: [M+H] + =532.20.

[0806] 1 H NMR(400MHz,DMSO-d6)δ8.97(s,1H),7.92(d,1H),7.65(s,1H),5.10(d,1H),3.71(s,2H),3.49(s,2 H),2.66-2.70(m,2H),2.59(s,3H),2.03(d,4H),1.75-1.78(m,1H),1.61-1.64(m,1H),0.98(d,6H).

[0807] Example 62: Synthesis of N-cyclopentyl-4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methylpicolinamide (Compound 062)

[0808] Synthesis of Compound 062: Refer to the synthesis method of Compound 031 in Example 31, replace 031-a with 062-a to obtain Compound 062 (10.5 mg, yield: 15.41%). LC-MS: [M+H] + =510.1.

[0809] 1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),7.94(s,2H),7.86(s,2H),5.07(s,1H),2.84(s ,3H),2.73-1.61(m,3H),2.57(s,3H),1.72-1.59(m,10H),0.98(s,3H),0.95(s,3H).

[0810] Example 63. Synthesis of 3-((2-(3-(dimethylamino)azetidine-1-carbonyl)-3-hydroxypyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 063)

[0811] Synthesis of Compound 063: Refer to the synthesis method of Compound 032 in Example 32, replacing 032-a with 063-a to obtain Compound 063 (21.8 mg). LC-MS: [M+H] + =511.20.

[0812] 1 H NMR(400MHz,DMSO-d6)δ7.71(s,1H),7.36(s,1H),5.13(s,1H),4.27(s,1H),4.08(s,1H),3.99–3.94(m,1H),3.74(s,2H),2 .97(s,1H),2.68(d,J=16.8Hz,1H),2.59(s,3H),2.06(s,6H),1.87–1.79(m,1H),1.66–1.58(m,1H),0.99(d,J=8.2Hz,6H).

[0813] Example 64. Synthesis of 3-((3-hydroxy-2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 064)

[0814] Synthesis of Compound 064: Refer to the synthesis method of Compound 032 in Example 32, replacing 032-a with 064-a to obtain Compound 064 (7.5 mg). LC-MS: [M+H] + =537.10.

[0815] 1H NMR (400MHz, DMSO-d6) δ8.88(s,1H),7.97(d,J=4.0Hz,1H),7.85(d,J=4.0Hz ,1H),5.08(d,J=4.0Hz,1H),4.10(d,J=12.0Hz,1H),3.83(d,J=24.0Hz,1H),3 .23–3.09(m,2H),3.02–2.86(m,2H),2.70(ddd,J=20.0,16.0,4.0Hz,2H),2.5 8(s,3H),2.15(s,3H),1.82–1.62(m,5H),1.53(m,1H),0.97(d,J=8.0Hz,6H).

[0816] Example 65. Synthesis of 3-((3-hydroxy-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)pyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 065)

[0817] 65.1 Preparation of Compound 065-1

[0818] Dissolve 028-4 (500 mg, 1.13 mmol) in ultra-dry dichloromethane (5 mL). Replace the nitrogen atmosphere three times. Slowly add boron tribromide (1.5 g, 5.99 mmol) at 0°C. Return the mixture to room temperature and stir overnight. Saturated aqueous sodium bicarbonate solution is slowly added to quench the reaction in an ice-water bath. Filter and concentrate the filtrate under reduced pressure. Purify by preparative HPLC (basic conditions) and freeze-dry to obtain compound 065-1 (219 mg). LC-MS: [M+H] + =429.10.

[0819] 65.2 Preparation of Compound 065

[0820] 065-1 (96.00 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (3 mL), and triethylamine (85.30 mg, 0.66 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (92.02 mg, 0.24 mmol) were added. The mixture was stirred at room temperature for 30 minutes, and 2-oxa-6-aza-spiro[3,3]heptane (19.63 mg, 0.20 mmol) was added. The mixture was reacted at room temperature overnight. After purification by preparative HPLC (basic conditions), the mixture was freeze-dried to give compound 065 (17.50 mg). LC-MS: [M+H] + =510.20.

[0821] 1 H NMR(400MHz,DMSO-d6)δ9.68(d,1H),8.80(d,1H),8.11(d,1H),8.06(d,1H),5.09(s,1H),4.89(s,2H),4.68-4.73(q ,4H),4.32(s,2H),2.65-2.78(m,2H),2.60(s,3H),1.74-1.80(m,1H),1.64-1.70(m,1H),1.01(s,1H),0.98(s,1H).

[0822] Example 66. Synthesis of 3-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-1-en-1-yl)amino)-2-hydroxy-N,N-dimethylbenzamide (Compound 066)

[0823] 66.1 Synthesis of Compound 066-1

[0824] 066-a (300.0 mg, 1.64 mmol) was dissolved in dichloromethane (10 mL), the nitrogen atmosphere was replaced three times, and oxalyl chloride (374.27 mg, 2.95 mmol) was slowly added dropwise at 0°C, followed by 2 drops of N,N-dimethylformamide, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in dichloromethane (10 mL). Triethylamine (0.68 mL, 4.91 mmol) and dimethylamine (147.72 mg, 3.28 mmol) were added and the mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 066-1 (180.0 mg, yield 52.27%). LC-MS: [M+H] + =211.05.

[0825] 66.2 Synthesis of Compound 066-2

[0826] Dissolve 066-1 (160.0 mg, 0.76 mmol) in ethanol (5 mL), add palladium on carbon (90.0 mg, 10% wt), replace the hydrogen three times, and react at room temperature for 3 hours. Filter, and concentrate the filtrate under reduced pressure to obtain compound 066-2 (120.0 mg, crude product), which is used directly in the next reaction. LC-MS: [M+H] + =181.10.

[0827] 66.3 Synthesis of Compound 066-3

[0828] 066-2 (115.0 mg, crude product) was dissolved in ethanol (5 mL), and N,N-diisopropylethylamine (247.44 mg, 1.91 mmol) and diethyl squarate (108.59 mg, 0.64 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 066-3 (158.0 mg). LC-MS: [M+H] + =305.05.

[0829] 66.4 Synthesis of Compound 066-4

[0830] 066-3 (50 mg, 0.16 mmol) was weighed into a reaction flask and dissolved in ethanol (5 mL). 010-5 (38 mg, 0.19 mmol) and N,N-diisopropylethylamine (41 mg, 0.32 mmol) were then added and reacted at 50°C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain compound 066 (57 mg). LC-MS: [M+H] + =455.20.

[0831] 1 H NMR (400MHz, DMSO-d6) δ8.62(d,J=9.6Hz,1H),7.80(dt,J=7.6,3.8Hz,1H),6.84(d,J=3.2Hz,2H),5.12(d,J=8.4Hz,1H ), 2.92 (s, 6H), 2.78–2.65 (m, 2H), 2.62 (d, J = 14.8Hz, 3H), 1.71 (ddd, J = 19.6, 13.7, 6.9Hz, 2H), 1.00 (d, J = 11.2Hz, 6H).

[0832] Example 67. Synthesis of 4-((2-((2-chloro-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 067)

[0833] 67.1 Synthesis of Compound 067-1

[0834] 010-1 (5 g, 22.82 mmol) was weighed and added to a reaction flask. Pyridine (50 mL) and thiourea (1.82 g, 23.96 mmol) were added. After stirring at room temperature overnight, the mixture was heated to 120°C and refluxed for 2 hours. The reaction solution was concentrated and water was added to precipitate a solid. The solid was filtered and the filter cake dried to obtain compound 067-1 (3.1 g, yield 64.93%). LC-MS: [M+H-NH2] + =180.00.

[0835] 67.2 Synthesis of Compound 067-2

[0836] 067-1 (500 mg, 2.55 mmol) was weighed into a reaction flask, concentrated sulfuric acid (3 mL) was added, the temperature was cooled to -10°C, and a solution of sodium nitrite (193.55 mg, 2.81 mmol) in water (3 mL) was added dropwise. The mixture was stirred at -10°C for 30 minutes. Sodium chloride (1490.22 mg, 25.5 mmol) and a solution of copper sulfate pentahydrate (6367.10 mg, 25.5 mmol) in water (3 mL) were added dropwise to the reaction mixture at 0°C. The mixture was allowed to warm to room temperature and react for 30 minutes. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 067-2 (250 mg, 45.50% yield). LC-MS: [M+H] + =216.0.

[0837] 67.3 Synthesis of Compound 067-3

[0838] Compound 067-2 (400 mg, 1.85 mmol) was weighed and added to a reaction flask. Ethanol (1 mL), ammonium acetate (1425.98 mg, 18.5 mmol), and sodium cyanoborohydride (350 mg, 5.55 mmol) were added and refluxed at 80°C for 12 hours. The reaction solution was concentrated, diluted with water (5 mL), and the pH was adjusted to 1-2 with hydrochloric acid (1 N). Extraction was performed with ethyl acetate (5 mL x 3). The organic phase was discarded, and the aqueous phase was adjusted to pH 12 with aqueous sodium hydroxide (6 N). Extraction was performed with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 067-3 (40 mg, yield 9.95%).

[0839] 67.4 Synthesis of Compound 067

[0840] Compound 001-5 (40 mg, 0.13 mmol) was weighed and added to a reaction flask. Ethanol (1 mL), N,N-diisopropylethylamine (33.60 mg, 0.26 mmol), and compound 067-3 (28.17 mg, 0.13 mmol) were added and stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (alkaline conditions) and freeze-dried to obtain compound 067 (5 mg). LC-MS: [M+H] + =476.10.

[0841] 1 H NMR(400MHz,DMSO-d6)δ11.63(s,0.5H),9.52(s,1H),8.99(s,1H),8.01(s,2H),5.36(d,1H),3.16( s,3H),3.04(s,3H),2.26(m,1H),1.93(m,1H),1.83(m,1H),1.75(m,1H),1.31(s,3H),1.23(s,3H).

[0842] Example 68. Synthesis of 4-((2-((2-bromo-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 068)

[0843] 68.1 Synthesis of Compound 068-1

[0844] 067-1 (2 g, 5.1 mmol) was weighed into a reaction flask, hydrobromic acid (20 mL) was added, the temperature was cooled to 0°C, and a solution of sodium nitrite (0.70 g, 10.2 mmol) in water (10 mL) was added dropwise. The mixture was stirred at 0°C for 30 min. The reaction mixture was added dropwise to a solution of cuprous bromide (2926.4 mg, 20.4 mmol) in hydrobromic acid (20 mL) at 0°C, and the temperature was naturally raised to room temperature for 2 hours. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 068-1 (1.05 g, yield 41.01%). LC-MS: [M+H] + =260.00.

[0845] 68.2 Synthesis of Compound 068-2

[0846] 068-1 (1.05 g, 4.04 mmol) was weighed into a reaction flask, and tetrahydrofuran (10 mL), tert-butylsulfenamide (0.45 g, 4.44 mmol), and tetraethyl titanate (2.30 g, 8.08 mmol) were added. The reaction was allowed to react at 65°C for 12 hours. The reaction solution was diluted with water (20 mL) and filtered. The filter cake was extracted with ethyl acetate (10 mL). The filtrate was then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 068-2 (0.76 g, 54.85% yield).

[0847] 68.3 Synthesis of Compound 068-3

[0848] 068-2 (710 mg, 1.95 mmol) was weighed into a reaction flask, methanol (10 mL) was added, the temperature was cooled to 0°C, sodium borohydride (36.88 mg, 0.97 mmol) was slowly added, and the temperature was naturally raised to room temperature with stirring for 2 hours. The reaction solution was added dropwise to saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 068-3 (650 mg, crude product).

[0849] 68.4 Synthesis of Compound 068-4

[0850] 068-3 (600 mg, 1.64 mmol) was weighed into a reaction flask, and 1,4-dioxane (5 mL) and a methanol solution of hydrogen chloride (1.6 mL, 6.56 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain compound 068-4 (350 mg, crude product).

