PRMT5 inhibitors

Abstract

Provided are a class of PRMT5 inhibitors represented by formula (X), or pharmaceutically acceptable salts, isotope variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof. The invention also provides a preparation method of the compound, a pharmaceutical composition containing the compound, and an application of the compound in prevention and treatment of cancers. # imgabs0 #

Description

PRMT5 inhibitors

[0001] The present invention claims priority to Chinese application CN202210898107.7 filed on July 28, 2022, Chinese application CN202211541013.0 filed on December 2, 2022, Chinese application CN202310484698.8 filed on April 28, 2023, and Chinese application CN202310897087.6 filed on July 20, 2023, which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention relates to a novel class of PRMT5 inhibitors, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof. The present invention also relates to methods for preparing the compounds, pharmaceutical compositions comprising the compounds, and the effects of the compounds in preventing and treating PRMT5-mediated diseases, such as cancer. Background Art

[0003] Protein arginine methyltransferase 5 (PRMT5) belongs to the class II PRMTs and is a S-adenosylmethionine (SAM)-dependent methyltransferase primarily responsible for symmetrically transferring the SAM methyl group to the terminal guanidinium nitrogen atom of arginine residues in histones and other proteins. In vivo, PRMT5 forms a complex with MEP50 (methylosome protein 50) for substrate recognition and localization. This complex is also required for PRMT5's catalytic activity in methyltransferases on histone 2A and histone 4. PRMT5 is a universal transcriptional repressor that regulates gene transcription and protein modification. Furthermore, PRMT5 plays a crucial role in tumor cell proliferation, differentiation, and apoptosis, making it a promising target for cancer therapy. However, PRMT5 is also essential for normal cells. PRMT5 knockout and siRNA knockdown studies have shown that inhibiting PRMT5 activity in normal tissues can cause numerous toxic side effects, including thrombocytopenia, infertility, skeletal muscle loss, and cardiac hypertrophy.

[0004] In 2016, multiple independent research groups reported that MTAP-deficient tumor cells have increased reliance on PRMT5 activity. MTAP deficiency upregulates intracellular levels of MTA (methylthioadenosine), a natural PRMT5 inhibitor. Therefore, MTAP-deficient tumor cells have increased reliance on PRMT5 activity, offering the potential to target MTAP-null tumor cells, specifically the PRMT5 / MTA complex, while sparing MTAP-WT cells.

[0005] The mechanisms of action of PRMT5 inhibitors under investigation include SAM-competitive inhibitors, substrate-competitive inhibitors, dual SAM-substrate competitive inhibitors, and MTA-synergistic inhibitors. Non-MTA-synergistic PRMT5 inhibitors indiscriminately inhibit PRMT5 activity and have been found to cause dose-limiting side effects such as thrombocytopenia, anemia, and neutropenia. MTA-synergistic inhibitors target the PRMT5 / MTA complex and are expected to inhibit MTAP-deficient tumor cells while eliminating their effects on MTAP-WT cells, potentially improving the therapeutic window.

[0006] Therefore, the development of PRMT5 inhibitors targeting the PRMT5 / MTA complex will have important clinical application value, and there is a demand for such inhibitors in the art.

[0007] Summary of the Invention

[0008] The present invention uses the PRMT5 / MTA complex as a target and develops a new class of small molecule inhibitors that can be used to treat various cancers.

[0009] The compounds of the present invention target the PRMT5 / MTA complex and are MTA-synergistic PRMT5 inhibitors. They exhibit excellent PRMT5 / MTA inhibitory activity and significant selectivity for the PRMT5 / SAM complex. Furthermore, they possess favorable ADMET (absorption-distribution-metabolism-excretion-toxicity) properties.

[0010] In one aspect, the present invention provides a compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0011] in,

[0012] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0013] L1 is NH or CHR x ;

[0014] L2 is CRx R y ;

[0015] L3 is -C(O)-, -S(O)- or -S(O)2-;

[0016] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0017] or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene;

[0018] Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-4 alkylene;

[0019] R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)(=NR a )R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R1s replace;

[0020] m = 0, 1, 2, 3, or 4;

[0021] R4 is selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0022] Or one R1 is connected to R4 to form -(CH2) q1 -X-(CH2) q2 -; wherein X is O, S, NH or CH2, q1=0, 1 or 2, q2=1, 2 or 3;

[0023] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0024] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0025] X3 is a C atom or a N atom, which is optionally replaced by R 2d replace;

[0026] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0027] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0028] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0029] Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0030] R 2d Selected from H, D, halogen, CN, NO2, ORa NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0031] R3 is selected from -C 1-6 Alkylene-OR a 、-C 1-6 Alkylene-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s1 and 1 R 3s2 replace;

[0032] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R;

[0033] R 1s and R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0034] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0035] R 3s2 Selected from H, D, -L-ORa 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0036] R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0037] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0038] wherein the above rings A, L1, L2, R x 、R y , R1, R 2a 、R 2b 、R 2c 、R 2d , R3, R4, L, R, R 1s 、R 2s 、R 3s 、R 3s1 、R 3s2 、R a 、R b and R c The various groups defined in are optionally deuterated, up to fully deuterated;

[0039] The condition is that when L2 is CR x R y 、When L3 is -S(O)- or -S(O)2-, R y With R 2d Combined to form vinylidene.

[0040] In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0041] in,

[0042] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0043] L1 is NH or CHR x ;

[0044] L2 is CR x R y ;

[0045] L3 is -C(O)-, -S(O)- or -S(O)2-;

[0046] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0047] or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene;

[0048] Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-4 alkylene;

[0049] R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0050] m = 0, 1, 2, 3, or 4;

[0051] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0052] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0053] X3 is a C atom or a N atom, which is optionally replaced by R 2d replace;

[0054] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0055] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0056] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0057] Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0058] R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0059] R3 is selected from -C 1-6 Alkylene-OR a 、-C 1-6 Alkylene-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s1 and 1 R 3s2 replace;

[0060] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R;

[0061] R 1s and R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0062] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0063] R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0064] R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0065] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0066] wherein the above rings A, L1, L2, R x 、R y , R1, R 2a 、R 2b 、R 2c 、R 2d , R3, L, R, R 1s 、R 2s 、R 3s 、R 3s1 、R 3s2 、R a 、R b and R c The various groups defined in are optionally deuterated, up to fully deuterated;

[0067] The condition is that when L2 is CR x R y 、When L3 is -S(O)- or -S(O)2-, R y With R 2d Combined to form vinylidene.

[0068] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.

[0069] In another aspect, the present invention provides a pharmaceutical composition containing a compound of the present invention and a pharmaceutically acceptable excipient, which further contains other therapeutic agents, such as those selected from the following target drugs / cell activity modulators, including CDK4 / 6 inhibitors, MAT2A inhibitors, MAPK1 / MAPK3 inhibitors, Type I PRMT inhibitors, EGFR inhibitors, SHP2 inhibitors, pan-KRAS inhibitors, KRASG12C inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, MALT1 inhibitors, MALT2 inhibitors, BTK inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, DNA methyltransferase (DNMT) inhibitors, EZH1 / 2 inhibitors, EZH2 inhibitors, Menin-MLL inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1 / 2 inhibitors, chemotherapy drugs, radiotherapy, STING agonists or immune checkpoint inhibitors / modulators.

[0070] In another aspect, the present invention provides use of the compound of the present invention in the preparation of a medicament for treating and / or preventing a PRMT5-mediated disease.

[0071] In another aspect, the present invention provides a method for treating and / or preventing a PRMT5-mediated disease in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutical composition of the present invention.

[0072] In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition of the present invention for use in treating and / or preventing a PRMT5-mediated disease.

[0073] In a specific embodiment, the present invention is used to treat and / or prevent cancer. In another specific embodiment, the present invention is used to treat and / or prevent the following cancers: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor), Kaposi's sarcoma, leiomyomas, hemangiomas, lipomas, neurofibromas, fibromas), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), Genitourinary tract: Kidney (adenocarcinoma, Wilms' tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma), choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: Hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: Gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; Bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, chronic exostosis of bone (osteocartilaginous exostoses), benign enchondromas, chondroblastomas, fibrochondromas, chondromyxofibromas, osteoid osteomas, and giant cell tumors; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningiosarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), Spinal neurofibroma, meningioma, glioma, sarcoma); Gynecology: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia, etc.), ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer);Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal: neuroblastoma.

[0074] In another specific embodiment, the PRMT5-mediated disease of the present invention is selected from the following cancers: malignant peripheral nerve sheath tumor, mesothelioma, glioblastoma multiforme, pancreatic cancer, bile duct cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer, astrocytoma, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, thymoma, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, squamous cell carcinoma of the lung, lung adenocarcinoma, oral cancer, ovarian cancer, kidney cancer and thyroid cancer and sarcoma.

[0075] In another specific embodiment, the PRMT5-mediated disease of the present invention is selected from MTAP-related cancers, such as hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer or head and neck cancer.

[0076] definition

[0077] Chemical definition

[0078] Definitions of specific functional groups and chemical terms are described in more detail below.

[0079] When a numerical range is listed, it is intended to include every value and sub-range within the stated 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.

[0080] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C 1-2Alkyl groups are preferred. 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term “C 1-6 "Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, 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).

[0081] “C 2-6 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl is preferred. 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 in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkenyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0082] “C 2-6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 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. 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 heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0083] “C 1-6 "Alkylene" refers to the removal of C 1-6 In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes 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- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0084] “C 2-6 "Alkenylene" refers to the removal of C 2-6 In some embodiments, C 2-4Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example, 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.

[0085] “C 2-6 "Alkynylidene" refers to the removal of C 2-6 In some embodiments, C 2-4 Alkyne is particularly preferred. Exemplary alkynyl includes, but is not limited to, ethynyl (-C≡C-), substituted or unsubstituted propynyl (-C≡CCH2-), and the like.

[0086] “C 0-6 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-6 Alkylene", "C 0-4 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-4 "Alkylene".

