Polycyclic compound functioning as mat2a inhibitor

Abstract

Provided in the present invention is a compound functioning as an MAT2A inhibitor. The compound is a compound represented by formula (A) or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof. Further provided in the present invention are a pharmaceutical composition comprising the compound, and the use thereof in the treatment of cancer.

Description

Polycyclic compounds as mat2a inhibitors TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to MAT2A inhibitors. BACKGROUND

[0002] Protein arginine methyltransferases (PRMTs) can methylate histones and non-histone proteins to regulate biological processes such as gene transcription, signal transduction, protein stability, cell proliferation, differentiation, apoptosis and tumor formation (Nat Rev Drug Discov. 2021 Jul; 20(7): 509-530). Currently, 11 PRMT family members have been found, which can be divided into types I, II and III according to the different ways of catalyzing arginine methylation. PRMT5 belongs to type II, and the form it catalyzes is symmetric dimethylation.

[0003] As an epigenetic enzyme, PRMT5 is involved in various biological processes, including transcriptional regulation, RNA metabolism, ribosome biosynthesis and cell cycle regulation. PRMT5 protein is overexpressed in various cancer types, including B and T cell lymphoma, metastatic melanoma, neuroblastoma, glioblastoma, ovarian cancer, breast cancer, etc. More and more evidence shows that it plays an important role in tumorigenesis and development (Cell Stress. 2020 Aug; 4(8): 199-215). On this basis, PRMT5 inhibitors have become a research hotspot for the development of tumor treatment drugs.

[0004] In 2016, a paper published in Science revealed that MTAP deletion has synthetic lethal effect with PRMT5 (Science. 2016 Mar 11; 351(6278): 1214-8.). MTAP has a high deletion rate in various solid tumors, including pancreatic cancer, glioma, etc. MTAP is an intracellular MTA degrading enzyme, and due to MTAP deletion, intracellular accumulation of MTA can occur, and MTA can compete with the functional substrate of PRMT5, the methylation donor SAM, for binding to PRMT5, thereby inhibiting part of the function of PRMT5. It is currently found that although the new generation of PRMT5 inhibitors (such as MRTX1719 and AMG193) have solved the problem of hematological side effects of the first generation, the clinical effective rate is still less than 50% (2024 AACR, 2024 ESMO), so how to further improve the drug efficacy will be required in the clinic. In addition, according to the biological mechanism, PRMT5 is used to methylate arginine protein substrates using SAM, and inhibition of MAT2A reduces endogenous SAM synthesis, so inhibition of MAT2A is expected to further inhibit PRMT5, thereby completely inhibiting MATP deletion tumor cells. In addition, MATP deletion has a synthetic lethal effect with MAT2A (Cancer cell, 2021, 39, 209-224). The development of high-activity MAT2A inhibitors will inhibit MATP deletion tumor cells, while having lower toxicity to normal cells.

[0005] Although progress has been made in MAT2A research (for example: in 2024, IDEAYA Biosciences reported the effect of its MAT2A inhibitor IDE397 in MATP deletion urothelial carcinoma and non-small cell lung cancer patients, ORR: 33%), but there is still a lack of more effective selective MAT2A inhibitors. SUMMARY

[0006] The inventors of the present application have found a novel structure of MAT2A inhibitors, which exhibit excellent selectivity for MAT2A deletion type compared to wild type.

[0007] In one aspect, the present application provides a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0008] wherein,

[0009] X1, X2, X3are each independently selected from -CH, N or -CR b ;

[0010] W1is selected from N or CR c ;

[0011] R1is selected from phenyl or 5-12 membered heteroaryl; R1may be optionally substituted with 1-5 R m substituted or 1-5 R5substituted;

[0012] R2is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-12 membered heterocyclyl, C 1-6 deuteroalkyl, -C(=O)R a , -S(O)2R a or OR a , wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-12 membered heterocyclyl, or C 1-6 deuteroalkyl is optionally substituted with 1, 2, 3, or 4 R x substituents;

[0013] R3is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-12 membered heterocyclyl, C 1-6 deuteroalkyl, -C(=O)R a , -S(O)2R a or OR a , wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-12 membered heterocyclyl, or C 1-6 deuteroalkyl is optionally substituted with 1, 2, 3, or 4 R x substituents;

[0014] or, R3, R2, and the nitrogen atom to which they are attached together form a 4-10 membered heterocyclyl comprising 0 or 1 additional heteroatoms selected from oxygen, nitrogen, or sulfur, and said 4-10 membered heterocyclyl is optionally substituted with 1, 2, 3, or 4 R x substituents;

[0015] R4is independently selected from H, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R a R a1 ), -OR a , 4-10 membered heterocyclyl, -SF5, or -SR a ;

[0016] R5is selected from -SRa ;

[0017] R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0018] X1 can form 4-6 membered heteroaryl, 4-6 membered heterocyclic or C with R4. 4-6 Cycloalkyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic or C 4- The 6-membered cycloalkyl group may optionally be converted by halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and / or X2 can form 4-6 membered heteroaryl, 4-6 membered heterocyclic, C with X3 4-6 Cycloalkyl or phenyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic, C 4-6 Cycloalkyl or phenyl groups may optionally be converted to halogens, C 1- 6-alkyl or C 1-6 Halogenated alkyl substitution;

[0019] At least one of X1 and R4 forming a loop (or X2 and X3 forming a loop) exists;

[0020] R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace;

[0021] R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups;

[0022] R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -SR a , -S(O)2R a , -N(R a R a1 ), -C(=O)R a , -P(=O)(R a R a1 ), or C 2-6 alkenyl;

[0023] R c is selected from H, halogen, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -CN, -S(O)2R d , -N(R a R a1 ), -C(=O)OR d , or 5-12 membered heteroaryl;

[0024] R a is selected from H, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxy, or C 1-6 haloalkyl;

[0025] R a1 is selected from H, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxy, or C 1-6 haloalkyl;

[0026] R d is selected from H, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4-8 membered heterocyclyl.

[0027] In another aspect, the present application provides specific compounds as exemplified herein.

[0028] In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present application and a pharmaceutically acceptable excipient, which further comprises another therapeutic agent. In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present application and a pharmaceutically acceptable excipient, which further comprises another therapeutic agent.

[0029] In another aspect, the present application provides a compound of the present application or a composition of the present application for use in the treatment and / or prevention of a MAT2A mediated disease.

[0030] In particular embodiments, the diseases treated by the present application include a cancer selected from acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, bile duct cancer, bladder cancer, brain cancer (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, large intestinal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell non-Hodgkin's lymphoma, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (e.g., cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more of the above leukemias / lymphomas;Multiple myeloma (MM), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma, malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), agnogenic myeloid metaplasia (AMM), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibroma (e.g., neurofibromatosis type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, or penile cancer.

[0031] Other objects and advantages of the application will be apparent to those skilled in the art from the ensuing detailed description, examples, and claims.

[0032] Definitions

[0033] Chemical Definitions

[0034] The definitions of specific functional groups and chemical terms are described in more detail below.

[0035] When a range of values is listed, it is intended to include each value and sub-range within the range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl groups.

[0036] "C 1-6 " refers to a straight chain or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl and C1-2 Alkyl is preferred. C 1-6 Examples of alkyl groups include: methyl (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), t-butyl (C4), sec-butyl (C4), i-butyl (C4), n-pentyl (C5), 3-pentyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), t-amyl (C5), and n-hexyl (C6). The term "C 1-6 Alkyl" also includes heteroalkyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl groups can be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0037] "C 2-6 Alkenyl" refers to a straight or branched chain hydrocarbon group having from 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl is preferred. C 2-6 Examples of alkenyl groups include: ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6 Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom

[0038] "C 2-6 Alkynyl" refers to a straight or branched chain hydrocarbon group having from 2 to 8 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl is preferred. C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. The term "C 2-6"Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted by one or more substituents, e.g., by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] "C 1-6 "Alkylene" refers to a divalent group formed by removing a pair of hydrogen atoms from a C 1-6 alkyl group, and can be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred. Unsubstituted alkylene groups include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups, e.g., alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- 2), and the like.

[0040] "C 2-6 "Arylene" refers to a divalent group formed by removing a pair of hydrogen atoms from a C 2-6 aryl group, and can be substituted or unsubstituted. In some embodiments, C 2-4Alkenylene groups are particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, e.g., alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0041] "C 2-6 Alkynylene" refers to a divalent radical, formed by the removal of two hydrogens from a C 2-6 Alkynyl group, and can be substituted or unsubstituted. In some embodiments, C 2-4 Alkynylene groups are particularly preferred. Exemplary alkynylene groups include, but are not limited to, ethynylene (-CºC-), substituted or unsubstituted propynylene (-CºCCH2-), and the like.

[0042] "Halo" or "halogen" means fluoro (F), chloro (CI), bromo (Br), and iodo (I).

[0043] Thus, "C 1-6 Haloalkyl" means a "C 1-6 Alkyl" group as described above, substituted by one or more halogen groups. In some embodiments, C 1-4 Haloalkyl groups are particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro- 1,1-dimethyl-ethyl, and the like. Haloalkyl groups can be substituted at any available attachment point, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0044] "C 1-6 Alkoxy" means an -OR group, wherein R is a C 1-6 Alkyl group as defined above. C 1-4 Alkoxy groups are preferred.

[0045] "C 1-6 Haloalkoxy" means a "C 1-6"Alkoxy" means an -O-alkyl group, wherein "alkyl" is as defined herein. In some embodiments, C 1-4 Haloalkoxyalkyl is particularly preferred, more preferably C 1-2 Haloalkoxyalkyl.

[0046] "Cycloalkyl" means a non-aromatic cyclic hydrocarbon group of from 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-10 Haloalkoxyalkyl is particularly preferred, more preferably C 4- 10 Cycloalkyl, C 5-10 Cycloalkyl, C 4-7 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl and C 3-4 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl. Cycloalkyl also includes ring systems in which an aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl rings, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons designates the number of carbons in the cycloalkyl ring system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. Cycloalkyl groups can be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0047] "3-12 membered heterocyclyl" refers to a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. In some embodiments, 3-10 membered heterocyclyl groups are preferred, which are 3- to 10-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 4-10 membered heterocyclyl groups are preferred, which are 4- to 10-membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, 5-10 membered heterocyclyl groups are preferred, which are 5- to 10-membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5-8 membered heterocyclyl groups are preferred, which are 5- to 8-membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3-7 membered heterocyclyl groups are preferred, which are 3- to 7-membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms; 3-6 membered heterocyclyl groups are preferred, which are 3- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; 4-7 membered heterocyclyl groups are preferred, which are 4- to 7-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; 4-6 membered heterocyclyl groups are preferred, which are 4- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; more preferred are 5-6 membered heterocyclyl groups, which are 5- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteratoms; more preferred are 3-5 membered heterocyclyl groups, which are 3- to 5-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteratom. Heterocyclyl groups also include ring systems in which the above-described heterocyclyl ring is fused to one or more cycloalkyl rings, wherein the point of attachment is on the cycloalkyl ring, or in which the above-described heterocyclyl ring is fused to one or more aryl or heteroaryl rings, wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited: dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited: triazolinyl, oxadiazolinyl, and thiadiazolinyl.Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxaheptanyl, and thianyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused with a C6 aryl ring (also referring herein to 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyranopyridyl, etc. The heterocyclic group may be optionally substituted with one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0048] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0049] "5-14 membered heteroaryl" refers to a radical of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. When the heteroaryl group contains no heteroatoms, the heteroaryl group is phenyl or naphthyl, etc. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or a nitrogen atom, as valence permits. Heteroaryl bicyclic systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which an above-described heteroaryl ring is fused with one or more cycloalkyl or heterocyclyl rings, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms indicates the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 6-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-9 membered heteroaryl is preferred, which is a 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbonA heteroaryl group can be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0050] "Alicyclyl," "heterocyclyl," "aryl," or "heteroaryl" are defined as above, minus an additional hydrogen to form a divalent radical, and can be substituted or unsubstituted. For example, "C 5-7 "Cycloalkyl" refers to a saturated carbocyclic radical of the specified number of carbon atoms. For example, "C 5-7 "Cycloalkyl" refers to a saturated carbocyclic radical of the specified number of carbon atoms. For example, "C 6-10 "Cycloalkyl" refers to a saturated carbocyclic radical of the specified number of carbon atoms. For example, "C 6-10 "Cycloalkyl" refers to a saturated carbocyclic radical of the specified number of carbon atoms. For example, "C

[0051] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted groups.

[0052] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa, -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa )3, -OSi(R aa )3, -C(=S)N(R bb )2, -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(Rcc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0053] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

[0054] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0055] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0056] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0057] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee-C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee )3、-OSi(R ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0058] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0059] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0060] R ggEach of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1- 6-alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1- 6-alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3, -C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1- 6-alkyl, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0061] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SORaa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0062] The term "deuterium (D or 2H)" is a stable isotope of hydrogen, which exists naturally at an abundance of 0.015 mol%. The term "deuteration" refers to the substitution of one or more hydrogen atoms (H) in a group or compound by the replacement of one hydrogen atom (D).

[0063] "Deuterated compound" refers to a compound in which one or more hydrogen atoms bonded to a carbon atom are replaced by one or more deuterium atoms. Similarly, "deuterated" refers to a chemical structure or organic group in which one or more hydrogen atoms bonded to a carbon atom are replaced by one or more deuterium atoms, such as "deuterated alkyl", "deuterated cycloalkyl", "deuterated heterocycloalkyl", "deuterated aryl", etc. For example, "deuterated alkyl" refers to an alkyl group as defined in this application, wherein at least one hydrogen atom bonded to a carbon atom is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to one deuterium atom; one carbon atom may be bonded to multiple deuterium atoms; multiple carbon atoms in an alkyl group may also be bonded to deuterium atoms. For example, deuterated methyl includes methyl-d3, in which three hydrogen atoms are replaced by deuterium atoms; it also includes monodeuterated methyl and dideuterated methyl. In some embodiments, the compounds of the present invention include deuterated compounds.

[0064] Other definitions

[0065] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0066] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0067] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0068] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0069] The term "combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present invention and other therapeutic agents. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. Detailed Implementation

[0070] In this document, “compound of the present invention” refers to the following compounds of formula (A) (including sub-formulas, such as formulas ((I), (V), (V-1), (V-2), (V-3), (V-4), (VI), (VI-1), (VI-2), (VII), (IX), (IX-1) etc.), their pharmaceutically acceptable salts, enantiomers, diastereomers or isotopic variants, and mixtures thereof.

[0071] In one embodiment, the present invention relates to a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0072] in,

[0073] X1, X2, and X3 are each independently selected from -CH, N, or -CR. b ;

[0074] W1 is selected from N or CR c ;

[0075] R1 is selected from phenyl or 5-12 heteroaryl groups; R1 may optionally be surrounded by 1-5 R groups.m Replacement or 1-5 R5s;

[0076] R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0077] R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0078] Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace;

[0079] R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) a R a1 -OR a 4-10 membered heterocyclic groups or -SR a ;

[0080] R5 is selected from -SR a ;

[0081] R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0082] X1 can form 4-6 membered heteroaryl, 4-6 membered heterocyclic or C with R4. 4-6 Cycloalkyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic or C 4- The 6-membered cycloalkyl group may optionally be converted by halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and / or X2 can form 4-6 membered heteroaryl, 4-6 membered heterocyclic, C with X3 4-6 Cycloalkyl or phenyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic, C 4-6 Cycloalkyl or phenyl groups may optionally be converted to halogens, C 1- 6-alkyl or C 1-6 Halogenated alkyl substitution;

[0083] At least one of X1 and R4 forming a loop (or X2 and X3 forming a loop) exists;

[0084] R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace;

[0085] R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups;

[0086] R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy groups, -SR a -S(O)2R a -N(R) a R a1 -C(=O)R a -P(=O)(R a R a1 ), or C 2-6 alkenyl;

[0087] R c Selected from H, halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -CN, -S(O)2R d -N(R) a R a1 -C(=O)OR d Or 5-12 heteroaryl groups;

[0088] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0089] R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0090] R d Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-8 membered heterocyclic groups.

[0091] In some embodiments, X1 can form a 4-6 membered heteroaryl group, a 4-6 membered heterocyclic group, or a C4 group with R4. 4-6 Cycloalkyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic or C 4-6 Cycloalkyl groups may optionally be converted to halogens, C 1-6 Alkyl or C 1-6Halogenated alkyl substitution.

[0092] In some implementations, X2 can form 4-6 membered heteroaryl, 4-6 membered heterocyclic, or C with X3. 4-6 Cycloalkyl or phenyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic, C 4-6 Cycloalkyl or phenyl groups may optionally be converted to halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0093] In some embodiments, X1 can form a 4-6 membered heteroaryl group, a 4-6 membered heterocyclic group, or a C4 group with R4. 4-6 Cycloalkyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic or C 4-6 Cycloalkyl groups may optionally be converted to halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution, and the ability of X2 to form 4-6 membered heteroaryl, 4-6 membered heterocyclic, and C-membered heterocyclic groups with X3. 4-6 Cycloalkyl or phenyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic, C 4-6 Cycloalkyl or phenyl groups may optionally be converted to halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0094] In another, more specific embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0095] in,

[0096] X1, X2, and X3 are each independently selected from -CH, N, or -CR. b ;

[0097] R1 is selected from phenyl or 5-12 heteroaryl groups; R1 may optionally be surrounded by 1-5 R groups. m Replacement or 1-5 R5s;

[0098] R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0099] R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0100] Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace;

[0101] R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) a R a1 -OR a 4-10 membered heterocyclic groups or -SR a ;

[0102] R5 is selected from -SR a ;

[0103] R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0104] X1 can form 4-6 membered heteroaryl, 4-6 membered heterocyclic or C with R4. 4-6 Cycloalkyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic or C 4- The 6-membered cycloalkyl group may optionally be converted by halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0105] X2 can form 4-6 membered heteroaryl groups, 4-6 membered heterocyclic groups, and C with X3. 4-6 Cycloalkyl or phenyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic, C 4-6 Cycloalkyl or phenyl groups may optionally be converted to halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0106] At least one of X1 and R4 forming a loop (or X2 and X3 forming a loop) exists;

[0107] R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace;

[0108] R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups;

[0109] R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -SR a -S(O)2R a -N(R) a R a1 -C(=O)R a -P(=O)(R a R a1 ) or C 2-6 alkenyl;

[0110] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0111] R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups.

[0112] In another, more specific embodiment, the present invention provides a compound of formula (V), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0113] in,

[0114] X1 is selected from -CH, N, or -CR b ;

[0115] X4 is selected from -CH or N;

[0116] The ring formed by X5 and X6 is a five-membered heteroaryl, a five-membered cycloalkyl, a five-membered heterocyclic group, a phenyl, a six-membered cycloalkyl, or a six-membered heterocyclic group;

[0117] X5 is selected from -CH=, -CH2, -CH2CH2, -N=, -C(=O), -S(O)2, O, S, N(R) a R a1 ) or -CR b ;

[0118] X6 is selected from -CH=, -CH2, -CH2CH2, -N=, -C(=O), -S(O)2, O, S, N(R) a R a1 ) or -CR b ;

[0119] R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0120] R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0121] Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace;

[0122] R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) a R a1 -OR a 4-10 membered heterocyclic groups or -SR a ;

[0123] R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0124] R7 is selected from H, halogen, or C. 1-6 Halogenated alkyl groups;

[0125] R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace;

[0126] R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups;

[0127] R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -SR a -S(O)2R a -N(R) a R a1 -C(=O)R a -P(=O)(R a R a1 ) or C 2-6 alkenyl;

[0128] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0129] R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0130] p is selected from 0, 1, or 2;

[0131] n is selected from 0, 1, 2, 3, 4, and 5.

[0132] In another, more specific embodiment, the present invention provides a compound of formula (V-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0133] in,

[0134] X1 is selected from -CH, N, or -CR b ;

[0135] X4 is selected from -CH or N;

[0136] R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0137] R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0138] Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace;

[0139] R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) a R a1 -OR a 4-10 membered heterocyclic groups or -SR a ;

[0140] R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0141] R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace;

[0142] R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups;

[0143] R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -SR a -S(O)2R a -N(R) a R a1 -C(=O)R a -P(=O)(R a R a1 ) or C 2-6 alkenyl;

[0144] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0145] R a1 Selected from H, C 1-6Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0146] n is selected from 0, 1, 2, 3, 4, and 5.

[0147] In another, more specific embodiment, the present invention provides a compound of formula (V-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0148] in,

[0149] X1 is selected from -CH, -N, or -CR b ;

[0150] X4 is selected from -CH or N;

[0151] X6 is selected from -CH, -N, -C(=O), -S(O)2, O, S, CF or -CMe;

[0152] R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0153] R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0154] Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace;

[0155] R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) a R a1 -OR a 4-10 membered heterocyclic groups or -SR a ;

[0156] R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0157] R x Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace;

[0158] R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups;

[0159] R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -SRa -S(O)2R a -N(R) a R a1 -C(=O)R a -P(=O)(R a R a1 ) or C 2-6 alkenyl;

[0160] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0161] R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0162] n is selected from 0, 1, 2, 3, 4, and 5.

[0163] In some implementations, X1 is N.

[0164] In some implementations, X6 is -CH.

[0165] In some implementations, R4 is selected from halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy or 4-10 membered heterocyclic group; wherein the C 3-6 The cycloalkyl or 4-10 membered heterocyclic group may be further substituted with 0-3 R6 groups, wherein the R6 groups are selected from halogens and C. 1-6 alkyl.