[0851] 68.5 Synthesis of Compound 068

[0852] 068-4 (50 mg, 0.19 mmol) was weighed into a reaction flask, and ethanol (2 mL), 001-5 (58.01 mg, 0.19 mmol), and N,N-diisopropylethylamine (49.02 mg, 0.38 mmol) were added. The mixture was stirred at 50°C for 2 hours. The reaction solution was concentrated, and the residue was purified by preparative HPLC to obtain compound 068 (37.2 mg). LC-MS: [M+H] + =520.05.

[0853] 1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),7.98(d,2H),5.36(s,1H),3.13(s,3H),3.03(s,3H), 2.25(s,1H),1.92(s,1H),1.85–1.77(m,1H),1.76–1.66(m,1H),1.31(s,3H),1.23(s,3H).

[0854] Example 69. Synthesis of 3-((3-hydroxy-2-(morpholine-4-carbonyl)pyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 069) hydrochloride

[0855] Synthesis of Compound 069: Refer to the synthesis method of Compound 031 in Example 31, replacing 031-a with 069-a to obtain the hydrochloride salt of Compound 069 (13 mg, yield 16.7%). LC-MS: [M+H] + =498.20.

[0856] 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),9.57(d,J=8.0Hz,1H),8.52(d,J=8.0Hz,1H),8.34(d,J=8.0Hz,1H),5.10(d,J=8.0Hz,1H),4.70– 4.67(m,2H),4.00–3.98(m,2H),3.66-3.53(m,4H),2.81–2.68(m,2H),2.62(s,3H),1.89-1.82(m,1H),1.70–1.64(m,1H),1.01(s,6H).

[0857] Example 70. Synthesis of 3-((3-hydroxy-2-(4-methylpiperazine-1-carbonyl)pyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)cyclobut-3-ene-1,2-one (Compound 070)

[0858] Synthesis of Compound 070: Refer to the synthesis method of Compound 031 in Example 31, replacing 031-a with 070-a to obtain Compound 070 (30.7 mg). LC-MS: [M+H] + =511.20.

[0859] 1H NMR(400MHz,DMSO-d6)δ7.62(d,1H),7.14(d,1H),5.09(s,1H),3.52(s,2H),3.17(s,2H),2.63-2.68 (m,2H),2.56(s,3H),2.25(t,2H),2.18(t,2H),2.12(s,3H),1.81(t,1H),1.58(t,1H),0.96(d,6H).

[0860] Example 71, 4-((2-((2-cyclopropyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)-3,4-dioxetane-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 071), (S)-4-((2-((2-cyclopropyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)-3,4-dioxetane-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (R)-4-((2-((2-cyclopropyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)-3,4-dioxetane-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (071A or 071B) and (R)-4-((2-((2-cyclopropyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)-3,4-dioxetane-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (071B or 071A)

[0861] 71.1 Synthesis of Compound 071-1

[0862] 068-1 (5 g, 19.22 mmol), cyclopropylboronic acid (2.15 g, 24.99 mmol), potassium phosphate (12.24 g, 57.66 mmol), palladium acetate (560 mg, 2.49 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (560 mg, 0.97 mmol) were added to a reaction flask in sequence, followed by tetrahydrofuran (70 mL). The nitrogen atmosphere was replaced three times, and the reaction was stirred at 80°C overnight. Water (100 mL) was added to the reaction flask to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 071-1 (1.96 g, yield 46%). LC-MS: [M+H] + =222.05.

[0863] 71.2 Synthesis of Compound 071-2

[0864] Synthesis of Compound 071: Refer to the synthesis method of Compound 016 in Example 16, replacing 016-4 with 071-1 to obtain Compound 071 (404 mg, yield 92%). LC-MS: [M+H] + =482.15.

[0865] 1 H NMR(400MHz,DMSO-d6)δ7.64(s,1H),7.18(d,1H),5.09(s,1H),2.90(s,3H),2.80(s,3H),2.61-2.69(m,2H), 2.29-2.33(m,1H),1.80-1.85(m,1H),1.57-1.62(m,1H),1.04-1.07(q,2H),0.98(d,6H),0.88-0.91(q,2H).

[0866] 71.3 Synthesis of Compound 071A or 071B

[0867] Compound 071 was further chirally resolved to give compounds 071A (144 mg) and 071B (115.4 mg).

[0868] HPLC method: CHIRALPAK AD-H, 4.6*250mm 5μm, flow rate: 0.8mL / min, column temperature: 30℃;

[0869] 071A:

[0870] Chiral purity: 100%, T R : 9.335min;

[0871] 1 H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.02(d,1H),7.92(s,1H),5.07(s,1H),3.11(s,3H),3.02(s,3H),2.63-2.70( m,2H),2.31-2.35(m,1H),1.71-1.78(m,1H),1.61-1.67(m,1H),1.06-1.09(d,2H),0.99(d,6H),0.89-0.92(m,2H).

[0872] 071B:

[0873] Chiral purity: 99.4%, T R :11.284min;

[0874] 1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.05(d,1H),7.95(s,1H),5.08(d,1H),3.14(s,3H),3.03(s,3H),2.63-2.74( m,2H),2.31-2.36(m,1H),1.72-1.79(m,1H),1.61-1.68(m,1H),1.06-1.09(d,2H),0.99(d,6H),0.89-0.92(m,2H).

[0875] Example 72. Synthesis of (R)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzofuran-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide (Compound 072A)

[0876] 72.1 Synthesis of Compound 072-3

[0877] Synthesis of Compound 072-3: Refer to the synthesis method of Compound 028-4 in Example 28, replacing 010-5 with 019-7 to obtain Compound 072-3 (77 mg). LC-MS: [M+H] + =481.25.

[0878] 72.2 Synthesis of Compound 072A

[0879] Dissolve 072-3 (77 mg, 0.16 mmol) in dichloromethane (1 mL). The reaction mixture was cooled to 0°C and slowly added dropwise with boron tribromide (1.60 mL, 1.60 mmol). The mixture was allowed to react at room temperature for 3 hours. The reaction mixture was poured into ice-cold methanol (5 mL) to quench the reaction. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (basic conditions) and freeze-dried to obtain compound 072A (6.3 mg, chiral purity: 88.9%). LC-MS: [M+H] + =467.20.

[0880] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),7.97(s,1H),7.81(s,1H),6.00(s,1H),4.76(d,J=7.4Hz,1H),4.04(s,1H),2.82(s ,3H),2.58(s,2H),2.20(s,3H),1.74–1.66(m,1H),1.60–1.52(m,1H),1.10(d,J=5.8Hz,6H),0.95(s,3H),0.90(s,3H).

[0881] Example 73. Synthesis of (S)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzofuran-4-yl)amino)cyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpicolinamide (Compound 073A)

[0882] 053-6 (90.0 mg, 0.28 mmol) was dissolved in ethanol (5 mL), and N,N-diisopropylethylamine (109.29 mg, 0.84 mmol) and 019-7 (75.79 mg, crude product) were added. The mixture was reacted at 50°C for 5 hours. The reaction solution was purified by preparative HPLC to obtain compound 073A (37.5 mg, chiral purity: 86.9%). LC-MS: [M+H] + =453.20.

[0883] 1 H NMR(400MHz,DMSO-d6)δ8.64(s,1H),7.67(d,J=4.0Hz,1H),7.20(s,1H),5 .94(s,1H),4.75(s,1H),3.36(q,J=8.0Hz,1H),3.14(q,J=8.0Hz,1H),2.80 (d,J=32.0Hz,3H),2.52(m,1H),2.41(m,1H),2.18(s,3H),1.78–1.68(m,1H ),1.57–1.44(m,1H),1.00(dt,J=24.0,8.0Hz,3H),0.91(d,J=12.0Hz,6H).

[0884] Example 74. Synthesis of (R)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzofuran-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methyl-N-propylpicolinamide (Compound 074A)

[0885] Synthesis of Compound 074A: Refer to the synthesis method of Compound 001 in Example 1, replace 001-11 with 019-7, and 001-5 with 041-5 to obtain Compound 074A (37.0 mg, chiral purity: 95.8%). LC-MS: [M+H] + =467.15.

[0886] 1H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.05(s,1H),7.94(s,1H),6.04(s,1H),4.77(d,J=8.0Hz,1H),3.50–3.39(m,2H),3.10( s,1H),3.01(s,1H),2.56(m,2H),2.21(s,3H),1.71(m,1H),1.64–1.50(m,3H),0.96(s,3H),0.92(s,3H),0.91–0.69(m,3H).

[0887] Example 75. Synthesis of (R)-N-cyclopropyl-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzofuran-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methylpicolinamide (Compound 075A)

[0888] 054-5 (200 mg, 0.60 mmol) was dissolved in anhydrous ethanol (3 mL), and N,N-diisopropylethylamine (233 mg, 1.80 mmol) and 019-7 (118 mg, 0.66 mmol) were added dropwise. The mixture was stirred at 50°C for 16 hours. The reaction solution was purified by preparative HPLC (basic conditions) and freeze-dried to obtain compound 075A (94.6 mg, chiral purity: 92.5%). LC-MS: [M+H] + =465.15.

[0889] 1 H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.01(d,1H),7.90(d,1H),6.02(s,1H),4.77(d,1H),2.98(s,3H),2.86-2.91(m ,1H),2.55-2.57(m,2H),2.21(s,3H),1.67-1.76(m,1H),1.55-1.61(m,1H),0.96(s,3H),0.91(s,3H),0.46(s,4H).

[0890] Example 76. Synthesis of (R)-3-((3-hydroxy-2-(4-methylisoxazol-5-yl)pyridin-4-yl)amino)-4-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzofuran-4-yl)amino)cyclobut-3-ene-1,2-dione (Compound 076A)

[0891] Synthesis of Compound 076A: Refer to the synthesis method of Compound 036 in Example 36, replacing 010-5 with 019-7 to obtain Compound 076A (7 mg, yield 6%). LC-MS: [M+H] + =449.15.

[0892] 1 H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.53(s,1H),8.11(s,2H),6.04(s,1H),4.79(d,J=8.0Hz,1H),2.62 –2.53(m,2H),2.22(s,3H),2.13(s,3H),1.76–1.71(m,1H),1.66-1.58(m,1H),0.97(s,3H),0.93(s,3H).

[0893] Example 77. Synthesis of 4-((3,4-dioxo-2-((3,5,5-trimethyl-4,5,6,7-tetrahydrobenzofuran-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 077)

[0894] 77.1 Synthesis of Compound 077-1

[0895] 003-a (8 g, 71.35 mmol) was weighed into a reaction flask, and ethanol (35 mL), water (15 mL), and ammonium acetate (5.5 g, 71.35 mmol) were added. The mixture was reacted at 80°C for 1 hour. Ethyl 2-chloroacetoacetate (18.0 g, 160.53 mmol) was then added and the mixture was reacted at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain compound 077-1 (5.5 g, yield 34.7%). LC-MS: [M+H] + =223.05.

[0896] 77.2 Synthesis of Compound 077-2

[0897] 077-1 (5.4 g, 24.3 mmol) was weighed into a reaction flask, methanol (48 mL) and water (24 mL) were added, and potassium hydroxide (8.18 g, 145.8 mmol) was slowly added. The mixture was stirred at room temperature overnight. Hydrochloric acid (15 mL, 6 N) was slowly added dropwise to the reaction solution to adjust the pH to 2-3. Ethyl acetate (100 mL x 3) was added for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 077-2 (4 g, yield 84.7%), which was used directly in the next step. LC-MS: [M+H] + =195.00.

[0898] 77.3 Synthesis of Compound 077-3

[0899] 077-2 (4 g, 20.6 mmol) was weighed into a reaction flask, and diethylene glycol (50 mL), copper powder (1.31 g, 20.6 mmol) and pyridine (1.31 g, 20.6 mmol) were added. The reaction was carried out at 170 ° C for 5 hours. The reaction solution was poured into water and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 77-3 (2.4 g, yield 77.7%).