[0087] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0088] Therefore, “C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl is 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. The haloalkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0089] “C 3-10"Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms, optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, C 5-10 Cycloalkyl, C 3-7 Cycloalkyl and C 3-6 Cycloalkyl is particularly preferred, more preferably C 5-7 Cycloalkyl and C 5-6 Cycloalkyl. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Cycloalkyl also includes cycloalkyl rings in which the substituents on any non-adjacent carbon atoms are linked to form a bridged ring, together forming a polycycloalkane sharing two or more carbon atoms. Cycloalkyl also includes cycloalkyl rings in which the substituents on the same carbon atom are linked to form a ring, together forming a polycycloalkane sharing one carbon atom. 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. A cycloalkyl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0090] “C 3-10 "Cycloalkylene" refers to the removal of C 3-10 In some embodiments, C 3-6 Cycloalkylene and C 3-4 Cycloalkylene is particularly preferred, and cyclopropylene is especially preferred.

[0091] "3-10 membered heterocyclyl" refers to a saturated or unsaturated radical of a 3- to 10-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, and optionally containing 1, 2, or 3 double or triple bonds. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, a 5-10 membered heterocyclyl is preferred, which is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3-7 membered heterocyclyl is preferred, which is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; a 5-7 membered heterocyclyl is preferred, which is a 5-7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 3-6 membered heterocyclyl is preferred, which is a 3-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 4-6 membered heterocyclyl is preferred, which is a 4-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; and a 5-6 membered heterocyclyl is more preferred, which is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the heterocyclyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Heterocyclyl also includes a heterocyclyl ring in which any substituents on non-adjacent carbon or nitrogen atoms are connected to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclyl also includes a heterocyclyl ring in which the substituents on the same carbon atom are connected to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxirane, and thiidine. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, 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 heterocyclyls containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyls containing three heteroatoms include, but are not limited to, hexahydrotriazinyl (triazinanyl). Exemplary 7-membered heterocyclyls containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyls fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyls) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyls fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyls) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl also includes the above-mentioned heterocyclyl and a cycloalkyl, heterocyclyl, aryl or heteroaryl group sharing one or two atoms to form a bridged ring or spirocycle. As long as the valence permits, the shared atom can be a carbon or nitrogen atom. Heterocyclyl also includes the above-mentioned heterocyclyl and heterocyclyl groups that may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0092] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which the above-described aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0093] "5-14 membered heteroaryl" refers to a group 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 arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent 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 other embodiments, 5-6 membered heteroaryls are particularly preferred and are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl or pyridonyl. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxepinyl, and thieptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. A heteroaryl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0094] The divalent groups formed by removing another hydrogen from the above-defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "subunits". The ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "cyclyls".

[0095] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0096] 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 、-NRbb 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(R cc )3、-B(R aa )2、-B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0097] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =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;

[0098] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0099] R bb Each of the following 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, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0100] R ccEach of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0101] R dd Each of the 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, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0102] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0103] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0104] R gg Each of the 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), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -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), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -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 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -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 1-6alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -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 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0105] Exemplary substituents on nitrogen atoms 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 、-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, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom ccThe groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd Group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0106] Other definitions

[0107] The term "cancer" includes, but is not limited to, the following cancers: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor), Kaposi's sarcoma, leiomyomas, hemangiomas, lipomas, neurofibromas, fibromas), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Urogenital tract: Kidney (adenocarcinoma, Wilms' tumor, lymphoma, leukemia); Bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma); Prostate (adenocarcinoma, sarcoma); Testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma); Choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: Hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: Gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; Bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, chronic exostosis of bone (osteocartilaginous bone). exostoses), benign enchondromas, chondroblastomas, fibrochondromas, chondromyxofibromas, osteoid osteomas, and giant cell tumors; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningiosarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), Spinal neurofibroma, meningioma, glioma, sarcoma); Gynecology: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia, etc.), ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer);Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal: neuroblastoma.

[0108] In one embodiment, the term "cancer" includes, but is not limited to, the following cancers: malignant peripheral nerve sheath tumor, mesothelioma, glioblastoma multiforme, pancreatic cancer, bile duct cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer, astrocytoma, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, thymoma, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, squamous cell carcinoma of the lung, adenocarcinoma of the lung, oral cancer, ovarian cancer, kidney cancer, and thyroid cancer, as well as sarcoma.

[0109] In one embodiment, the term "cancer" includes, but is not limited to, the following cancers: hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.

[0110] The term "treat" as used herein relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. The noun "treat" as used herein relates to the action of the verb treat, which is as just defined.

[0111] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0112] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0113] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention, the salts are equivalent to their respective free acids.

[0114] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate, and the like. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginate, gluconate, galacturonate, and the like are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0115] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females 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, e.g., 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.

[0116] "Disease," "disorder," and "condition" are used interchangeably herein.

[0117] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduce the severity of, or delay or slow the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0118] Generally, an "effective amount" of a compound is an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0119] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effects of other therapeutic agents.

[0120] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.

[0121] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. BRIEF DESCRIPTION OF THE DRAWINGS

[0122] Figures 1 to 4 show the results of in vivo pharmacodynamic studies in the LU99CDX model. Specific implementation plan

[0123] Herein, "compounds of the present invention" refers to the compounds of the following formula (I), formula (II), etc., and pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof.

[0124] Herein, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood that (unless otherwise specified) all optical isomers and mixtures thereof are encompassed. In addition, unless otherwise specified, all isomeric compounds encompassed by the present invention may occur in both Z and E forms with carbon-carbon double bonds. Compounds that exist in different tautomeric forms are not limited to any particular tautomer, but are intended to encompass all tautomeric forms.

[0125] In one embodiment, the present invention relates to a compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0126] in,

[0127] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0128] L1 is NH or CHR x ;

[0129] L2 is CR x R y ;

[0130] L3 is -C(O)-, -S(O)- or -S(O)2-;

[0131] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0132] or CR x R y Together to form C=O, C=S or C3-6 cycloalkylene;

[0133] Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-4 alkylene;

[0134] R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)(=NR a )R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0135] m = 0, 1, 2, 3, or 4;

[0136] R4 is selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0137] Or an R1 is connected to R4 to form -(CR ss R ss ) q1 -X-(CR ss R ss ) q2-(preferably -(CH2) q1 -X-(CH2) q2 -); wherein X is O, S, NH or CH2, q1=0, 1 or 2, q2=1, 2 or 3, R ss Independently selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R ss and the carbon atoms to which they are attached together to form C 3-10 Cycloalkyl;

[0138] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0139] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0140] X3 is a C atom or a N atom, which is optionally replaced by R 2d replace;

[0141] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0142] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0143] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0144] Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0145] R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0146] R3 is selected from -C 1-6 Alkylene-OR a 、-C 1-6 Alkylene-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s1 and 1 R 3s2 replace;

[0147] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R;

[0148] R 1s and R 2s Independently selected from H, D, halogen, CN, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or two R 1s and the atoms they are connected to form C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0149] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0150] R 3s2Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0151] Or, R 3s1 、R 3s2 and the carbon atoms to which they are attached together to form C 3-10 Cycloalkyl;

[0152] R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0153] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0154] wherein the above rings A, L1, L2, R x 、R y , R1, R 2a 、R 2b 、R 2c 、R 2d , R3, R4, L, R, R 1s 、R 2s 、R 3s 、R 3s1 、R 3s2 、R a 、R b and R c The various groups defined in are optionally deuterated, up to fully deuterated;

[0155] The condition is that when L2 is CR x R y 、When L3 is -S(O)- or -S(O)2-, R y With R 2d Combined to form vinylidene.

[0156] In another embodiment, the present invention is directed to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0157] in,

[0158] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0159] L1 is NH or CHR x ;

[0160] L2 is CR x R y ;

[0161] L3 is -C(O)-, -S(O)- or -S(O)2-;

[0162] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0163] or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene;

[0164] Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-4 alkylene;

[0165] R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b Rc 、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0166] m = 0, 1, 2, 3, or 4;

[0167] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0168] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0169] X3 is a C atom or a N atom, which is optionally replaced by R 2d replace;

[0170] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0171] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0172] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0173] Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0174] R2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0175] R3 is selected from -C 1-6 Alkylene-OR a 、-C 1-6 Alkylene-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s1 and 1 R 3s2 replace;

[0176] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R;

[0177] R 1s and R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0178] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0179] R3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0180] R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0181] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0182] wherein the above rings A, L1, L2, R x 、R y , R1, R 2a 、R 2b 、R 2c 、R 2d , R3, L, R, R 1s 、R 2s 、R 3s 、R 3s1 、R 3s2 、R a 、R b and R c The various groups defined in are optionally deuterated, up to fully deuterated;

[0183] The condition is that when L2 is CR x R y 、When L3 is -S(O)- or -S(O)2-, R y With R 2d Combined to form vinylidene.

[0184] Ring A

[0185] In one embodiment, Ring A is C 6-10 Aryl, preferably phenyl; in another embodiment, ring A is a 5-10 membered heteroaryl, preferably a 5-10 membered heteroaryl, such as phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, especially pyridyl or pyridazinyl.

[0186] L1, L2, and L3

[0187] In one embodiment, L1 is NH; in another embodiment, L1 is CHR x In another embodiment, L1 is NH and L2 is CR x R y , -L1-L2- is preferably -L1-L2- is preferably In another embodiment, L1 is CHR x And L2 is CR x R y , -L1-L2- is preferably In another embodiment, L3 is -C(O)-; in another embodiment, L3 is -S(O)-; in another embodiment, L3 is -S(O)2-.

[0188] R x and R y

[0189] In one embodiment, R x and R y is H; in another embodiment, R x and R y is D; in another embodiment, R x and R y C 1-6 Alkyl; in another embodiment, R x and R y C 1-6 Haloalkyl, preferably CF3; in another embodiment, CR x R y Together they form C=O; in another embodiment, CR x R y Together they form C=S; in another embodiment, CR x R y Together they form C 3-6 Cycloalkylene, preferably cyclopropylene; in another embodiment, L1 is CHR x And L2 is CR x R y , and the two R x In another embodiment, L1 is CHR x And L2 is CR x R y , and the two R x Groups combine to form C 1-4 Alkylene, preferably cyclopropylene.