[0166] In some embodiments, R4 is selected from F, Cl, Br, -OCF2H, -CF2CF2H, -CF2CH3, -CH2CF3, and -CF3. In some embodiments, R4 is selected from cyclopropyl, cyclobutyl, and aziridine, wherein the group is optionally substituted with a halogen.

[0167] In some implementations, X4 is N. In some implementations, X4 is CH.

[0168] In some implementation schemes, R m Selected from halogens, C 1-6 Alkyl, C 3-6 cycloalkyl and C1-6 Halogenated alkyl groups.

[0169] In some implementation schemes, R m Selected from CF3, CHF2, methyl, ethyl and cyclopropyl.

[0170] In some implementations, R2 is selected from H or C. 1-6 alkyl.

[0171] In some implementations, R3 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl, wherein the C 1-6 Alkyl groups are optionally coated with one R x Instead, the R x Selected from C 3-6 Cycloalkyl or 5-10 heteroaryl groups.

[0172] In some implementations, R2 and R3 are each H. In some implementations, R2 is H and R3 is C. 1-6 Alkyl group. In some embodiments, R2 is C2. 1-6 Alkyl group, and R3 is C 1-6 Alkyl group. In some embodiments, R2 is H and R3 is a halocarbon group. 1-6 Alkyl group. In some embodiments, R2 is H and R3 is C. 3-6 Cycloalkyl.

[0173] In some embodiments, R2 is H, and R3 is methyl or ethyl. In some embodiments, R2 is methyl or ethyl, and R3 is methyl or ethyl. In some embodiments, R2 is H, and R3 is CH2CF3. In some embodiments, R2 is H, and R3 is cyclopropyl. In some embodiments, R2 is H, and R3 is methyl, further substituted with cyclopropyl or pyridyl.

[0174] In another, more specific embodiment, the present invention provides a compound of formula (V-3), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0175] in,

[0176] X1 is selected from -CH, N, or -CF;

[0177] X4 is selected from -CH or N;

[0178] R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0179] R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0180] Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace;

[0181] R4 is independently selected from H, F, Cl, methyl, cyclopropyl, cyclobutyl, CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, OMe, -SCF3 or -SCF2H;

[0182] R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0183] R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a Ra1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace;

[0184] R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups;

[0185] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0186] R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0187] n is selected from 0, 1, 2, 3, 4, and 5.

[0188] In some implementations, X1 is N.

[0189] In some embodiments, R4 is selected from F, Cl, -OCF2H, -CF2CF2H, -CF2CH3, -CH2CF3, and -CF3. In some embodiments, R4 is selected from cyclopropyl and cyclobutyl.

[0190] In some implementations, X4 is N. In some implementations, X4 is CH.

[0191] In some implementation schemes, R m Selected from halogens, C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Halogenated alkyl groups.

[0192] In some implementation schemes, R m Selected from CF3, CHF2, methyl, ethyl and cyclopropyl.

[0193] In some implementations, R2 is selected from H or C. 1-6 alkyl.

[0194] In some implementations, R3 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl, wherein the C 1-6 Alkyl groups are optionally coated with one R x Instead, the R x Selected from C 3-6 Cycloalkyl or 5-10 heteroaryl groups.

[0195] In some implementations, R2 and R3 are each H. In some implementations, R2 is H and R3 is C. 1-6 alkyl.

[0196] In some implementations, R2 is C 1-6 Alkyl group, and R3 is C 1-6 alkyl.

[0197] In some implementations, R2 is H, and R3 is halogenated C. 1-6 alkyl.

[0198] In another, more specific embodiment, the present invention provides a compound of formula (V-4), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0199] in,

[0200] X1 is selected from -CH or N;

[0201] X4 is selected from -CH or N;

[0202] R2 is selected from H, methyl, ethyl, trifluoroethyl, difluoroethyl, cyclopropyl, or deuterated methyl;

[0203] R3 is selected from H, methyl, ethyl, trifluoroethyl, difluoroethyl, cyclopropyl, or deuterated methyl;

[0204] R4 is independently selected from H, F, Cl, Br, methyl, cyclopropyl, cyclobutyl, -CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, -SCF3 or -SCF2H;

[0205] R mSelected from H, F, Cl, Br, I, methyl, ethyl, cyclopropyl, isopropyl, deuterated methyl, -CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, SCF3 or SCF2H.

[0206] In another, more specific embodiment, the compound of formula (V-4), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, has two transtransisomers:

[0207] in,

[0208] X1 is selected from -CH or N;

[0209] X4 is selected from -CH or N;

[0210] R2 is selected from H, methyl, ethyl, trifluoroethyl, difluoroethyl, cyclopropyl, or deuterated methyl;

[0211] R3 is selected from H, methyl, ethyl, trifluoroethyl, difluoroethyl, cyclopropyl, or deuterated methyl;

[0212] R4 is independently selected from H, F, Cl, Br, methyl, cyclopropyl, cyclobutyl, -CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, -SCF3 or -SCF2H;

[0213] R m Selected from H, F, Cl, Br, I, methyl, ethyl, cyclopropyl, isopropyl, deuterated methyl, -CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, SCF3 or SCF2H.

[0214] In another, more specific embodiment, the present invention provides a compound of formula (VI), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0215] in,

[0216] X1 is selected from -CH, -N, or -CR b ;

[0217] X4 is selected from -CH or N;

[0218] R2 is selected from H and C. 1-6 Alkyl, C1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0219] R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0220] Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace;

[0221] R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -N(R) a R a1 -OR a 4-10 membered heterocyclic groups or -SR a ;

[0222] R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0223] R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace;

[0224] R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups;

[0225] R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -SR a -S(O)2R a -N(R) a R a1 -C(=O)R a -P(=O)(R a R a1 ), or C 2-6 alkenyl;

[0226] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0227] R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0228] n is selected from 0, 1, 2, 3, 4, and 5.

[0229] In another, more specific embodiment, the present invention provides a compound of formula (VI-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0230] in,

[0231] X4 is selected from -CH or N;

[0232] R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0233] R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0234] R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace;

[0235] R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups;

[0236] Alternatively, R3, R2 and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen or sulfur, and the 4-10 membered heterocyclic group may optionally be substituted with OH, NH2 or F;

[0237] R4 is independently selected from H, F, Cl, Br, methyl, ethyl, cyclopropyl, cyclobutyl, CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, -SCF3 or -SCF2H;

[0238] R m Selected from H, F, Cl, Br, I, methyl, ethyl, cyclopropyl, deuterated methyl, CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, SCF3 or SCF2H;

[0239] n is selected from 0, 1, 2, and 3.

[0240] In another, more specific embodiment, the present invention provides a compound of formula (VI-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0241] in,

[0242] X4 is selected from -CH or N;

[0243] R2 is selected from H, methyl, ethyl, trifluoroethyl, difluoroethyl, cyclopropyl, or deuterated methyl;

[0244] R3 is selected from H, methyl, ethyl, trifluoroethyl, difluoroethyl, cyclopropyl, or deuterated methyl;

[0245] R4 is independently selected from H, F, Cl, Br, methyl, ethyl, cyclopropyl, cyclobutyl, CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, SCF3, or SCF2H;

[0246] R m Selected from H, F, Cl, Br, I, methyl, ethyl, cyclopropyl, deuterated methyl, CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, SCF3 or SCF2H.

[0247] In another, more specific embodiment, the compound of formula (VI-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, has two transtransisomers:

[0248] in,

[0249] X4 is selected from -CH or N;

[0250] R2 is selected from H, methyl, ethyl, trifluoroethyl, difluoroethyl, cyclopropyl, or deuterated methyl;

[0251] R3 is selected from H, methyl, ethyl, trifluoroethyl, difluoroethyl, cyclopropyl, or deuterated methyl;

[0252] R4 is independently selected from H, F, Cl, Br, methyl, ethyl, cyclopropyl, cyclobutyl, CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, SCF3, or SCF2H;

[0253] R m Selected from H, F, Cl, Br, I, methyl, ethyl, cyclopropyl, deuterated methyl, CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, SCF3 or SCF2H.

[0254] In another, more specific embodiment, the present invention provides a compound of formula (VII), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0255] in,

[0256] X1 is selected from -CH=, -N=, or -CR. b ;

[0257] X4 is selected from CH or N;

[0258] R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0259] R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0260] Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace;

[0261] R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a 4-10 member heterocyclic groups or -SR a ;

[0262] R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0263] R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace;

[0264] R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups;

[0265] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0266] R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0267] R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -SR a -S(O)2R a -N(R) a R a1-C(=O)R a -P(=O)(R a R a1 ) or C 2-6 alkenyl;

[0268] n is selected from 0, 1, 2, 3, 4, and 5.

[0269] In another, more specific embodiment, the present invention provides a compound of formula (IX), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0270] in,

[0271] X1 is selected from -CH or N;

[0272] X4 is selected from -CH or N;

[0273] R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0274] R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace;

[0275] Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace;

[0276] R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a 4-10 member heterocyclic groups or -SR a ;

[0277] R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0278] R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace;

[0279] R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups;

[0280] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0281] R a1Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0282] n is selected from 0, 1, 2, 3, 4, and 5.

[0283] In another, more specific embodiment, the present invention provides a compound of formula (IX-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0284] in,

[0285] X1 is selected from -CH or N;

[0286] X4 is selected from -CH or N;

[0287] R2 is selected from H, methyl, trifluoroethyl, difluoroethyl, cyclopropyl, deuterated methyl, -C(=O)Me, -S(O)2Me or OMe;

[0288] R3 is selected from H, methyl, trifluoroethyl, difluoroethyl, cyclopropyl, deuterated methyl, -C(=O)Me, -S(O)2Me or OMe;

[0289] Alternatively, R3, R2 and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen or sulfur, and the 4-10 membered heterocyclic group may optionally be substituted with OH, NH2 or F;

[0290] R4 is independently selected from H, F, Cl, Br, methyl, deuterated methyl, ethyl, cyclopropyl, cyclobutyl, -CF3, -CF2H, -CF2CH3, -CF2CD3, -OCF3, -OCF2H, -N(Me)2, -OMe, -SCF3 or -SCF2H;

[0291] R m Selected from H, D, F, Cl, Br, methyl, deuterated methyl, ethyl, deuterated ethyl, cyclopropyl, cyclobutyl, -CF3, -CF2H, -CF2CH3, -CF2CD3, -OCF3, -OCF2H, -N(Me)2, -OMe, -SCF3 or -SCF2H.

[0292] In a more specific embodiment, the present invention provides a compound, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein said compound is selected from:

[0293] In another, more specific embodiment, the invention provides a compound, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0294] In another, more specific embodiment, the invention provides a compound, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0295] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0296] The compounds of this invention may also exist as tautomers. A compound is not limited to any particular tautomer, but is intended to encompass all tautomer forms.

[0297] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (A), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotopically labeled compounds of formula (A) of the present invention and their prodrugs can generally be prepared by using readily available isotopically labeled reagents instead of non-isotopically labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0298] As used herein, in the specification and claims, “H” refers to hydrogen and includes any stable isotopes of hydrogen, namely 1H and D. In embodiments in which an atom is designated as “H”, no work has been done to enrich the atom with a specific isotope of hydrogen, and therefore those skilled in the art will understand that such hydrogen atoms may be present at approximately the natural abundance concentration of hydrogen.

[0299] As used herein, “1H” refers to protium. When an atom in a compound of the present invention or a pharmaceutically acceptable salt thereof is designated as protium, protium is present at the designated location at a concentration of at least the natural abundance of protium.

[0300] As used in this article, “D”, “d” and “2H” refer to deuterium.

[0301] Pharmaceutical Compositions and Kits

[0302] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as the "active component") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the compound of the present invention.

[0303] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0304] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0305] Dosage

[0306] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0307] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0308] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0309] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0310] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) allows for a more rapid delivery, causing the concentration of the active component in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV intravenous infusion, thereby providing a steady-state concentration of the active component in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0311] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, the compositions are provided in unit dose form for the purpose of precise dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0312] Example

[0313] The reagents used in this invention are commercially available reagents that are purchased directly or synthesized using common methods known in the art.

[0314] Note 1 on commonly used abbreviations:

[0315] Notes on commonly used abbreviations 2:

[0316] :(SS)-DACH-Phenyl Trost, :R-2-Me-CBS-oxazabolidine, :DBU.

[0317] The specific reaction routes or steps in the following examples are used in this invention, as detailed below:

[0318] Example 1: Synthesis of intermediates a1-a4

[0319] Step 1: Dissolve raw material a1-1 (500 mg, 2.13 mmol) in 5 mL of thionyl chloride, heat to 50 °C and react for 4 hours, then stop the reaction. Remove the solvent under reduced pressure to obtain crude product a1-2.

[0320] Step 2: Ice bath. Dissolve intermediate a1-2 from the previous step in 10 mL of DCM, and slowly add ammonia water (5.0 mL). React the mixture at room temperature for 2 hours, then stop the reaction. Remove the solvent under reduced pressure, add 50 mL of ice water to the system, extract with dichloromethane, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 1) to obtain a white solid a1 (470 mg). Two-step yield: 92%. LCMS ESI-MS m / z: 236 [M+H] + .

[0321] Step 1: Dissolve raw material a2-1 (1.3 g, 4.53 mmol) in 15 mL of dichloromethane, add (COCl)2 (756 mg, 6.0 mmol), and add 3 drops of anhydrous DMF. React at room temperature for 2 hours, then stop the reaction. Remove the solvent under reduced pressure to obtain crude product a2-2.

[0322] Step 2: Ice bath. Dissolve intermediate a1-2 from the previous step in 12 mL of DCM, and slowly add ammonia water (3.0 mL). React the mixture at room temperature for 2 hours, then stop the reaction. Remove the solvent under reduced pressure, add 50 mL of ice water to the system, extract with dichloromethane, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 1) to obtain a yellow solid a2 (700 mg). Two-step yield: 54%. LCMS ESI-MS m / z: 287 [M+H] + .

[0323] Following the synthetic routes of compounds a1 or a2, and using similar starting materials / intermediates, the following target intermediates were synthesized.

[0324] Synthesis of intermediate a5

[0325] Step 1: Dissolve 10 g (64.5 mmol) of starting material a5-1 in 200 mL of dichloromethane, add 3-chloroperoxybenzoic acid (m-CPBA, 22.3 g, 129 mmol), heat to 45 °C and react for 4 hours. Stop the reaction and filter. Remove the solvent under reduced pressure. Separate the crude product by flash column chromatography (DCM / MeOH, 10 / 1) to obtain compound a5-2 (8.0 g), yield: 72%. LCMS ESI-MS m / z: 172 [M+H] + .

[0326] Step 2: Ice bath. Dissolve intermediate a1-2 (8.0 g, 46.7 mmol) from the previous step in 120 mL of 1,4-dioxane, and slowly add 80 mL of POCl3. React the mixture at 100 °C for 5 hours, then stop the reaction. Add 500 mL of ice water to the system, adjust the pH to approximately 8 with saturated sodium bicarbonate solution, extract with dichloromethane, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (PE / EA, 5 / 1) to obtain a yellow oily substance a5 (5.6 g), yield: 63%. LCMS ESI-MS m / z: 190 [M+H] + .

[0327] Synthesis of intermediate a6

[0328] Step 1: Under nitrogen protection at -78°C, intermediate a5 (5.6 g, 36.0 mmol) was dissolved in 56 mL of anhydrous tetrahydrofuran, and nBuLi (17.3 mL, 43.2 mmol, 2.5 M) was slowly added dropwise. The mixture was reacted at -78°C for 1 hour. Dry ice (10 g) was added to the reaction solution, and the reaction was continued for another hour before being stopped. The reaction was quenched with 100 mL of ice water, the pH was adjusted to approximately 4 with dilute hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a white solid a6-1 (5.6 g), yield: 81%. LCMS ESI-MS m / z: 234 [M+H] + .

[0329] Step 2: Dissolve the intermediate a6-1 (5.6 g, 24.0 mmol) from the previous step in 56 mL of thionyl chloride, heat to 80 °C and react for 2 hours. Stop the reaction and remove the solvent under reduced pressure. Dissolve the mixture in 56 mL of acetonitrile, slowly add ammonia (56 mL), and react the mixture at room temperature for 1 hour. Stop the reaction. Remove the solvent under reduced pressure, add 50 mL of ice water to the system, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate to give a yellow solid a6 (4.0 g), yield: 72%. LCMS ESI-MS m / z: 233 [M+H] + .

[0330] Synthesis of intermediate a7

[0331] Step 1: Methyl 2,6-difluoro-4-chlorobenzoate a7-1 (5.0 g, 24.2 mmol) and Cs₂CO₃ (23.9 g, 72.6 mmol) were dissolved in 100 mL of DMF. Starting material a7-2 (3.41 g, 25.4 mmol) was slowly added dropwise. The mixture was reacted at 100 °C for 2 hours. The reaction was quenched with 100 mL of ice water, the pH was adjusted to approximately 5 with dilute hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain a white solid a7-3 (6.0 g), yield: 77%.

[0332] Step 2: Dissolve 12 g of polyphosphate (PPA) in 100 mL of chlorobenzene, heat to 100 °C, add intermediate a7-3 (6.0 g, 18.75 mmol) from the previous step, and react at 100 °C for 1 hour, then stop the reaction. Dissolve the mixture in 500 mL of ice water, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (PE / EA, 1 / 1) to obtain a yellow solid a7 (1.5 g), yield: 35%.

[0333] Synthesis of intermediate a8

[0334] Step 1: Intermediate a7 (1.5 g, 6.56 mmol) was dissolved in 25 mL of a mixture of tetrahydrofuran and water (v / v, 5 / 1), and LiOH (787 mg, 32.8 mmol) was slowly added dropwise. The mixture was reacted at 40 °C for 2 hours. 50 mL of ice water was added to the reaction solution, the pH was adjusted to approximately 5 with dilute hydrochloric acid, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain intermediate a8-1 (1.1 g), yield: 78%. LCMS ESI-MS m / z: 213 [MH] - .

[0335] Step 2: Dissolve the intermediate a8-1 (1.0 g, 4.66 mmol) from the previous step in 20 mL of thionyl chloride, heat to 80 °C and react for 1 hour, then cool to room temperature and remove the solvent under reduced pressure. Dissolve the mixture in 20 mL of 1,4-dioxane, add ammonia (5.0 mL), and react at 20 °C for 1 hour, then stop the reaction. Dissolve the mixture in 50 mL of ice water, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (PE / EA, 1 / 2) to obtain a yellow solid a8 (600 mg), yield: 60%. LCMS ESI-MS m / z: 214 [M+H] + .

[0336] Synthesis of intermediates a9-a10

[0337] Step 1: Methyl 2,6-difluoro-4-bromobenzoate a9-1 (5.0 g, 20.2 mmol) and Cs₂CO₃ (19.5 g, 60.0 mmol) were dissolved in 100 mL of DMF. Starting material a7-2 (2.81 g, 21.0 mmol) was slowly added dropwise. The mixture was reacted at 100 °C for 2 hours. The reaction was quenched with 100 mL of ice water, the pH was adjusted to approximately 5 with dilute hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain a white solid a9-2 (5.9 g), yield: 80%.

[0338] Step 2: Dissolve 12 g of polyphosphate (PPA) in 100 mL of chlorobenzene, heat to 100 °C, add intermediate a9-2 (5.9 g, 16.2 mmol) from the previous step, and react at 100 °C for 1 hour, then stop the reaction. Dissolve the mixture in 500 mL of ice water, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (PE / EA, 1 / 1) to obtain a yellow solid a9-3 (2.0 g), yield: 45%.

[0339] Step 3: Dissolve intermediate a9-3 (2.0 g, 7.35 mmol) from the previous step in a 25 mL mixture of tetrahydrofuran and water (v / v, 5 / 1). Slowly add LiOH (882 mg, 36.7 mmol). React the mixture at 40 °C for 2 hours. Add 50 mL of ice water to the reaction solution, adjust the pH to approximately 5 with dilute hydrochloric acid, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate to obtain intermediate a9-4 (1.5 g), yield: 79%. LCMS ESI-MS m / z: 257 [MH] - .

[0340] Step 4: Dissolve the intermediate a9-4 (1.5 g, 5.81 mmol) from the previous step in 20 mL of thionyl chloride, heat to 80 °C and react for 1 hour, then cool to room temperature and remove the solvent under reduced pressure. Dissolve the mixture in 20 mL of 1,4-dioxane, add ammonia (5.0 mL), and react at 20 °C for 1 hour, then stop the reaction. Dissolve the mixture in 50 mL of ice water, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (PE / EA, 1 / 2) to obtain a yellow solid a9 (1.3 g), yield: 87%. LCMS ESI-MS m / z: 258 [M+H] + .

[0341] Following the synthetic route of compound a9, and using similar starting materials / intermediates, the following target intermediate was synthesized.

[0342] Synthesis of intermediate a11

[0343] Step 1: Under nitrogen protection, intermediate a9-3 (1.0 g, 3.66 mmol) and starting material H9-1 (1.98 g, 5.49 mmol) were dissolved in 12 mL of 1,4-dioxane. Catalyst Pd(PPh3)2Cl2 (260 mg, 0.37 mmol) was added, and the reaction was carried out at room temperature for 5 minutes. The temperature was then raised to 90 °C and the reaction continued for 16 hours. The mixture was filtered, and the solvent was removed by vacuum distillation. The mixture was dissolved in 10 mL of tetrahydrofuran, placed in an ice bath, and dilute hydrochloric acid (2 M, 2 mL) was added. The mixture was reacted at 30 °C for 2 hours, and the reaction was stopped. 50 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 10 / 1) to obtain compound a11-1 (580 mg), yield: 67%.