[0900] 77.4 Synthesis of Compound 077-4

[0901] 077-3 (2.1 g, 13.98 mmol) was weighed into a reaction flask, tetrahydrofuran (30 mL) was added, nitrogen was protected, the temperature was lowered to 0°C, potassium tert-butoxide (6.27 g, 38.03 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The temperature was then lowered to 0°C, and iodomethane (7.94 g, 55.92 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water (300 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = (20 / 1 to 5 / 1)) to give compound 077-4 (2 g, yield 80.2%). LC-MS: [M+H] + =179.05.

[0902] 77.5 Synthesis of Compound 077-5

[0903] 077-4 (0.6 g, 3.37 mmol) was weighed into a reaction flask, and methanol (20 mL), ammonium acetate (5.2 g, 67.4 mmol), and sodium cyanoborohydride (2.12 g, 33.7 mmol) were added. The mixture was stirred at 80°C under nitrogen for 12 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8-9. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = (30 / 1 to 20 / 1) to obtain compound 077-5 (0.3 g). LC-MS: [M-NH2] + =163.05.

[0904] 77.6 Synthesis of Compound 077

[0905] 001-5 (80 mg, 0.26 mmol) was weighed into a reaction flask, and ethanol (3 mL), 077-5 (47 mg, 0.26 mmol), and N,N-diisopropylethylamine (100 mg, 0.78 mmol) were added. The mixture was stirred at 55°C for 12 hours. The mixture was purified by preparative HPLC (basic conditions) to obtain compound 077 (54.6 mg, 47.5% yield). LC-MS: [M+H] + =439.15.

[0906] 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=8.0Hz,1H),8.08(d,J=8.0Hz,1H),7.94(s,1H),7.33(s,1H),4.82(d,J=12.0Hz,1H),3.13 (s,3H),3.02(s,3H),2.64-2.55(m,2H),1.85(d,J=4.0Hz,3H),1.76-1.68(m,1H),1.59-1.54(m,1H),0.95(d,J=4.0Hz,6H).

[0907] Example 78, 4-((2-((5,5-dimethyl-4,5,6,7-tetrahydrobenzofuran-4-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 078), (S)-4-((2-((5,5-dimethyl-4,5,6,7-tetrahydrobenzofuran-4-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (R)-4-((2-((5,5-dimethyl-4,5,6,7-tetrahydrobenzofuran-4-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 078A or 078B)

[0908] 78.1 Synthesis of Compound 078-1

[0909] 078-a (5.00 g, 36.72 mmol) was dissolved in N,N-dimethylformamide (120 mL), the nitrogen atmosphere was replaced three times, sodium hydride (5.88 g, 146.88 mmol) was added at 0°C, stirred for 40 minutes, and then iodomethane (20.85 g, 146.88 mmol) was added. The mixture was returned to room temperature and reacted overnight. The reaction solution was added dropwise to cold water (100 mL) to quench the reaction. The aqueous phase was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give compound 078-1 (4.00 g). LC-MS: [M+H] + =165.05.

[0910] 78.2 Synthesis of Compound 078-2

[0911] 078-1 (1.70 g, 8.80 mmol) was dissolved in anhydrous methanol (20 mL), the nitrogen atmosphere was replaced three times, and ammonium acetate (13.57 g, 176.00 mmol) was added. After stirring for 10 minutes, sodium cyanoborohydride (8.29 g, 132.00 mmol) was added. After stirring at room temperature for 10 minutes, the temperature was raised to 80°C and the reaction was refluxed overnight. The reaction solution was adjusted to pH 8-9 with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (300 mL × 3). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 078-2 (4.7 g, crude product). LC-MS: [M+H] + =149.05.

[0912] 78.3 Synthesis of Compound 078

[0913] Dissolve 001-5 (277.81 mg, 0.91 mmol) in anhydrous ethanol (3 mL), add N,N-diisopropylethylamine (705.65 mg, 5.46 mmol) and 078-2 (300 mg, 1.82 mmol), and stir at room temperature overnight. The reaction solution was purified by preparative HPLC (alkaline conditions) and freeze-dried to obtain compound 078 (414 mg). LC-MS: [M+H] + =425.15.

[0914] 78.4 Synthesis of Compounds 078A and 078B

[0915] Compound 078 was further chirally resolved to give compounds 078A (120.4 mg) and 078B (133.7 mg).

[0916] HPLC method: CHIRALPAK AD-H, 4.6*250mm 5μm, 20% ethanol / n-hexane, 0.8mL / min, 30℃;

[0917] 078A:

[0918] Chiral purity: 99.8%, T R =8.185min;

[0919] 1 H NMR(400MHz,DMSO-d6)δ8.69(d,1H),8.06(d,1H),7.90(s,1H),7.53(s,1H),6.46(s,1H),4.85(d,1H),3.1 1(s,3H),3.01(s,3H),2.57-2.63(m,2H),1.70-1.75(m,1H),1.60-1.65(m,1H),0.97(s,3H),0.92(s,3H).

[0920] 078B:

[0921] Chiral purity: 93.7%, T R =7.152min;

[0922] 1H NMR(400MHz,DMSO-d6)δ8.69(d,1H),8.06(d,1H),7.91(s,1H),7.54(s,1H),6.47(s,1H),4.85(d,1H),3.1 1(s,3H),3.01(s,3H),2.57-2.66(m,2H),1.70-1.75(m,1H),1.60-1.65(m,1H),0.97(s,3H),0.92(s,3H).

[0923] Example 79, 4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide (Compound 079), (S)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide Synthesis of (R)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide (079A or 079B) and (R)-4-((3,4-dioxo-2-((2,5,5-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide (079B or 079A)

[0924] 79.1 Synthesis of Compound 079

[0925] Synthesis of Compound 079: Refer to the synthesis method of Compound 001 in Example 1, replace 001-11 with 020-4, and 001-5 with 015-5 to obtain Compound 079 (80.5 mg). LC-MS: [M+H] + =484.10.

[0926] 1 H NMR (400MHz, DMSO-d6) δ8.80(s,1H),8.02(s,1H),7.93(s,1H),4.98(d,J=9.8Hz,1H),4.45(d,J=251.4Hz,1H),2.85(s,3H ),2.80(s,1H),2.77–2.67(m,1H),2.58(s,3H),1.78–1.68(m,1H),1.69–1.58(m,1H),1.13(s,6H),0.97(d,J=7.6Hz,6H).

[0927] 79.2 Synthesis of Compounds 079A and 079B

[0928] 079 was further chirally resolved to give 079A (13.0 mg) and 079B (14.7 mg).

[0929] HPLC method: CHIRALPAK AD-H, 4.6*250mm 5μm, 20% isopropanol / n-hexane, 0.8mL / min, 30℃;

[0930] 079A:

[0931] Chiral purity: 99.2%, T R :14.105min;

[0932] 1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.00(s,1H),7.87(s,1H),4.97(d,J=9.8Hz,1H),4.40(d,J=269.8Hz,1H),2.83(s,3H),2.77 (s,1H),2.74–2.67(m,1H),2.58(s,3H),1.77–1.67(m,1H),1.61(d,J=13.2Hz,1H),1.11(d,J=5.4Hz,6H),0.96(d,J=5.2Hz,6H).

[0933] 079B:

[0934] Chiral purity: 95.7%, T R :6.676min;

[0935] 1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),7.98(s,1H),7.84(s,1H),4.96(d,J=9.6Hz,1H),4.38(d,J=276.7Hz,1H),2.81(s,3H),2.7 6(s,1H),2.71(t,J=12.5Hz,1H),2.57(s,3H),1.70(d,J=7.0Hz,1H),1.62(s,1H),1.10(d,J=6.3Hz,6H),0.96(d,J=4.0Hz,6H).

[0936] Example 80. Synthesis of 4-((2-((5,5-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 080)

[0937] 80.1 Synthesis of Compound 080-1

[0938] 080-a (1.5 g, 9.85 mmol) was weighed into a reaction flask, tetrahydrofuran (15 mL) was added, the temperature was cooled to 0°C, iodomethane (4.22 g, 29.55 mmol) and sodium tert-butoxide (2.84 g, 29.55 mmol) were added, and the mixture was stirred at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 080-1 (1.2 g, yield 67.55%). LC-MS: [M+H] + =181.00.

[0939] 80.2 Synthesis of Compound 080-2

[0940] 080-1 (200 mg, 1.11 mmol) was weighed into a reaction flask, and ethanol (1 mL), ammonium acetate (256.68 mg, 3.33 mmol), and sodium cyanoborohydride (209.26 mg, 3.33 mmol) were added. The mixture was stirred at 60°C overnight. The reaction solution was concentrated under reduced pressure, diluted with water (10 mL), and the pH was adjusted to 2 with hydrochloric acid (1 N). The mixture was extracted with ethyl acetate (5 mL x 3). The aqueous phase was adjusted to pH 12 with aqueous sodium hydroxide solution (1 mol / L), and extracted with ethyl acetate (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 080-2 (56 mg, yield 27.60%). LC-MS: [M-NH2] + =165.00.

[0941] 80.3 Synthesis of Compound 080

[0942] 001-5 (80 mg, 0.26 mmol) was weighed into a reaction flask, and ethanol (2 mL), N,N-diisopropylethylamine (67.20 mg, 0.52 mmol), and 080-2 (47.14 mg, 0.26 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by HPLC preparative chromatography (alkaline conditions) and freeze-dried to obtain compound 080 (60.8 mg). LC-MS: [M+H] + =441.15.

[0943] 1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.09(d,1H),8.00(s,1H),7.37(d,1H),6.96(d,1H),4.96( d,1H),3.16(s,3H),3.04(s,3H),2.91–2.71(m,2),1.82–1.63(m,2),0.99(s,3H),0.95(s,3H).

[0944] Example 81. Synthesis of 3-((3-hydroxy-2-(morpholine-4-carbonyl)pyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 081)

[0945] 81.1 Synthesis of Compound 081-1

[0946] Weigh 053-1 (3 g, 0.23 mmol) into a reaction flask, add dichloromethane (20 mL), triethylamine (4.42 g, 43.68 mmol) and 069-a (1.52 g, 17.47 mmol). The reaction solution was stirred at room temperature for 2 hours, water (50 mL) was added, and the organic layer was separated. The aqueous phase was extracted with dichloromethane (30 mL × 2). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1-1 / 1) to give compound 081-1 (2.7 g, yield 72.24%). LC-MS: [M+H] + =257.00.

[0947] 81.2 Synthesis of Compound 081-2

[0948] Synthesis of Compound 081: Refer to the synthesis method of Compound 001 in Example 1, replace 001-1 with 081-1, and replace 001-11 with 018-5 to obtain Compound 081 (45.5 mg). LC-MS: [M+H] + =481.10.

[0949] 1 H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.35(s,1H),5.96(s,1H),4.88(s,1H),3 .59(s,8H),2.35(m,2H),2.22(s,3H),1.65(m,1H),1.46(m,1H),0.95(s,6H).

[0950] Example 82. Synthesis of 3-((2-chloro-3-hydroxypyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 082)

[0951] 82.1 Synthesis of Compound 082-1

[0952] 082-a (400 mg, 2.52 mmol) was dissolved in N,N-dimethylformamide (5 mL), cooled to 0°C, and sodium hydride (202 mg, 5.04 mmol) and 001-b (644 mg, 3.78 mmol) were slowly added. The reaction was stirred at room temperature for 6 hours. The reaction solution was slowly poured into a saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL×3), and the organic phases were combined and washed with saturated brine (20 mL). After drying over anhydrous sodium sulfate, the filtrate was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 082-1 ​​(450 mg, yield 63.11%).

[0953] 82.2 Synthesis of Compound 082

[0954] Synthesis of Compound 082: Refer to the synthesis method of Compound 049 in Example 49, replacing 036-5 with 082-1 ​​to obtain Compound 082 (12.1 mg). LC-MS: [M+H] + =402.05.

[0955] 1 H NMR(400MHz,DMSO-d6)δ8.92(s,1H),7.58(s,1H),6.90(s,1H),5.92(s,1H),4.93(s,1 H), 2.40–2.24 (m, 2H), 2.21 (s, 3H), 1.59 (s, 1H), 1.42 (s, 1H), 0.91 (d, J = 16.2Hz, 6H).