[0190] R1

[0191] In one embodiment, R1 is H; in another embodiment, R1 is D; in another embodiment, R1 is halogen; in another embodiment, R1 is CN; in another embodiment, R1 is NO2; in another embodiment, R1 is -L-OR a In another embodiment, R1 is -L-SR a In another embodiment, R1 is -L-NR b R c In another embodiment, R1 is SF5; In another embodiment, R1 is C(O)R a In another embodiment, R1 is C(O)OR a In another embodiment, R1 is C(O)NR b R c In another embodiment, R1 is OC(O)R a In another embodiment, R1 is NR b C(O)R c In another embodiment, R1 is S(O)R a In another embodiment, R1 is S(O)2R a In another embodiment, R1 is S(O)(=NR a )R a In another embodiment, R1 is S(O)OR a In another embodiment, R1 is S(O)2OR a In another embodiment, R1 is S(O)NR b R c In another embodiment, R1 is S(O)2NR b R c In another embodiment, R1 is P(O)(R a )2; In another embodiment, R1 is C 1-6 Alkyl; in another embodiment, R1 is C 1-6 In another embodiment, R1 is C 2-6 In another embodiment, R1 is C 2-6 Alkynyl; in another embodiment, R1 is -LC 3-7 Cycloalkyl; in another embodiment, R1 is -L-3-7 membered heterocyclyl; in another embodiment, R1 is -LC 6-10In another embodiment, R1 is -L-5-10 membered heteroaryl; In another embodiment, R1 is optionally replaced by 1, 2 or 3 R 1s replace.

[0192] In a more specific embodiment, R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; In another more specific embodiment, R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; In another more specific embodiment, R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; In another more specific embodiment, R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclyl; In another more specific embodiment, R1 is selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C3-6 Cycloalkyl or 4-6 membered heterocyclyl; In another more specific embodiment, R1 is selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 In another more specific embodiment, R1 is selected from H, D, CN, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 5-6 membered heterocyclyl; In another more specific embodiment, R1 is selected from H, D, CN, OR a 、C 1-6 Alkyl, C 1-6 In another more specific embodiment, R1 is selected from CF3, CN, OCF3, OCH2CH3, In another more specific embodiment, R1 is selected from CF3, CN, OCF3, OCH2CH3, In another more specific embodiment, R1 is selected from CF3.

[0193] m

[0194] In one embodiment, m=0; in another embodiment, m=1; in another embodiment, m=2; in another embodiment, m=3; in another embodiment, m=4.

[0195] R4

[0196] In one embodiment, R4 is H; in another embodiment, R4 is D; in another embodiment, R4 is C 1-6 Alkyl; in another embodiment, R4 is C 1-6 In another embodiment, R1 and R4 are linked to form -(CR ss R ss ) q1 -X-(CR ss R ss ) q2 -, wherein X is O, S, NH or CH2, q1 = 0, 1 or 2, q2 = 1, 2 or 3, R ss Independently selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R ss and the carbon atoms to which they are attached together to form C 3-10 Cycloalkyl, such as C 3-6Cycloalkyl; In another embodiment, R1 and R4 are linked to form -(CH2) q1 -X-(CH2) q2 -, wherein X is O, S, NH or CH2, q1 = 0, 1 or 2, q2 = 1, 2 or 3; in another embodiment, R1 and R4 are linked to form -(CH2) q1 -X-(CH2) q2 -, wherein X is O, S, NH or CH2, q1 = 0 or 1, q2 = 1 or 2; in another embodiment, R1 and R4 are linked to form -(CH2) q1 -X-(CH2) q2 -, wherein X is O, S or NH2, q1=0 or 1, q2=1 or 2.

[0197] X1, X2 and X3

[0198] In one embodiment, X1 is a C atom; in another embodiment, X1 is a N atom; in another embodiment, X1 is CR 2b In another embodiment, X1 is NR 2b In one embodiment, X2 is a C atom; in another embodiment, X2 is a N atom; in another embodiment, X2 is CR 2c In another embodiment, X2 is NR 2c In one embodiment, X3 is a C atom; in another embodiment, X3 is a N atom; in another embodiment, X3 is CR 2d In another embodiment, X3 is NR 2d .

[0199] In a more specific embodiment, Selected from In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for

[0200] In a more specific embodiment, X1, X2 and their substituents together form C 5-10 In another more specific embodiment, X1, X2 and their substituents together form a 5-10 membered heterocyclic group; In another more specific embodiment, X1, X2 and their substituents together form a C 6-10 Aryl; in another more specific embodiment, X1, X2 and their substituents together form a 5-10 membered heteroaryl; in another more specific embodiment, X1, X2 and their substituents together form a C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; In another more specific embodiment, X1, X2 and their substituents together form Preferred Formation Preferred Formation Preferred Formation

[0201] R 2a

[0202] In one embodiment, R 2a is H; in another embodiment, R 2a is D; in another embodiment, R 2a is CN; in another embodiment, R 2a OR a In another embodiment, R 2a NR b R c In another embodiment, R 2a C(O)OR a In another embodiment, R 2a C(O)NR b R c .

[0203] In a more specific embodiment, R 2a Selected from H, D, CN, OR a or NR b R c In another more specific embodiment, R 2a Selected from OR a or NR b R c In another more specific embodiment, R 2a Selected from OMe or NH2, preferably NH2.

[0204] R 2b

[0205] In one embodiment, R 2b is H; in another embodiment, R 2b is D; in another embodiment, R 2b is halogen; in another embodiment, R 2b C(O)OR a In another embodiment, R 2b C(O)NR b R c In another embodiment, R 2b C 1-6 Alkyl; in another embodiment, R 2b C 1-6 haloalkyl; in another embodiment, R 2b C 3-10 Cycloalkyl; in another embodiment, R 2b It is a 3-10 membered heterocyclic group.

[0206] In a more specific embodiment, R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 2b Selected from H, D, halogen, C(O)NR b R c 、C 1-6 Alkyl, C 1-6 haloalkyl or 4-6 membered heterocyclyl; in another more specific embodiment, R 2b Selected from H, D, halogen, C(O)NR b R c 、C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 2b Selected from H, D, halogen, C(O)NR b R c or C 1-6 Alkyl; in another more specific embodiment, R 2b Selected from H, F, Cl, Br, Me, CH2CH3, C(O)NH2 or In another more specific embodiment, R 2b Selected from H, F, Cl, Br, Me, CH2CH3 or C(O)NH2, preferably selected from Me or C(O)NH2.

[0207] R 2c

[0208] In one embodiment, R 2c is H; in another embodiment, R 2c is D; in another embodiment, R 2c is halogen; in another embodiment, R 2c C 1-6 Alkyl; in another embodiment, R 2c C 1-6 Halogenated alkyl.

[0209] In a more specific embodiment, R 2c is selected from H, halogen or Me; preferably selected from H or Me.

[0210] R 2d

[0211] In one embodiment, R 2d is H; in another embodiment, R 2d is D; in another embodiment, R 2d is halogen; in another embodiment, R 2d is CN; in another embodiment, R 2d is NO2; in another embodiment, R 2d OR a In another embodiment, R 2d NR b R c In another embodiment, R 2d C 1-6 Alkyl; in another embodiment, R 2d C 1-6 haloalkyl; in another embodiment, R 2d C 5-10 Cycloalkyl; in another embodiment, R 2d is a 5-10 membered heterocyclic group; in another embodiment, R 2d C 6-10 Aryl; In another embodiment, R 2d It is a 5-10 membered heteroaryl group.

[0212] In a more specific embodiment, R 2d Selected from H, D, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 2d Select from H or D.

[0213] R3

[0214] In one embodiment, R3 is -C 1-6 Alkylene-OR a In another embodiment, R3 is -C 1-6 Alkylene-NR b R c In another embodiment, R3 is C 1-6 Alkyl; in another embodiment, R3 is C 1-6 In another embodiment, R3 is C 2-6 In another embodiment, R3 is C 2-6 Alkynyl; in another embodiment, R3 is -LC 3-10 Cycloalkyl; in another embodiment, R3 is -L-3-10 membered heterocyclyl; in another embodiment, R3 is -LC 6-10 Aryl; in another embodiment, R3 is -L-5-10 membered heteroaryl; in another embodiment, R3 is optionally replaced by 1, 2 or 3 R 3s1 and 1 R 3s2 replace.

[0215] In a more specific embodiment, R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; In another more specific embodiment, R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 In another more specific embodiment, R3 is selected from Me, Et, iPr, cyclopropyl, cyclobutyl,

[0216] L

[0217] In one embodiment, L is a chemical bond; in another embodiment, L is C 1-6 Alkylene; in another embodiment, L is C 2-6 Alkenylene; in another embodiment, L is C 2-6 Alkyne; in another embodiment, L is optionally substituted with 1, 2, or 3 R.

[0218] R 1s

[0219] In one embodiment, R 1s is H; in another embodiment, R 1sis D; in another embodiment, R 1s is halogen; in another embodiment, R 1s is CN; in another embodiment, R 1s =0; in another embodiment, R 1s C(O)OR a In another embodiment, R 1s C(O)NR b R c In another embodiment, R 1s C 1-6 Alkyl; in another embodiment, R 1s C 1-6 haloalkyl; in another embodiment, R 1s C 2-6 alkenyl; in another embodiment, R 1s C 2-6 Alkynyl; in another embodiment, R 1s C 3-10 Cycloalkyl; in another embodiment, R 1s is a 3-10 membered heterocyclic group; in another embodiment, R 1s C 6-10 Aryl; In another embodiment, R 1s is a 5-10 membered heteroaryl; in another embodiment, two R 1s and the atoms they are connected to form C 3-10 Cycloalkyl; in another embodiment, two R 1s and the atoms to which they are attached together form a 3-10 membered heterocyclic group.

[0220] In one embodiment, R 2s is H; in another embodiment, R 2s is D; in another embodiment, R 2s is halogen; in another embodiment, R 2s =0; in another embodiment, R 2s C(O)OR a In another embodiment, R 2s C(O)NR b R c In another embodiment, R 2s C 1-6 Alkyl; in another embodiment, R 2s C 1-6 haloalkyl; in another embodiment, R 2s C 2-6 alkenyl; in another embodiment, R2s C 2-6 Alkynyl; in another embodiment, R 2s C 3-10 Cycloalkyl; in another embodiment, R 2s is a 3-10 membered heterocyclic group; in another embodiment, R 2s C 6-10 Aryl; In another embodiment, R 2s It is a 5-10 membered heteroaryl group.

[0221] In a more specific embodiment, R 1s Selected from H, D, halogen, =O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; in another more specific embodiment, R 1s Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclyl; in another more specific embodiment, R 1s Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 1s Selected from H, D, halogen, C(O)OR a 、C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 1s Selected from halogen or C(O)OCH3.

[0222] In a more specific embodiment, R 2s Selected from H, D, halogen, =O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; in another more specific embodiment, R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 2s Selected from H, D, =O, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 2s is selected from H, D, =O or Me.