[0344] 1H NMR (400MHz, DMSO-d6) δ8.30(d,J=2.4Hz,1H),7.98(d,J=11.6Hz,1H),7.47(d,J=2.0Hz,1H),3.97(s,3H),2.70(s,3H).

[0345] Step 2: Under nitrogen protection in an ice bath, the intermediate a11-1 (580 mg, 2.46 mmol) from the previous step was dissolved in 6 mL of dichloromethane. DAST (3172 mg, 19.7 mmol) was slowly added. The mixture was reacted at 60 °C for 16 hours, after which the reaction was stopped. 50 mL of ice water was added to the reaction mixture, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 1) to give compound a11-2 (510 mg), yield: 80%.

[0346] Step 3: Ice bath reaction. Dissolve compound a11-2 (460 mg, 1.78 mmol) from the previous step in 4 mL of tetrahydrofuran, add LiOH (2 M, 1 mL) aqueous solution, heat to 60 °C and react for 2 hours, then stop the reaction. Add 20 mL of ice water to the reaction solution, adjust the pH to approximately 5 with dilute hydrochloric acid aqueous solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate, and obtain a yellow solid a11-3 (430 mg). LCMS ESI-MS m / z: 245 [M+H] + .

[0347] Step 4: Ice bath reaction. Dissolve compound a11-3 (430 mg, 1.76 mmol) and NH4Cl (141 mg, 2.64 mmol) from the previous step in 4 mL of DMF. Add DIEA (682 mg, 5.28 mmol) and HATU (1.0 g, 2.64 mmol). Heat to 30 °C and react for 2 hours, then stop the reaction. Add 20 mL of ice water to the reaction solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate to give a yellow solid a11 (380 mg), yield: 89%. LCMS ESI-MS m / z: 244 [M+H] + .

[0348] Synthesis of intermediate a12

[0349] Step 1: Under nitrogen protection in an ice bath, dissolve starting material a12-1 (20 g, 93.43 mmol) in 200 mL of dichloromethane, then slowly add ethoxycarbonyl isothiocyanate a12-2 (12.25 g, 93.43 mmol). React the mixture at 30 °C for 2 hours, precipitating a solid, which is then filtered. The filter cake is washed with n-hexane and dried to give compound a12-3 (30.4 g), yield: 94%. LCMS ESI-MS m / z: 344.9 / 346.9 [M+H] + .

[0350] 1 H NMR (400MHz, DMSO-d6) δ = 11.52 (br s, 1H), 11.36 (br s,1H),7.76(s,1H),7.49(s,1H),5.12(s,2H),4.97(s,2H),4.21(q,J=7.1Hz,2H),1.26(t,J=7.1Hz,3H).

[0351] Step 2: Dissolve the intermediate a12-3 (30.4 g, 88.0 mmol) and K2CO3 (36.51 g, 264.2 mmol) from the previous step in 300 mL of acetone, add MeI (12.5 g, 88.06 mmol), and react at 30 °C for 2 hours. Stop the reaction. Remove the solvent under reduced pressure, add 100 mL of ice water to the reaction mixture, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate to give a yellow solid a12-4 (30.5 g), yield: 96%. LCMS ESI-MS m / z: 359.1 / 361.1 [M+H] + .

[0352] Step 3: Dissolve the intermediate a12-4 (30.5 g, 84.9 mmol) from the previous step in 150 mL of N-methylpyrrolidone (NMP), heat to 180 °C and react for 1 hour, then stop the reaction. Add 500 mL of ice water to the reaction solution, precipitate the solid, and filter. Dry the filter cake to obtain a yellow solid a12-5 (16.4 g), yield: 62%. LCMS ESI-MS m / z: 313.0 / 315.0 [M+H] + .

[0353] Step 4: Ice bath. Dissolve the intermediate a12-5 (5.3 g, 16.9 mmol) from the previous step in 200 mL of dichloromethane. Slowly add oxaloyl chloride (8.59 g, 67.68 mmol) and anhydrous DMF (4.95 g, 67.68 mmol). Heat to 5 °C and react for 2 hours, then stop the reaction. Add 500 mL of ice water to the reaction solution, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (nHex / EA, 8 / 1) to give a yellow solid a12-6 (1.52 g), yield: 27%. LCMS ESI-MS m / z: 331.0 / 335.0 [M+H] + .

[0354] 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.80 (t, J = 3.1Hz, 2H), 5.25 (t, J = 3.2Hz, 2H), 2.65 (s, 3H).

[0355] Step 5: In an ice bath, dissolve the intermediate a12-6 (880 mg, 2.65 mmol) and bis(4-methoxybenzyl)amine a12-7 (955 mg, 3.71 mmol) in 25 mL of dichloromethane. Slowly add TEA (804 mg, 7.95 mmol) dropwise. Heat to 65 °C and react for 48 hours, then stop the reaction. Add 100 mL of ice water to the reaction solution, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (nHex / EA, 10 / 1) to obtain a yellow solid a12 (790 mg), yield: 54%. LCMS ESI-MS m / z: 552.1 / 554.1 [M+H] + .

[0356] 1 H NMR(400MHz, CDCl3)δ7.93(s,1H),6.95-6.91(m,4H),6.85-6.81(m,4H),5.67(br s,2H),5.20(t,J=2.6Hz,2H),4.34(s,4H),3.81(s,6H),2.58(s,3H).

[0357] Synthesis of intermediate a13

[0358] Step 1: In an ice bath, intermediate a12 (3.4 g, 6.15 mmol) was dissolved in 50 mL of dichloromethane. mCPBA (3.0 g, 14.76 mmol) was slowly added, and the reaction was carried out at 0 °C for 1 hour. The reaction was then stopped. 100 mL of ice water and 40 mL of saturated sodium sulfite solution were added to the reaction mixture. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid a13-1 (3.55 g), yield: 99%. LCMS ESI-MS m / z: 584.2 / 586.0 [M+H] + .

[0359] Step 2: An ice bath was used to dissolve intermediate a13-1 (3.5 g, 5.99 mmol) in 50 mL of a mixed solution of tetrahydrofuran and water (v / v, 3 / 2). A 5 mL aqueous solution of KOH (3.36 g, 59.9 mmol) was slowly added. The reaction was carried out at 20°C for 2 hours, after which the reaction was stopped. 100 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 7 with dilute hydrochloric acid. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was washed with methyl tert-butyl ether and dried to obtain a yellow solid a13 (2.5 g), yield: 80%. LCMS ESI-MS m / z: 522.1 / 524.1 [M+H] + [PMB = 4-methoxybenzyl]

[0360] 1 H NMR (400MHz, DMSO-d6) δ7.43(s,1H),7.01(d,J=8.6Hz,4H),6.89(d,J=8.6Hz,4H),5.48(br s,2H),4.98(s,2H),4.24(br s,4H),3.73(s,6H).

[0361] Synthesis of intermediate a14

[0362] Step 1: At -78℃, dissolve starting materials a14-1 (2.0 g, 6.25 mmol) and a14-2 (780 mg, 6.25 mmol) in 10 mL of anhydrous tetrahydrofuran. Slowly add nBuLi (2.8 mL, 2.5 M), stir for 30 minutes, then raise the temperature to 0℃ and continue the reaction for 2 hours. Stop the reaction. Add 100 mL of ice water to the reaction solution, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (nHex / EA, 6 / 1) to obtain an oily substance a14-3 (530 mg), yield: 31%.

[0363] 1H NMR (400MHz, DMSO-d6+D2O) δ8.01(d,J=2.0Hz,1H),7.30(d,J=12.0Hz,1H),7.13(d,J=2.0Hz,1H),5.90(t,J=152Hz,1H)),3.91(s,3H).

[0364] Step 2: Under nitrogen protection in an ice bath, the intermediate a14-3 (530 mg, 1.95 mmol) from the previous step was dissolved in 10 mL of dichloromethane. DAST (4.71 g, 29.25 mmol) was slowly added. The mixture was reacted at 40 °C for 12 hours, after which the reaction was stopped. 50 mL of ice water was added to the reaction mixture, and the solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (nHex / EA, 6 / 1) to give compound a14-4 (480 mg), yield: 84%. LCMS ESI-MS m / z: 295.1 [M+H] + .

[0365] Step 3: Ice bath reaction. Dissolve the intermediate a14-4 (480 mg, 1.63 mmol) from the previous step in a 6 mL mixture of tetrahydrofuran and water (v / v, 1 / 1). Slowly add LiOH-H2O (195 mg, 8.15 mmol). React the mixture at 20 °C for 4 hours, then stop the reaction. Add 50 mL of ice water to the reaction solution, adjust the pH to approximately 3 with dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain compound a14-5 (380 mg), yield: 83%. LCMS ESI-MS m / z: 281.0 [M+H] + .

[0366] Step 4: Ice bath. Dissolve intermediate a14-5 (380 mg, 1.36 mmol) from the previous step in 2 mL of tetrahydrofuran, add SOCl2 (2 mL), heat to 70 °C and react for 4 hours. Stop the reaction and remove the solvent under reduced pressure. Add 1 mL of ammonia water to the reaction solution and react at room temperature for 1 hour. Stop the reaction. Add 10 mL of ice water to the reaction solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (nHex / EA, 3 / 2) to obtain intermediate a14 (300 mg), yield: 78%. LCMS ESI-MS m / z: 280.0 [M+H] + .

[0367] Synthesis of intermediate a15

[0368] Step 1: Dissolve starting material a15-1 (20 g, 130.2 mmol) in 400 mL of dichloromethane, add m-CPBA (67.4 g, 390.7 mmol), and react at 25 °C for 6 hours. Stop the reaction, and a solid precipitates. Remove the solvent from the filtrate under reduced pressure. Separate the crude product by flash column chromatography (DCM / MeOH, 50 / 1) to give compound a15-2 (10.0 g), yield: 43%. LCMS ESI-MS m / z: 170 [M+H] + .

[0369] Step 2: Ice bath reaction. Dissolve the intermediate a15-2 (10.0 g, 58.97 mmol) from the previous step in 50 mL of 1,4-dioxane, and slowly add POCl3 (50 mL). React the mixture at 100 °C for 12 hours, then stop the reaction. Add 500 mL of ice water to the system, adjust the pH to approximately 9 with ammonia solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (PE / EA, 100 / 1) to obtain a white solid a15-3 (6.0 g), yield: 53%. LCMS ESI-MS m / z: 188 [M+H] + .

[0370] Step 3: Under nitrogen protection at -78℃, intermediate a15-3 (6.0 g, 31.91 mmol) was dissolved in 60 mL of anhydrous tetrahydrofuran, and nBuLi (11.5 mL, 28.7 mmol, 2.5 M) was slowly added dropwise. The mixture was reacted at -78℃ for 1 hour. Dry ice (6 g) was added to the reaction solution, and the reaction was continued for 0.25 hours before being stopped. The reaction was quenched with 100 mL of ice water, the pH was adjusted to approximately 4 with acetic acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (10 mmol / L HCOOH, 1 / 1)) to give a white solid a15-4 (3.0 g), yield: 40%. LCMS ESI-MS m / z: 232 [M+H] + .

[0371] Step 4: Ice bath reaction. Dissolve the intermediate a15-4 (1.0 g, 4.31 mmol) from the previous step in 10 mL of dichloromethane, add oxaloyl chloride (821 mg, 6.47 mmol), and react at 0 °C for 1 hour. Stop the reaction and remove the solvent under reduced pressure. Dissolve the mixture in 11 mL of acetonitrile, add 11 mL of ammonia, and react the mixture at 0 °C for 1 hour. Stop the reaction. Add 50 mL of ice water to the system, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (PE / EA, 3 / 7) to obtain a white solid a15 (0.8 g), yield: 78%. LCMS ESI-MS m / z: 231 [M+H] + .

[0372] Synthesis of intermediates a16-a21, a28-a29, a32

[0373] Step 1: Under nitrogen protection, intermediate a15 (800 mg, 3.46 mmol) and (COCl)2 (659 mg, 5.19 mmol) were dissolved in 8 mL of dichloroethane DCE. The mixture was heated to 80 °C and reacted for 1 hour. The solvent was removed by vacuum evaporation. The mixture was dissolved in 12 mL of anhydrous DCE and placed in an ice bath. 2-Methyl-3-aminopyridine b2-1 (562 mg, 5.19 mmol) was added to the mixture. The mixture was reacted at 20 °C for 0.25 hours, and then the reaction was stopped. 50 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give compound a16-1 (400 mg), yield: 31%. LCMS ESI-MS m / z: 365 [M+H] + .

[0374] Step 2: Under nitrogen protection in an ice bath, compound a16-1 (400 mg, 1.1 mmol) from the previous step was dissolved in 8 mL of DMF, and Cs₂CO₃ (714 mg, 2.19 mmol) was added. The mixture was reacted at 60 °C for 1 hour, and then the reaction was stopped. 40 mL of ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was washed with acetonitrile and dried to give compound a16 (300 mg), yield: 79%. LCMS ESI-MS m / z: 329 [M+H] + .

[0375] Following the synthetic route of compound a16, and using similar starting materials / intermediates, the following target intermediate was synthesized.

[0376] Synthesis of intermediates a22-a27, a30-a31

[0377] Under nitrogen protection, intermediate a17 (900 mg, 2.59 mmol) was dissolved in 9 mL of ethyl acetate solution (30%) containing HBr, and reacted at 110 °C for 5 hours. 30 mL of water was added to the reaction mixture, and the pH was adjusted to approximately 8 with an ammonia solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (DCM / MeOH, 10 / 1) to give a yellow solid a22 (0.7 g), yield: 69%. LCMS ESI-MS m / z: 392 [M+H] + .

[0378] Following the synthetic route of compound a22, and using similar starting materials / intermediates (such as intermediates a16-a21, a28-a29, a32, etc.), the following target intermediates were synthesized.

[0379] Synthesis of intermediates b1-b3

[0380] Step 1: Under nitrogen protection in an ice bath, intermediate a1 (470 mg, 1.95 mmol) was dissolved in 8 mL of anhydrous tetrahydrofuran, and (COCl)2 (368 mg, 2.9 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at 80 °C for 1.5 hours. The solvent was removed by vacuum distillation to obtain a red oily substance. The mixture was dissolved in 15 mL of anhydrous tetrahydrofuran, and 2-chloroaniline b1-1 (297 mg, 2.34 mmol) was added. The reaction was carried out at room temperature for 2 hours, and then the reaction was stopped. The mixture was filtered, and 100 mL of water was added to the reaction solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. Crude product b1-2 (240 mg) was obtained, yield: 32%. LCMS ESI-MS m / z: 388 [M+H] + .

[0381] Step 2: Dissolve the crude product b1-2 (240 mg, 0.62 mmol) from the previous step in 11 mL of tetrahydrofuran, add tBuONa (173 mg, 1.8 mmol), and react at 50 °C for 4 hours. Stop the reaction. Remove the solvent under reduced pressure, add 50 mL of ice water to the reaction solution, adjust the pH to approximately 6 with dilute hydrochloric acid, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash reversed column chromatography (column: C18; CH3CN / H2O, 1 / 1) to obtain a yellow solid b1-3 (170 mg), yield: 78%. LCMS ESI-MS m / z: 353 [M+H] + .

[0382] Step 3: Ice bath reaction. Dissolve intermediate b1-3 (170 mg, 0.48 mmol) and DIEA (155 mg, 1.2 mmol) from the previous step in 10 mL of 1,4-dioxane, add 3 mL of POCl3, and heat to 110 °C for 4 hours. Stop the reaction. Add 100 mL of ice water to the reaction solution, adjust the pH to approximately 8 with saturated sodium bicarbonate solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by flash reversed column chromatography (C18, CH3CN / H2O, 3 / 5) to obtain a yellow solid b1 (130 mg), yield: 73%. LCMS ESI-MS m / z: 370 [M+H] + .

[0383] Following the synthetic route of compound b1, and using similar starting materials / intermediates, the following target intermediate was synthesized.

[0384] Synthesis of intermediates b4-b5, b16-b21

[0385] Step 1: Under nitrogen protection in an ice bath, intermediate a6 (1.5 g, 6.5 mmol) was dissolved in 80 mL of anhydrous DCE, and (COCl)2 (1.1 g, 9.1 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at 80 °C for 1 hour. The solvent was removed by vacuum distillation to obtain a red oily substance. The mixture was dissolved in 40 mL of DCE, and 2-chloroaniline b1-1 (870 mg, 6.8 mmol) was added. The reaction was carried out at room temperature for 2 hours, and then the reaction was stopped. The mixture was filtered, and 100 mL of water was added to the reaction solution. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (10 mM HCOOH)) to give a white solid b4-2 (1.6 g), yield: 65%. LCMS ESI-MS m / z: 386 [M+H] + .

[0386] Step 2: Ice bath. Dissolve the intermediate b4-2 (200 mg, 0.52 mmol) from the previous step in 2 mL of tetrahydrofuran, add KHMDS (1.04 mL, 1 M) in tetrahydrofuran solution, and react at room temperature for 14 hours. Stop the reaction. Remove the solvent under reduced pressure, add 50 mL of ice water to the reaction solution, adjust the pH to approximately 6 with acetic acid, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash reversed column chromatography (column: C18; CH3CN / H2O (10 mM HCOOH), 4 / 1), to obtain a white solid b4 (120 mg), yield: 66%. LCMS ESI-MS m / z: 350 [M+H] + .

[0387] Step 1: Under nitrogen protection in an ice bath, intermediate a6 (1.5 g, 6.5 mmol) was dissolved in 15 mL of anhydrous DCE, and (COCl)2 (1.14 g, 9.1 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at 80 °C for 1 hour. The solvent was removed by vacuum distillation to obtain an oily substance. The mixture was dissolved in 10 mL of DCE, and 2-amino-3-cyclopropylpyridine b16-1 (1.3 g, 9.65 mmol) was added. The reaction was carried out at room temperature for 1 hour, and then the reaction was stopped. The mixture was filtered, and 50 mL of water was added to the reaction solution. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 10 / 1) to give a white solid b16-2 (2.0 g), yield: 79%. LCMS ESI-MS m / z: 393 [M+H] + .

[0388] Step 2: Ice bath reaction. Dissolve intermediate b16-2 (2.0 g, 5.08 mmol) from the previous step in 40 mL of DMF, add Cs₂CO₃ (3.3 g, 10.17 mmol), heat to 70 °C and react for 4 hours. Stop the reaction and cool to room temperature. Add 150 mL of ice water to the reaction solution, adjust the pH to approximately 6 with acetic acid, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate. After crystallization of the crude product (PE / EA, 10 / 1, 30 mL), a white solid b6 (1.5 g) is obtained, yield: 83%. LCMS ESI-MS m / z: 357 [M+H] + .

[0389] Step 3: Intermediate B16 (500 mg, 1.4 mmol) was dissolved in 5 mL of ethyl acetate solution of HBr (30%), and the mixture was heated to 110 °C and reacted for 12 hours. The reaction was then stopped and cooled to room temperature. 100 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 7 with ammonia. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. A white solid, B7 (280 mg), was obtained, yield: 50%. LCMS ESI-MS m / z: 401 [M+H] + .

[0390] Following the synthetic routes of compounds b4, b16, or b17, and using similar starting materials / intermediates (such as 2-methyl-3-aminopyridine), the following target intermediates were synthesized.

[0391] Synthesis of intermediates b6-b7

[0392] Under nitrogen protection, intermediate b4 (640 mg, 1.83 mmol) was dissolved in 8 mL of ethyl acetate solution (30%) containing HBr, and reacted at 110 °C for 12 hours. 100 mL of water was added to the reaction solution, and the pH was adjusted to approximately 8 with a saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (DCM / MeOH, 10 / 1) to give a white solid b6 (0.5 g), yield: 69%. LCMS ESI-MS m / z: 394 [M+H] + .

[0393] Following the synthetic route of compound b6, and using similar starting materials / intermediates (such as intermediate b5), the following target intermediate was synthesized.

[0394] Synthesis of intermediates b8 and b12

[0395] Step 1: Under nitrogen protection, 3-bromo-5-fluoropyridine b8-1 (14.0 g, 79.55 mmol) was dissolved in 200 mL of dichloromethane, and starting material b8-2 (15.4 g, 71.59 mmol) was added. The reaction was carried out at 20 °C for 16 hours. The solvent was removed by vacuum distillation, and the mixture was washed with hexane to obtain a white solid salt b8-3 (15 g), yield: 54%. LCMS ESI-MS m / z: 191.9 [M+H] + .

[0396] Step 2: Under nitrogen protection, intermediate b8-3 (15.0 g, 38.33 mmol) and ethyl propynate b8-4 (7.66 g, 78.12 mmol) from the previous step were dissolved in 200 mL of DMF, and K2CO3 (16.2 g, 117 mmol) was added. The reaction mixture was reacted at 20 °C for 16 hours. 500 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (nHex / EA, 4 / 1) to give a white solid b8-5 (800 mg, verified by two-dimensional NMR), yield: 7%. LCMS ESI-MS m / z: 286.9 / 288.9 [M+H] + .

[0397] 1 H NMR (400MHz, CDCl3) δ8.49(t,J=2.4Hz,1H),8.43(s,1H),7.64(dd,J=1.8,7.7Hz,1H),4.38(q,J=7.2Hz,2H),1.42(t,J=7.2Hz,3H).