[0956] Example 83. Synthesis of 3-((3-hydroxy-2-(1-methyl-1H-imidazol-2-yl)pyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 083)

[0957] 83.1 Synthesis of Compound 083-1

[0958] 083-a (10 g, 53.31 mmol) and N,N-diisopropylamine (20.7 g, 159.93 mmol) were dissolved in N,N-dimethylformamide (100 mL). 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24.3 g, 63.97 mmol) and dimethylhydroxylamine hydrochloride (5.7 g, 58.64 mmol) were slowly added at 0°C. The reaction system was warmed to room temperature and reacted for 15 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 083-1 (11.4 g, 92.71% yield).

[0959] 83.2 Synthesis of Compound 083-2

[0960] 083-1 (6.0 g, 26.01 mmol) was dissolved in dichloromethane (50 mL), replaced with nitrogen three times, and cooled to -78°C. A solution of diisobutylaluminum hydride in n-hexane (39.02 mL, 39.02 mmol, 1 M) was slowly added dropwise, and the reaction was maintained at -78°C for 2 hours. Methanol (10 mL) was slowly added at -78°C to quench the reaction. Saturated aqueous potassium sodium tartrate (200 mL) was then added, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 083-2 (2.2 g, 49.29% yield).

[0961] 83.3 Synthesis of Compound 083-3

[0962] 083-2 (2.0 g, 11.69 mmol) was dissolved in ethanol (20 mL). Aqueous ammonia (9.3 mL, 25%) was added at 0°C and stirred for 30 minutes. Glyoxal (7.4 mL, 40%) was then added and stirred at 0°C for 30 minutes. The mixture was then warmed to room temperature and the reaction continued for 2 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 083-3 (1.1 g, yield 49.11%). LC-MS: [M+H] + =210.00.

[0963] 83.4 Synthesis of Compound 083-4

[0964] Dissolve 083-3 (1.2 g, 5.72 mmol) in dimethyl sulfoxide (10 mL), add potassium hydroxide (963 mg, 17.17 mmol), stir at room temperature for 0.5 hours, then cool to 0°C in an ice bath. Slowly add iodomethane (894 mg, 6.3 mmol) dropwise, return to room temperature, and continue reacting for 2 hours. The reaction solution is diluted with water (20 mL) and extracted with dichloromethane (20 mL × 3). The organic phases are combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound 083-4 (800 mg, yield 62.49%). LC-MS: [M+H] + =224.00.

[0965] 83.5 Synthesis of Compound 083-5

[0966] 083-4 (800 mg, 3.58 mmol), tert-butyl carbamate (629 mg, 5.37 mmol), potassium carbonate (989 mg, 7.15 mmol), tris(dibenzylideneacetone)dipalladium (300 mg, 0.4 mmol) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (150 mg, 0.4 mmol) were dissolved in 1,4-dioxane (10 mL), replaced with nitrogen three times, and heated to 100°C for 3 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 083-5 (340 mg, yield 31.23%). LC-MS: [M+H] + =305.05.

[0967] 83.6 Synthesis of Compound 083-6

[0968] 083-5 (500 mg, 1.12 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (5 mL, 4 M) and allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (alkaline conditions) and freeze-dried to obtain compound 083-6 (300 mg, 87.66% yield).

[0969] 83.7 Synthesis of Compound 083

[0970] Synthesis of Compound 083: Refer to the synthesis method of Compound 082 in Example 82, replacing 082-a with 083-6 to obtain Compound 083 (0.9 mg). LC-MS: [M+H] + =448.10.

[0971] 1 H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.76(s,1H),8.06(d,1H),8.04(d,1H),7.45(s,1H),7.20(s,1H),6.01(s,1H), 4.88(s,1H),4.20(s,1H),2.33-2.43(m,2H),2.24(s,3H),1.60-1.67(m,1H),1.49-1.53(m,1H),0.97-0.98(d,6H).

[0972] Example 84. Synthesis of 3-(3-hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridin-4-yl)amino-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-3-ene-1,2-dione (Compound 084)

[0973] 84.1 Synthesis of Compound 084-1

[0974] At room temperature, 084-a (20 g, 114.9 mmol) and concentrated sulfuric acid (60 mL) were added to a reaction flask, cooled to 0°C, and nitric acid (20 mL, 287.4 mmol, diluted with concentrated sulfuric acid (60 mL)) was slowly added dropwise. Stir at room temperature for 5 hours. The reaction solution was slowly poured into ice water (500 mL) and extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 084-1 (14.4 g). LC-MS: [M+H] + =218.90.

[0975] 84.2 Synthesis of Compound 084-2

[0976] At room temperature, 084-1 (3.5 g, 16.1 mmol) was dissolved in methanol / acetonitrile (4 mL / 20 mL). (Trimethylsilyl)diazomethane (2 M, 40 mL, 80.3 mmol) was added dropwise at 0°C and stirred at 25°C for 2 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 084-2 (3.2 g). LC-MS: [M+H] + =232.90.

[0977] 84.3 Synthesis of Compound 084-3

[0978] 084-2 (2.8 g, 12.02 mmol) was weighed into a reaction flask. 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.03 g, 14.42 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (4.40 g, 6.01 mmol), cesium carbonate (11.75 g, 36.06 mmol), 1,4-dioxane (20 mL), and water (4 mL) were added. The atmosphere was then purged with nitrogen three times. The reaction was continued at 90°C for 2 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (200 mL). After drying over anhydrous sodium sulfate, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 084-3 (4.3 g). LC-MS: [M+H] + =237.00.

[0979] 84.4 Synthesis of Compound 084-4

[0980] 084-3 (0.9 g, 3.81 mmol) was weighed into a reaction flask, and palladium on carbon (0.41 g, 3.81 mmol, 10% wt) and methanol (10 mL) were added. The hydrogen atmosphere (0.01 g, 3.81 mmol) was replaced three times, and the reaction was allowed to proceed at room temperature for 6 hours. The reaction mixture was filtered to remove the palladium on carbon, and the filtrate was concentrated by distillation under reduced pressure to obtain compound 084-4 (0.7 g, crude product). LC-MS: [M+H] + =209.05.

[0981] 84.5 Synthesis of Compound 084

[0982] Synthesis of Compound 084: Refer to the synthesis method of Compound 082 in Example 82, replacing 082-a with 084-4 to obtain Compound 084 (4.4 mg). LC-MS: [M+H] + =452.15.

[0983] 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),7.89(s,1H),7.55(s,1H),5.96(s,1H),4.87(s,1H),4.76(d,J=9.6Hz,1H),3.97(d,J=10.8Hz ,1H),3.54(s,1H),2.35(d,J=17.2Hz,2H),2.22(s,3H),1.84(s,1H),1.58(d,J=33.6Hz,6H),1.44(d,J=14.4Hz,1H),0.95(s,6H).

[0984] Example 85. Synthesis of 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N-methyl-N-propylpicolinamide (Compound 085)

[0985] Synthesis of Compound 085: Refer to the synthesis method of Compound 001 in Example 1, replace 001-5 with 041-5, and 001-11 with 018-5 to obtain Compound 085 (54.2 mg). LC-MS: [M+H] + =467.15.

[0986] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.04(s,1H),7.94(s,1H),5.99(s,1H),4.86(d,J=8.0Hz,1H),3.52–3.38(m,3H),3.09(s,1H) ,3.00(s,1H),2.38(m,2H),2.23(s,3H),1.67–1.54(m,3H),1.54–1.43(m,1H),0.95(d,J=4.0Hz,6H),0.81(dt,J=68.0,8.0Hz,3H).

[0987] Example 86, 4-((2-((2,2-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 086), (S)-4-((2-((2,2-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (R)-4-((2-((2,2-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 086A or 086B) and (R)-4-((2-((2,2-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 086B or 086A)

[0988] 86.1 Synthesis of Compound 086-1

[0989] Potassium tert-butoxide (3.68 g, 32.83 mmol) was dissolved in tetrahydrofuran (20 mL), the atmosphere was replaced with nitrogen three times, the reaction mixture was cooled to 0°C, and stirred for 0.25 hours. 086-a (2.00 g, 13.68 mmol) was dissolved in tetrahydrofuran (4 mL) and slowly added dropwise to the reaction mixture. The mixture was stirred at this temperature for 1 hour, followed by the addition of iodomethane (5.05 g, 35.57 mmol) and stirring at 0°C for 1 hour. The reaction mixture was poured into water (30 mL) to quench the reaction, and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 086-1 (2.30 g, 96.49% yield). LC-MS: [M+H] + =175.05.

[0990] 86.2 Synthesis of Compound 086-2

[0991] At room temperature, 086-1 (1.00 g, 5.74 mmol) was dissolved in methanol (20 mL). Ammonium acetate (7.96 g, 103.32 mmol) and sodium cyanoborohydride (3.25 g, 51.66 mmol) were added to the reaction solution, which was then heated to 80°C for 16 hours. Saturated aqueous sodium bicarbonate solution (30 mL) was slowly added to the reaction solution to adjust the pH to 8-9. The solution was then extracted with dichloromethane (60 mL × 3). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 086-2 (0.80 g, 79.53% yield).

[0992] 86.3 Synthesis of Compound 086

[0993] 086-2 (60 mg, 0.34 mmol) was dissolved in ethanol (2.5 mL), and 001-5 (100 mg, 0.34 mmol) and N,N-diisopropylethylamine (220 mg, 1.70 mmol) were added. The mixture was stirred at 50°C for 2 hours. The reaction solution was purified by HPLC and freeze-dried to obtain compound 086 (24.2 mg). LC-MS: [M+H] + =435.15.

[0994] 1H NMR (400MHz, DMSO-d6) δ8.78(d,J=7.2Hz,1H),8.08(d,J=5.4Hz,1H),7.94(s,1H),7.30–7.16(m,4H),5.02(d,J=9.8Hz,1H),3. 13(s,3H),3.02(s,3H),2.83(dd,J=14.8,7.0Hz,2H),1.75(dt,J=13.4,6.6Hz,1H),1.67–1.58(m,1H),0.96(d,J=13.2Hz,6H).

[0995] 86.4 Synthesis of Compounds 086A and 086B

[0996] 086 was further chirally resolved to give 086A (283.8 mg) and 086B (286.0 mg). LC-MS: [M+H] + =452.10.

[0997] HPLC method: CHIRALPAK AD-H, 4.6*250 mm 5 μm, 20% ethanol / n-hexane, 0.8 mL / min, 30°C.

[0998] 086A:

[0999] Chiral purity: 97.6%, T R :6.388min;

[1000] 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),8.04(d,J=5.4Hz,1H),7.91(s,1H),7.26–7.13(m,4H),4.98(d,J=9.8Hz,1H),3.09(s ,3H),2.98(s,3H),2.78(dt,J=18.4,9.2Hz,2H),1.71(dt,J=13.4,6.8Hz,1H),1.63–1.54(m,1H),0.93(d,J=12.8Hz,6H).

[1001] 086B:

[1002] Chiral purity: 98.8%, T R :7.115min;

[1003] 1H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.09(d,J=5.2Hz,1H),7.97(s,1H),7.30–7.15(m,4H),5.02(d,J=9.8Hz,1H),3.14(s ,3H),3.03(s,3H),2.83(dd,J=15.8,7.0Hz,2H),1.75(dt,J=13.4,6.6Hz,1H),1.68–1.57(m,1H),0.96(d,J=12.8Hz,6H).

[1004] Example 87, 4-((2-((8-fluoro-2,2-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 087), (S)-4-((2-((8-fluoro-2,2-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (R)-4-((2-((8-fluoro-2,2-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 087A or 087B)

[1005] 87.1 Synthesis of Compound 087-1

[1006] Acetic anhydride (6.93 g, 67.92 mmol) was added to a 250 mL reaction flask, followed by anhydrous ethanol (78 mL). The temperature was lowered to 0°C. A solution of 087-a (5 g, 33.96 mmol) in anhydrous ethanol (16 mL) was then added dropwise to the reaction flask. The mixture was allowed to return to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure to yield compound 087-1 (7 g, crude product). LC-MS: [M+H] + =190.05.