[0223] R 3s1

[0224] In one embodiment, R 3s1 is H; in another embodiment, R 3s1 is D; in another embodiment, R 3s1 is halogen; in another embodiment, R 3s1 C 1-6 Alkyl; in another embodiment, R 3s1 C 1-6 haloalkyl; in another embodiment, R 3s1 C 2-6 alkenyl; in another embodiment, R 3s1 C 2-6 Alkynyl; in another embodiment, R 3s1 C 3-10 Cycloalkyl; in another embodiment, R 3s1 is a 3-10 membered heterocyclic group; in another embodiment, R 3s1 C 6-10 Aryl; In another embodiment, R 3s1 It is a 5-10 membered heteroaryl group.

[0225] In a more specific embodiment, R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; in another more specific embodiment, R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl; in another more specific embodiment, R 3s1 Selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl; in another more specific embodiment, R 3s1 Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; in another more specific embodiment, R 3s1 is selected from H, Me or cyclopropyl; preferably selected from H or Me.

[0226] R 3s2

[0227] In one embodiment, R 3s2 is H; in another embodiment, R 3s2 is D; in another embodiment, R 3s2 For-L-OR a In another embodiment, R 3s2 -L-NR b R c In another embodiment, R 3s2 C 1-6 Alkyl; in another embodiment, R 3s2 C 1-6 haloalkyl; in another embodiment, R 3s2 C 3-10 Cycloalkyl; in another embodiment, R 3s2 is a 5-10 membered heterocyclic group; in another embodiment, R 3s2 C 6-10 Aryl; In another embodiment, R 3s2 is a 5-10 membered heteroaryl; in another embodiment, R 3s2 Optionally 1, 2 or 3 R 3s replace.

[0228] In a more specific embodiment, R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; in another more specific embodiment, R 3s2Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl, 5-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; in another more specific embodiment, R 3s2 Selected from H, D, -L-OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl, phenyl or 5-10 membered heteroaryl; in another more specific embodiment, R 3s2 Selected from H, D, Me, CF3, CH2OCH3, cyclopropyl, Preferably selected from C 5-7 Cycloalkyl, 5-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably C 5-7 Cycloalkyl, such as cyclopropyl; preferably Et.

[0229] In another more specific embodiment, R 3s1 、R 3s2 and the carbon atoms to which they are attached together to form C 3-10 Cycloalkyl, such as C 3-6 Cycloalkyl.

[0230] R

[0231] In one embodiment, R is H; in another embodiment, R is D; in another embodiment, R is halogen; in another embodiment, R is C 1-6 Alkyl; in another embodiment, R is C 1-6 Halogenated alkyl.

[0232] R 3s

[0233] In one embodiment, R 3s is H; in another embodiment, R 3s is D; in another embodiment, R 3s is halogen; in another embodiment, R 3s C 1-6 Alkyl; in another embodiment, R 3s C 1-6 Halogenated alkyl.

[0234] R a 、R b and R c

[0235] In one embodiment, R a 、R b and R c are independently H; in another embodiment, R a 、R b and R c is independently D; in another embodiment, R a 、R b and R c Independently C 1-6 Alkyl; in another embodiment, R a 、R b and R c Independently C 1-6 haloalkyl; in another embodiment, R a 、R b and R c Independently C 3-10 Cycloalkyl; in another embodiment, R a 、R b and R c is independently a 3-10 membered heterocyclyl; in another embodiment, R a 、R b and R c Independently C 6-10 Aryl; In another embodiment, R a 、R b and R c are independently 5-10 membered heteroaryl; in another embodiment, R b 、R c Together with the atoms to which they are attached, they form a 5-10 membered heterocyclic group, preferably a 5-6 membered heterocyclic group.

[0236] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of Ring A can be combined with L1, L2, L3, R x 、R y , R1, m, X1, X2, X3, R 2a 、R 2b 、R 2c 、R 2d , R3, L, R, R 1s 、R 2s 、R 3s 、R 3s1 、R 3s2 、R a 、R b and R cThe present invention is intended to include all of these technical solutions, which are not listed one by one due to space limitations.

[0237] In a more specific embodiment, the present invention provides a compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0238] in,

[0239] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0240] L1 is NH or CHR x ;

[0241] L2 is CR x R y ;

[0242] L3 is -C(O)-, -S(O)- or -S(O)2-;

[0243] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0244] or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene;

[0245] Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-4 alkylene;

[0246] R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2Ra 、S(O)(=NR a )R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0247] m = 0, 1, 2, 3, or 4;

[0248] R4 is selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0249] Or one R1 is connected to R4 to form -(CH2) q1 -X-(CH2) q2 -; wherein X is O, S, NH or CH2, q1=0, 1 or 2, q2=1, 2 or 3;

[0250] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0251] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0252] X3 is a C atom or a N atom, which is optionally replaced by R 2d replace;

[0253] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0254] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0255] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0256] Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0257] R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0258] R3 is selected from -C 1-6 Alkylene-OR a 、-C 1-6 Alkylene-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s1 and 1 R 3s2 replace;

[0259] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R;

[0260] R 1s and R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0261] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0262] R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0263] R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0264] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0265] wherein the above rings A, L1, L2, R x 、R y , R1, R 2a 、R 2b 、R 2c 、R 2d , R3, R4, L, R, R 1s 、R 2s 、R 3s 、R 3s1、R 3s2 、R a 、R b and R c The various groups defined in are optionally deuterated, up to fully deuterated;

[0266] The condition is that when L2 is CR x R y 、When L3 is -S(O)- or -S(O)2-, R y With R 2d Combined to form vinylidene.

[0267] In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0268] in,

[0269] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0270] L1 is NH or CHR x ;

[0271] L2 is CR x R y ;

[0272] L3 is -C(O)-, -S(O)- or -S(O)2-;

[0273] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0274] or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene;

[0275] Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-4 alkylene;

[0276] R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)Ra 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0277] m = 0, 1, 2, 3, or 4;

[0278] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0279] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0280] X3 is a C atom or a N atom, which is optionally replaced by R 2d replace;

[0281] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0282] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0283] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0284] Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0285] R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0286] R3 is selected from -C 1-6 Alkylene-OR a 、-C 1-6 Alkylene-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s1 and 1 R 3s2 replace;

[0287] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R;

[0288] R 1s and R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0289] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0290] R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0291] R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0292] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0293] wherein the above rings A, L1, L2, R x 、R y , R1, R 2a 、R 2b 、R 2c 、R 2d , R3, L, R, R 1s 、R 2s 、R 3s 、R 3s1 、R 3s2 、R a 、R b and R c The various groups defined in are optionally deuterated, up to fully deuterated;

[0294] The condition is that when L2 is CRx R y 、When L3 is -S(O)- or -S(O)2-, R y With R 2d Combined to form vinylidene.

[0295] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein ring A is phenyl or a 5-6 membered heteroaryl group; preferably phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0296] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH, L2 is CR x R y ;-L1-L2- is preferably -L1-L2- is preferably

[0297] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is CHR x , L2 is CR x R y ;-L1-L2- is preferably

[0298] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L3 is -C(O)-.

[0299] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10Aryl or -L-5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group; preferably selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; preferably selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl or 5-6 membered heterocyclic group; preferably selected from H, D, CN, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group; preferably selected from H, D, CN, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl or 5-6 membered heterocyclic group; preferably selected from CF3, CN, OCF3, OCH2CH3, Preferably selected from CF3, CN, OCF3, OCH2CH3, Preferred is CF3.

[0300] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R1 and R4 are linked to form -(CH2) q1 -X-(CH2) q2 -; wherein X is O, S, NH or CH2, q1 = 0 or 1, q2 = 1 or 2; preferably, R1 and R4 are connected to form -(CH2) q1 -X-(CH2) q2 -; wherein X is O, S or NH, q1=0 or 1, q2=1 or 2.

[0301] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein, Selected from Preferably

[0302] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2a Selected from H, D, CN, OR a or NR b R c ; preferably selected from OR a or NR b R c ; preferably selected from OMe or NH2; preferably NH2.

[0303] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, halogen, C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl or 4-6 membered heterocyclic group; preferably selected from H, D, halogen, C(O)NRb R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, C(O)NR b R c or C 1-6 Alkyl; preferably selected from H, F, Cl, Br, Me, CH2CH3, C(O)NH2 or Preferably selected from H, F, Cl, Br, Me, CH2CH3 or C(O)NH2; preferably selected from Me or C(O)NH2.

[0304] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2c Selected from H or Me.

[0305] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; preferably formed Preferred Formation Preferred Formation Preferred Formation

[0306] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2d Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H or D.

[0307] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; preferably selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; preferably selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; preferably selected from Me, Et, iPr, cyclopropyl, cyclobutyl,

[0308] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1s Selected from H, D, halogen, =O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group; preferably selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, C(O)OR a 、C 1-6 Alkyl or C 1-6 The haloalkyl group is preferably selected from halogen or C(O)OCH3.

[0309] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2sSelected from H, D, halogen, =O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, =O, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably selected from H, D, =O or Me.

[0310] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; preferably selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; preferably selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; preferably selected from H, Me or cyclopropyl; preferably selected from H or Me.

[0311] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl, 5-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably selected from H, D, -L-OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl, phenyl or 5-10 membered heteroaryl; preferably selected from H, D, Me, CF3, CH2OCH3, cyclopropyl, Preferably selected from C 5-7 Cycloalkyl, 5-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably C 5-7 Cycloalkyl, such as cyclopropyl; preferably Et.

[0312] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the following structural formula:

[0313] wherein each group is as defined above.