[0398] Step 3: Under nitrogen protection, intermediate B8-5 (478 mg, 1.67 mmol) was dissolved in 60 mL of concentrated hydrochloric acid, and the mixture was heated to 50 °C and reacted for 5 hours, then cooled to room temperature. 50 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (nHex / THF, 20 / 1) to give a white solid B8 (250 mg), yield: 70%. LCMS ESI-MS m / z: 214.9 / 216.9 [M+H] + .

[0399] Following the synthetic route of compound b8, and using similar starting materials / intermediates, the following target intermediate was synthesized.

[0400] Synthesis of intermediates b9 and b13

[0401] Step 1: Under nitrogen protection, intermediate b8 (230 mg, 1.07 mmol), cyclopropylboronic acid (139 mg, 1.6 mmol), and Cs₂CO₃ (697 mg, 2.14 mmol) were dissolved in 6 mL of a mixed solution of 1,4-dioxane and water (v / v, 5 / 1). Catalyst cataCxiumAPdG₃ (78 mg, 0.11 mmol) was added, and the reaction was carried out at room temperature for 5 minutes. The temperature was then raised to 100 °C and the reaction was continued for 1 hour. The mixture was filtered. 50 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (nHex / THF, 50 / 1) to obtain intermediate b9-1 (152 mg), yield: 66%. LCMS ESI-MS m / z: 177.0 [M+H] + .

[0402] 1 H NMR (400MHz, CD3OD) δ8.40(d,J=2.5Hz,1H),7.94(d,J=2.3Hz,1H),6.85-6.77(m,2H),2.26-2.15(m,1H),1.18-1.08(m,2H),0.91-0.83(m,2H).

[0403] Step 2: Under nitrogen protection, at -78°C, intermediate b9-1 (100 mg, 0.57 g) was dissolved in 13 mL of anhydrous tetrahydrofuran. A solution of lithium magnesium chloride (2,2,6,6-tetramethylpiperidine) in tetrahydrofuran (TMPMgCl-LiCl, 2.85 mL, 1 M) was slowly added dropwise. After stirring for 3 hours, dry ice (500 mg) of CO2 was added, and the temperature was slowly raised to 0°C. The reaction was continued for 30 minutes, then stopped. The reaction was quenched with 50 mL of ice water. Impurities were extracted with ethyl acetate, and the aqueous phase was retained. The pH of the aqueous phase was adjusted to approximately 2 with dilute hydrochloric acid. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give compound b9-2 (40 mg), yield: 32%. LCMS ESI-MS m / z: 221.1 [M+H] + .

[0404] Step 3: Under nitrogen protection, intermediate b9-2 (40 mg, 0.18 mmol) and DIEA (70 mg, 0.54 mmol) from the previous step were dissolved in 2 mL of DMF. HATU (82 mg, 0.22 mmol) and NH4Cl (14 mg, 0.25 mmol) were added, and the mixture was heated to 30 °C and reacted for 2 hours. The reaction was then stopped. 10 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated by flash column chromatography (nHex / THF, 1 / 1) to obtain intermediate b9 (35 mg), yield: 89%. LCMS ESI-MS m / z: 220.1 [M+H] + .

[0405] 1 H NMR (400MHz, CD3OD) δ8.03(d,J=2.5Hz,1H),6.96(d,J=2.5Hz,1H),6.85(d,J=11.0Hz,1H),2.30-2.21(m,1H),1.22-1.14(m,2H),0.97-0.90(m,2H).

[0406] Following the synthetic route of compound b9, and using similar starting materials / intermediates, the following target intermediate was synthesized.

[0407] Synthesis of intermediates b10-b11, b14-b15

[0408] Step 1: Under nitrogen protection, intermediate b4 (320 mg, 0.91 mmol) and starting material H9-1 (363 mg, 1.01 mmol) were dissolved in 4 mL of 1,4-dioxane. Catalyst Pd(PPh3)2Cl2 (106 mg, 0.09 mmol) was added, and the reaction was carried out at room temperature for 5 minutes. The temperature was then raised to 100 °C and the reaction continued for 12 hours. The mixture was filtered, and the solvent was removed by vacuum distillation. The mixture was dissolved in 4 mL of tetrahydrofuran and placed in an ice bath. Dilute hydrochloric acid (2 M, 4 mL) was added to the mixture, and the reaction was carried out at 30 °C for 0.5 hours. The reaction was then stopped. 50 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with ammonia solution. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 4 / 1) to give intermediate b10-1 (260 mg), yield: 80%. LCMS ESI-MS m / z: 358 [M+H] + .

[0409] Step 2: Under nitrogen protection in an ice bath, dissolve intermediate b10-1 (260 mg, 0.73 mmol) from the previous step in 6 mL of dichloromethane. Slowly add DAST (2.1 g, 13.0 mmol). React the mixture at 75°C for 12 hours, then stop the reaction. Add 50 mL of ice water to the reaction mixture and adjust the pH to approximately 8 with saturated sodium bicarbonate solution. Extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. Separate the crude product by flash reversed column chromatography (C18, CH3CN / H2O (0.1% HCOOH), 4 / 1) to obtain intermediate b10 (250 mg), yield: 91%. LCMS ESI-MS m / z: 380 [M+H] + .

[0410] Following the synthetic route of compound b10, and using similar starting materials / intermediates (such as intermediates b5, b16-b21, etc.), the following target intermediate was synthesized.

[0411] Synthesis of intermediates c1, c3, c25-c26

[0412] Step 1: Under nitrogen protection, starting materials c1-1 (5.0 g, 32.05 mmol) and c1-2 (2.69 g, 32.05 mmol) were dissolved in 50 mL of methanol. KOH (3.58 g, 64 mmol) was added, and the reaction was carried out at room temperature for 18 hours. The reaction was then stopped, and the mixture was filtered. 100 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 6 with dilute hydrochloric acid. The solution was extracted with dichloromethane and concentrated to obtain a yellow oily substance c1-3 (2.2 g). Yield: 39%. LCMS ESI-MS m / z: 177 [M+H] + .

[0413] Step 2: Under nitrogen protection, intermediate C1-3 (1.0 g, 5.68 mmol) and starting material C1-4 (2.58 g, 11.36 mmol) from the previous step were dissolved in 13 mL of POCl3. The mixture was heated to 100 °C and reacted for 7 hours, after which the reaction was stopped. 100 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with ammonia. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash column chromatography (PE / EA, 1 / 1) to obtain intermediate C1 (250 mg), yield: 21%. LCMS ESI-MS m / z: 213 [M+H] + .

[0414] Step 1: Under nitrogen protection in an ice bath, dissolve the starting material C25-1 (40.0 g, 167.9 mmol) and NaH (10.1 g, 251.9 mmol, 60%) in 450 mL of anhydrous tetrahydrofuran and react at room temperature for 13 hours. Then stop the reaction. Add 500 mL of ice water to the reaction solution, extract with dichloromethane, and concentrate to obtain a yellow oily substance C25-2 (34 g).

[0415] Step 2: Under nitrogen protection, the intermediate C25-2 (34.0 g, crude) and malononitrile (17.5 g, 265.4 mmol) from the previous step were dissolved in 340 mL of methanol. Imidazole (36.1 g, 530.8 mmol) was added, and the mixture was heated to 50 °C and reacted for 4 hours. The reaction was then stopped. 500 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 6 with dilute hydrochloric acid. The mixture was extracted with dichloromethane, and the solvent was removed under reduced pressure. The mixture was then dissolved in 440 mL of a mixed solution of DMF and water (v / v, 17 / 5), and the mixture was heated to 100 °C and reacted for 6 hours. The reaction was then stopped. 500 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash column chromatography (DCM / MeOH, 6 / 1) to obtain compound C25-3 (23 g). The two-step yield was 65%. LCMS ESI-MS m / z: 213 [M+H] + .

[0416] Step 3: Under nitrogen protection, the intermediate C25-3 (1.0 g, 4.71 mmol) and the starting material C1-4 (2.0 g, 8.96 mmol) from the previous step were dissolved in 3 mL of POCl3. The mixture was heated to 100 °C and reacted for 13 hours, after which the reaction was stopped. 20 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with ammonia. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 1 / 1) to obtain intermediate C25-4 (150 mg), yield: 13%. LCMS ESI-MS m / z: 249 [M+H] + .

[0417] Step 4: Under nitrogen protection, intermediate C25-4 (5.8 g, 23.29 mmol) from the previous step was dissolved in 30 mL of a mixed solution of concentrated sulfuric acid and water (v / v, 5 / 1). The mixture was heated to 90 °C and reacted for 2 hours, after which the reaction was stopped. The reaction solution was slowly poured into 40 mL of ice water, precipitating a solid. The solid was filtered, and the filter cake was dried to obtain intermediate C25 (4.0 g), yield: 64%. LCMS ESI-MS m / z: 267 [M+H] + .

[0418] Step 5: Under nitrogen protection, intermediate C25 (110 mg, 0.41 mmol) and (COCl)2 (24.2 mL, 0.56 mmol) were dissolved in 2 mL of dichloroethane (DCE). The mixture was heated to 80 °C and reacted for 1 hour. The solvent was removed by vacuum distillation. The mixture was dissolved in 2 mL of anhydrous DCE and placed in an ice bath. 2-Chloroaniline B1-1 (58 mg, 0.45 mmol) was added to the mixture, and the mixture was reacted at 20 °C for 0.25 hours. The reaction was then stopped. 50 mL of ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 5 / 3) to give compound C26-1 (61 mg), yield: 35%. LCMS ESI-MS m / z: 420 [M+H] + .

[0419] Step 6: Under nitrogen protection, dissolve compound C26-1 (60 mg, 0.14 mmol) from the previous step in 2 mL of DMF, add Cs₂CO₃ (139.4 mg, 0.43 mmol), and react the mixture at 65 °C for 3 hours. Stop the reaction. Add 10 mL of ice water to the reaction mixture, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (PE / EA, 8 / 1) to obtain compound C26 (50 mg), yield: 91%. LCMS ESI-MS m / z: 384 [M+H] + .

[0420] Following the synthetic route of compound c1 or c25, and using similar starting materials / intermediates, the following target intermediate was synthesized.

[0421] Synthesis of intermediates c2, c4-c9, c13-c22, c38

[0422] Step 1: Under nitrogen protection, intermediate d1 (1.0 g, 4.35 mmol) and DIEA (700 mg, 5.4 mmol) were dissolved in 13 mL of dichloromethane. Trichloroethyl chloroformate C13-1 (1.13 g, 5.4 mmol) was added, and the mixture was reacted at room temperature for 30 minutes. The temperature was then raised to 80 °C and the reaction was continued for 1 hour. The solvent was removed by vacuum distillation. The mixture was dissolved in 10 mL of anhydrous tetrahydrofuran and placed in an ice bath. 2-Chloroaniline B1-1 (381 mg, 3.0 mmol) and NaH (120 mg, 3 mmol, 60%) were added to the mixture. The mixture was reacted at 0 °C for 4 hours, and the reaction was stopped. 50 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed-column chromatography (C18, CH3CN / H2O, 5 / 3) to give compound c13-2 (201 mg), yield: 12%. LCMS ESI-MS m / z: 384 [M+H] + .

[0423] Step 2: Under nitrogen protection in an ice bath, compound C13-2 (3.7 g, 9.66 mmol) from the previous step was dissolved in 12 mL of tetrahydrofuran. LiHMDS (9.7 mL, 1 M) was added dropwise. The mixture was reacted at room temperature for 3 hours, then the reaction was stopped. 50 mL of ice water was added to the reaction mixture, and the solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 4 / 1) to give compound C13 (2.2 g), yield: 18%. LCMS ESI-MS m / z: 348 [M+H] + .

[0424] Step 3: Under nitrogen protection, intermediate C13 (350 mg, 1.01 mmol), cyclopropylboronic acid (259 mg, 3.01 mmol), and K3PO4 (640 mg, 3.01 mmol) were dissolved in a 7 mL LMF and water mixture (v / v, 5 / 1). Catalyst Pd(dppf)Cl2 (74 mg, 0.1 mmol) was added, and the reaction was carried out at room temperature for 30 minutes. The temperature was then raised to 100 °C and the reaction was continued for 1 hour. The mixture was filtered. 50 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O (0.1% TFA), 4 / 1) to obtain intermediate C2 (172 mg), yield: 48%. LCMS ESI-MS m / z: 354 [M+H] + .

[0425] Under nitrogen protection, intermediate b4 (370 mg, 1.06 mmol), cyclopropylboronic acid (273 mg, 3.17 mmol), and K2CO3 (438 mg, 3.17 mmol) were dissolved in 7 mL of a mixed solution of 1,4-dioxane and water (v / v, 6 / 1). Catalyst Pd(dppf)Cl2 (77 mg, 0.11 mmol) was added, and the reaction was carried out at room temperature for 5 minutes. The temperature was then raised to 100 °C and the reaction was continued for 12 hours. The mixture was filtered. 50 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O (0.1% TFA), 4 / 1) to give intermediate c9 (230 mg), yield: 61%. LCMS ESI-MS m / z: 356 [M+H] + .

[0426] Following the synthetic routes of compounds c2, c9, or c13, and using similar starting materials / intermediates (such as intermediates b4-b10), the following target intermediates were synthesized.

[0427] Synthesis of intermediates c10-c11, c23-c24, c41

[0428] Intermediate compound C13 (1.1 g, 3.17 mmol) was dissolved in 30 mL of a mixed solution of hydrobromic acid and acetic acid (30%), and the mixture was heated to 110 °C and reacted for 6 hours. The reaction was then stopped. The mixture was slowly poured into 100 mL of ice water, and the pH was adjusted to approximately 8 with a saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 1) to give a yellow solid C10 (700 mg), yield: 56%. LCMS ESI-MS m / z: 392 [M+H] + .

[0429] Following the synthetic route of compound C10, and using similar starting materials / intermediates (such as intermediates C8, C17-C21, etc.), the following target intermediates were synthesized.

[0430] Synthesis of intermediates C12, C27-C36, C39-C40

[0431] Step 1: Under nitrogen protection in an ice bath, intermediate a9 (490 mg, 1.91 mmol) was dissolved in 10 mL of anhydrous DCE, and (COCl)2 (484 mg, 3.81 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at 80 °C for 1 hour. The solvent was removed by vacuum distillation to obtain a red oily substance. The mixture was dissolved in 10 mL of DCE, and 2-chloroaniline b1-1 (484 mg, 3.81 mmol) was added. The mixture was reacted at room temperature for 2 hours, and then the reaction was stopped. The mixture was filtered, and 30 mL of ice water was added to the reaction solution. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (10 mM HCOOH)) to obtain a yellow solid c12-1 (400 mg), yield: 51%. LCMS ESI-MS m / z: 411 [M+H] + .

[0432] Step 2: Ice bath reaction. Dissolve intermediate C12-1 (400 mg, 0.97 mmol) from the previous step in 4 mL of tetrahydrofuran, add KHMDS (2.2 mL, 1 M), and heat to 40 °C for 4 hours. Stop the reaction. Remove the solvent under reduced pressure, add 50 mL of ice water to the reaction solution, adjust the pH to approximately 6 with acetic acid, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash reversed column chromatography (column: C18; CH3CN / H2O (0.075% TFA), 1 / 1) to obtain intermediate C12 (250 mg), yield: 66%. LCMS ESI-MS m / z: 391 [M+H] + .

[0433] Following the synthetic route of compound C12, and using similar starting materials / intermediates (such as intermediates A10, A14, C37, etc.), the following target intermediate was synthesized.

[0434] Synthesis of intermediate C37

[0435] Step 1: Under nitrogen protection, intermediate a9 (500 mg, 1.94 mmol) and cesium carbonate (1.9 g, 5.82 mmol) were dissolved in 11 mL of a mixture of DMF and water (v / v, 10 / 1). Catalyst tBuBrettphosPdG3 (174 mg, 0.19 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at 100 °C for 3 hours. 30 mL of ice water was added to the reaction mixture, and impurities were extracted with ethyl acetate. The aqueous phase was retained. The pH of the aqueous phase was adjusted to approximately 2 with dilute hydrochloric acid, and the mixture was extracted again with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (nHex / EA, 1 / 30) to give a yellow solid c37-1 (380 mg), yield: 85%. LCMS ESI-MS m / z: 196 [M+H] + .

[0436] Step 2: In an ice bath, intermediate C37-1 (320 mg, 1.64 mmol) and sodium 2-chloro-2,2-difluoroacetate (630 mg, 4.1 mmol) from the previous step were dissolved in 6 mL of a mixture of DMF and water (v / v, 6 / 1). K₂CO₃ (450 mg, 3.28 mmol) was added, and the mixture was heated to 100 °C and reacted for 2 hours. The reaction was then stopped. 50 mL of ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (nHex / EA, 1 / 6) to obtain intermediate C37 (380 mg), yield: 88%. LCMS ESI-MS m / z: 246 [M+H] + .

[0437] 1 H NMR (400MHz, DMSO-d6) δ8.13(d,J=2.3Hz,1H),8.06(s,1H),7.88(s,1H),7.46(t,J=73.1Hz,1H),7.15(d,J=11.3Hz,1H),7.05(d,J=2.3Hz,1H).

[0438] Synthesis of intermediates d1-d2

[0439] Intermediate C1 (3.0 g, 14.2 mmol) was dissolved in 24 mL of a mixed solution of sulfuric acid and water (v / v, 5 / 1). The mixture was heated to 90 °C and reacted for 6 hours, after which the reaction was stopped. The mixture was slowly poured into 100 mL of ice water, and the pH was adjusted to approximately 8 with a saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 1) to give a yellow solid d1 (3.1 g), yield: 95%. LCMS ESI-MS m / z: 231 [M+H] + .

[0440] Following the synthetic route of compound d1, and using similar starting materials / intermediates, the following target intermediate was synthesized.

[0441] Synthesis of intermediates d3-d4

[0442] Step 1: Under nitrogen protection, intermediate a9 (1.8 g, 6.98 mmol), NaI (1.05 g, 6.98 mmol), and 3-bromo-1,1-difluorocyclobutane d3-1 (2.39 g, 13.96 mmol) were dissolved in 20 mL of N,N-dimethylacetamide (DMA). The catalyst, nickel(II) bromide ethylene glycol dimethyl ether complex (0.49 g, 1.40 mmol), the ligand pyridine-2,6-dimethylamidine (230 mg, 1.4 mmol), and zinc powder (2.28 g, 34.9 mmol) were added. The mixture was heated to 65 °C and reacted for 6 hours, then filtered. The solvent was removed under reduced pressure. The crude product was separated by flash column chromatography (nHex / EA, 1 / 20) to give compound d3-2 (1.5 g), yield: 73%. LCMS ESI-MS m / z: 270 [M+H] + .

[0443] Step 2: Compound d3-2 (1.5 g, 6.43 mmol) and oxaloyl chloride (1.14 g, 9.0 mmol) from the previous step were dissolved in 23 mL of dichloroethane. The mixture was heated to 80 °C and reacted for 1 hour, then cooled to room temperature. 2-Methyl-3-aminopyridine b2-1 (1.44 g, 13.36 mmol) was added to the reaction mixture, and the mixture was reacted at room temperature for 1 hour. The solvent was removed by vacuum distillation, and 50 mL of ice water was added to the reaction mixture. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give compound d3-3 (1.3 g), yield: 91%. LCMS ESI-MS m / z: 404 [M+H] + .

[0444] Step 3: Under nitrogen protection, compound d3-3 (0.5 g, 1.24 mmol) from the previous step was dissolved in 8 mL of toluene. NaH (0.5 g, 12.4 mmol, 60%) was added, and the mixture was heated to 120 °C and reacted for 16 hours. The mixture was then cooled to room temperature. 50 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give compound d3 (150 mg), yield: 31%. LCMS ESI-MS m / z: 384 [M+H] + .

[0445] Following the synthetic route of compound d3, and using similar starting materials / intermediates, the following target intermediate was synthesized.

[0446] Synthesis of intermediates d5-d6

[0447] Under nitrogen protection, intermediate C28 (50 mg, 0.13 mmol), K2CO3 (56 mg, 0.4 mmol), and cyclopropylboronic acid (20 mg, 0.19 mmol) were dissolved in 6 mL of a mixed solution of 1,4-dioxane and water (v / v, 5 / 1). Catalyst Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, and the mixture was heated to 95 °C and reacted for 2 hours. The mixture was then filtered. The solvent was removed under reduced pressure, and the crude product was separated by flash column chromatography (nHex / EA, 3 / 2) to give compound d5 (40 mg), yield: 93%. LCMS ESI-MS m / z: 334 [M+H] + .

[0448] Following the synthetic route of compound d5, and using similar starting materials / intermediates (such as intermediate c35), the following target intermediate was synthesized.

[0449] Synthesis of intermediate d7

[0450] Step 1: Under nitrogen protection, intermediate C28 (150 mg, 0.4 mmol), Cs₂CO₃ (391 mg, 1.2 mmol), and starting material d7-1 (80 mg, 0.6 mmol) were dissolved in 6 mL of 1,4-dioxane. Catalyst Pd(dppf)Cl₂ (30 mg, 0.04 mmol) and ligand Xantphos (23 mg, 0.04 mmol) were added. The mixture was heated to 95 °C and reacted for 12 hours, followed by filtration. The solvent was removed under reduced pressure. The crude product was separated by flash column chromatography (nHex / EA, 3 / 2) to obtain compound d7 (80 mg), yield: 52%. LCMS ESI-MS m / z: 385 [M+H] + .