[1007] 87.2 Synthesis of Compound 087-2

[1008] At 0°C, 087-1 (13 g, 68.69 mmol) was dissolved in acetone (280 mL). Potassium permanganate (33.11 g, 209.50 mmol) and a 15% aqueous magnesium sulfate solution (34 mL) were added. The mixture was allowed to return to room temperature and stirred overnight. The reaction solution was filtered through celite, the solids were washed with water and dichloromethane, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (300 mL x 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 087-2 (7 g, 50% yield). LC-MS: [M+H] + =204.05.

[1009] 87.3 Synthesis of Compound 087-3

[1010] 087-2 (7 g, 34.44 mmol) was dissolved in hydrochloric acid (6 N, 100 mL) and stirred at 90°C for 2 hours. Ice was added to the system, and then aqueous sodium hydroxide solution (2 M) was added to adjust the pH to 8-9. The aqueous phase was extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 087-3 (5 g, 90% yield). LC-MS: [M+H] + =162.00.

[1011] 87.4 Synthesis of Compound 087-4

[1012] At 0°C, 087-3 (2 g, 12.41 mmol) was dissolved in dichloromethane (90 mL). Boron trifluoride etherate (2.64 g, 18.62 mmol) was added and stirred for 10 minutes. A solution of tert-butyl nitrite (1.54 g, 14.89 mmol) in dichloromethane (13 mL) was then slowly added. The mixture was stirred at 0°C for 1 hour, diluted with n-heptane (90 mL), and stirred for 10 minutes. The solvent was removed, and n-heptane (90 mL) was added to the solid. The mixture was heated at 100°C for 1 hour. The reaction mixture was cooled to room temperature, dissolved in ethyl acetate (100 mL), washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 087-4 (914 mg, 44% yield). LC-MS: [M+H] + =165.00.

[1013] 87.5 Synthesis of Compound 087-5

[1014] 087-4 (914 mg, 5.57 mmol) was dissolved in ultra-dry tetrahydrofuran (15 mL), and sodium hydride (490.16 mg, 12.25 mmol, 60% wt dispersion in mineral oil) was added portionwise. The mixture was stirred at room temperature for 20 minutes, and then iodomethane (0.73 mL, 11.70 mmol) was slowly added. The mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (150 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 19 / 1) to obtain compound 087-5 (725 mg, yield 68%). LC-MS: [M+H] + =193.00.

[1015] 87.6 Synthesis of Compound 087-6

[1016] 087-5 (205 mg, 1.07 mmol) was dissolved in anhydrous ethanol (3 mL), and hydroxylamine hydrochloride (297.42 mg, 4.28 mmol) and sodium acetate (175.54 mg, 2.14 mmol) were added. The reaction mixture was stirred at 80°C overnight. The reaction solution was concentrated under reduced pressure, and water (15 mL) was added to the concentrate. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 087-6 (210 mg, 95% yield). LC-MS: [M+H] + =208.00.

[1017] 87.7 Synthesis of Compound 087-7

[1018] 087-6 (210 mg, 1.01 mmol) was dissolved in methanol (1 mL), and zinc powder (330.32 mg, 5.05 mmol) and hydrochloric acid (2 M, 3 mL) were added. The reaction was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was slowly added dropwise to the reaction solution to adjust the pH to 8-9. The solution was then extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 087-7 (84 mg, 43% yield). LC-MS: [M+H] + =177.05.

[1019] 87.8 Synthesis of Compound 087

[1020] 087-7 (84 mg, 0.43 mmol) was dissolved in anhydrous ethanol (2 mL), and N,N-diisopropylethylamine (168.52 mg, 1.30 mmol) and 001-5 (132.69 mg, 0.43 mmol) were added. The mixture was stirred at room temperature overnight. After purification by HPLC (acidic conditions), the pH was adjusted to 8-9 with sodium bicarbonate and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was concentrated under reduced pressure and freeze-dried to obtain compound 087 (101.8 mg). LC-MS: [M+H] + =453.10.

[1021] 1 H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.04(t,2H),7.32(q,1H),7.06(m,2H),5.15(d,1H),3.12(s,3 H),3.01(s,3H),2.83-2.92(m,2H),1.70-1.76(m,1H),1.51-1.54(m,1H),1.02(s,3H),0.91(s,3H).

[1022] 87.9 Synthesis of Compounds 087A and 087B

[1023] 087 was further chirally resolved to give 087A (32.2 mg) and 087B (33.5 mg). LC-MS: [M+H] + =453.05.

[1024] HPLC method: CHIRALPAK AD-H, 4.6*250 mm 5 μm, 10% isopropanol / n-hexane, 0.8 mL / min, 30°C.

[1025] 087A:

[1026] Chiral purity: 98.4%, T R :6.920min;

[1027] 1 H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.00(t,2H),7.32(dd,1H),7.05(dd,2H),5.14(d,1H), 3.09(s,3H),2.99(s,3H),2.84(m,2H),1.72(m,1H),1.51(m,1H),1.02(s,3H),0.90(s,3H).

[1028] 087B:

[1029] Chiral purity: 96.7%, TR :7.591min;

[1030] 1 H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.02(t,2H),7.32(dd,1H),7.06(dd,2H),5.15(d,1H),3 .11(s,3H),3.01(s,3H),2.87(dt,2H),1.73(td,1H),1.53(dd,1H),1.02(s,3H),0.91(s,3H).

[1031] Example 88. Synthesis of 4-((2-((7,7-dimethyl-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 088)

[1032] Synthesis of Compound 088: Refer to the synthesis method of Compound 002 in Example 2, except that 002-a is replaced with 088-a to obtain Compound 088 (4.4 mg). LC-MS: [M+H] + =452.15.

[1033] 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),7.89(s,1H),7.55(s,1H),5.96(s,1H),4.87(s,1H),4.76(d,J=9.6Hz,1H),3.97(d,J=10.8Hz ,1H),3.54(s,1H),2.35(d,J=17.2Hz,2H),2.22(s,3H),1.84(s,1H),1.58(d,J=33.6Hz,6H),1.44(d,J=14.4Hz,1H),0.95(s,6H).

[1034] Example 89. Synthesis of 4-((2-((6,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-5-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 089)

[1035] Synthesis of Compound 089: Refer to the synthesis method of Compound 002 in Example 2, except that 002-a is replaced with 089-a to obtain Compound 089 (79.6 mg). LC-MS: [M+H] + =436.10.

[1036] 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.43(s,1H),8.39(t,1H),8.09(t,1H),7.98(s,1H),7.33(t,1H), 5.05(t,1H),3.15(s,3H),3.04(s,3H),2.82-2.86(m,2H),1.69-1.79(m,2H),1.01(s,3H),0.92(s,3H).

[1037] Example 90. Synthesis of 4-((2-((6,6-difluoro-2-methyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 090)

[1038] 90.1 Preparation of Compound 090-1

[1039] 018-2 (1.5 g, 9.99 mmol) was weighed into a reaction flask, tetrahydrofuran (15 mL) was added, and the temperature was cooled to -78°C under nitrogen. Lithium bistrimethylsilylamide (29.97 mmol, 29.97 mL, 1 M) was slowly added dropwise. The reaction was allowed to proceed at -78°C for 0.5 hour. A solution of N-fluorobisbenzenesulfonamide (9.45 g, 29.97 mmol) in tetrahydrofuran (10 mL) was then added. The mixture was returned to room temperature and stirred overnight. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 090-1 (0.35 g). LC-MS: [M+H] + =186.95.

[1040] 90.2 Preparation of Compound 090

[1041] Synthesis of Compound 090: Refer to the synthesis method of Compound 002 in Example 2, except that 002-1 is replaced with 090-1 to obtain Compound 090 (2.1 mg). LC-MS: [M+H] + =447.00.

[1042] 1H NMR (400MHz, DMSO-d6) δ9.14(s,1H),7.99(s,1H),7.97(s,1H),6.10(s,1H),5.60(t,J=7.6Hz ,1H),3.08(d,J=37.6Hz,6H),2.68–2.54(m,2H),2.37(dd,J=17.2,15.2Hz,2H),2.26(s,3H).

[1043] Example 91, 4-((2-((2-cyclopropyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 091), (R)-4-((2-((2-cyclopropyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (S)-4-((2-((2-cyclopropyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 091A or 091B) and (S)-4-((2-((2-cyclopropyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 091B or 091A)

[1044] 91.1 Preparation of Compound 091-1A

[1045] A mixture of 050-3A (1.6 g, 6.58 mmol) and 050-3B (0.48 g, 1.97 mmol) was dissolved in 1,4-dioxane (40 mL) and water (4 mL). Cyclopropylboronic acid (2.26 g, 26.32 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.07 g, 1.32 mmol), and potassium carbonate (5.46 g, 39.48 mmol) were added sequentially. The atmosphere was purged with nitrogen and the reaction was incubated at 90°C for 2 h. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain a mixture of 091-1A and 091-1B (1.3 g).

[1046] The mixture of 091-1A and 091-1B (1.3 g) was separated and purified by HPLC (trifluoroacetic acid system). The two fractions were concentrated under reduced pressure from acetonitrile and extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 019-1A (800 mg, yield 80.00%). LC-MS: [M+H] + =205.10.

[1047] 1 H NMR (400MHz, CDCl3) δ5.94(s,1H),2.67(t,J=6.0Hz,2H),1.92(t,J=5.8Hz,3H),1.17(s,6H),1.04–0.88(m,4H).

[1048] 91.2 Preparation of Compound 091

[1049] Synthesis of Compound 091: Refer to the synthesis method of Compound 002 in Example 2, except that 002-1 is replaced with 091-1A to obtain Compound 091 (136.7 mg, yield 41.09%). LC-MS: [M+H] + =465.10.

[1050] 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),7.98(d,J=5.3Hz,1H),7.81(d,J=5.1Hz ,1H),5.92(s,1H),4.83(d,J=7.1Hz,1H),2.99(d,J=20.8Hz,6H),2.92–2.77( m,1H),2.34(s,1H),1.87(dd,J=8.6,3.9Hz,1H),1.57(s,1H),1.45(s,1H),0. 93 (d, J = 3.8 Hz, 6H), 0.83 (dd, J = 8.3, 2.0 Hz, 2H), 0.61 (dd, J = 8.6, 3.7 Hz, 2H).

[1051] 91.3 Preparation of Compounds 091A and 091B

[1052] Compound 091 (130 mg, 0.280 mmol) was further chirally resolved to give compound 091A (51 mg, yield 39.23%) and compound 091B (51 mg, yield 39.23%).

[1053] 091A:

[1054] Chiral purity: 99.1%, T R:14.694min;

[1055] 1 H NMR (400MHz, DMSO-d6) δ8.79(s,1H),8.05(d,J=5.3Hz,1H),7.94(s,1H),5.95(s,1H),4.84(d,J=9.1Hz, 1H),3.12(s,3H),3.02(s,3H),2.45–2.26(m,2H),1.88(td,J=8.4,4.2Hz,1H),1.59(dd,J=14.6,7.2Hz, 1H), 1.55–1.38 (m, 1H), 0.95 (d, J = 5.0Hz, 6H), 0.84 (d, J = 8.3Hz, 2H), 0.70–0.52 (m, 2H).

[1056] 091B:

[1057] Chiral purity: 97.6%, T R :19.258min;

[1058] 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.06(d,J=5.1Hz,1H),7.96(s,1H),5 .96(s,1H),4.84(d,J=9.4Hz,1H),3.14(s,3H),3.03(s,3H),2.38(dd,J=28 .4,12.4Hz,2H),1.97–1.82(m,1H),1.60(dt,J=14.3,7.1Hz,1H),1.48(d,J =13.6Hz,1H),0.95(d,J=5.6Hz,6H),0.89–0.77(m,2H),0.76–0.52(m,2H).