[0314] In a more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is a compound of formula (II), wherein,

[0315] L1 is NH or CHR x ;

[0316] L2 is CR x R y ;

[0317] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0318] or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene;

[0319] Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-4 alkylene;

[0320] Z1 is CH or N;

[0321] R1 is H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0322] m=0, 1, 2 or 3, preferably m=0;

[0323] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0324] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0325] X3 is a C atom or a N atom, which is optionally replaced by R 2d replace;

[0326] R 2a Selected from H, D, OR a or NR b R c ;

[0327] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0328] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0329] Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2sreplace;

[0330] R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0331] R 1s Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group;

[0332] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0333] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0334] R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl, 5-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0335] L is a chemical bond or C 1-6 Alkylene, optionally substituted with 1, 2 or 3 R;

[0336] R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0337] R a 、R b and R cIndependently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0338] Among them, L1, L2, R x 、R y , Z1, R1, R 2a 、R 2b 、R 2c 、R 2d 、R 1s 、R 2s 、R 3s1 、R 3s2 ,L,R,R 3s 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0339] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0340] L1 is NH or CHR x ;

[0341] L2 is CR x R y ;

[0342] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0343] or CR x R y Together to form C=O, C=S or C 3-4 cycloalkylene;

[0344] Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-3 alkylene;

[0345] Z1 is CH or N;

[0346] R1 is selected from H, D, halogen, CN, OR a NRb R c 、C 1-6 Alkyl, C 1-6 haloalkyl or 5-6 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1, 2 or 3 R 1s replace;

[0347] m=0, 1, 2 or 3, preferably m=0;

[0348] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0349] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0350] X3 is a C atom or a N atom, which is optionally replaced by R 2d replace;

[0351] R 2a is NH2;

[0352] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0353] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0354] Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0355] R 2d Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0356] R 1s Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0357] R 2s Selected from H, D, =O, C1-6 Alkyl or C 1-6 alkyl halide;

[0358] R 3s1 Selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0359] R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl, 5-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0360] L is a chemical bond or C 1-3 Alkylene, optionally substituted with 1, 2 or 3 R;

[0361] R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0362] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0363] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0364] L1 is NH or CHR x ;

[0365] L2 is CR x R y ;

[0366] where R x and R y H, D, C independently 1-3 Alkyl or C 1-3 alkyl halide;

[0367] or CR x R yTogether they form C=O or cyclopropylene;

[0368] Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-2 alkylene;

[0369] Z1 is CH or N;

[0370] R1 is selected from H, D, CN, OR a 、C 1-6 Alkyl, C 1-6 A haloalkyl group or a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0371] m=0, 1, 2 or 3, preferably m=0;

[0372] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0373] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0374] X3 is a C atom or a N atom, which is optionally replaced by R 2d replace;

[0375] R 2a is NH2;

[0376] R 2b Selected from H, D, halogen, C(O)NR b R c 、C 1-6 Alkyl, C 1-6 a haloalkyl group or a 4-6 membered heterocyclic group;

[0377] R 2c Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0378] Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s Replacement; Preferred

[0379] R 2d Selected from H or D;

[0380] R 1sSelected from H, D, halogen, C(O)OR a 、C 1-6 Alkyl or C 1-6 Haloalkyl, preferably halogen or C(O)OCH3;

[0381] R 2s is selected from H, D, ═O or Me;

[0382] R 3s1 Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0383] R 3s2 Selected from H, D, -L-OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl, phenyl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s substituted; preferably, R 3s2 Selected from H, D, Me, CF3, CH2OCH3, cyclopropyl,

[0384] L is a chemical bond or C 1-3 Alkylene, preferably methylene, optionally substituted with 1, 2 or 3 R;

[0385] R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0386] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0387] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0388] L1 is NH;

[0389] L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S;

[0390] R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0391] m = 0, 1, 2, 3, or 4;

[0392] X1 is a C atom, which is R 2b replace;

[0393] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0394] X3 is a C atom, which is R 2d replace;

[0395] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0396] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b Rc 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0397] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0398] Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0399] R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0400] Z1 is CH;

[0401] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R;

[0402] R 1s and R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0403] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0404] R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0405] R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0406] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0407] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0408] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0409] L1 is NH;

[0410] L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S;

[0411] R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)Ra NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0412] m = 0, 1, 2, 3, or 4;

[0413] X1 is a C atom, which is R 2b replace;

[0414] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0415] X3 is a C atom, which is R 2d replace;

[0416] R 2a Selected from H, D, CN, OR a or NR b R c ;

[0417] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0418] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0419] Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0420] R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0421] Z1 is CH;

[0422] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene;

[0423] R 1s and R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0424] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0425] R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0426] R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0427] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、Rc and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0428] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0429] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0430] L1 is NH;

[0431] L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S;

[0432] R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0433] m = 0, 1, 2, 3, or 4;

[0434] X1 is a C atom, which is R 2b replace;

[0435] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0436] X3 is a C atom, which is R 2d replace;

[0437] R 2a Selected from H, D, CN, OR a or NR b R c ;

[0438] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0439] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0440] Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0441] R 2d Selected from H, D, halogen, CN, NO2, C 1-6 Alkyl or C 1-6 alkyl halide;

[0442] Z1 is CH;

[0443] L is a chemical bond or C 1-6 alkylene;

[0444] R 1s and R 2s Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0445] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0446] R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0447] R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0448] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0449] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0450] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0451] L1 is NH;

[0452] L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S;

[0453] R1 is selected from H, D, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b Rc 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0454] m = 0, 1, 2, 3, or 4;

[0455] X1 is a C atom, which is R 2b replace;

[0456] X2 is a C atom, which is R 2c replace;

[0457] X3 is a C atom, which is R 2d replace;

[0458] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0459] R 2b Selected from C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 alkyl halide;

[0460] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0461] Or X1, X2 and their substituents together form a 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0462] R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C6-10 Aryl or 5-10 membered heteroaryl;

[0463] Z1 is CH;

[0464] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R;

[0465] R 1s and R 2s Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0466] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0467] R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0468] R and R 3s Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0469] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0470] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0471] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0472] L1 is NH;

[0473] L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S;

[0474] R1 is selected from H, D, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0475] m = 0, 1, 2, 3, or 4;

[0476] X1 is a C atom, which is R 2b replace;

[0477] X2 is a C atom, which is R 2c replace;

[0478] X3 is a C atom, which is R 2d replace;

[0479] R 2a Selected from H, D, CN, OR a or NR bR c ;

[0480] R 2b Selected from C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 alkyl halide;

[0481] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0482] Or X1, X2 and their substituents together form a 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0483] R 2d is selected from H, D, halogen or CN;

[0484] Z1 is CH;

[0485] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene;

[0486] R 1s and R 2s Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0487] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0488] R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0489] R a 、R band R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0490] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0491] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0492] L1 is NH;

[0493] L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S;

[0494] R1 is selected from H, D, OR a SR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0495] m = 0, 1, 2, 3, or 4;

[0496] X1 is a C atom, which is R 2b replace;

[0497] X2 is a C atom, which is R 2c replace;

[0498] X3 is a C atom, which is R 2d replace;

[0499] R 2a Selected from OR a or NR b R c ;

[0500] R 2b Selected from C(O)OR a 、C(O)NRb R c 、C 1-6 Alkyl, C 1-6 alkyl halide;

[0501] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0502] Or X1, X2 and their substituents together form a 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0503] R 2d is selected from H, D, halogen or CN;

[0504] Z1 is CH;

[0505] L is a chemical bond or C 1-6 alkylene;

[0506] R 1s and R 2s Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0507] R 3s1 Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0508] R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0509] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0510] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0511] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0512] L1 is NH;

[0513] L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S;

[0514] R1 is selected from H, D, OR a SR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0515] m = 0, 1, 2, 3, or 4;

[0516] X1 is a C atom, which is R 2b replace;

[0517] X2 is a C atom, which is R 2c replace;

[0518] X3 is a C atom, which is R 2d replace;

[0519] R 2a Selected from OR a or NR b R c ;

[0520] R 2b Selected from C(O)OR a 、C(O)NR b R c or C 1-6 alkyl;

[0521] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0522] Or X1, X2 and their substituents together form a 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0523] R 2d is selected from H, D, halogen or CN;

[0524] Z1 is CH;

[0525] L is a chemical bond or C 1-6 alkylene;

[0526] R 1s and R 2s Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0527] R 3s1 Selected from Me;

[0528] R 3s2 Selected from Et;

[0529] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0530] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0531] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0532] L1 is NH;

[0533] L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S;

[0534] R1 is selected from H, D, OR a SR a NR b R c、C(O)R a 、S(O)R a 、S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0535] m = 0, 1, 2, 3, or 4;

[0536] X3 is a C atom, which is R 2d replace;

[0537] R 2a Selected from OR a or NR b R c ;

[0538] X1, X2 and their substituents together form a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0539] R 2d is selected from H, D, halogen or CN;

[0540] Z1 is CH;

[0541] R 1s and R 2s Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0542] R 3s1 Selected from H or D;

[0543] R 3s2 Selected from C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

[0544] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0545] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0546] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0547] L1 is NH;

[0548] L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S;

[0549] R1 is selected from H, D, OR a SR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0550] m = 0, 1, 2, 3, or 4;

[0551] X3 is a C atom, which is R 2d replace;

[0552] R 2a Selected from OR a or NR b R c ;

[0553] X1, X2 and their substituents together form a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0554] R 2d is selected from H, D, halogen or CN;

[0555] Z1 is CH;

[0556] L is a chemical bond or C 1-6 alkylene;

[0557] R 1s and R 2s Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0558] R 3s1 Selected from C 1-4 Alkyl or C 1-4 alkyl halide;

[0559] R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0560] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0561] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0562] In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0563] L1 is NH or CHR x ;

[0564] L2 is CR x R y ;

[0565] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0566] or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene;

[0567] Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-4 alkylene;

[0568] Z1 is CH or N;

[0569] R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0570] m=0, 1, 2 or 3, preferably m=0;

[0571] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0572] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0573] X3 is a C atom or a N atom, which is optionally replaced by R 2d replace;

[0574] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0575] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0576] Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0577] R 2d Selected from H or D;

[0578] R 1s Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group;

[0579] R 2sSelected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0580] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0581] R 3s Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0582] p=0, 1, 2 or 3, preferably p=0;

[0583] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0584] Among them, L1, L2, R x 、R y , Z1, R1, R 2b 、R 2c 、R 1s 、R 2s 、R 3s1 、R 3s 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0585] In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0586] L1 is NH or CHR x ;

[0587] L2 is CR x R y ;

[0588] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0589] or CR x R y Together to form C=O, C=S or C 3-4 cycloalkylene;

[0590] Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-3 alkylene;

[0591] Z1 is CH or N;

[0592] R1 is selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 haloalkyl or 5-6 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1, 2 or 3 R 1s replace;

[0593] m=0, 1, 2 or 3, preferably m=0;

[0594] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0595] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0596] X3 is a C atom or a N atom, which is optionally replaced by R 2d replace;

[0597] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0598] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0599] Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0600] R 2d Selected from H or D;

[0601] R 1s Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0602] R 2s Selected from H, D, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0603] R 3s1 Selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0604] R 3s Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0605] p=0, 1, 2 or 3, preferably p=0;