[0451] Synthesis of intermediate d8

[0452] Step 1: Under nitrogen protection, intermediate a9 (500 mg, 1.94 mmol), NaI (580 mg, 3.88 mmol), and (1R,2R)-(-)-N,N-dimethylcyclohexane-1,2-diamine (140 mg, 0.97 mmol) were dissolved in 10 mL of 1,4-dioxane. Catalyst CuI (150 mg, 0.78 mmol) was added, and the mixture was heated to 105 °C and reacted for 16 hours. The mixture was then filtered. The solvent was removed under reduced pressure, and the crude product was separated by flash column chromatography (nHex / EA, 3 / 1) to give compound d8-1 (450 mg), yield: 76%. LCMS ESI-MS m / z: 306 [M+H] + .

[0453] Step 2: In a nitrogen-protected glove box, intermediate d8-1 (390 mg, 1.28 mmol) was dissolved in 10 mL of DMF, and the catalyst trifluoromethyl(1,10-phenanthroline)copper(phen)CuCF3 (800 mg, 2.56 mmol) was added. The mixture was heated to 85 °C and reacted for 16 hours, followed by filtration. The solvent was removed under reduced pressure, and the crude product was separated by flash column chromatography (nHex / EA, 3 / 2) to obtain compound d8 (120 mg), yield: 28%. LCMS ESI-MS m / z: 248 [M+H] + .

[0454] Synthesis of intermediate d9

[0455] In a nitrogen-protected glove box, intermediate d8-1 (400 mg, 1.55 mmol) and 1,1,1-trifluoro-2-iodoethane (980 mg, 4.65 mmol) were dissolved in 10 mL of N,N-dimethylacetamide (DMA). Catalyst NiI2 (48 mg, 0.16 mmol), manganese powder Mn (260 mg, 4.65 mmol), ligand 1,1'-bis(diphenylphosphine)ferrocene dppf (86 mg, 0.16 mmol), and ligand 4,4'-di-tert-butyl-2,2'-bipyridine dtbpy (45 mg, 0.16 mmol) were added. The mixture was heated to 85 °C and reacted for 16 hours, then filtered. The mixture was extracted with ethyl acetate by adding 50 mL of ice water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated by flash column chromatography (nHex / EA, 1 / 4) to give compound d9 (280 mg), yield: 62%. LCMS ESI-MS m / z: 262 [M+H] + .

[0456] 1 H NMR (400MHz, CD3OD) δ7.92(d,J=2.1Hz,1H),7.17(d,J=11.1Hz,1H),7.05(d,J=2.1Hz,1H),3.83(q,J=10.8Hz,2H).

[0457] Synthesis of intermediate e1

[0458] Step 1: Under nitrogen protection and in an ice bath, dissolve starting material e1-1 (1.9 g, 9.92 mmol) in 40 mL of dichloromethane, add liquid bromine (12.6 g, 79.36 mmol), and heat the mixture to 25 °C for 1 hour. Add 50 mL of ice water and 200 mL of saturated sodium sulfite aqueous solution to the mixture, extract with dichloromethane, dry to anhydrous sodium sulfate, remove solvent under reduced pressure, and separate the crude product by flash reversed column chromatography (column: C18, CH3CN / H2O (0.1% TFA), 1 / 1) to obtain compound e1-2 (1.9 g), yield: 70%. LCMS ESI-MS m / z: 275 [M+H] + .

[0459] Step 2: Under nitrogen protection, intermediate e1-2 (1.9 g, 6.89 mmol) and NaHCO3 (500 mg, 6.89 mmol) from the previous step were dissolved in 40 mL of ethanol. Chloroacetaldehyde e1-3 (5.4 g, 68.98 mmol) was added, and the mixture was heated to 105 °C and reacted for 2 hours. 150 mL of ice water was added to the mixture, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and solvent removal under reduced pressure. The crude product was separated by flash reversed column chromatography (column: C18, CH3CN / H2O (0.1% TFA), 4 / 1) to give compound e1 (1.3 g), yield: 63%. LCMS ESI-MS m / z: 299 [M+H] + .

[0460] Synthesis of intermediate e2

[0461] Step 1: Under nitrogen protection, at -78°C, dissolve the starting material e1 (1.3 g, 4.34 mmol) in 3 mL of anhydrous tetrahydrofuran, and add nBuLi (3.8 mL, 2.5 M in THF) dropwise. After the addition is complete, stir at this temperature for 30 minutes. Add dry ice CO2 (500 mg) to the mixture and continue the reaction for 15 minutes, then stop the reaction. Quench the reaction with 10 mL of acetic acid, and remove the solvent under reduced pressure. Separate the crude product by flash reversed column chromatography (column: C18, CH3CN / H2O (0.1% TFA), 1 / 4) to give compound e2-1 (0.2 g), yield: 17%. LCMS ESI-MS m / z: 265 [M+H] + .

[0462] Step 2: In an ice bath, intermediate e2-1 (200 mg, 0.75 mmol) and (COCl)2 (143.9 mg, 1.13 mmol) were dissolved in 4 mL of anhydrous dichloromethane. DMF (0.1 mL) was added, and the reaction was carried out at 0 °C for 0.5 hours. The solvent was then removed by vacuum evaporation. The reaction solution was dissolved in 2 mL of acetonitrile, and ammonia (4 mL) was added. The reaction was continued in an ice bath for another 0.5 hours, and then the reaction was stopped. 20 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O (10 mmol / L NH4HCO3), 20 / 1) to give a white solid e2 (50 mg), yield: 25%. LCMS ESI-MS m / z: 264 [M+H] + .

[0463] Example 2: Synthesis of target molecules P1-P3

[0464] Step 1: Under nitrogen protection, intermediate b1 (100 mg, 0.27 mmol) and ammonia in isopropanol solution (2 M, 2 mL) were dissolved in 3 mL of 1,4-dioxane. The mixture was reacted at 40 °C for 4 hours. The solvent was removed by vacuum distillation, and the crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 4 / 5) to give compound P1-1 (71 mg), yield: 75%. LCMS ESI-MS m / z: 351 [M+H] + .

[0465] Step 2: Under nitrogen protection, compound P1-1 (71 mg, 0.20 mmol) from the previous step was dissolved in 2 mL of 1,4-dioxane, and the catalyst copper trifluoromethylthio(2,2-bipyridine) (87 mg, 0.21 mmol) was added. The mixture was heated to 105 °C and reacted for 3 hours, followed by filtration. The solvent was removed under reduced pressure, and the crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 3 / 1) to obtain the target compound P1 (13.4 mg), yield: 18%. LCMS ESI-MS m / z: 373 [M+H] + .

[0466] 1 H NMR (400MHz, DMSO-d6) δ8.56 (d, J = 8.0, 1H), 8.44-8.38 (m, 2H), 7.61 -7.59 (m, 1H), 7.47-7.38 (m, 4H)

[0467] Following the synthetic route of compound P1, and using similar starting materials or intermediates (such as intermediates b2-b3), the following target molecules were synthesized.

[0468] * indicates a chiral center that has not been split.

[0469] Example 3: Synthesis of target molecules H1-H3, H5-H8, H34-H37, H51-H53, H72-H73

[0470] Step 1: In an ice bath, intermediate C13 (1.0 g, 2.88 mmol) and DIEA (558 mg, 4.32 mmol) were dissolved in 13 mL of 1,4-dioxane. POCl3 (6 mL) was added, and the mixture was heated to 110 °C and reacted for 4 hours. The reaction was then stopped. 100 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 2) to give a yellow solid H1-1 (330 mg). Yield: 31%. LCMS ESI-MS m / z: 366 [M+H] + .

[0471] Step 2: The compound H1-1 (100 mg, 0.27 mmol) from the previous step and a methanol solution of ammonia (2 M, 2 mL) were dissolved in 3 mL of 1,4-dioxane. The mixture was reacted at room temperature for 1 hour. The solvent was removed by vacuum distillation, and the crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 1) to obtain the target compound H1 (40 mg), yield: 43%. LCMS ESI-MS m / z: 347 [M+H] + .

[0472] 1 H NMR(300MHz,DMSO-d6)δ8.47(s,1H),7.68–7.59(m,1H),7.51–7.44(m,2H),7.42–7.34(m,1 H), 6.99 (s, 1H), 3.49 (t, J = 7.6Hz, 2H), 2.89 (dd, J = 8.7, 6.8Hz, 2H), 2.19 (q, J = 7.5Hz, 2H).

[0473] Following the synthetic route of compound H1, and using similar starting materials or intermediates (such as intermediates b2-b4, c1-c22, c27, c39-c40, d1-d7, etc.), the following target molecules were synthesized.

[0474] * indicates a chiral center that has not been split.

[0475] Example 4: Synthesis of target molecule H4

[0476] Under nitrogen protection, compound H1 (100 mg, 0.29 mmol), dimethylamine hydrochloride (47 mg, 0.58 mmol), and Cs₂CO₃ (150 mg, 0.46 mmol) were dissolved in 2 mL of 1,4-dioxane. Catalyst Pd₂dba₂ (26.3 mg, 0.03 mmol) and ligand Xphos (41.2 mg, 0.09 mmol) were added. The reaction was carried out at room temperature for 5 minutes, then heated to 90 °C and continued for 4 hours. The mixture was filtered. 50 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed-column chromatography (C18, CH₃CN / H₂O (0.1% TFA), 4 / 1) to give the target molecule H4 (17.8 mg), yield: 17%. LCMS ESI-MS m / z: 356 [M+H] + .

[0477] 1 H NMR(300MHz,DMSO-d6)δ7.60–7.55(m,1H),7.44–7.38(m,2H),7.33–7.28(m,1H), 3.20(t,J=7.6Hz,2H), 3.01(t,J=7.4Hz,2H), 2.81(s,6H), 2.04(q,J=7.8Hz,2H).

[0478] Example 5: Synthesis of target molecules H9-H10, H18-H24, H32-H33, H40-H49, H54, H81

[0479] Step 1: Under nitrogen protection, compound C13 (850 mg, 2.45 mmol) and starting material H9-1 (1.77 g, 4.90 mmol) were dissolved in 15 mL of 1,4-dioxane. Catalyst Pd(PPh3)4 (290 mg, 0.25 mmol) was added, and the reaction was carried out at room temperature for 5 minutes. The temperature was then raised to 100 °C and the reaction continued for 1 hour. The mixture was filtered, and the solvent was removed by vacuum distillation. The mixture was dissolved in 10 mL of tetrahydrofuran, placed in an ice bath, and dilute hydrochloric acid (2 M, 2 mL) was added. The mixture was reacted at 30 °C for 5 hours, and the reaction was stopped. 50 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 1) to obtain compound H9-2 (480 mg), yield: 55%. LCMS ESI-MS m / z: 356 [M+H] + .

[0480] Step 2: Under nitrogen protection in an ice bath, compound H9-2 (480 mg, 1.35 mmol) from the previous step was dissolved in 6 mL of dichloromethane. DAST (328 mg, 2.0 mmol) was slowly added. The mixture was reacted at 50 °C for 13 hours, after which the reaction was stopped. 50 mL of ice water was added to the reaction mixture, and the solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 1) to give compound H9-3 (220 mg), yield: 43%. LCMS ESI-MS m / z: 378 [M+H] + .

[0481] Step 3: Ice bath reaction. Dissolve compound H9-3 (220 mg, 0.58 mmol) and DIEA (226 mg, 1.75 mmol) from the previous step in 10 mL of acetonitrile, add POCl3 (444 mg, 2.9 mmol), heat to 80 °C and react for 2 hours, then stop the reaction. Add 100 mL of ice water to the reaction solution, adjust the pH to approximately 8 with saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate, and obtain a yellow solid H9-4 (crude). LCMS ESI-MS m / z: 396 [M+H] + .

[0482] Step 4: The crude compound H9-4 from the previous step and 2 mL of ammonia solution were dissolved in 3 mL of 1,4-dioxane. The mixture was reacted at 35 °C for 1 hour. The solvent was removed by vacuum distillation, and the crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 1) to obtain the target compound H9 (49.1 mg). Overall yield of the two steps: 22%. LCMS ESI-MS m / z: 377 [M+H] + .

[0483] 1 H NMR(300MHz,DMSO-d6)δ8.51(s,1H),7.70–7.57(m,1H),7.53–7.32(m,3H),7.06(s,1H),3. 41(t,J=7.6Hz,2H),3.02(dq,J=8.5,4.1Hz,2H),2.26–2.02(m,2H),1.55(t,J=19.2Hz,3H).

[0484] Step 1: Under nitrogen protection, intermediate C12 (260 mg, 0.66 mmol) and starting material H9-1 (264 mg, 0.73 mmol) were dissolved in 3 mL of 1,4-dioxane. Catalyst Pd(PPh3)4 (77 mg, 0.07 mmol) was added, and the reaction was carried out at room temperature for 5 minutes. The temperature was then raised to 100 °C and the reaction continued for 1 hour. The mixture was filtered, and the solvent was removed by vacuum distillation. The mixture was dissolved in 10 mL of tetrahydrofuran and placed in an ice bath. Dilute hydrochloric acid (3 M, 1 mL) was added to the mixture, and the mixture was reacted at 30 °C for 2 hours. The reaction was then stopped. 30 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (DCM / MeOH, 10 / 1) to obtain compound H40-1 (200 mg), yield: 85%. LCMS ESI-MS m / z: 355 [M+H] + .

[0485] Step 2: Under nitrogen protection in an ice bath, compound H40-1 (200 mg, 0.56 mmol) from the previous step was dissolved in 5 mL of dichloromethane. DAST (909 mg, 5.64 mmol) was slowly added. The mixture was reacted at 50 °C for 16 hours, after which the reaction was stopped. 20 mL of ice water was added to the reaction mixture, and the solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 1) to give compound H40-2 (90 mg), yield: 42%. LCMS ESI-MS m / z: 377 [M+H] + .

[0486] Step 3: Ice bath reaction. Dissolve compound H40-2 (90 mg, 0.24 mmol) and DIEA (113 mg, 0.87 mmol) from the previous step in 4 mL of acetonitrile. Add POCl3 (183 mg, 1.19 mmol). Heat to 80 °C and react for 2 hours. Stop the reaction and remove the solvent under reduced pressure. Add 20 mL of ice water to the reaction solution. Adjust the pH to approximately 7 with a saturated sodium bicarbonate aqueous solution. Extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate to obtain a yellow solid H40-3 (80 mg). LCMS ESI-MS m / z: 395 [M+H] + .

[0487] Step 4: The compound H40-3 (80 mg, 0.2 mmol) from the previous step and the isopropanol solution (2 mL, 17 M) were dissolved in 3 mL of acetonitrile. The mixture was reacted at 30 °C for 1 hour. The solvent was removed by vacuum distillation, and the crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 1) to obtain the target compound H40 (47.1 mg), yield: 62%. LCMS ESI-MS m / z: 376 [M+H] + .

[0488] 1 H NMR (400MHz, DMSO-d6) δ8.60(s,1H),8.26(s,1H),7.87–7.70(m,1H),7.69–7.45(m,4H),7.18(s,1H),6.30(s,1H),1.93(t,J=20.0Hz,3H).

[0489] Following the synthetic routes of compounds H9 or H40, and using similar starting materials or intermediates (such as intermediates c1-c22, c26-c35, d1-d7, etc.), the following target molecules were synthesized.

[0490] * indicates a chiral center that has not been split.

[0491] Example 6: Synthesis of target molecule H11

[0492] Step 1: In an ice bath, intermediate C9 (55 mg, 0.155 mmol) and DIEA (60 mg, 0.47 mmol) were dissolved in 3 mL of dichloromethane. Trifluoroacetic anhydride Tf₂O (67 mg, 0.32 mmol) was added, and the mixture was reacted at 0 °C for 1 hour. The mixture was filtered, and the solvent was removed by vacuum distillation. 5 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give compound H₁₁-1 (crude). LCMS ESI-MS m / z: 488 [M+H] + .

[0493] Step 2: The crude compound H11-1 from the previous step and a methanol solution of ammonia (2M, 0.5mL) were dissolved in 1mL of 1,4-dioxane. The mixture was reacted at 50°C for 1 hour. The solvent was removed under reduced pressure, and the crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 1 / 1) to obtain the target compound H11 (5.7mg). Overall yield of the two steps: 10%. LCMS ESI-MS m / z: 355 [M+H] + .

[0494] 1 H NMR(300MHz,DMSO-d6)δ11.56(s,1H),8.46(s,1H),7.68–7.55(m,1H),7.53–7.38(m,3H),6.78(s,1H),6.62(dd,J=17.8,11.3Hz,1H), 5.68(dd,J=11.3,1.9Hz,1H),5.50(dd,J=17.8,1.9Hz,1H),2.06(dq,J=8.0,3.9Hz,1H),0.60(d,J=8.4Hz,2H),0.35(d,J=4.6Hz,2H).

[0495] Example 7: Synthesis of target molecules H12-H13, H17, H25-H27, H55-H67, H74-H80

[0496] Step 1: Under nitrogen protection, intermediate C10 (400 mg, 1.02 mmol) and CuI (97 mg, 0.51 mmol) were dissolved in 3 mL of DMF. Compound H12-1 (230 mg, 1.2 mmol) was added, and the mixture was reacted at 100 °C for 12 hours. The mixture was then filtered. 15 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 2 / 1) to give compound H12-2 (150 mg), yield: 39%. LCMS ESI-MS m / z: 382 [M+H] + .

[0497] Step 2: Dissolve compound H12-2 (150 mg, 0.39 mmol) and DIEA (155 mg, 1.2 mmol) from the previous step in 3 mL of acetonitrile, add POCl3 (306 mg, 2.0 mmol), react at 80 °C for 1 hour, filter, and remove the solvent by vacuum distillation. Add 25 mL of ice water to the reaction solution, adjust the pH to approximately 8 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Dissolve the compound in 2 mL of methanol, add ammonia in methanol solution (2 M, 1.5 mL), react at 50 °C for 1 hour, stop the reaction, and remove the solvent by vacuum distillation. Separate the crude product by flash reversed column chromatography (C18, CH3CN / H2O, 2 / 3) to obtain compound H12 (15.2 mg). LCMS ESI-MS m / z: 381 [M+H] + .

[0498] 1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),7.60–7.54(m,1H),7.45–7.39(m,2H),7.38– 7.33(m,1H),7.11(s,1H),3.43(t,J=7.6Hz,2H),2.99(m,2H),2.22–2.08(m,2H).

[0499] Step 1: Under nitrogen protection, intermediate C12 (250 mg, 0.64 mmol) and CuI (122 mg, 0.64 mmol) were dissolved in 5 mL of DMF. Compound H12-1 (368 mg, 1.92 mmol) was added, and the mixture was reacted at 130 °C for 16 hours. The mixture was then filtered. 15 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (DCM / MeOH, 10 / 1) to give compound H17-1 (28 mg), yield: 12%. LCMS ESI-MS m / z: 381 [M+H] + .

[0500] Step 2: Dissolve compound H17-1 (28 mg, 0.07 mmol) from the previous step in 2 mL of acetonitrile, add POCl3 (34 mg, 0.22 mmol), and react at 80 °C for 2 hours. Remove the solvent by vacuum distillation. Add 25 mL of ice water to the reaction solution, adjust the pH to approximately 8 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Dissolve the compound in 1 mL of acetonitrile, add ammonia in isopropanol solution (17 M, 2.0 mL), and react at 30 °C for 1 hour. Stop the reaction and remove the solvent by vacuum distillation. Separate the crude product by flash reversed column chromatography (C18, CH3CN / H2O, 2 / 3) to obtain compound H17 (5.2 mg). LCMS ESI-MS m / z: 380 [M+H] + .

[0501] 1 H NMR (400MHz, DMSO-d6) δ8.82(s,1H),8.36(s,1H),7.79(s,2H),7.67–7.53(m,3H),7.22(s,1H),6.43(s,1H).

[0502] Step 1: Intermediate d8 (100 mg, 0.4 mmol) was dissolved in 2 mL of DCE, and oxalyl chloride (61 mg, 0.48 mmol) was added. The mixture was reacted at 80 °C for 1 hour, and the solvent was removed by vacuum distillation. The mixture was then dissolved in 2 mL of DCE, and 2,3-dihydro-4-aminobenzofuran H55-1 (110 mg, 0.8 mmol) was added. The mixture was reacted at room temperature for 1 hour, and the reaction was stopped. 15 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give compound H55-2 (100 mg), yield: 61%. LCMS ESI-MS m / z: 409 [M+H] + .

[0503] Step 2: In an ice bath, dissolve compound H55-2 (90 mg, 0.22 mmol) and NaH (44 mg, 1.1 mmol, 60%) in 3 mL of toluene. Add oxaloyl chloride (61 mg, 0.48 mmol). React at 120 °C for 1 hour, then stop the reaction. Add 15 mL of ice water to the reaction solution, adjust the pH to approximately 7 with dilute hydrochloric acid, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain compound H55-3 (70 mg), yield: 82%. LCMS ESI-MS m / z: 389 [M+H] + .

[0504] Step 3: Dissolve compound H55-3 (60 mg, 0.15 mmol) and DIEA (97 mg, 0.75 mmol) from the previous step in 2 mL of 1,4-dioxane, add POCl3 (69 mg, 0.45 mmol), react at 100 °C for 1 hour, filter, and remove the solvent by vacuum distillation. Add 25 mL of ice water to the reaction solution, adjust the pH to approximately 8 with ammonia solution, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Dissolve the compound in 2 mL of methanol, add ammonia in methanol solution (2 M, 1.5 mL), react at 20 °C for 3 hours, stop the reaction, and remove the solvent by vacuum distillation. The crude product is separated by preparative HPLC (column: Phenomenex Synergi C18 150*30 mm*4 μm, mobile phase: water (0.225% formic acid), mobile phase B: acetonitrile, flow rate: 25.00 mL / min) to obtain compound H55 (11.88 mg). LCMS ESI-MS m / z: 388 [M+H] + .