[1059] Example 92: Synthesis of 3-hydroxy-4-((2-((2-isopropyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N,N-dimethylpicolinamide (Compound 092)

[1060] 92.1 Preparation of Compound 092-1

[1061] 055-1 (0.7 g, 4.24 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (0.86 g, 8.48 mmol) and di-tert-butyl dicarbonate (1.02 g, 4.66 mmol) were added. The mixture was allowed to react overnight at room temperature. The reaction solution was diluted with water (20 mL) and extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1-10 / 1) to obtain compound 092-1 (0.53 g, yield 47.15%). LC-MS: [M-NHBoc] + =149.05.

[1062] 92.2 Preparation of Compound 092-2

[1063] 092-1 (340 mg, 1.28 mmol) was dissolved in tetrahydrofuran (7 mL), the atmosphere was replaced with nitrogen, the temperature was lowered to -78°C, and n-butyllithium (163.99 mg, 2.56 mmol) was slowly added dropwise. The temperature was raised to 0°C and the reaction was allowed to react for 0.5 h. The temperature was then lowered to -78°C, and a solution of iodine (487.32 mg, 1.92 mmol) in tetrahydrofuran (1.5 mL) was added dropwise. After the addition was complete, the temperature was raised to 0°C and the reaction was allowed to react for 2 h. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) in an ice bath, and saturated aqueous sodium sulfite (5 mL) was added and stirred for 10 min. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain compound 092-2 (270 mg, 53.86% yield). LC-MS: [M-NHBoc] + =274.85.

[1064] 92.3 Preparation of Compound 092-3

[1065] Compound 092-2 (200 mg, 0.51 mmol) was dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL). 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (128.55 mg, 0.77 mmol), tetrakis(triphenylphosphine)palladium (58.93 mg, 0.051 mmol), and sodium carbonate (162.16 mg, 1.53 mmol) were added sequentially. The atmosphere was purged with nitrogen and the mixture was reacted at 70°C for 2 h. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound 092-3 (100 mg, yield 64.05%). LC-MS: [M+H] + =306.05.

[1066] 92.4 Preparation of Compound 092-4

[1067] 094-3 (60 mg, 0.20 mmol) was dissolved in ethanol (5 mL), and 10% wt palladium on carbon (8 mg) was added. The mixture was allowed to react at room temperature under a hydrogen atmosphere for 2 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 092-4 (55 mg, 91.06% yield). LC-MS: [M-NHBoc] + =191.05.

[1068] 92.5 Preparation of Compound 092-5

[1069] 092-4 (45 mg, 0.15 mmol) was weighed and dissolved in methanol (3 mL). A methanolic solution of hydrogen chloride (1 mL, 4 M) was added and the mixture was allowed to react at room temperature for 3 h. The reaction solution was concentrated to dryness under reduced pressure to obtain compound 092-5 (40 mg). The crude product was used directly in the next step. LC-MS: [M-NH2] + =191.05.

[1070] 92.6 Preparation of Compound 092

[1071] 092-5 (30 mg, 0.14 mmol) was weighed and dissolved in ethanol (5 mL). 001-5 (42.74 mg, 0.14 mmol) and N,N-diisopropylethylamine (54.28 mg, 0.42 mmol) were added and reacted at 60°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (alkaline conditions). The fraction was concentrated under reduced pressure and lyophilized to obtain compound 092 (4.1 mg, yield 6.03%). LC-MS: [M+H] + =467.10.

[1072] 1 H NMR (400MHz, DMSO-d6) δ8.80(s,1H),8.06(d,J=5.1Hz,1H),7.97(s,1H),5.99(s,1H),4.86(d,J=8.7Hz,1H),3.14(s,3H),3.03(s,3H),2.87(dt ,J=13.8,6.9Hz,1H),2.38(dd,J=24.2,16.0Hz,2H),1.61(d,J=8.1Hz,1H),1.49(d,J=13.8Hz,1H),1.16(d,J=6.9Hz,6H),0.96(d,J=4.3Hz,6H).

[1073] Example 93, 4-((2-((2-chloro-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 093), (R)-4-((2-((2-chloro-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (S)-4-((2-((2-chloro-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 093A or 093B) and (S)-4-((2-((2-chloro-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 093B or 093A)

[1074] 93.1 Preparation of Compound 093-1

[1075] 092-1 (0.5 g, 1.88 mmol) was weighed into a reaction flask and dissolved in N,N-dimethylformamide (5 mL). N-chlorosuccinimide (0.30 g, 2.26 mmol) was then added and allowed to react at 50°C for 1 hour. The reaction solution was poured into water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 093-1 (0.2 g). LC-MS: [M-NHBoc] + =182.95.

[1076] 93.2 Preparation of Compound 093-2

[1077] 093-1 (0.12 g, 0.40 mmol) was weighed into a reaction flask and dissolved in 1,4-dioxane (2 mL). A solution of hydrogen chloride in 1,4-dioxane (0.1 mL, 0.40 mmol, 4 M) was added. The reaction was allowed to react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain compound 093-2 (0.07 g), which was used directly in the next reaction. LC-MS: [M-NH2] + =182.95.

[1078] 93.3 Preparation of Compound 093

[1079] 001-5 (0.1 g, 0.33 mmol) was weighed into a reaction flask, and 093-2 (0.072 g, 0.36 mmol), N,N-diisopropylethylamine (0.085 g, 0.66 mmol), and ethanol (4 mL) were added. The mixture was reacted at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC to obtain compound 093 (0.1 g). LC-MS: [M+H] + =459.00.

[1080] 93.4 Preparation of Compounds 093A and 093B

[1081] Compound 093 was further chirally resolved to give compounds 093A (12.7 mg) and 093B (17.0 mg).

[1082] HPLC method: CHIRALPAK AD-H, 4.6*250mm 5μm, 15% isopropanol / n-hexane, 0.8mL / min, column temperature: 30℃;

[1083] 093A:

[1084] Chiral purity: 99.0%, T R :11.953min;

[1085] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.03(d,J=5.2Hz,1H),7.93(s,1H),6.43(s,1H),4.90(d,J=8.0Hz,1 H), 3.07 (d, J = 38.8Hz, 6H), 2.46–2.30 (m, 2H), 1.61 (d, J = 6.8Hz, 1H), 1.55 (s, 1H), 0.97 (d, J = 7.6Hz, 6H).

[1086] 093B:

[1087] Chiral purity: 98.2%, T R :8.535min;

[1088] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.03(d,J=5.2Hz,1H),7.93(s,1H),6.43(s,1H),4.90(d,J=8.0Hz,1 H), 3.07 (d, J = 38.8Hz, 6H), 2.46–2.30 (m, 2H), 1.61 (d, J = 6.8Hz, 1H), 1.55 (s, 1H), 0.97 (d, J = 7.6Hz, 6H).

[1089] Example 94. Synthesis of 3-hydroxy-4-((2-((2-(hydroxymethyl)-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N,N-dimethylpicolinamide (Compound 094)

[1090] 94.1 Preparation of Compound 094-1

[1091] 018-3 (3 g, 18.27 mmol) was weighed and dissolved in tetraethyl titanate (60 mL). Tert-butylsulfenamide (3.32 g, 27.41 mmol) was added and the mixture was reacted at 100°C overnight using a water separator. After the reaction solution was cooled to room temperature, it was slowly poured into an icy aqueous ammonium chloride solution (100 mL). Ethyl acetate (100 mL) was added and the mixture was vigorously stirred for 10 min. The mixture was filtered and the filter cake was rinsed with ethyl acetate (100 mL). The filtrate was separated and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1-0 / 1) to obtain compound 094-1 (0.83 g, yield 16.99%). LC-MS: [M+H] + =268.00.

[1092] 94.2 Preparation of Compound 094-2

[1093] 094-1 (0.8 g, 2.99 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0°C, and sodium borohydride (0.34 g, 8.97 mmol) was added, followed by methanol (2 mL). The reaction was continued at 0°C for 1 h. Under ice-cooling conditions, saturated aqueous ammonium chloride (10 mL) was added dropwise to quench the reaction. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (40 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1-2 / 1) to obtain compound 094-2 (0.64 g, 79.40% yield). LC-MS: [M+H] + =270.05.

[1094] 94.3 Preparation of Compound 094-3

[1095] 094-2 (340 mg, 1.26 mmol) was dissolved in tetrahydrofuran (10 mL). The atmosphere was replaced with nitrogen and the temperature was lowered to -78°C. n-Butyllithium (86.48 mg, 1.35 mmol) was added dropwise. The reaction temperature was maintained at -78°C for 0.5 h, then raised to 0°C for 2 h. The temperature was then lowered to -78°C, N,N-dimethylformamide (328.91 mg, 4.5 mmol) was added, the reaction temperature was maintained at -78°C for 1 h, and then raised to 0°C for 1 h. The reaction was quenched by the dropwise addition of saturated aqueous ammonium chloride (5 mL) under ice-cooling. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to afford compound 094-3 (200 mg, 53.28% yield). LC-MS: [M+H] + =298.05.

[1096] 94.4 Preparation of Compound 094-4

[1097] 094-3 (150 mg, 0.50 mmol) was dissolved in methanol (6 mL), cooled to 0°C, and sodium borohydride (56.75 mg, 1.5 mmol) was added. The mixture was allowed to warm to room temperature and allowed to react for 1 h. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) in an ice bath, diluted with water (5 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 094-4 (135 mg, 89.39% yield). LC-MS: [M+H] + =300.05.

[1098] 94.5 Preparation of Compound 094-5

[1099] 094-4 (140 mg, 0.47 mmol) was dissolved in dichloromethane (5 mL). A solution of hydrogen chloride in 1,4-dioxane (1.5 mL, 4 M) was added and the mixture was allowed to react at room temperature for 0.5 h. The reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (5 mL). The aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 094-5 (90 mg, 98.58% yield). The crude product was used directly in the next step. LC-MS: [M+NH2] + =179.05.

[1100] 94.6 Preparation of Compound 094-6

[1101] 094-5 (90 mg, 0.46 mmol) was dissolved in dichloromethane (3 mL). Tert-butyldimethylsilyl chloride (76.26 mg, 0.51 mmol) and imidazole (34.45 mg, 0.51 mmol) were added and allowed to react at room temperature for 1 h. The reaction solution was diluted with water (5 mL), and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 094-6 (140 mg, 98.13% yield). LC-MS: [M-NH2] + =293.10.

[1102] 94.7 Preparation of Compound 094-7

[1103] 094-6 (140 mg, 0.45 mmol) was weighed and dissolved in ethanol (3 mL). 001-5 (137.38 mg, 0.45 mmol) and N,N-diisopropylethylamine (174.47 mg, 1.35 mmol) were added sequentially and reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and the residue was added with water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL × 2). The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0-10 / 1) to obtain compound 094-7 (110 mg, yield 42.76%). LC-MS: [M+H] + =569.25.

[1104] 94.8 Preparation of Compound 094

[1105] 094-7 (100 mg, 0.18 mmol) was weighed and dissolved in tetrahydrofuran (5 mL). Pyridine hydrofluoride (0.5 mL) was added and the mixture was allowed to react at room temperature for 1 h. The reaction solution was adjusted to pH 8-9 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure to obtain a crude product (100 mg). The organic and aqueous phases were purified by high-performance liquid chromatography (alkaline conditions) separately. The fractions were concentrated under reduced pressure and lyophilized to obtain compound 094 (21.6 mg, 26.47% yield). LC-MS: [M+H] + =455.10.

[1106] 1H NMR (400MHz, DMSO-d6) δ8.96(s,1H),7.66(d,J=4.6Hz,1H),7.15(d,J=4.7Hz,1H),6.15(s,1H),4.94(s,1H),4.32 (s,2H),2.90(s,3H),2.80(s,3H),2.47–2.28(m,2H),1.74(d,J=9.2Hz,1H),1.45(d,J=13.4Hz,1H),0.96(s,6H).