[0606] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0607] In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0608] L1 is NH or CHR x ;

[0609] L2 is CR x R y ;

[0610] where R x and R y H, D, C independently 1-3 Alkyl or C 1-3 alkyl halide;

[0611] or CR x R y Together they form C=O or cyclopropylene;

[0612] Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-2 alkylene;

[0613] Z1 is CH or N;

[0614] R1 is selected from H, D, CN, OR a 、C 1-6 Alkyl, C 1-6 A haloalkyl group or a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0615] m=0, 1, 2 or 3, preferably m=0;

[0616] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0617] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0618] X3 is a C atom or a N atom, which is optionally replaced by R 2d replace;

[0619] R 2b Selected from H, D, halogen, C(O)NR b R c 、C 1-6 Alkyl, C 1-6 a haloalkyl group or a 4-6 membered heterocyclic group;

[0620] R 2c Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0621] Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0622] R 2d Selected from H or D;

[0623] R 1s Selected from H, D, halogen, C(O)OR a 、C 1-6 Alkyl or C 1-6 Haloalkyl, preferably halogen or C(O)OCH3;

[0624] R 2s is selected from H, D, ═O or Me;

[0625] R 3s1 Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0626] R 3s Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0627] p=0, 1, 2 or 3, preferably p=0;

[0628] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0629] In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0630] L1-L2 is:

[0631] Z1 is CH or N;

[0632] R1 is CF3, CN, OCF3, OCH2CH3, Preferably CF3;

[0633] m=0;

[0634] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0635] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0636] X3 is a C atom or a N atom, which is optionally replaced by R 2d replace;

[0637] R 2b H, F, Cl, Br, Me, CH2CH3, C(O)NH2 or

[0638] R 2c is H or Me;

[0639] Or X1, X2 and their substituents together form:

[0640] R 2d is H;

[0641] R 3s1 is H, Me or cyclopropyl;

[0642] R 3s is H;

[0643] p=0.

[0644] In a more specific embodiment, the present invention provides a compound of formula (IV), (IV-1), (IV-1a), (IV-1b), (IV-2), (IV-2a) or (IV-2b) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0645] R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0646] m = 0, 1, or 2;

[0647] R4 is selected from H or D;

[0648] X1 is a C atom, which is R 2b replace;

[0649] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0650] X3 is a C atom, which is R 2d replace;

[0651] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0652] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0653] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0654] Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0655] R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0656] Z1 is CH;

[0657] Z2 is CR1 or N;

[0658] Z3 is CR1 or N;

[0659] When Z2 is CR1, R1 and R4 are connected to form -(CH2) q1 -X-(CH2) q2 -; wherein X is O, S, NH or CH2, q1=0, 1 or 2, q2=1, 2 or 3;

[0660] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R;

[0661] R 1s and R 2s Independently selected from H, D, halogen, CN, ═O, OR a NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or two R 1s and the atoms they are connected to form C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, halogen, CN, =O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0662] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0663] R 3s2 Selected from H, D, -L-OR a 、-L-NRb R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0664] R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0665] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0666] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0667] In a more specific embodiment, the present invention provides a compound of formula (IV), (IV-1), (IV-1a), (IV-1b), (IV-2), (IV-2a) or (IV-2b) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0668] R1 is selected from H, D, halogen, CN, NO2, OR a SR a NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0669] m = 0, 1, or 2;

[0670] R4 is selected from H or D;

[0671] X1 is a C atom, which is R 2b replace;

[0672] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0673] X3 is a C atom, which is R 2d replace;

[0674] R 2a Selected from H, D, CN, OR a or NR b R c ;

[0675] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0676] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0677] Or X1, X2 and their substituents together form C 5-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0678] R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl or C 1-6alkyl halide;

[0679] Z1 is CH;

[0680] Z2 is CR1, and R1 and R4 are connected to form -(CH2) q1 -X-(CH2) q2 -; wherein X is O, S, NH or CH2, q1=0 or 1, q2=1 or 2;

[0681] Z3 is CR1 or N;

[0682] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R;

[0683] R 1s and R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0684] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0685] R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0686] R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C1-6 alkyl halide;

[0687] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0688] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0689] In a more specific embodiment, the present invention provides a compound of formula (IV), (IV-1), (IV-1a), (IV-1b), (IV-2), (IV-2a) or (IV-2b) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0690] R1 is selected from H, D, halogen, CN, NO2, OR a SR a NR b R c 、SF5、C(O)R a 、S(O)R a 、S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 4-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0691] m = 0, 1, or 2;

[0692] R4 is selected from H or D;

[0693] X1 is a C atom, which is R 2b replace;

[0694] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0695] X3 is a C atom, which is R 2d replace;

[0696] R2a Selected from OR a or NR b R c ;

[0697] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0698] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0699] Or X1, X2 and their substituents together form C 5-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0700] R 2d Selected from H, D, halogen, CN, NO2, C 1-6 Alkyl or C 1-6 alkyl halide;

[0701] Z1 is CH;

[0702] Z2 is CR1, and R1 and R4 are connected to form -(CH2) q1 -X-(CH2) q2 -; wherein X is O, S or NH, q1=0 or 1, q2=1 or 2;

[0703] Z3 is CR1 or N;

[0704] L is a chemical bond or C 1-6 alkylene;

[0705] R 1s and R 2s Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0706] R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0707] R3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace;

[0708] R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0709] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group;

[0710] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0711] In the most specific embodiment, the present invention provides a compound of formula (X) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the compound is selected from the following:

[0712] In the most specific embodiment, the present invention provides a compound of formula (X) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the compound is selected from the following:

[0713] In the most specific embodiment, the present invention provides a compound of formula (X) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the compound is selected from the following:

[0714] In the most specific embodiment, the present invention provides a compound of formula (X) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the compound is selected from the following:

[0715] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present 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 enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0716] The compounds of the present invention may exist as tautomers. Tautomers are functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can convert between each other, but the more stable isomer usually predominates. The most prominent examples are the enol and keto tautomers.

[0717] Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates." When the solvent is water, the complex is referred to as a "hydrate." The present invention encompasses all solvates of the compounds of the present invention.

[0718] The term "solvate" refers to a form of a compound or its salt that is combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in a crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in the solution state and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0719] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by the general formula R·x H2O, for example, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5 H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2 H2O) and hexahydrates (R·6 H2O)).

[0720] The compounds of the present invention can be in amorphous or crystalline form (polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can cause one crystalline form to dominate. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0721] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I) but for which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually 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, 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 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (A) of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0722] In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo, for example by hydrolysis in the blood, into its active form that has a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.

[0723] A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such a prodrug is administered to a patient. Prodrugs are typically prepared by modifying functional groups in such a way that the modification can be cleaved to produce the parent compound by conventional manipulation or in vivo. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, can cleave to form a hydroxyl, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide, and benzoate / amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of compounds of formula (A). In addition, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, and the like can be used. Esters themselves can be active and / or can be hydrolyzed under human in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily decompose in the human body to release the parent acid or a salt thereof.

[0724] The present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (A) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present invention.

[0725] Pharmaceutical compositions and kits

[0726] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

[0727] Pharmaceutically acceptable excipients used in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0728] Suitable formulations for administering the compounds of the present invention will be readily apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions (particularly solutions for injection (subcutaneous, intravenous, intramuscular) and infusion (injection)), elixirs, syrups, cachets, emulsions, inhalants, or dispersible powders. The content of the one or more pharmaceutically active compounds should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight, of the composition as a whole, i.e., an amount sufficient to achieve the dosage range specified below. If necessary, the specified dosage may be administered several times a day.

[0729] The present invention also includes kits (e.g., pharmaceutical packaging). The kits provided may include a compound of the 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 compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0730] Drug administration

[0731] Pharmaceutical compositions provided by the invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion technology.

[0732] Typically, an effective amount of the compounds provided herein is administered. The amount of compound actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0733] When used to prevent the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0734] The pharmaceutical compositions provided herein can also be administered long-term ("chronic administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within the therapeutic window.

[0735] 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 injection, for example, in order 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 ingredient by the body, for example, an intramuscular or subcutaneous bolus dose slowly releases the active ingredient, and the bolus (for example, by IV intravenous drip) delivered directly to the vein can be delivered more quickly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the bolus dose can be first given, and then continuous infusion.

[0736] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the compositions are provided in unit dosage form. 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 amount of active substance suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is typically a minor 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 and processing aids useful for forming the desired dosage form.

[0737] For oral dosage, a representative regimen is one to five oral doses per day, particularly two to four oral doses, typically three oral doses. Using these dosage administration modes, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, with preferred doses each providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0738] To provide blood levels similar to, or lower than, those obtained with an injectable dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0739] From about 1 to about 120 hours, and particularly from 24 to 96 hours, the injected dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To achieve adequate steady-state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered. For a 40 to 80 kg human patient, the maximum total dose may not exceed about 2 g / day.

[0740] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0741] Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0742] Typically, transdermal compositions are formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components that enhance the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.

[0743] The compounds of the present invention may also be administered by transdermal devices.Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or various solid matrices.

[0744] The above components for oral administration, injection or topical administration are representative only. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0745] The compounds of the invention can also be administered in sustained release form or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0746] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar portion, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0747] Indications

[0748] In MTAP-deficient tumors, developing MTA-synergistic PRMT5 inhibitors could provide therapeutic benefits to a large number of cancer patients. The compounds of this invention exert their therapeutic effects by negatively regulating the activity of MTA-bound PRMT5 in tumor cells, particularly against MTAP-deficient cells or various MTAP-associated tumor cells.

[0749] In some embodiments, the MTA-synergistic PRMT5 inhibitors described herein can treat a variety of cancers, including but not limited to tumor types such as malignant peripheral nerve sheath tumor, mesothelioma, glioblastoma multiforme, pancreatic cancer, bile duct cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer, astrocytoma, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, thymoma, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, squamous cell carcinoma of the lung, lung adenocarcinoma, oral cancer, ovarian cancer, kidney cancer and thyroid cancer, as well as sarcoma.