[0505] 1H NMR (400MHz, DMSO-d6) δ8.65(s,1H),8.33(d,J=2.3Hz,1H),7.69(s,1H),7.32(t,J=8.0Hz,1H),7.20(s ,1H),6.94(d,J=8.0Hz,1H),6.81(d,J=7.9Hz,1H),6.67(s,1H),4.48-4.64(m,2H),3.01-2.78(m,2H).

[0506] Following the synthetic routes of compounds H12, H17, or H55, and using similar starting materials or intermediates (such as intermediates c11-c24, c39, c41, d1-d9, etc.), the following target molecules were synthesized.

[0507] Example 8: Synthesis of target molecules H14-H15

[0508] Step 1: Under nitrogen protection, intermediate a8 (50 mg, 0.23 mmol) was dissolved in 2 mL of DCE, and oxalyl chloride (58 mg, 0.46 mmol) was added. The reaction was carried out at 80 °C for 1 hour, then cooled to 20 °C. Compound 2-chloroaniline b1-1 (116 mg, 0.92 mmol) was added to the reaction solution, and the reaction was carried out at room temperature for 1 hour, then the reaction was stopped. 35 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 2 / 1) to give compound H14-1 (40 mg), yield: 48%. LCMS ESI-MS m / z: 367 [M+H] + .

[0509] Step 2: At -20℃, compound H14-1 (40 mg, 0.11 mmol) from the previous step was dissolved in 3 mL of anhydrous tetrahydrofuran. KHMDS (0.1 mL, 0.22 mmol, 2.5 M) was added, and the mixture was slowly heated to 40℃ and reacted for 2 hours. The reaction was then stopped. 25 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 2 / 3) to give compound H14-2 (30.2 mg), yield: 79%. LCMS ESI-MS m / z: 347 [M+H] + .

[0510] Step 3: Ice bath reaction. Compound H14-2 (30 mg, 0.09 mmol) from the previous step was dissolved in 5 mL of phosphorus oxychloride. DIEA (24 mg, 0.18 mmol) was added, and the mixture was slowly heated to 80 °C and reacted for 2 hours. The reaction was then stopped, and the solvent was removed by vacuum distillation to obtain crude H14-3. The mixture was dissolved in 5 mL of 1,4-dioxane, and a solution of ammonia in isopropanol (5 mL, 2.5 M) was slowly added dropwise at 0 °C. The reaction was continued at room temperature for 2 hours, and then stopped. The reaction solution was quenched with 30 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 2 / 1) to obtain compound H14 (19.5 mg), yield: 62%. LCMS ESI-MS m / z: 347 [M+H] + .

[0511] 1 H NMR (400MHz, DMSO-d6) δ8.65(s,2H),8.33(d,J=2.4Hz,1H),7.85–7.83(m,1H),7.68–7.66(m,2H),7.63–7.60(m,2H),7.25(d,J=2.0Hz,1H).

[0512] Following the synthetic route of compound H14, and using similar starting materials or intermediates (such as intermediate a9), the following target molecule was synthesized.

[0513] Example 9: Synthesis of target molecules H28-H31

[0514] Step 1: Under nitrogen protection, intermediate C10 (300 mg, 0.76 mmol) and bipyridine-trifluoromethylthiocopper catalyst (490 mg, 1.53 mmol) were dissolved in 9 mL of 1,4-dioxane and reacted at 120 °C for 48 hours. The mixture was then filtered. 55 mL of ice water was added to the reaction solution, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O (0.1% TFA), 4 / 1) to give compound H28-1 (140 mg), yield: 44%. LCMS ESI-MS m / z: 414 [M+H] + .

[0515] Step 2: Dissolve compound H28-1 (130 mg, 0.31 mmol) and DIEA (122 mg, 0.94 mmol) from the previous step in 3 mL of 1,4-dioxane, add POCl3 (241 mg, 1.57 mmol), slowly heat to 80 °C and react for 1 hour, then cool to room temperature and remove the solvent under reduced pressure. Add 7 mL of ammonia in isopropanol solution (2 M), react at room temperature for 1 hour, and stop the reaction. Add 30 mL of ice water to the reaction solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash reversed column chromatography (C18, CH3CN / H2O (0.1% HCOOH), 2 / 3) to obtain compound H28 (8.5 mg), yield: 7%. LCMS ESI-MS m / z: 413 [M+H] + .

[0516] 1 H NMR(300MHz,DMSO-d6)δ8.43(s,1H),7.58(dd,J=5.8,3.7Hz,1H),7.42(dt,J=7.6,3.9Hz,2H),7 .38–7.28(m,1H),6.98(s,1H),3.44(t,J=7.6Hz,2H),2.87–2.68(m,2H),2.20(q,J=7.5Hz,2H).

[0517] 19 F NMR(282MHz,DMSO-d6)δ-38.52.

[0518] Step 1: Under nitrogen protection, NaHS (63 mg, 1.12 mmol) and intermediate C11 (210 mg, 0.56 mmol) were dissolved in 4 mL of DMF and reacted at 100 °C for 2 hours. K2CO3 (155 mg, 1.12 mmol) and sodium 2-Cl-2,2-difluoroacetate (171 mg, 1.12 mmol) were added to the reaction solution, and the reaction was continued at 105 °C for 1 hour, after which the reaction was stopped. 35 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O (0.1% TFA), 4 / 1) to give compound H31-1 (250 mg), yield: 78%. LCMS ESI-MS m / z: 377 [M+H] + .

[0519] Step 2: Dissolve compound H31-1 (250 mg, 0.66 mmol) and DIEA (257 mg, 1.99 mmol) from the previous step in 6 mL of acetonitrile, add POCl3 (509 mg, 3.32 mmol), slowly heat to 80 °C and react for 2 hours, then cool to room temperature and remove the solvent under reduced pressure. Add 3 mL of ammonia water to the reaction solution and react at room temperature for 0.25 hours, then stop the reaction. Add 30 mL of ice water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate. The crude product is separated by preparative HPLC (column: XBridge Prep OBD C18 Column 30*150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3), mobile phase B: CH3CN, flow rate: 60 mL / min) to obtain compound H31 (20.4 mg), yield: 8%. LCMS ESI-MS m / z: 376 [M+H] + .

[0520] 1 H NMR (300MHz, DMSO-d6) δ8.50(dd,J=4.8,1.6Hz,1H),8.40(s,1H),7.60(dd,J=7.9,1.7Hz,1H),7.36(dd,J=7.9,4. 8Hz, 1H), 6.99 (t, J = 55.9Hz, 2H), 3.44 (d, J = 7.5Hz, 2H), 2.71 (t, J = 7.6Hz, 2H), 2.20 (q, J = 7.5Hz, 2H), 2.14 (s, 3H).

[0521] Following the synthetic routes of compounds H28 or H31, and using similar starting materials or intermediates (such as intermediate C23), the following target molecules were synthesized.

[0522] Example 10 Synthesis of target molecule H16

[0523] Under nitrogen protection, compound H15 (30 mg, 0.08 mmol), cyclopropylboronic acid (14 mg, 0.16 mmol), and Cs₂CO₃ (79 mg, 0.24 mmol) were dissolved in 3 mL of 1,4-dioxane. Catalyst Pd₂(dba)₃ (9 mg, 0.01 mmol) and ligand Xantphos (6 mg, 0.01 mmol) were added, and the reaction was carried out at 80 °C for 2 hours. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was separated by flash reversed column chromatography (C18, CH₃CN / H₂O, 2 / 1) to give compound H16 (1.5 mg), yield: 5%. LCMS ESI-MS m / z: 352 [M+H] + .

[0524] 1 H NMR (400MHz, DMSO-d6) δ 8.37(s,2H),8.18(d,J=2.0Hz,1H),7.82–7.75(m,1H),7.64–7.61(m,2H),7.54–7.52(m,1H), 7.44(s,1H),7.31(d,J=2.0Hz,1H),2.35–2.26(m,1H),1.15–1.06(m,2H),0.93–0.89(m,1H).

[0525] Example 11 Synthesis of target molecules H38-H39

[0526] Step 1: Under nitrogen protection, intermediate b6 (100 mg, 0.25 mmol) and CuI (39 mg, 0.20 mmol) were dissolved in 2 mL of DMF. Compound H12-1 (54 mg, 0.28 mmol) and hexamethylphosphoric triamine (HMPA) (195 mg, 1.09 mmol) were added, and the mixture was reacted at 100 °C for 1 hour. The mixture was then filtered. 15 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 9 with ammonia. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 4 / 1) to obtain compound H38-1 (48 mg), yield: 49%. LCMS ESI-MS m / z: 384 [M+H] + .

[0527] Step 2: Dissolve compound H38-1 (48 mg, 0.13 mmol) and DIEA (49 mg, 0.38 mmol) from the previous step in 2 mL of acetonitrile, add POCl3 (96 mg, 0.63 mmol), react at 80 °C for 1 hour, filter, and remove the solvent by vacuum distillation. Add 25 mL of ice water to the reaction solution, adjust the pH to approximately 8 with ammonia, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Dissolve the compound in 2 mL of methanol, add a methanol solution of ammonia (2 M, 1.5 mL), react at 50 °C for 0.25 hours, stop the reaction, and remove the solvent by vacuum distillation. The crude product was preparatively separated by HPLC (column: XBridge Prep OBD C18 Column 30*150mm, 5μm; mobile phase A: H2O (10mmol / L NH4HCO + 0.05% NH3H2O; mobile phase B: CH3CN; flow rate: 60mL / min; retention time: 8min) to give compound H38 (10.3mg), yield: 22%. LCMS ESI-MS m / z: 383 [M+H] + .

[0528] 1 H NMR(300MHz,DMSO-d6)δ8.62(s,1H),7.66–7.56(m,1H),7.49–7.42(m,2H) ,7.42–7.36(m,1H),7.34(s,1H),5.04(t,J=8.6Hz,2H),3.55–3.34(m,2H).

[0529] 19 F NMR(282MHz,DMSO-d6)δ-66.45.

[0530] Under nitrogen protection, compound H38 (25 mg, 0.065 mmol) and NBS (35 mg, 0.20 mmol) were dissolved in 0.5 mL of carbon tetrachloride (CCl4), and compound azobisisobutyronitrile (AIBN) (10.7 mg, 0.065 mmol) was added. The reaction was carried out at 85 °C for 1 hour, and then the reaction was stopped. 15 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xselect CSH Prep C18 OBD Column, 19*250 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO + 0.05% NH3H2O, mobile phase B: CH3CN, flow rate: 20 mL / min, retention time: 9.5 min) to obtain compound H39 (2.9 mg), yield: 12%. LCMS ESI-MS m / z: 381 [M+H]+ .

[0531] 1 H NMR (300MHz, DMSO-d6) δ8.86(s,1H),8.42(d,J=2.4Hz,1H),7.74(s,1H),7.70–7.58(m,1H),7.56–7.42(m,3H),7.32(dt,J=3.5,1.8Hz,1H).

[0532] 19 F NMR(282MHz,DMSO-d6)δ-65.63.

[0533] Example 12 Synthesis of target molecules H68-H69

[0534] Step 1: Under nitrogen protection, intermediate C9 (130 mg, 0.37 mmol) and NBS (130 mg, 0.73 mmol) were dissolved in 3 mL of carbon tetrachloride (CCl4). Azobisisobutyronitrile (AIBN) (60 mg, 0.37 mmol) was added, and the reaction was carried out at 80 °C for 0.5 hours. The reaction was then stopped. 15 mL of ice water was added to the reaction solution, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 4 / 1) to give compound H68-1 (40 mg), yield: 31%. LCMS ESI-MS m / z: 354 [M+H] + .

[0535] Step 2: The compounds H68-1 (40 mg, 0.11 mmol) and DIEA (44 mg, 0.34 mmol) from the previous step were dissolved in 1 mL of 1,4-dioxane. POCl3 (86 mg, 0.57 mmol) was added, and the reaction was carried out at 80 °C for 0.5 hours. The solvent was then removed by vacuum distillation. The compound was then dissolved in 1 mL of ammonia water, and the reaction was carried out at 50 °C for 0.25 hours. The reaction was stopped, and the solvent was removed by vacuum distillation. The crude product was separated by preparative HPLC (column: XBridge Prep OBD C18 Column 19*250 mm, 5 μm; mobile phase A: H2O, mobile phase B: CH3CN, flow rate: 60 mL / min, retention time: 9.27 min) to obtain compound H68 (7.7 mg, purity: 99.3%), yield: 19%. LCMS ESI-MS m / z: 353 [M+H] + .

[0536] 1H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.17(d,J=2.2Hz,1H),7.62(dd,J=6.0,3.5Hz,1H),7.49–7.42(m,3H),7.37(dd, J=6.0,3.5Hz,1H),7.33(s,1H),2.45(dt,J=7.9,3.7Hz,1H),0.94(td,J=7.9,3.0Hz,2H),0.62(tt,J=3.4,1.8Hz,2H).

[0537] Following the synthetic route of compound H68, and using similar starting materials or intermediates (such as intermediate C38), the following target molecules were synthesized.

[0538] Example 13 Synthesis of target molecules H70-H71

[0539] Step 1: Under nitrogen protection, intermediate b10 (250 mg, 0.66 mmol) and NBS (234 mg, 1.32 mmol) were dissolved in 5 mL of carbon tetrachloride (CCl4). Azobisisobutyronitrile (AIBN) (108 mg, 0.66 mmol) was added, and the reaction was carried out at 80 °C for 0.5 hours. The reaction was then stopped. 15 mL of ice water was added to the reaction solution, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (0.1% TFA), 4 / 1) to give compound H70-1 (66 mg), yield: 27%. LCMS ESI-MS m / z: 378 [M+H] + .

[0540] Step 2: Compound H70-1 (66 mg, 0.18 mmol) and DIEA (68 mg, 0.53 mmol) from the previous step were dissolved in 2 mL of 1,4-dioxane. POCl3 (134 mg, 0.88 mmol) was added, and the reaction was carried out at 80 °C for 0.5 hours. The solvent was then removed by vacuum distillation. The compound was dissolved in 1 mL of ammonia water, and the reaction was carried out at 30 °C for 0.25 hours. The reaction was stopped, and the solvent was removed by vacuum distillation. The crude product was separated by preparative HPLC (column: XBridge Prep OBD C18 Column 30*150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3 + 0.05% NH3 H2O), mobile phase B: CH3CN, flow rate: 60 mL / min, retention time: 6.88 min) to obtain compound H70 (24.5 mg, purity: 99.1%), yield: 37%. LCMS ESI-MS m / z: 377 [M+H]+ .

[0541] 1 H NMR (300MHz, DMSO-d6) δ8.76 (s, 1H), 8.32 (d, J = 2.3Hz, 1H), 7.65 (dt, J = 8.4, 3.0H z,2H),7.48(dq,J=7.0,5.3Hz,3H),7.23(q,J=2.2Hz,1H),1.70(t,J=19.2Hz,3H).

[0542] Following the synthetic route of compound H70, and using similar starting materials or intermediates (such as intermediate b11), the following target molecule was synthesized.

[0543] Example 14 Synthesis of target molecule H50

[0544] Step 1: Under nitrogen protection, intermediate a11 (150 mg, 0.62 mmol) and oxalyl chloride (236 mg, 1.86 mmol) were dissolved in 3 mL of dichloroethane and stirred at 80 °C for 2 hours, then cooled to room temperature. 2-Bromoaniline H50-1 (639 mg, 3.72 mmol) was added to the reaction mixture, and the reaction was continued at room temperature for 2 hours. The reaction was then stopped, and the solvent was removed by vacuum distillation. The mixture was dissolved in 5 mL of dichloroethane, and KHMDS (6.2 mL, 1 M) was added. The reaction was continued at room temperature for 4 hours, then stopped. 20 mL of ice water was added to the mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 3 / 2) to give compound H50-2 (60 mg), yield: 23%. LCMS ESI-MS m / z: 421 [M+H] + .

[0545] Step 2: Under nitrogen protection, the compound H50-2 (60 mg, 0.14 mmol) and POCl3 (107 mg, 0.7 mmol) from the previous step were dissolved in 3 mL of 1,4-dioxane. DIEA (180 mg, 1.4 mmol) was added, and the mixture was reacted at 105 °C for 2 hours. After cooling to room temperature, the solvent was removed by vacuum evaporation. The mixture was then dissolved in 2 mL of ammonia in isopropanol (7 M), and the reaction was stopped at room temperature for 1 hour. 20 mL of ice water was added to the mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O, 2 / 1) to give compound H50 (1.6 mg), yield: 3%. LCMS ESI-MS m / z: 420 [M+H] + .

[0546] 1 H NMR (400MHz, DMSO-d6) δ8.62–8.54(m,1H),8.26(d,J=2.4Hz,1H),7.93–7.87(m,1H),7.61( s,1H),7.55–7.51(m,1H),7.21–7.16(m,2H),6.67–6.64(m,1H),6.28(s,1H),1.92(s,3H).

[0547] Example 15 Synthesis of target molecules H82-H92, H100-H102

[0548] Step 1: Under nitrogen protection, TMSCF3 (60 mg, 0.42 mmol), KF (24.4 mg, 0.42 mmol), and CuI (80 mg, 0.42 mmol) were dissolved in 2 mL of DMF. After stirring at room temperature for 2 hours, a DMF solution (1 mL) of intermediate a27 (105 mg, 0.28 mmol) was added. The reaction was carried out at 80 °C for 6 hours, and then the reaction was stopped. 35 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 5 / 1) to give compound H82-1 (50 mg), yield: 49%. LCMS ESI-MS m / z: 362 [M+H] + .

[0549] Step 2: Under nitrogen protection, compound H82-1 (50 mg, 0.13 mmol) and DIEA (54 mg, 0.4 mmol) from the previous step were dissolved in 2 mL of 1,4-dioxane. POCl3 (105 mg, 0.67 mmol) was added, and the mixture was reacted at 100 °C for 0.5 hours. After cooling to room temperature, the solvent was removed by vacuum evaporation. The mixture was cooled to an ice bath, and 2 mL of ammonia solution was added. The reaction was continued for 20 minutes under ice bath conditions, and then the reaction was stopped. 20 mL of ice water was added to the mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xselect CSH Prep C18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (0.1% HCOOH), mobile phase B: CH3CN; flow rate: 60 mL / min; retention time: 9.7 min) to obtain compound H82 (24 mg), yield: 50%. LCMS ESI-MS m / z: 361 [M+H] + .

[0550] 1H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.35(d,J=2.4Hz,1H),7.59(s,1H),7.38–7.23(m,4H),7.12(m,J=7.3,1.7Hz,1H),1.90(s,3H).

[0551] Step 1: Under nitrogen protection, intermediate a19 (500 mg, 1.53 mmol) and starting material H9-1 (661 mg, 1.82 mmol) were dissolved in 5 mL of 1,4-dioxane. Catalyst Pd(PPh3)4 (176 mg, 0.15 mmol) was added, and the reaction was carried out at room temperature for 5 minutes. The temperature was then raised to 100 °C and the reaction was continued for 2 hours. The reaction was stopped, and the mixture was filtered. 20 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The mixture was dissolved in dilute hydrochloric acid (6 M), and the mixture was reacted at 20 °C for 0.5 hours. The reaction was stopped. 10 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with ammonia. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O, 1 / 1) to obtain compound H83-1 (236 mg), yield: 44%. LCMS ESI-MS m / z: 336 [M+H] + .

[0552] Step 2: Under nitrogen protection in an ice bath, compound H83-1 (236 mg, 0.7 mmol) from the previous step was dissolved in 3 mL of chloroform. DAST (4.0 g, 24.6 mmol) was slowly added. The mixture was reacted at 80 °C for 1 hour, after which the reaction was stopped. 50 mL of ice water was added to the reaction mixture, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O (10 mmol / L HCOOH), 4 / 1) to give compound H83-2 (76 mg), yield: 30%. LCMS ESI-MS m / z: 358 [M+H] + .

[0553] Step 3: Under nitrogen protection and in an ice bath, dissolve compound H83-2 (76 mg, 0.21 mmol) and DIEA (83 mg, 0.64 mmol) from the previous step in 1 mL of 1,4-dioxane, add POCl3 (163 mg, 1.1 mmol), heat to 80 °C and react for 0.5 hours, cool to room temperature, and remove the solvent under reduced pressure. Cool the mixture to an ice bath, add 1 mL of ammonia solution, react in an ice bath for 30 minutes, and then stop the reaction. Add 20 mL of ice water to the mixture, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate. The crude product is separated by preparative HPLC (column: Xselect CSH Prep C18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 20 mL / min; retention time: 10.4 min) to obtain compound H83 (28 mg), yield: 37%. LCMS ESI-MS m / z: 357 [M+H] + .

[0554] 1 H NMR (300MHz, DMSO-d6) δ8.65(s,1H),8.31(d,J=2.3Hz,1H),7.74(s,1H),7.33(m,3H),7.13(m,2H),1.95(s,3H),1.74-1.61(s,3H).

[0555] Following the synthetic routes of compounds H82 or H83, and using similar starting materials or intermediates (such as intermediates a16-a32), the following target molecules were synthesized.