[1107] Example 95. Synthesis of 4-((3,4-dioxo-2-((3,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 095)

[1108] 95.1 Synthesis of Compound 095-1

[1109] 095-a (0.58 g, 5.91 mmol) was weighed into a reaction flask and dissolved in tetrahydrofuran (5 mL). The nitrogen atmosphere was replaced three times, and n-butyllithium (0.42 g, 6.50 mmol) and N,N,N',N'-tetramethylethylenediamine (0.76 g, 6.50 mmol) were added at -78°C. The mixture was refluxed for 0.5 h, then cooled to -78°C. A solution of carbon tetrabromide (1.29 g, 3.90 mmol) in tetrahydrofuran was slowly added dropwise, and stirred for 12 h. Saturated aqueous ammonium chloride (15 mL) was added to the reaction mixture at -78°C to quench the reaction. The mixture was then extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 095-1 (0.5 g).

[1110] 95.2 Synthesis of Compound 095-2

[1111] 095-1 (0.1 g, 0.56 mmol) was weighed into a reaction flask and dissolved in tetrahydrofuran (3 mL). The nitrogen atmosphere was replaced three times, and n-butyllithium (0.039 g, 0.62 mmol) was added at -78°C. After 0.5 h, cyclobutanone (0.043 g, 0.62 mmol) was added, and the mixture was stirred at -78°C for 1 h. Saturated aqueous ammonium chloride (15 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (15 mL x 3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 095-2 (0.05 g). LC-MS: [M-OH] +=151.00.

[1112] 95.3 Synthesis of Compound 095-3

[1113] 095-2 (0.4 g, 2.38 mmol) was weighed into a reaction flask, and water (250 mL) and acetonitrile (250 mL) were added. Cerium ammonium nitrate (3.26 g, 5.95 mmol) was then added at 0°C and stirred at 60°C for 30 seconds. Saturated aqueous sodium sulfite solution (100 mL) was added to the reaction solution to quench the reaction. Ethyl acetate (100 mL x 3) was then added for extraction. The organic phases were combined and washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 095-3 (0.15 g). LC-MS: [M+H] + =167.00.

[1114] 95.4 Synthesis of Compound 095

[1115] Synthesis of Compound 095: Refer to the synthesis method of Compound 002 in Example 2, except that 002-a is replaced with 095-3 to obtain Compound 095 (32.5 mg). LC-MS: [M+H] + =455.20.

[1116] 1 H NMR (400MHz, DMSO-d6) δ8.91(s,1H),8.05(d,J=5.2Hz,1H),7.94(s,1H),7.09(s,1H),5.09(d,J=9.6Hz,1H),3.08(d,J =42.4Hz,6H),2.49–2.43(m,2H),2.09(s,3H),1.75–1.69(m,1H),1.66(dd,J=13.2,6.4Hz,1H),0.98(d,J=18.4Hz,6H).

[1117] Example 96, 4-((2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 096), (S)-4-((2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide Synthesis of (R)-4-((2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-7-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 096A or 096B)

[1118] Synthesis of Compound 096: Refer to the synthesis method of Compound 095 in Example 95, except that 096-a is replaced with 095-1 to obtain Compound 096 (250 mg). LC-MS: [M+H] + =441.10.

[1119] Compound 096 was further chirally resolved to give compounds 096A (0.0843 g) and 096B (0.0824 g).

[1120] HPLC method: CHIRALPAK AD-H, 4.6*250mm 5μm, 15% ethanol-n-hexane, 0.8mL / min, 30℃;

[1121] 096A:

[1122] Chiral purity: 99.2%, T R =11.943min;

[1123] 1 H NMR (400MHz, DMSO-d6) δ8.94(s,1H),8.06(d,J=5.2Hz,1H),7.96(s,1H),7.47(d,J=5.2Hz,1H),6.89(d,J=5.2Hz,1 H), 5.12 (d, J = 9.6Hz, 1H), 3.09 (d, J = 44.0Hz, 6H), 2.65 (d, J = 9.6Hz, 2H), 1.76–1.61 (m, 2H), 0.98 (d, J = 18.8Hz, 6H).

[1124] 096B:

[1125] Chiral purity: 99.5%, T R=9.788min;

[1126] 1 H NMR (400MHz, DMSO-d6) δ8.94(s,1H),8.06(d,J=4.8Hz,1H),7.96(s,1H),7.47(d,J=5.2Hz,1H),6.89(d,J=5.2Hz,1H), 5.12(d,J=9.6Hz,1H), 3.09(d,J=44.4Hz,6H), 2.64(tt,J=14.4,7.5Hz,2H), 1.77–1.61(m,2H), 0.98(d,J=18.8Hz,6H).

[1127] Example 97. Synthesis of 4-((3,4-dioxo-2-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-7-yl)amino)cyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Compound 097)

[1128] Synthesis of Compound 097: Refer to the synthesis method of Compound 095 in Example 95, except that 095-1 is replaced with 097-a to obtain Compound 097 (51.1 mg). LC-MS: [M+H] + =455.10.

[1129] 1 H NMR (400MHz, DMSO-d6) δ8.88(s,1H),8.04(d,J=5.2Hz,1H),7.94(s,1H),6.55(s,1H),5.02(d,J=9.6Hz,1H),3.08(d,J=42.0 Hz, 6H), 2.56 (dd, J=12.4, 6.2Hz, 2H), 2.38 (s, 3H), 1.69 (dt, J=12.8, 6.3Hz, 1H), 1.63–1.54 (m, 1H), 0.97 (d, J=15.2Hz, 6H).

[1130] Example 98. Synthesis of 3-((2-(3-fluoropyrrolidine-1-carbonyl)-3-hydroxypyridin-4-yl)amino)-4-((2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)amino)-cyclobut-3-ene-1,2-dione (Compound 098)

[1131] 98.1 Synthesis of Compound 098-1

[1132] 098-a (9 g, 58.77 mmol) was weighed into a reaction flask, water (500 mL) was added, and liquid bromine (28.2 g, 176.31 mmol) was slowly added dropwise. The reaction was allowed to react at room temperature for 12 hours. The reaction solution was poured into water (300 mL) and extracted with ethyl acetate (300 mL × 3). The organic phases were combined, washed with saturated sodium sulfite aqueous solution (200 mL), then with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 098-1 (14 g, 76.61% yield, crude product). LC-MS: [M+H] + =311.75.

[1133] 98.2 Synthesis of Compound 098-2

[1134] 098-1 (14 g, 45.03 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (100 mL) and cesium carbonate (44.02 g, 135.1 mmol) were added. The temperature was lowered to 0°C, and benzyl bromide (9.24 g, 54.04 mmol) was slowly added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was poured into water (500 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were combined and washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 098-2 (7 g, yield 33.44%). LC-MS: [M+H] + =401.85.

[1135] 98.3 Synthesis of Compound 098-3

[1136] 098-2 (6.7 g, 16.71 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (50 mL), sodium formate (1.25 g, 18.38 mmol), and tetrakis(triphenylphosphine)palladium (0.97 g, 0.84 mmol) were added. The mixture was reacted at 80°C under nitrogen for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 098-3 (3 g, yield 55.74%). LC-MS: [M+H] + =323.95.

[1137] 98.4 Synthesis of Compound 098-4

[1138] 098-3 (1 g, 3.1 mmol) was weighed into a reaction flask, and 1,4-dioxane (10 mL), tert-butyl carbamate (0.73 g, 6.2 mmol), cesium carbonate (3.03 g, 9.3 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.15 g, 0.31 mmol), and palladium acetate (0.07 g, 0.31 mmol) were added. The mixture was protected by nitrogen and reacted at 100°C for 12 h. The reaction solution was poured into water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 098-4 (0.88 g, yield 79.81%). LC-MS: [M+H] + =359.10.

[1139] 98.5 Synthesis of Compound 098-5

[1140] 098-4 (0.2 g, 0.56 mmol) was weighed into a reaction flask, and tetrahydrofuran (3 mL), water (1 mL), and lithium hydroxide (0.067 g, 2.8 mmol) were added. The mixture was stirred at room temperature for 1 hour. Hydrochloric acid was added to the reaction solution to adjust the pH to 4-5, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 098-5 (0.18 g, yield 88.1%), which was used directly in the next step without purification. LC-MS: [M+H] + =345.10.

[1141] 98.6 Synthesis of Compound 098-6

[1142] 098-5 (0.18 g, 0.52 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (5 mL), (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (237.26 mg, 0.62 mmol), N,N-diisopropylethylamine (201.61 mg, 1.56 mmol), and 098-b (55.6 mg, 0.62 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 098-6 (0.2 g, yield 86.7%). LC-MS: [M+H] + =416.15.

[1143] 98.7 Synthesis of Compound 098-7

[1144] 098-6 (0.18 g, 0.48 mmol) was weighed into a reaction flask, and methanol (5 mL) and palladium on carbon (102 mg, 0.96 mmol, 10% wt) were added. The hydrogen atmosphere was replaced and stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filter cake was washed with methanol (10 mL x 2). The filtrate was concentrated under reduced pressure to obtain compound 098-7 (0.22 g, crude product). This was used directly in the next step. LC-MS: [M+H] + =326.10.

[1145] Synthesis of 98.8 Compound 098-8

[1146] 098-7 (0.22 g, 0.68 mmol) was weighed into a reaction flask, and dichloromethane (2 mL) and a solution of hydrogen chloride in 1,4-dioxane (1.7 mL, 6.8 mmol, 4 N) were added. The mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain compound 098-8 (0.13 g, crude product). This was used directly in the next step. LC-MS: [M+H] + =226.05.

[1147] 98.9 Synthesis of Compound 098-9

[1148] 098-...

Claims

1. A compound represented by formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof: R 1 is a 5-12 membered heteroaryl, a 3-8 membered heterocycloalkyl, a C 3-5 Cycloalkyl or C 6-8 Cycloalkyl; wherein The 5-12 membered heteroaryl group is optionally substituted by 1, 2, 3 or 4 R 1-1 Substituted, the 3-8 membered heterocycloalkyl and the C 6-8 The cycloalkyl group is optionally substituted by 1, 2, 3 or 4 R 1-2 Substitute, the C 3-5 The cycloalkyl group is optionally substituted by 1, 2, 3 or 4 R 1-3 replace; Among them, when R 1 When it is a C5 cycloalkyl group, the C5 cycloalkyl group is substituted by 1, 2, 3 or 4 R 1-3 Replace; when R 1 When it is a C6 cycloalkyl group, the C6 cycloalkyl group is substituted by 1, 2, 3 or 4 R 1-2 replace; Each R 1-1 are the same or different and are independently halogen, CN, OH, -COOH, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-5 Cycloalkyl or C 1-6 Deuterated alkyl, wherein the C 1-6 Alkyl and C 3-5 The cycloalkyl group is optionally substituted by 1, 2, 3 or 4 groups independently selected from -OH, halogen and C 1-6 substituted by an alkyl substituent; Each R 1-2 The same or different, independently of each other, are C 1-6 Alkyl, halogen, C 6-10 Aryl or 5-9 membered heteroaryl, wherein the C 1-6 Alkyl, C 6- 10 Aryl and 5-9 membered heteroaryl are optionally substituted by 1, 2, 3 or 4 independently selected from C 1-6 Alkyl and halogen substituents, or R on two adjacent carbon atoms 1-2 Together with the carbon atom to which it is attached, it forms a phenyl group; Each R 1-3 The same or different, independently of each other, are C 1-6 alkyl, halogen or 5-9 membered heteroaryl, wherein the C 1-6 The alkyl and 5-9 membered heteroaryl groups are optionally substituted by 1, 2, 3 or 4 independently selected C 1-6 Alkyl and halogen substituents; R 2 -C(=O)NR a R b , 5-9 membered heteroaryl, -C(=O)R z , C 1-6 Alkyl, halogen, cyano, 4-10 membered heterocycloalkyl, C 3-8 Cycloalkyl, -S(=O)2-C 1-6 Alkyl or -S(=NH)-C 1-6 alkyl, wherein the 5-9 membered heteroaryl, C 1-6 Alkyl, 4-10 membered heterocycloalkyl, C 3-8 Cycloalkyl, -S(=O)2-C 1-6 Alkyl and -S(=NH)-C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R 2-1 replace; Each R 2-1 The same or different, independently of each other, are C 1-6 alkyl, halogen, cyano, oxo (=O) or -OH, wherein the C 1-6 Alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from -OH, halogen and oxo (=O); R a and R b Each independently is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-8 membered heteroaryl, C 1-6 Alkoxy or C 1-6 Deuterated alkyl, or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4-10 membered heterocycloalkyl or 5-9 membered heteroaryl group containing one N heteroatom and optionally one or two additional heteroatoms selected from O, N and S; wherein said C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-8 membered heteroaryl, 4-10 membered heterocycloalkyl and 5-9 membered heteroaryl are optionally substituted by 1, 2, 3 or 4 R a-1 replace; Each R a-1 The same or different, independently of each other, are H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, -OH, -N(C 1- 6 alkyl)(C 1-6 alkyl) or oxo (=O); R z C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R z-1 replace; Each R z-1 The same or different, independently of each other, are C 1-6 Alkyl, halogen, oxo (=O), cyano, -OH or -N(C 1-3 Alkyl)(C 1-3 alkyl); R 3 -OH, halogen, oxo (=O), cyano, C 1-6 Alkyl or C 1-6 Alkoxy; preferably, R 3 It is -OH or Cl.