[0750] More specifically, these compounds can be used to treat: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, etc.), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, etc.), stomach (tumor, lymphoma, leiomyosarcoma, etc.), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma, etc.), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, etc.), Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma Tumors: ovarian cancer (tumor, neurofibroma, fibroma, etc.); colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma, etc.); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor, etc.), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, etc.), prostate (adenocarcinoma, sarcoma, etc.), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma, etc.); liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct cancer: gallbladder cancer, ampullary carcinoma, bile duct cancer, etc.; bone: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma, etc.). ), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor of bone; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, deforming osteitis, etc.), meninges (meningiomas, meningiosarcomas, gliomas, etc.), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealoma, etc.), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, etc.), spinal neurofibromas, meningiomas, gliomas, sarcomas, etc.); gynecology: uterus (endometrial cancer, etc.), cervix (cervical cancer, preneoplastic cervical dysplasia etc.), ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, etc.), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma, etc.), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, etc.), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma, etc.), fallopian tube cancer, etc.; Hematology: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, etc.), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), etc.;Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, etc.; Adrenal gland: neuroblastoma, etc.;

[0751] Combination therapy

[0752] The MTA-synergistic PRMT5 inhibitor of the present invention can be combined with other drugs to treat cancer, including at least one target drug / cell activity regulator, including CDK4 / 6 inhibitors, MAT2A inhibitors, MAPK1 / MAPK3 inhibitors, Type I PRMT inhibitors, EGFR inhibitors, SHP2 inhibitors, pan-KRAS inhibitors, KRASG12C inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, MALT1 inhibitors, MALT2 inhibitors, BTK inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, DNA methyltransferase (DNMT) inhibitors, EZH1 / 2 inhibitors, EZH2 inhibitors, Menin-MLL inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1 / 2 inhibitors, chemotherapy drugs, radiotherapy, STING agonists or immune checkpoint inhibitors / regulators, etc.

[0753] Example

[0754] The starting materials and reagents used herein are either commercially available or prepared by synthetic methods generally known in the art.

[0755] 1. Synthesis of Example 1

[0756] 1.1 Synthesis of Intermediate 1-1

[0757] Di-tert-butyl dicarbonate (18 g), triethylamine (13 g), and 4-dimethylaminopyridine (0.8 g) were added to a solution of 2-amino-3-methyl-5-nitropyridine (5 g) in dichloromethane (50 mL) and stirred at room temperature for 3 hours. The mixture was extracted with ethyl acetate (100*3 mL), and the organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 5 / 1) to obtain 1-1 as a white solid (10 g, yield 82%). LC-MS: M+Na + =376.1.

[0758] 1.2 Synthesis of intermediate 1-2

[0759] 10% palladium on carbon (2 g) was added to a solution of compound 1-1 (10 g) in methanol (100 mL), and stirred at room temperature for 2 hours under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a light yellow solid 1-2 (9.2 g). LC-MS: M+H + =324.2.

[0760] 1.3 Synthesis of intermediate 1-3

[0761] At 0°C, under a nitrogen atmosphere, ethyl acetyl chloride (830 mg) and triethylamine (620 mg) were added to a solution of 1-2 (2 g) in dichloromethane (20 mL) and stirred at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted with dichloromethane (10*3 mL). The organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 2 / 1) to give 1-3 (2.5 g, yield 80%) as a white solid. LC-MS: M+H + =424.0.

[0762] 1.4 Synthesis of Intermediates 1-4

[0763] Lithium hydroxide (240 mg) was added to a solution of 1-3 (3 g) in methanol (10 mL) and water (10 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, diluted with water (20 mL), and the pH was adjusted to 6 with 1N hydrochloric acid solution. The mixture was filtered and the filter cake was dried to obtain 1-4 (1 g) as a white solid. LC-MS: M+H + =396.2.

[0764] 1.5 Synthesis of intermediate 1-5

[0765] Triethylamine (1080 mg) was added to a solution of (R)-1-(pyrimidin-2-yl)ethanamine hydrochloride (2 g) in 1,2-dichloroethane (100 mL). The mixture was stirred at room temperature for 1 hour. 5-Trifluoromethylpyridine-2-carboxaldehyde (1.8 g) was added, and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (3.2 g) was added, and the mixture was stirred at room temperature for 1 hour. Dichloromethane (50 mL) was added, and the mixture was washed sequentially with saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL), and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, dichloromethane / methanol = 100 / 0 to 100 / 3) to obtain 1-5 as a light yellow oil (1.8 g, 64% yield). LC-MS: M+H + =283.1.

[0766] 1.6 Synthesis of intermediate 1-6

[0767] At 0°C, under nitrogen protection, phosphorus oxychloride (38 mg) was added dropwise to a pyridine (2 mL) solution of 1-4 (50 mg) and 1-5 (36 mg), and stirred at 0°C for 1 hour. The mixture was concentrated under reduced pressure, and an aqueous sodium bicarbonate solution (10 mL) and water (20 mL) were added to the residue, and extracted with ethyl acetate (10*3 mL). The organic phase was washed with a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, dichloromethane / methanol = 10 / 1) to give a yellow solid 1-6 (20 mg, yield 32%). LC-MS: M+H + =660.0.

[0768] 1.7 Synthesis of Compound 1

[0769] Trifluoroacetic acid (2 mL) was added to a solution of 1-6 (20 mg) in dichloromethane (6 mL) and the mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC (column: Gemini 5u C18 150 x 21.2 mm; mobile phase: [H2O(NH3)-ACN]; B%: 2%-10%, 6 min) to afford 1 (5 mg, 20% yield) as a white solid. LC-MS: M+H + =460.2. 1 H NMR(400MHz,DMSO-d6)δppm 10.52-10.35(m,1H),8.82-8.73(m,2H),8.14-7.32(m,6H),5.73-5.60(m,3H),5.20-4.57(m,2H),2.03-1.96(m,3H),1.66-1.52(m,3H).

[0770] 2. Synthesis of Example 2

[0771] 2.1 Synthesis of Intermediate 2-1

[0772] Di-tert-butyl dicarbonate (565 mg) was added to a solution of 4-dimethylaminopyridine (6.8 mg), triethylamine (112.9 mg) and 7-bromo-1,3-dihydrofuro[3,4-c]pyridin-4-amine (120 mg) in dichloromethane (5 mL) and stirred at room temperature for 2 hours. The organic phase was washed with saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 5 / 1-2 / 1) to give 2-1 as a white solid (160 mg, yield 65.6%). LC-MS: M+Na + =437.1,439.1.

[0773] 2.2 Synthesis of compound 2-2

[0774] Cuprous iodide (18.1 mg), cesium carbonate (200 mg), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (110.2 mg) were added to a solution of trifluoroacetamide (71.7 mg) and compound 2-1 (100 mg) in dioxane (5 mL). The mixture was stirred at 110°C for 16 hours under nitrogen, cooled to room temperature, and extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, dichloromethane / ethyl acetate = 5 / 1 to 1 / 1) to obtain compound 2-2 (34 mg, 38.7% yield) as a white solid. LC-MS: M+H + =352.0.

[0775] 2.3 Synthesis of compound 2-3

[0776] Under ice-cooling, ethyl oxalyl chloride (139.8 mg) was added to a solution of triethylamine (121.2 mg) and 2-2 (240 mg) in dichloromethane (5 mL). The mixture was stirred at room temperature for 1 hour. The organic phase was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 5 / 1-2 / 1) to obtain 2-3 (230 mg, 74.6% yield) as a white solid. LC-MS: M+H + =451.9.

[0777] 2.4 Synthesis of Compound 2-4

[0778] Add sodium hydroxide (38.2 mg) to a solution of 2-3 (230 mg) in methanol (5 mL) and water (1 mL). Stir at room temperature for 1 hour, adjust the pH to 6 with 1N dilute hydrochloric acid, extract with ethyl acetate (10 mL*3), wash the organic phase with saturated sodium chloride solution (5 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure and lyophilize to obtain 2-4 as a white solid (170 mg, yield 71.9%). LC-MS: M+H + =424.2.

[0779] 2.5 Synthesis of Compound 2-5

[0780] Phosphorus oxychloride (36.2 mg) was added to a pyridine (2 mL) solution of 1-5 (40 mg) and 2-4 (50 mg) under ice bath and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution (1 mL) was added and extracted with ethyl acetate (5 mL * 3). The organic phase was washed with saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 3 / 1-1 / 1) to give a brown solid 2-5 (22 mg, yield 30.6%). LC-MS: M+H + =688.2.

[0781] 2.6 Synthesis of compound 2

[0782] Under ice-cooling, trifluoroacetic acid (0.5 mL) was added to a solution of 2-5 (22 mg) in dichloromethane (1.5 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.05% NH3); B%: 5%-10%, 20 min) to give 2 as a white solid (3.6 mg, yield 23.2%). LC-MS: M+H + =488.0. 1 H NMR(400MHz,CD3OD)δppm 8.69-8.62(m,2H),8.59(d,J=4.8Hz,1H),7.91(d,J=8.4Hz,1H),7.79-7.63(m,1H),7.52-7.39(m,1H),7.24-7.15(m,1 H),5.78-5.66(m,1H),5.23-5.04(m,1H),4.94-4.92(m,1H),4.86-4.79(m,3H),4.71-4.63(m,1H),1.64-1.49(m,3H).

[0783] 3. Synthesis of Example 3

[0784] 3.1 Synthesis of Intermediate 3-1

[0785] 5-Trifluoromethylpyridine-2-carboxaldehyde (200.0 mg) and acetic acid (102.0 mg) were added to a solution of methylamine (70.9 mg) in 1,2-dichloroethane (5 mL) and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (484.2 mg) was added and stirred at room temperature for 0.5 hours. Saturated sodium carbonate solution (10 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 3-1 (150.0 mg, 72.0% yield) as a white solid. LC-MS m / z (ESI): 191.1 [M+H] + .

[0786] 3.2 Synthesis of Intermediate 3-2

[0787] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120.2 mg) and N,N-diisopropylethylamine (40.8 mg) were added to a solution of 1-4 (62.2 mg) and 3-1 (36.0 mg) in N,N-dimethylformamide (5 mL) and stirred at room temperature for 5 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 3-2 as a black oil (21.0 mg, yield 22.3%). LC-MS m / z (ESI): 568.0 [M+H] + .

[0788] 3.3 Synthesis of compound 3

[0789] Under ice, trifluoroacetic acid (2 mL) was added to a solution of 3-2 (21.0 mg) in dichloromethane (2 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150×19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-10%, 20 min) to afford the formate salt of 3 as a white solid (2.3 mg, 16.9% yield). LC-MS m / z (ESI): 368.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.86(s,1H),8.14-8.01(m,2H),7.62-7.55(m,2H),4.84(s,1H),4.59(s,1H),3.28-3.05(m,3H),2.15-2.11(m,3H).