[0556] Example 16 Synthesis of target molecules H93-H99, H103-H110

[0557] Step 1: Under nitrogen protection, TMSCF3 (190 mg, 1.33 mmol), KF (58.1 mg, 1.0 mmol), and CuI (190 mg, 1.0 mmol) were dissolved in 5 mL of DMF. After stirring at room temperature for 2 hours, a DMF solution (1 mL) of intermediate b7 (250 mg, 0.67 mmol) was added. The reaction was carried out at 100 °C for 1 hour, and then the reaction was stopped. 25 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 3 / 1) to give compound H93-1 (80 mg), yield: 33%. LCMS ESI-MS m / z: 365 [M+H] + .

[0558] Step 2: Under nitrogen protection, compound H93-1 (80 mg, 0.22 mmol) and DIEA (85 mg, 0.66 mmol) from the previous step were dissolved in 2 mL of 1,4-dioxane. POCl3 (168 mg, 1.1 mmol) was added, and the mixture was reacted at 100 °C for 0.5 h. After cooling to room temperature, the solvent was removed by vacuum evaporation. The mixture was cooled to an ice bath, and 2 mL of ammonia solution was added. The reaction was continued for 20 min under ice bath conditions, and then stopped. 20 mL of ice water was added to the mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xselect CSH Prep C18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (0.1% HCOOH), mobile phase B: CH3CN; flow rate: 60 mL / min; retention time: 8.05 min) to obtain compound H93 (6.5 mg), yield: 8%. LCMS ESI-MS m / z: 364 [M+H] + .

[0559] 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.47(dd,J=4.8,1.7Hz,1H),7.59(dd,J=7.9,1 .6Hz,1H),7.38–7.31(m,2H),5.03(t,J=8.6Hz,2H),3.45–3.36(m,2H),2.13(s,3H).

[0560] 19 F NMR(376MHz,DMSO-d6,ppm)δ-66.44.

[0561] Step 1: Under nitrogen protection, intermediate b11 (40 mg, 0.11 mmol) and DIEA (43 mg, 0.33 mmol) were dissolved in 1 mL of 1,4-dioxane, and POCl3 (85 mg, 0.55 mmol) was added. The mixture was reacted at 100 °C for 0.5 h, cooled to room temperature, and the solvent was removed by vacuum evaporation. The mixture was cooled to an ice bath, and 1 mL of ammonia solution was added. The reaction was stopped at room temperature for 15 min. 20 mL of ice water was added to the mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xselect CSH Prep C18OBD Column, 30*150 mm, 5 μm; mobile phase A: water (0.1% HCOOH), mobile phase B: CH3CN; flow rate: 60 mL / min; retention time: 8.4 min) to give compound H94 (19.1 mg), yield: 48%. LCMS ESI-MS m / z: 360 [M+H] + .

[0562] 1 H NMR (400MHz, DMSO-d6, ppm) δ8.47(dd,J=4.8,1.7Hz,1H),8.14(s,1H),7.58(dd,J=7.9,1.7Hz,1H),7.35(dd,J =7.9,4.8Hz,1H),7.26(s,1H),4.99(t,J=8.7Hz,2H),3.44–3.28(m,2H),2.13(s,3H),1.58(t,J=19.2Hz,3H).

[0563] 19 F NMR(376MHz,DMSO-d6,ppm)δ-88.70,-89.40,-89.69,-90.38.

[0564] Step 2: In an ice bath, compound H94 (40 mg, 0.11 mmol) was dissolved in 1 mL of anhydrous tetrahydrofuran. NaH (4.0 mg, 0.16 mmol) was added, and the mixture was stirred at 0°C for 30 minutes. MeI (18.9 mg, 0.13 mmol) was added, and the reaction was continued at room temperature for another 30 minutes. The reaction was then stopped. Acetic acid was added to quench the reaction, and the pH was adjusted to approximately 7. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xselect CSH Prep C18 OBD Column, 19*250 mm, 5 μm; mobile phase A: water (0.1% HCOOH), mobile phase B: CH3CN; flow rate: 20 mL / min; retention time: 11.8 min) to obtain compound H95 (8.2 mg), yield: 20%. LCMS ESI-MS m / z: 374 [M+H] + .

[0565] 1 H NMR (400MHz, DMSO-d6) δ8.47(dd,J=4.8,1.6Hz,1H),8.34(s,1H),7.85(d,J=4.9Hz,1H),7.57(dd,J=7.8,1.7Hz,1H),7.35( dd,J=7.9,4.8Hz,1H),5.00(t,J=8.7Hz,2H),3.40–3.32(m,2H),3.03(d,J=4.7Hz,3H),2.12(s,3H),1.57(t,J=19.2Hz,3H).

[0566] 19 F NMR(376MHz, DMSO)δ-88.59,-89.28,-89.57,-90.26.

[0567] Step 1: Under nitrogen protection, intermediate b20 (220 mg, 0.63 mmol), cyclopropylboronic acid (164 mg, 1.91 mmol), and K2CO3 (265 mg, 1.91 mmol) were dissolved in 5 mL of a mixed solution of 1,4-dioxane and water (v / v, 4 / 1). Catalyst Pd(dppf)Cl2 (52 mg, 0.06 mmol) was added, and the reaction was carried out at 100 °C for 12 hours. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O, 3 / 1) to give compound H97-1 (85 mg), yield: 38%. LCMS ESI-MS m / z: 351 [M+H] + .

[0568] Step 2: Under nitrogen protection, compound H97-1 (85 mg, 0.24 mmol) and DIEA (94 mg, 0.72 mmol) were dissolved in 2 mL of 1,4-dioxane, and POCl3 (185 mg, 1.2 mmol) was added. The mixture was reacted at 100 °C for 0.5 h, cooled to room temperature, and the solvent was removed by vacuum evaporation. The mixture was cooled to an ice bath, and 1 mL of ammonia solution was added. The reaction was stopped at room temperature for 15 min. 20 mL of ice water was added to the mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xselect CSH Prep C18OBD Column, 30*150 mm, 5 μm; mobile phase A: water (0.1% HCOOH), mobile phase B: CH3CN; flow rate: 60 mL / min; retention time: 8.68 min) to obtain compound H97 (38.3 mg), yield: 45%. LCMS ESI-MS m / z: 350 [M+H] + .

[0569] 1 H NMR (300MHz, DMSO-d6, ppm) δ8.51 (dd, J=4.7, 1.7Hz, 1H), 8.21 (s, 1H), 7.46 ( dd,J=7.9,1.7Hz,1H),7.31(dd,J=7.9,4.7Hz,1H),6.96(s,1H),4.95(t,J=8. 7Hz,2H),3.27(t,J=8.8Hz,2H),2.35(qd,J=7.4,4.0Hz,2H),1.85(dq,J=8.2 ,4.1Hz,1H),1.01(t,J=7.5Hz,3H),0.78(t,J=7.1Hz,2H),0.46–0.39(m,2H).

[0570] Following the synthetic routes of compounds H93 or H94 / H95 or H97, and using similar starting materials or intermediates (such as intermediates b4-b21), the following target molecules were synthesized.

[0571] Example 17 Synthesis of target molecule Z1

[0572] Step 1: Under nitrogen protection, the starting material 5-bromo-4-fluoro-1,3-benzothiazole Z1-1 (1.5 g, 6.46 mmol), Zn(CN)2 (607 mg, 5.17 mmol), and the ligand bisphenylphosphine ferrocene dppf (286 mg, 0.51 mmol) were dissolved in 13 mL of NMP. The catalyst Pd2(dba)3 (295 mg, 0.32 mmol) was added, and the reaction was carried out at 110 °C for 5 hours, followed by cooling to room temperature. 50 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (C18, CH3CN / H2O (0.1% TFA), 4 / 1) to give compound Z1-2 (500 mg), yield: 43%. LCMS ESI-MS m / z: 179 [M+H] + .

[0573] Step 2: Under nitrogen protection, 5-cyano-4-fluoro-1,3-benzothiazole Z1-2 (0.5 g, 2.8 mmol) was dissolved in 11 mL of concentrated sulfuric acid and reacted at 50 °C for 2 hours, then cooled to room temperature. The mixture was poured into 50 mL of ice water, the pH was adjusted to approximately 8 with ammonia, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 10 / 1) to give compound Z1-3 (230 mg), yield: 42%. LCMS ESI-MS m / z: 197 [M+H] + .

[0574] Step 3: Compound Z1-3 (230 mg, 1.17 mmol) and (COCl)2 (208 mg, 1.64 mmol) from the previous step were added to 3 mL of dichloroethane. The mixture was slowly heated to 80 °C and reacted for 1 hour, then cooled to room temperature. 2-Methyl-3-aminopyridine b2-1 (130 mg, 1.2 mmol) was added to the reaction solution, and the mixture was reacted at room temperature for 2 hours. The reaction was then stopped. 30 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 8 / 1) to give compound Z1-4 (159 mg), yield: 41%. LCMS ESI-MS m / z: 331 [M+H] + .

[0575] Step 4: Compound Z1-3 (159 mg, 0.48 mmol) and NaH (77 mg, 1.92 mmol, 60%) from the previous step were added to 3 mL of anhydrous tetrahydrofuran and reacted slowly at 50 °C for 2 hours, then cooled to room temperature. 30 mL of ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 10 / 1) to give compound Z1-5 (110 mg), yield: 74%. LCMS ESI-MS m / z: 311 [M+H] + .

[0576] Step 5: Dissolve compound Z1-5 (110 mg, 0.35 mmol) and DIEA (137 mg, 1.06 mmol) from the previous step in 3 mL of acetonitrile, add POCl3 (272 mg, 1.77 mmol), heat to 80 °C and react for 2 hours, then cool to room temperature and remove the solvent under reduced pressure. Add 2 mL of ammonia water to the reaction solution and react at room temperature for 0.25 hours, then stop the reaction. Add 30 mL of ice water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate. The crude product is separated by preparative HPLC (column: XBridge Prep OBD C18 Column 30*150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3), mobile phase B: CH3CN, flow rate: 60 mL / min) to obtain compound Z1 (29.6 mg), yield: 27%. LCMS ESI-MS m / z: 310 [M+H] + .

[0577] 1 H NMR(300MHz, DMSO-d6)δ8.96(s,1H),8.48(d,J=4.8Hz,1H),8.19(t,J=12.8Hz,3H),8 .01(d,J=8.7Hz,1H),7.54(d,J=8.0Hz,1H),7.28(dd,J=7.9,4.8Hz,1H),2.15(s,3H).

[0578] Example 18 Synthesis of target molecule Z2

[0579] Step 1: Under nitrogen protection, intermediate e2 (50 mg, 0.19 mmol) and oxalyl chloride (36 mg, 0.28 mmol) were dissolved in 1 mL of dichloroethane and stirred at 80 °C for 1 hour, then cooled to room temperature. 2-Chloroaniline b1-1 (40 mg, 0.31 mmol) was added to the reaction mixture, and the reaction was continued at room temperature for 0.5 hours. The reaction was then stopped, and the solvent was removed by vacuum distillation. 20 mL of ice water was added to the mixture, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (10 mmol / L NH4HCO3), 5 / 1) to give compound Z2-1 (25 mg), yield: 35%. LCMS ESI-MS m / z: 381 [M+H] + .

[0580] Step 2: Dissolve compound Z2-1 (25 mg, 0.07 mmol) and DIEA (25 mg, 0.21 mmol) from the previous step in 5 mL of 1,4-dioxane, add POCl3 (51 mg, 0.35 mmol), heat to 80 °C and react for 1 hour, then cool to room temperature and remove the solvent under reduced pressure. Add 2 mL of ammonia water to the reaction solution and react at room temperature for 0.25 hours, then stop the reaction. Add 10 mL of ice water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate. The crude product is separated by preparative HPLC (column: Xselect CSH Prep Column, 30*150 mm, 5 μm; mobile phase A: H2O (0.1% HCOOH), mobile phase B: CH3CN, flow rate: 60 mL / min) to obtain compound Z2 (5.3 mg), yield: 21%. LCMS ESI-MS m / z: 310 [M+H] + .

[0581] 1 H NMR (400MHz, DMSO-d6) δ9.23(d,J=4.7Hz,1H),8.60(d,J=4.7Hz,1H),7.92(d,J=2.6Hz,1H),7.87–7 .77(m,1H),7.49(m,J=8.0,1.4Hz,1H),7.31(td,J=7.6,1.5Hz,1H),7.17–7.02(m,2H),6.67(s,1H).

[0582] Example 19 Synthesis of target molecules Z3-Z4, Z7

[0583] Step 1: Under nitrogen protection, intermediate b9 (30 mg, 0.11 mmol) and oxaloyl chloride (27 mg, 0.21 mmol) were dissolved in 1 mL of dichloroethane and stirred at 80 °C for 1 hour, then cooled to room temperature. 2-Methyl-3-aminopyridine b2-1 (45 mg, 0.42 mmol) was added to the reaction mixture, and the reaction was continued at room temperature for 0.5 hours. The reaction was then stopped, and the solvent was removed by vacuum distillation. 20 mL of ice water was added to the mixture, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give compound Z3-1 (30 mg), yield: 62%. LCMS ESI-MS m / z: 354.2 [M+H] + .

[0584] Step 2: Under nitrogen protection in an ice bath, compound Z3-1 (30 mg, 0.085 mmol) from the previous step was dissolved in 1 mL of toluene. NaH (14 mg, 0.34 mmol, 60%) was added, and the mixture was heated to 120 °C and reacted for 1 hour. The mixture was then cooled to room temperature. 10 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 7 with dilute hydrochloric acid. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound Z3-2 (20 mg), yield: 71%. LCMS ESI-MS m / z: 334.1 [M+H] + .

[0585] Step 3: Dissolve compound Z3-2 (20 mg, 0.06 mmol) and DIEA (39 mg, 0.3 mmol) from the previous step in 3 mL of 1,4-dioxane, add POCl3 (28 mg, 0.18 mmol), heat to 80 °C and react for 3 hours, cool to room temperature, and remove the solvent under reduced pressure. Add 1 mL of ammonia to the reaction solution, react at room temperature for 0.5 hours, and stop the reaction. Add 10 mL of ice water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate. The crude product is separated by preparative HPLC (column: 40-WePure Biotech XP tC18 150×30 mm, 7 μm; mobile phase A: H2O (0.05% ammonia + 10 mM NH4HCO3), mobile phase B: CH3CN, flow rate: 25 mL / min) to obtain compound Z3 (3.0 mg, Purity 99.79%), yield: 15%. LCMS ESI-MS m / z: 333.2 [M+H] + .

[0586] 1H NMR (400MHz, CD3OD) δ8.65(dd,J=1.4,4.9Hz,1H),8.16(d,J=2.5Hz,1H),7.81(dd,J=1.4,8.0Hz,1H),7.55(dd,J=4.9, 7.9Hz,1H),7.09(d,J=2.5Hz,1H),5.92(s,1H),2.32(s,3H),2.29-2.22(m,1H),1.18-1.06(m,2H),0.72-0.60(m,2H).

[0587] Following the synthetic route of compound Z3, and using similar starting materials or intermediates (such as methylamine hydrochloride, starting material b1-1, etc.), the following target molecules were synthesized.

[0588] Axial chiral resolution of compound Z7 (presumed configuration):

[0589] Splitting conditions:

[0590] Chromatographic column: CHIRALPAK IF, 5 μm, 250 mm x 20 mm; Mobile phase A: n-hexane (0.5% NH3 (2 M in MeOH)), Mobile phase B: (EtOH / DCM, 1 / 1); Flow rate: 20 mL / min; Retention time of Z7a (min): 12.22; Retention time of Z7b (min): 15.45; LCMS ESI-MS m / z: 347.2 [M+H] + .

[0591] Z7a: 1 H NMR (400MHz, DMSO-d6) δ10.19(q,J=4.7Hz,1H),8.62(dd,J=4.8,1.6Hz,1H),8.23(d,J=2.5Hz,1H),7.73(dd,J=7.9,1.7Hz,1H),7.47(dd,J=7.9,4. 8Hz,1H),7.14(d,J=2.5Hz,1H),5.81(s,1H),3.17(d,J=4.8Hz,3H),2.38– 2.26(m,1H),2.20(s,3H),1.15–0.96(m,2H),0.60(tt,J=4.9,2.5Hz,2H).

[0592] Z7b: 1H NMR (400MHz, DMSO-d6) δ10.19(q,J=4.7Hz,1H),8.62(dd,J=4.8,1.6Hz,1H),8.23(d,J=2.5Hz,1H),7.73(dd,J=7.9,1.7Hz,1H),7.47(dd,J=7.9,4. 8Hz,1H),7.14(d,J=2.5Hz,1H),5.81(s,1H),3.17(d,J=4.8Hz,3H),2.38– 2.26(m,1H),2.20(s,3H),1.15–0.96(m,2H),0.60(tt,J=4.9,2.5Hz,2H).

[0593] Example 20 Synthesis of target molecule Z5

[0594] Step 1: Intermediate a13 (1.0 g, 1.91 mmol), pyridine (1.51 g, 19.1 mmol), and 2-methylpyridine-3-boronic acid Z5-1 (520 mg, 3.82 mmol) were dissolved in 30 mL of DMF. 4,4'-di-tert-butyl-2,2'-bipyridine BBBPY (510 mg, 1.91 mmol) and catalyst Cu(OTf)2 (2.07 g, 5.73 mmol) were added. The reaction mixture was reacted at 50 °C under oxygen conditions (2 atm) for 12 hours, cooled to room temperature, and filtered. 200 mL of ice water was added to the reaction solution, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by preparative HPLC (column: 58-Phenomenex Gemini NX C18 150×40mm, 5μm; mobile phase A: H2O (0.1% TFA), mobile phase B: CH3CN, flow rate: 60mL / min) to give compound Z5-2 (350mg), yield: 30%. LCMS ESI-MS m / z: 613.2 / 615.2 [M+H] + .

[0595] Step 2: Under nitrogen protection, compound Z5-2 (340 mg, 0.55 mmol), tetramethylammonium chloride (603 mg, 5.5 mmol), and L-proline (13 mg, 0.11 mmol) from the previous step were dissolved in 30 mL of ethanol. Cu₂O catalyst (7.9 mg, 0.055 mmol) was added, and the reaction was carried out at 110 °C for 48 hours. After cooling to room temperature, the mixture was filtered. 100 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Ultimate C18 150*40 mm*5 μm; mobile phase A: H₂O (0.1% TFA), mobile phase B: CH₃CN, flow rate: 25 mL / min) to obtain compound Z5-3 (33 mg), yield: 10%. LCMS ESI-MS m / z: 569.2 [M+H] + .

[0596] Step 3: Under nitrogen protection, compound Z5-3 (30 mg, 0.053 mmol) from the previous step was dissolved in 0.2 mL of trifluoroacetic acid and reacted in a microwave at 100 °C for 3 hours, then cooled to room temperature. 10 mL of ice water was added to the reaction solution, the pH was adjusted to approximately 8 with ammonia, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by thin-layer chromatography (TLC) (EA) to obtain compound Z5-4 (10 mg), yield: 52%. LCMS ESI-MS m / z: 330.1 [M+H] + .

[0597] Step 4: Dissolve compound Z5-4 (10 mg, 0.032 mmol) and DIEA (16.5 mg, 0.13 mmol) from the previous step in 0.3 mL of 1,4-dioxane, add POCl3 (9.8 mg, 0.064 mmol), heat to 80 °C and react for 1 hour, then cool to room temperature and remove the solvent under reduced pressure. Add 0.3 mL of ammonia to the reaction solution and react at room temperature for 0.5 hours, then stop the reaction. Add 10 mL of ice water to the reaction solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate. The crude product was preparatively separated by HPLC (column: 40-WePure Biotech XP tC18 150×30mm, 7μm; mobile phase A: H2O (0.05% ammonia + 10mM NH4HCO3), mobile phase B: CH3CN, flow rate: 25mL / min) to give compound Z5 (1.74mg, purity 98.6%), yield: 17%. LCMS ESI-MS m / z: 328.9 [M+H] + .

[0598] 1H NMR (400MHz, CDCl3) δ8.70 (d, J = 3.2Hz, 1H), 7.54 (d, J = 6.8Hz, 1H), 7.43-7.40 (m, 1H), 6.36 (s, 1H), 5.63 (s, 2H), 5.18 (s, 2H).

[0599] Example 21 Synthesis of target molecule Z6

[0600] Step 1: Under nitrogen protection, intermediate B13 (400 mg, 1.54 mmol) was dissolved in 5 mL of dichloroethane. The starting material, 1-chloro-2-isocyanate benzene Z6-1 (355 mg, 2.31 mmol), was added. The mixture was heated to 120 °C and stirred for 17 hours, then cooled to room temperature. 20 mL of ice water was added to the reaction mixture, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration to obtain compound Z6-2 (300 mg), yield: 40%. LCMS ESI-MS m / z: 366.9 [M+H] + .

[0601] Step 2: Under nitrogen protection in an ice bath, compound Z6-2 (250 mg, 0.68 mmol) from the previous step was dissolved in 5 mL of toluene. NaH (164 mg, 4.1 mmol, 60%) was added, and the mixture was heated to 120 °C and reacted for 1 hour. The mixture was then cooled to room temperature. 10 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 7 with dilute hydrochloric acid. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound Z6-2 (200 mg), yield: 85%. LCMS ESI-MS m / z: 347.0 [M+H] + .