2. The compound according to claim 1, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: R 1 is 8-10 membered heteroaryl, 6 membered heterocycloalkyl, C 3-5 cycloalkyl or C6 cycloalkyl; the 8-10 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 R 1-1 The 6-membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 R 1-2 Substituted; the C6 cycloalkyl is substituted by 1, 2, 3 or 4 R 1-2 Replacement; said C 3-5 The cycloalkyl group is optionally substituted by 1, 2, 3 or 4 R 1-3 Replacement; Among them, when R 1 When it is a C5 cycloalkyl group, the C5 cycloalkyl group is substituted by 1, 2, 3 or 4 R 1-3 Replace, when R 1 When it is a C6 cycloalkyl group, the C6 cycloalkyl group is substituted by 1, 2, 3 or 4 R 1-2 replace; Preferably, R 1 In the above, the 5-12 membered heteroaryl group is an 8-10 membered heteroaryl group; preferably, the 5-12 membered heteroaryl group is selected from: Preferably, R 1 In the above, the 5-12 membered heteroaryl group is selected from: Preferably, R 1 In the embodiment, the 3-8 membered heterocycloalkyl is a 4-6 membered azacycloalkyl or a 4-6 membered oxacycloalkyl; preferably, the 3-8 membered heterocycloalkyl is a 6 membered azacycloalkyl; more preferably, the 3-8 membered heterocycloalkyl is a 3-azabicyclo[3.1.0]hexyl or a 2-azabicyclo[3.1.0]hexyl, for example Preferably Preferably, R 1 In the C 3-5 The cycloalkyl group is selected from: Preferably, R 1 In the C 6-8 The cycloalkyl group is a monocyclic or bicyclic cycloalkyl group; preferably, the C 6-8 Cycloalkyl is selected from cyclohexyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, cycloheptyl, bicyclo[2.2.1]heptyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[3.1.1]heptyl, cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and bicyclo[5.1.0]octyl, for example Preferably 3. The compound according to claim 1 or 2, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: R 1-1 Halogen, CN, OH, -COOH, oxo (=O), C 1-4 Alkyl or C 3-5 Cycloalkyl, wherein the C 1-4 Alkyl and C 3-5 Cycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from -OH and halogen; Preferably, R 1-2 C 1-3 Alkyl, halogen or C6 aryl, wherein the C 1-3 The C6 alkyl and C6 aryl groups are optionally substituted by 1, 2, 3 or 4 groups independently selected from C 1-3 Alkyl and halogen substituents, or R on two adjacent carbon atoms 1-2 Together with the carbon atom to which it is attached, it forms a phenyl group; Preferably, R 1-3 C 1-3 alkyl or 5-6 membered heteroaryl, wherein the C 1-3 The alkyl and 5-6 membered heteroaryl groups are optionally substituted by 1, 2, 3 or 4 groups independently selected from C 1-3 Alkyl and halogen substituents; Preferably, R 1-1 is F, Cl, Br, CN, methyl, -CH2F, -CHF2, -CF3, CH2OH, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or cyclopropyl; Preferably, R 1-2 is F, phenyl, or R on two adjacent carbon atoms 1-2 Together with the carbon atom to which it is attached, it forms a phenyl group; Preferably, R 1-3 is methyl, ethyl, n-propyl, isopropyl, pyrazolyl or pyridinyl; the pyrazolyl and pyridinyl are optionally substituted by 1, 2 or 3 substituents independently selected from F and methyl; Preferably, R 1-3 Methyl, ethyl, 4. The compound according to any one of claims 1 to 3, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: R 1 for 5. The compound according to any one of claims 1 to 4, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: R 2 -C(=O)NR a R b , 5-6 membered heteroaryl, -C(=O)R z , C 1-6 Alkyl, halogen, cyano, 4-6 membered heterocycloalkyl, C 3-4 Cycloalkyl, -S(=O)2-C 1-6 Alkyl or -S(=NH)-C 1-6 alkyl, wherein the 5-6 membered heteroaryl, C 1-6 Alkyl, 4-6 membered heterocycloalkyl, C 3- 4-cycloalkyl, -S(=O)2-C 1-6 Alkyl and -S(=NH)-C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R 2-1 Substituted, wherein R a , R b , R z and R 2-1 Each independently has the definition as described in any one of claims 1 to 4; Preferably, R a and R b Each independently is H, C 1-4 Alkyl, C 3-5 Cycloalkyl, 6-membered heteroaryl or C 1-3 Alkoxy, or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4-8 membered heterocycloalkyl or 6-9 membered heteroaryl containing one N heteroatom and optionally 1 or 2 additional heteroatoms selected from O, N and S, wherein said C 1-4 Alkyl, C 3-5 Cycloalkyl, 6-membered heteroaryl, 4-8-membered heterocycloalkyl and 6-9-membered heteroaryl are optionally substituted by 1, 2, 3 or 4 R a-1 Substitution, where R a-1 Having the definition of any one of claims 1 to 4; Preferably, R z C 1-4 Alkyl, C 3-5 Cycloalkyl, 5-9 membered heteroaryl or 4-8 membered heterocycloalkyl, wherein the C 3-5 Cycloalkyl, 5-9 membered heteroaryl and 4-8 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R z-1 Substitution, where R z-1 Having the definition of any one of claims 1 to 4; Preferably, R a H, C 1-4 Alkyl or C 3-5 Cycloalkyl, wherein the C 1-4 Alkyl and C 3-5 The cycloalkyl group is optionally substituted by 1, 2, 3 or 4 R a-1 replace; Preferably, R b C 1-4 Alkyl, C 3-5 Cycloalkyl, 6-membered heteroaryl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl, C 3-5 Cycloalkyl and 6-membered heteroaryl are optionally substituted by 1, 2, 3 or 4 R a-1 replace; Preferably, the R a H, methyl, ethyl, or cyclopropyl; Preferably, the R b is methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, pyridyl, According to an embodiment of the present invention, the R a and R b together with the nitrogen atom to which it is attached, form a tetrahydropyrrolyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, diazabicyclo[3.2.1]octanyl, oxazaspiro[3.3]heptyl or isoindolyl; said tetrahydropyrrolyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, diazabicyclo[3.2.1]octanyl, oxazaspiro[3.3]heptyl and isoindolyl being optionally substituted by 1, 2, 3 or 4 R a-1 replace; Preferably, R 2 wherein the 5-6 membered heteroaryl is pyridyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl or isothiazolyl; Preferably, R 2 wherein the 4-6 membered heterocycloalkyl group is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, tetrahydropyrrolyl or morpholinyl; Preferably, R 2 In the C 3-4 Cycloalkyl is cyclopropyl; Preferably, R z wherein the 5-9 membered heteroaryl group is isoindolyl, pyridyl or isoxazolyl; Preferably, R z wherein the 4-8 membered heterocycloalkyl group is tetrahydropyrrolyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, diazabicycloalkyl, Cyclo[3.2.1]octanyl, oxazaspiro[3.3]heptyl or tetrahydropyranyl; Preferably, R z In the C 3-5 Cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl; Preferably, each R 2-1 are the same or different and are independently H, methyl, F, oxo (=O), cyano or Preferably, each R a-1 are the same or different and are independently H, methyl, ethyl, F, -N(CH3)(CH3), -CH2F, -CHF2, -CF3 or -OCH3; Preferably, each R z-1 are the same or different and are independently H, methyl, ethyl, F, cyano or -N(CH3)(CH3); Preferably, R 2 for 6. The compound according to any one of claims 1 to 5, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) has a structure represented by the following formula (Ia) or (Ib): Among them, R 1 , R 2 and R 3 Having the definition of any one of claims 1 to 5; Preferably, the compound represented by formula (I) has a structure represented by the following formula (II), (II-a) or (II-b): in, Ring A is C 5-7 Cycloalkyl, 5-7 membered heterocycloalkyl or phenyl; Ring B is a 5-6 membered heteroaryl, a 5 membered heterocycloalkyl or a phenyl group; X and Y are each independently C, CH or N; R 1-1 and R 2 As defined in any one of claims 1 to 5, s is 0, 1, 2 or 3; Preferably, the compound represented by formula (I) has a structure represented by formula (III) or (IV): in, Ring A is C 5-7 Cycloalkyl, 5-7 membered heterocycloalkyl or phenyl; Ring B is a 5-6 membered heteroaryl, a 5 membered heterocycloalkyl or a phenyl group; X and Y are each independently C, CH or N; s is 0, 1, 2, or 3; R a , R b , R z and R 1-1 Having the definition of any one of claims 1 to 5; Preferably, the compound represented by formula (I) has the structure represented by the following formula (I-1): Among them, ring A is C 5-7 Cycloalkyl, 5-7 membered heterocycloalkyl or phenyl; Ring B is a 5-6 membered heteroaryl, a 5 membered heterocycloalkyl or a phenyl group; X and Y are each independently C, CH or N; s is 0, 1, 2, or 3; R 1-1 Having the definition of any one of claims 1 to 5; Preferably, ring A is cyclohexyl, cyclopentyl, cycloheptyl, tetrahydrofuranyl, phenyl, tetrahydropyrrolyl, piperidinyl or 4-azaspiro[2.4]heptyl; Preferably, ring B is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, phenyl, isothiazolyl, furanyl, tetrahydrofuranyl, thienyl or pyridyl; Preferably, the for Preferably, the Selected from:

7. The compound according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) has the structure shown below: Preferably, the compound represented by formula (I) has the structure shown below: Preferably, the compound represented by formula (I) has the structure shown below:

8. A method for preparing the compound according to any one of claims 1 to 7, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, comprising the following steps: Compound 1 reacts with compound 2 to obtain a compound represented by formula (I); wherein R1, R2 and R3 each independently have the definition as described in any one of claims 1 to 7, R 0 C 1-6 alkyl.

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 7, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof.

10. Use of the compound according to any one of claims 1 to 7, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 9 in the preparation of a drug; Preferably, the drug is a drug for diagnosing, preventing and / or treating a disease or condition mediated by CCR6 receptor; Preferably, the drug is a CCR6 antagonist; Preferably, the disease or disorder is an allergic disease, psoriasis, contact hypersensitivity, Sjögren's syndrome, dry eyes, or multiple sclerosis; Preferably, the disease or disorder is rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, systemic onset rheumatoid arthritis, oligoarticular rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile idiopathic arthritis (JIA), juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, giant cell arteritis or secondary osteoarthritis caused by inflammatory diseases; Preferably, the disease or disorder is inflammatory bowel disease (IBD), Crohn's disease or ulcerative colitis.

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