[0602] Step 3: Dissolve compound Z6-2 (70 mg, 0.2 mmol) and DIEA (129 mg, 1.0 mmol) from the previous step in 2 mL of 1,4-dioxane, add POCl3 (92 mg, 0.6 mmol), heat to 100 °C and react for 1 hour, then cool to room temperature and remove the solvent under reduced pressure. Add 0.5 mL of ammonia to the reaction solution and react at room temperature for 0.5 hours, then stop the reaction. Add 10 mL of ice water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate. The crude product is separated by preparative HPLC (column: Phenomenex Synergi C18 150 × 30 mm × 4 μm; mobile phase A: H2O (0.225% HCOOH), mobile phase B: CH3CN, flow rate: 25 mL / min) to obtain compound Z6 (22 mg, Purity 98.9%), yield: 30%. LCMS ESI-MS m / z: 345.9 [M+H] + .

[0603] 1 H NMR (400MHz, DMSO-d6) δ9.46(s,1H),8.88(s,1H),8.31(d,J=2.5Hz,1H),7.81-7.74(m,1H),7.64-7.51(m,3H),7.07(d,J=2.5Hz,1H),6.52(s,1H).

[0604] Example 22: MAT2A Enzyme Activity Level Test

[0605] 22.1 Materials and Instruments

[0606] Operating steps:

[0607] 1. Using an Echo 655, transfer 200 nL of the diluted compound working solution to each well of the reaction plate (3702, Corning).

[0608] 2. Seal the reaction plate with a sealing film and centrifuge at 1000 RPM for 1 minute.

[0609] 3. Prepare a 1x buffer solution.

[0610] 4. Prepare a 2× enzyme solution using 1× reaction buffer.

[0611] 5. Add 10 μL of 2× enzyme solution to the reaction plate. Seal the plate with sealing film, centrifuge at 1000 RPM for 1 minute, and incubate at 25°C for 30 minutes in the dark.

[0612] 6. Prepare a mixture of 2× enzyme substrate L-Methionine and ATP using 1× reaction buffer.

[0613] 7. Add 10 μL of 2× enzyme substrate and ATP mixture to the reaction plate, centrifuge at 1000 RPM for 1 minute, and react at 25°C in the dark for 60 minutes.

[0614] 8. Add 20 μL of detection reagent to each well.

[0615] 9. Centrifuge at 1000 RPM for 60 seconds, then incubate at 25°C in the dark for 15 minutes.

[0616] 10. Set up the microplate reader and read the fluorescence change signal at 630nm.

[0617] Table 22.2: Inhibitory effects of compounds on MAT2A enzyme

[0618] (IDE397-Structure) (Compare with A1, refer to WO2022143864 for synthesis) (Compare with A2, refer to WO2023066283 for synthesis) (Compare with A3 and refer to WO2023116696 for synthesis).

[0619] The above results indicate that the molecule of this invention has a good inhibitory effect on MAT2A enzyme.

[0620] The above experimental results show that the pyridine ring core has a higher enzyme inhibition effect compared with the benzene ring core (such as H70, H39, H101 compared with H17, such as H82 compared with H17, etc.).

[0621] Example 23

[0622] MTAP-deficient cells, due to the accumulation of MTA, partially inhibit PRMT5 methyltransferase, and their proliferation is sensitive to MAT2A inhibitors; while MTAP wild-type (MTAP normal) cells do not have the MTA accumulation effect, and PRMT5 methyltransferase is unaffected. Therefore, these cells are MAT2A-independent. By testing the activities of both, the inhibitory and selective effects of the molecule of the present invention on MAT2A at the cellular level are demonstrated.

[0623] HCT116 wild-type and MTAP-deficient HCT116 cells were cultured in MCCOYS 5A medium containing 10% FBS and 1% penicillin-streptomycin and incubated at 37°C in a 5% CO2 incubator. 40 μL of cell suspension was added to each well of a 384-well microplate. Using an Echo reader, 40 nmL of different concentrations of compounds were added to each well, and the plates were incubated at 37°C in a 5% CO2 incubator for 7–10 days. 40 μL of CTG solution (Promega, Cat No. G7573) was added to each well, and the plates were incubated at 37°C in a 5% CO2 incubator in the dark for 30 minutes. The luminescence values ​​were read using an Envision multi-plate reader (Perkin Elmer, catalog number Envision 2104). The light signal was directly proportional to the amount of ATP in the system, and the ATP content directly represented the number of viable cells in the system. IC50 50 Value calculation: Y = Lower platform signal + (Upper platform signal - Lower platform signal) / (1 + 10^(LogIC)) 50 -X)×Hill slope))

[0624] X: Log value of compound concentration; Y: Inhibition rate (%)

[0625] Table 23.1: 2D antiproliferative effects of the compounds on HTC116-MTAP del and wild-type colorectal cancer HCT-116 cell lines.

[0626] ND = Not tested. The above experimental results indicate that the superior compounds of this invention have a significant anti-proliferative effect on MTAP-deficient tumor cells by inhibiting MAT2A, while the inhibition on wild-type cells is weaker, which may lead to higher safety. Some molecules have better activity and selectivity than control molecules.

[0627] Example 24: Liver microsomal stability test of the compound

[0628] The liver microsomal stability of the compounds of this invention was studied. The test compounds were co-incubated with liver microsomes of different species with or without the addition of NADPH. The final concentrations of the test compounds, NADPH, and liver microsomes in the test system were 1 μM, 1 mM, and 0.5 mg / mL, respectively. The concentrations of the compounds in the supernatant at different time points within 60 minutes were measured, and pharmacokinetic parameters (e.g., clearance rate Cl) were calculated. int ).

[0629] This result indicates that the molecules of the present invention have good metabolic stability (especially in the human body).

[0630] Table 24.1 Stability of compounds in human microsomes

[0631] ND = Untested

[0632] Table 24.2 Stability of compounds in mouse microsomes

[0633] The above results indicate that the molecules of this invention have good metabolic stability in liver microsomes.

[0634] The above experimental results indicate that the pyridine ring core has a lower metabolic rate in mice compared to the benzene ring core (such as H39, H82, H101 and Z7, compared to H40 and H17).

[0635] Example 25: Membrane permeability evaluation experiment: MDCK-MDR1 assays

[0636] The membrane permeability of the molecule of this invention is evaluated in order to predict its permeability to the brain.

[0637] Specifically: 1. Pre-incubate MDCK-MDR1 cells at a density of 1.56*102 61. Cells / mL were seeded into 96-well plates and incubated at 37°C for 7 days; 2. The MDCKII-MDR1 plates were removed from the incubator, washed twice with preheated HBSS (10mM HEPES, pH 7.4), and then incubated at 37°C for 30 minutes; 3. The stock solution of the test compound was diluted with DMSO to obtain a 0.2mM solution, and then diluted with HBSS (10mM HEPES, pH 7.4) to obtain a 1μM working solution. The blank control group was diluted with DMSO to obtain a 0.2mM solution, and then diluted with HBSS (10mM HEPES, pH 7.4) to obtain a 1μM working solution. The final concentration of DMSO in the culture system was 0.5%; 4. The drug transport rate from the top to the outer side of the substrate was determined. 125μL of the 1μM test compound solution was added to the Transwell insert (top chamber), and 50μL of sample (D0 sample) was immediately transferred from the top chamber to a new 96-well plate. Fill the wells (outer chamber of the substrate) of the receiver plate with 235 μL of HBSS (10 mM HEPES, pH 7.4) and incubate at 37°C for 2 hours. At the end of incubation, transfer 50 μL of sample from both the donor and recipient sides to the wells of a new 96-well plate, and then add 4 volumes of cold acetonitrile containing an appropriate internal standard (IS). Before LC-MS / MS analysis, mix 100 μL of the supernatant with an appropriate volume of ultrapure water. app =(V A ×[drug] acceptor ) / (Area×Time×[drug]initial,donor)

[0638] Where V A The value is the volume of the acceptor pore (in mL), and Area is the surface area of ​​the membrane (0.143 cm² for the permeable scaffold in the Transwell-96 well). 2 ), where time is the total transportation time (in seconds). Efflux Ratio = P app ( B-A ) / P app ( A-B )

[0639] Table 25.1 MDCK-MDR1 permeabilization data of the molecules of this invention

[0640] The above results indicate that most molecules of the present invention have good membrane permeability, and are expected to achieve higher brain concentrations when administered in vivo.

[0641] Example 26: Pharmacokinetic Evaluation Experiment in Mice

[0642] CD1 female mice were used as test animals, and the drugs were administered orally or intravenously (oral dose was 10 mg / kg, intravenous dose was 2 mg / kg).

[0643] Experimental protocol: Three mice were administered the oral medication, and three mice were administered the intravenous medication. For oral administration, plasma samples were collected before (0 h) and after (0.25, 0.5, 1, 2, 4, 8, 24 h). For intravenous administration, plasma samples were collected before (0 h) and after (0.083, 0.25, 0.5, 1, 2, 4, 8, 24 h). The plasma concentrations of mice after oral and intravenous administration were determined by LC / MS / MS. The collected data were calculated using AB Sciex QTRAP 6500 software. The experimental results are as follows:

[0644] Table 26.1 Pharmacokinetic data of the molecules of this invention in mice

[0645] Table 26.2 Pharmacokinetic data of the molecules of this invention in mice

[0646] Table 26.3 Pharmacokinetic data of the present invention molecules in mice

[0647] ND = Untested

[0648] The above experimental results indicate that the compound of the present invention has good oral absorption and high in vivo exposure, which is expected to bring about higher therapeutic effects.

[0649] The above experimental results indicate that the pyridine ring core has a higher in vivo exposure compared to the benzene ring core (e.g., H70, H101 compared to H40, H82 compared to H43, etc.), which is expected to lead to higher therapeutic effects.

[0650] The above experimental results indicate that the pyridine ring core has a higher in vivo exposure compared to the benzene ring core (e.g., Z7 compared to H40, H43, etc.), which is expected to lead to higher therapeutic effects.

Claims

Compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: in, X1, X2, and X3 are each independently selected from -CH, N, or -CR. b ; W1 is selected from N or CR c ; R1 is selected from phenyl or 5-12 heteroaryl groups; R1 may optionally be surrounded by 1-5 R groups. m Replacement or 1-5 R5s; R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace; R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a 4-10 membered heterocyclic groups, -SF5 or -SR a ; R5 is selected from -SR a ; R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups; X1 can form 4-6 membered heteroaryl, 4-6 membered heterocyclic or C with R4. 4-6 Cycloalkyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic or C 4-6 Cycloalkyl groups may optionally be converted to halogens, C 1-6 Alkyl or C 1-6 Haloalkyl substitution; and / or X2 can form 4-6 membered heteroaryl, 4-6 membered heterocyclic, C with X3 4-6 Cycloalkyl or phenyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic, C 4-6 Cycloalkyl or phenyl groups may optionally be converted to halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; At least one of X1 and R4 forming a cycle (or X2 and X3 forming a cycle) exists; R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace; R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups; R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -SR a -S(O)2R a -N(R) a R a1 -C(=O)R a -P(=O)(R a R a1 ) or C 2-6 alkenyl; R c Selected from H, halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -CN, -S(O)2R d -N(R) a R a1 -C(=O)OR d Or 5-12 heteroaryl groups; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl and C 1-6 Halogenated alkyl groups; R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl and C 1-6 Halogenated alkyl groups; R d Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4-8 membered heterocyclic groups. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, is a compound of formula (I): in, X1, X2, and X3 are each independently selected from -CH, N, or -CR. b ; R1 is selected from phenyl or 5-12 heteroaryl groups; R1 may optionally be surrounded by 1-5 R groups. m Replacement or 1-5 R5s; R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace; R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a 4-10 membered heterocyclic groups and -SR a ; R5 is selected from -SR a ; R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups; X1 can form 4-6 membered heteroaryl, 4-6 membered heterocyclic or C with R4. 4-6 Cycloalkyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic or C 4-6 Cycloalkyl groups may optionally be converted to halogens, C 1-6 Alkyl or C 1-6 Haloalkyl substitution; and / or X2 can form 4-6 membered heteroaryl, 4-6 membered heterocyclic, C with X3 4-6 Cycloalkyl or phenyl; the 4-6 membered heteroaryl, 4-6 membered heterocyclic, C 4-6 Cycloalkyl or phenyl groups may optionally be converted to halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; At least one of X1 and R4 forming a loop (or X2 and X3 forming a loop) exists; R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace; R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups; R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -SR a -S(O)2R a -N(R) a R a1 -C(=O)R a -P(=O)(R a R a1 ) or C 2-6 alkenyl; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl and C 1-6 Halogenated alkyl groups; and R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl and C 1-6 Halogenated alkyl groups. The compound of claim 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, is a compound of formula (V): in, X1 is selected from -CH, N, or -CR b ; X4 is selected from -CH or N; The ring formed by X5 and X6 is a five-membered heteroaryl, a five-membered cycloalkyl, a five-membered heterocyclic group, a phenyl, a six-membered cycloalkyl, or a six-membered heterocyclic group; X5 is selected from -CH=, -CH2, -CH2CH2, -N=, -C(=O), -S(O)2, O, S, N(R) a R a1 ) or -CR b ; X6 is selected from -CH=, -CH2, -CH2CH2, -N=, -C(=O), -S(O)2, O, S, N(R) a R a1 ) or -CR b ; R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace; R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a 4-10 member heterocyclic groups or -SR a ; R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups; R7 is selected from H, halogen, or C. 1-6 Halogenated alkyl groups; R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace; R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups; R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -SR a -S(O)2R a -N(R) a R a1 -C(=O)R a -P(=O)(R a R a1 ) or C 2-6 alkenyl; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl and C 1-6 Halogenated alkyl groups; R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl and C 1-6 Halogenated alkyl groups; p is selected from 0, 1, or 2; and n is selected from 0, 1, 2, 3, 4, and 5. The compound of claim 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, is a compound of formula (V-1): in, X1 is selected from -CH, N, or -CR b ; X4 is selected from -CH or N; R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace; R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a 4-10 membered heterocyclic groups and -SR a ; R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups; R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace; R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups; R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -SR a -S(O)2R a -N(R) a R a1 -C(=O)R a -P(=O)(R a R a1 ) or C 2-6 alkenyl; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; and n is selected from 0, 1, 2, 3, 4, and 5. The compound of claim 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, is a compound of formula (V-2): in, X1 is selected from -CH, -N, or -CR b ; X4 is selected from -CH or N; X6 is selected from -CH, -N, -C(=O), -S(O)2, O, S, CF or -CMe; R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace; R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a 4-10 member heterocyclic groups or -SR a ; R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups; R x Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace; R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups; R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -SR a -S(O)2R a -N(R) a R a1 -C(=O)R a -P(=O)(R a R a1 ) or C 2-6 alkenyl; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl and C 1-6 Halogenated alkyl groups; R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl and C 1-6 Halogenated alkyl groups; and n is selected from 0, 1, 2, 3, 4, and 5. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein X1 is N. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein X6 is -CH. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein R4 is selected from halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy or 4-10 membered heterocyclic group; wherein the C 3-6 The cycloalkyl or 4-10 membered heterocyclic group may be further substituted with 0-3 R6 groups, wherein the R6 groups are selected from halogens and C. 1-6 alkyl. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein R4 is selected from F, Cl, Br, -OCF2H, -CF2CF2H, -CF2CH3, -CH2CF3, and -CF3. In some embodiments, R4 is selected from cyclopropyl, cyclobutyl, and aziridine, wherein the group is optionally substituted with a halogen. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein X4 is N. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein X4 is CH. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein R m Selected from halogens, C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Halogenated alkyl groups. The compound of claim 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein R m Selected from CF3, CHF2, methyl, ethyl and cyclopropyl. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein R2 is selected from H or C. 1-6 alkyl. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein R3 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl, wherein the C 1-6 Alkyl groups are optionally coated with one R x Instead, the R x Selected from C 3-6 Cycloalkyl or 5-10 heteroaryl groups. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein R2 and R3 are each H; R2 is H and R3 is C 1-6 alkyl; R2 is C 1-6 Alkyl group, and R3 is C 1-6 alkyl; R2 is H, and R3 is halogenated C. 1-6 Alkyl; or R2 is H and R3 is C 3-6 Cycloalkyl. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein R2 is H, and R3 is methyl or ethyl; R2 is methyl or ethyl, and R3 is methyl or ethyl. R2 is H, and R3 is CH2CF3; R2 is H, and R3 is cyclopropyl; or R2 is H, and R3 is methyl, which is further substituted with cyclopropyl or pyridyl. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, is a compound of formula (V-3): in, X1 is selected from N or -CF; X4 is selected from -CH or N; R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace; R4 is independently selected from H, F, Cl, methyl, cyclopropyl, cyclobutyl, CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, OMe, -SCF3 or -SCF2H; R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups; R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace; R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; n is selected from 0, 1, 2, 3, 4, and 5. The compound of claim 18, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, is a compound of formula (V-4): in, X1 is N; X4 is either -CH or N; R2 is selected from H, methyl, ethyl, trifluoroethyl, difluoroethyl, cyclopropyl, or deuterated methyl; R3 is selected from H, methyl, ethyl, trifluoroethyl, difluoroethyl, cyclopropyl, or deuterated methyl; R4 is independently selected from H, F, Cl, Br, methyl, cyclopropyl, cyclobutyl, -CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, -SCF3 or -SCF2H; R m Selected from H, F, Cl, Br, I, methyl, ethyl, cyclopropyl, isopropyl, deuterated methyl, -CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, SCF3 or SCF2H. The compound of claim 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, is a compound of formula (VI): in, X1 is selected from -CH, -N, or -CR b ; X4 is selected from -CH or N; R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace; R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a 4-10 member heterocyclic groups or -SR a ; R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups; R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace; R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; R b Selected from halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -SR a -S(O)2R a -N(R) a R a1 -C(=O)R a -P(=O)(R a R a1 ) and C 2-6 alkenyl; n is selected from 0, 1, 2, 3, 4, and 5. The compound of claim 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, is a compound of formula (VI-1): in, X4 is selected from -CH or N; R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; Alternatively, R3, R2 and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen or sulfur, and the 4-10 membered heterocyclic group may optionally be substituted with OH, NH2 or F; R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace; R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups; R4 is independently selected from H, F, Cl, Br, methyl, ethyl, cyclopropyl, cyclobutyl, CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, -SCF3 or -SCF2H; R m Selected from H, F, Cl, Br, I, methyl, ethyl, cyclopropyl, deuterated methyl, CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, SCF3 or SCF2H; n is selected from 0, 1, 2, and 3. The compound of claim 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, is a compound of formula (VI-2): in, X4 is selected from -CH or N; R2 is selected from H, methyl, ethyl, trifluoroethyl, difluoroethyl, cyclopropyl, or deuterated methyl; R3 is selected from H, methyl, ethyl, trifluoroethyl, difluoroethyl, cyclopropyl, or deuterated methyl; R4 is independently selected from H, F, Cl, Br, methyl, ethyl, cyclopropyl, cyclobutyl, CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, SCF3, or SCF2H; R m Selected from H, F, Cl, Br, I, methyl, ethyl, cyclopropyl, deuterated methyl, CF3, -CF2H, -CF2CH3, -CF2CD3, -CF2CF2H, -CF2CF3, -CH2CF3, -OCF3, -OCF2H, -OMe, SCF3 or SCF2H. The compound of claim 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, is a compound of formula (IX): in, X1 is selected from -CH or N; X4 is selected from -CH or N; R2 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; R3 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 1-6 Deuterated alkyl groups, -C(=O)R a -S(O)2R a OR a Wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic or C 1-6 Any one of the deuterated alkyl groups may optionally be surrounded by one, two, three, or four R groups. x replace; Alternatively, R3, R2, and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and the 4-10 membered heterocyclic group may optionally be surrounded by 1, 2, 3, or 4 R atoms. x replace; R4 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a 4-10 member heterocyclic groups or -SR a ; R4 can be optionally replaced by 0-3 R6 atoms, where R6 is selected from H, D, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups; R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a1 ), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl may optionally be surrounded by one, two or three R m replace; R m Selected from H, D, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a1 -OR a -SR a Or 4-10 membered heterocyclic groups; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; R a1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; n is selected from 0, 1, 2, 3, 4, and 5. The compound of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, is a compound of formula (IX-1): in, X1 is selected from -CH or N; X4 is selected from -CH or N; R2 is selected from H, methyl, trifluoroethyl, difluoroethyl, cyclopropyl, deuterated methyl, -C(=O)Me, -S(O)2Me or OMe; R3 is selected from H, methyl, trifluoroethyl, difluoroethyl, cyclopropyl, deuterated methyl, -C(=O)Me, -S(O)2Me or OMe; Alternatively, R3, R2 and the nitrogen atom they are attached to form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen or sulfur, and the 4-10 membered heterocyclic group may optionally be substituted with OH, NH2 or F; R4 is independently selected from H, F, Cl, Br, methyl, deuterated methyl, ethyl, cyclopropyl, cyclobutyl, -CF3, -CF2H, -CF2CH3, -CF2CD3, -OCF3, -OCF2H, -N(Me)2, -OMe, -SCF3 or -SCF2H; R m Selected from H, D, F, Cl, Br, methyl, deuterated methyl, ethyl, deuterated ethyl, cyclopropyl, cyclobutyl, -CF3, -CF2H, -CF2CH3, -CF2CD3, -OCF3, -OCF2H, -N(Me)2, -OMe, -SCF3 or -SCF2H. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is selected from: A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is selected from: A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is selected from: The compound of any one of claims 1-27 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, for the treatment and / or prevention of MAT2A-mediated diseases. The compound of claim 28 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein the mediated disease is cancer. A pharmaceutical composition comprising a compound of any one of claims 1-27 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof and a pharmaceutically acceptable excipient.

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