[0790] 4. Synthesis of Example 4

[0791] 4.1 Synthesis of Intermediate 4-1

[0792] 30-7 (30.0 mg), 1-propylphosphonic anhydride (45.0 mg), and N,N-diisopropylethylamine (15.0 mg) were added to a solution of 16-1 (35.0 mg) in N,N-dimethylformamide (1 mL). The mixture was stirred at room temperature for 12 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1-1 / 1) to obtain a light yellow solid 4-1 (30.0 mg, yield 65.8%). LC-MS m / z (ESI): 662.3 [M+H] + .

[0793] 4.2 Synthesis of compound 4

[0794] Under ice, trifluoroacetic acid (0.5 mL) was added to a solution of 4-1 (30.0 mg) in dichloromethane (1 mL). The mixture was stirred at room temperature for 2 hours, adjusted to pH 8 with saturated sodium carbonate solution, extracted with dichloromethane (5 mL x 3), and concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.05% NH3); B%: 5%-10%, 20 min) to afford 4 (6.40 mg, 30.6% yield) as a white solid. LC-MS m / z (ESI): 462.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.68(s,1H),8.96-8.91(m,1H),8.29-8.20(m,1H),7.92-7.84(m,1H),7.66(d,J=4Hz,1H),7.53(d,J=8Hz,1H),6.24-6.18 (m,2H),4.91-4.75(m,2H),4.28-4.23(m,3H),3.57-3.45(m,2H),2.67-2.57(m,1H),1.97-1.84(m,2H),1.83-1.66(m,4H).

[0795] 5. Synthesis of Example 5

[0796] 5.1 Synthesis of Intermediate 5-1

[0797] Under ice, n-propylphosphonic anhydride (260.0 mg) and N,N-diisopropylethylamine (84.1 mg) were added to a solution of 25-5 (100.0 mg) and 8-1 (77.0 mg) in N,N-dimethylformamide (3 mL). The mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 × 19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-60%, 20 min) to afford 5-1 (20.8 mg, 10.8% yield) as a white solid. LC-MS m / z (ESI): 454.0 [M+H] + .

[0798] 5.2 Synthesis of compound 5

[0799] Compound 5-1 (20.8 mg) was purified by SFC (column: CHIRALPAK AD-H 250×20 mm, 5 μm; mobile phase: 40% IPA (0.2% NH4OH)) to obtain a white solid 5-P1 (5.8 mg, yield 36.8%). LC-MS m / z (ESI): 454.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 11.04-10.79(m,1H),8.92-8.83(m,1H),8.58-8.49(m,1H),8.40-8.37(m,1H),8.24-8.14(m,1H),7.78-7.69(m,2H) ,7.59-7.57(m,1H),4.75-4.58(m,2H),3.99-3.92(m,4H),1.67-1.43(m,2H),1.19-1.03(m,3H),0.85-0.78(m,3H);

[0800] A white solid 5-P2 (4.5 mg, yield 42.1%) was obtained. LC-MS m / z (ESI): 454.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 11.04-10.80(m,1H),8.93-8.83(m,1H),8.58-8.49(m,1H),8.40-8.15(m,2H),7.79-7.57(m,3H) ,4.75-4.57(m,2H),4.01-3.92(m,4H),1.68-1.45(m,2H),1.19-1.04(m,3H),0.84-0.78(m,3H).

[0801] 6. Synthesis of Example 6

[0802] 6.1 Synthesis of Intermediate 6-1

[0803] Acetic anhydride (5.4 g) was added to a solution of 2-amino-3-methyl-5-bromopyridine (5.0 g) in acetic acid (40 mL) and stirred at 120°C for 4 hours. The mixture was cooled to 50°C and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed sequentially with saturated sodium bicarbonate solution (100 mL) and saturated sodium chloride solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 6-1 (4.5 g, 73% yield) as a white solid. LC-MS m / z (ESI): 229.0, 231.1 [M+H] + .

[0804] 6.2 Synthesis of Intermediate 6-2

[0805] Methyl acrylate (1.1 g), N,N-diisopropylethylamine (2.2 g), palladium acetate (0.2 g), and tris(o-methylphenyl)phosphine (0.5 g) were added to a solution of compound 6-1 (2.0 g) in N,N-dimethylformamide (40 mL) and stirred at 100°C for 16 hours. After cooling to room temperature, the reaction solution was slowly poured into ice water (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to obtain a pale yellow solid 6-2 (1.6 g, 80% yield). LC-MS m / z (ESI): 235.0 [M+H] + .

[0806] 6.3 Synthesis of Intermediate 6-3

[0807] Sodium hydroxide (70.0 mg) was added to a solution of 6-2 (0.2 g) in methanol (5 mL) and water (5 mL) at 0°C and stirred at 70°C for 5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was adjusted to pH 6 with 1M hydrochloric acid and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid 6-3 (100.0 mg). The crude product was used directly in the next reaction. LC-MS m / z (ESI): 179.0 [M+H] + .

[0808] 6.4 Synthesis of Compound 6

[0809] 6-3 (38.0 mg), tripyrrolidinylphosphonium bromide hexafluorophosphate (103.0 mg), and triethylamine (46.0 mg) were added to 1-5 (50.0 mg) in N,N-dimethylacetamide (2 mL) and stirred at room temperature for 16 hours. The mixture was filtered under reduced pressure, and the filtrate was purified by HPLC (column: Gemini5u C18 150 x 21.2 mm; mobile phase: [water (FA)-ACN]; B%: 2%-10%, 10 min) to afford the formate salt of 6 as a white solid (10 mg, 12% yield). LC-MS m / z (ESI): 443.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 8.89-8.71(m,3H),8.15-8.05(m,1H),8.00-7.73(m,2H),7.54-7.31(m,3H),7.25-6.74(m,1H),6.25-6.2 2(m,2H),5.59-5.88(m,1H),5.19-4.88(m,1H),4.85-4.42(m,1H),2.06-1.98(m,3H),1.63-1.42(m,3H).

[0810] 7. Synthesis of Example 7

[0811] 7.1 Synthesis of Intermediate 7-1

[0812] Di-tert-butyl dicarbonate (14.6 g), triethylamine (10.8 g), and 4-dimethylaminopyridine (0.7 g) were added to a solution of 2-amino-3-methyl-5-bromopyridine (5.0 g) in dichloromethane (50 mL). The mixture was stirred at room temperature for 2 hours, then water (100 mL) was added and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 7-1 (9.3 g, 85.5% yield) as a white solid. LC-MS m / z (ESI): 796.9 [2M+H] + .

[0813] 7.2 Synthesis of Intermediate 7-2

[0814] Methyl acrylate (0.7 g), N,N-diisopropylethylamine (1.3 g), and palladium acetate (0.1 g) were added to a solution of compound 7-1 (2.0 g) in N,N-dimethylformamide (20 mL) and stirred at 100°C under nitrogen for 16 hours. After cooling to room temperature, the reaction solution was slowly added to ice water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain 7-2 (1.4 g, yield 63.6%) as a white solid. LC-MS m / z (ESI): 393.1 [M+H] + .

[0815] 7.3 Synthesis of Intermediate 7-3

[0816] At 0°C, under a nitrogen atmosphere, sodium hydride (1.5 g, 60%) was added to a solution of trimethylsulfoxide iodide (1.3 g) in dimethylsulfoxide (5 mL) and stirred for 1 hour. Compound 7-2 (1.4 g) was added, the mixture was slowly warmed to room temperature, and stirred for 16 hours. 1M hydrochloric acid (20 mL) was added to adjust the pH to 6, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 7-3 (400.0 mg, yield 52.1%) as a white solid. LC-MS m / z (ESI): 393.1 [M+H] + .

[0817] 7.4 Synthesis of Intermediate 7-4

[0818] Lithium hydroxide (14.1 mg) was added to a mixture of compound 7-3 (90.0 mg) in methanol (5 mL) and water (5 mL), and stirred at 50°C for 2 hours. The mixture was cooled to room temperature, adjusted to pH 6 with 1M hydrochloric acid, and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid 7-4 (50 mg, 34.4% yield). The crude product was used directly in the next reaction. LC-MS m / z (ESI): 293.1 [M+H] + .

[0819] 7.5 Synthesis of Intermediate 7-5

[0820] 7-4 (50.0 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (101.0 mg), and N,N-diisopropylethylamine (46.5 mg) were added to 1-5 (45.0 mg) in N,N-dimethylformamide (2 mL) and stirred at room temperature for 2 hours. Ice water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 7-5 (20.0 mg, 32.3% yield) as a yellow solid. LC-MS m / z (ESI): 557.2 [M+H] + .

[0821] 7.6 Synthesis of Compound 7

[0822] Trifluoroacetic acid (2 mL) was added to a solution of 7-5 (20.0 mg) in dichloromethane (6 mL) and the mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by HPLC (column: Gemini 5u C18 150 x 21.2 mm; mobile phase: [water (TFA)-ACN]; B%: 2%-10%, 8 min) to afford the trifluoroacetic acid salt of 7 as a white solid (8.0 mg, 57.4% yield). LC-MS m / z (ESI): 457.0 [M+H] + . 1H NMR(400MHz,MeOD-d4)δppm 8.76(d,J=4.8Hz,1H),8.68(d,J=4.8Hz,2H),8.01-7.91(m,1H),7.66-7.57(m,1H),7.42-7.41(m,1H),7.38-7.26(m,2 H),6.05-5.83(m,1H),5.25-4.69(m,2H),2.57-2.28(m,1H),2.26-1.98(m,4H),1.71-1.60(m,4H),1.41-1.16(m,1H).

[0823] 8. Synthesis of Example 8

[0824] 8.1 Synthesis of Intermediate 8-1

[0825] 5-Trifluoromethylpyridine-2-carboxaldehyde (200.0 mg) and acetic acid (137.0 mg) were added to a solution of 2-aminobutane (166.0 mg) in 1,2-dichloroethane (5 mL) and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (485.0 mg) was added and stirred at room temperature for 30 minutes. Water (30 mL) was added and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 8-1 as a yellow oil (200.0 mg, yield 75.5%). LC-MS m / z (ESI): 233.1 [M+H] + .

[0826] 8.2 Synthesis of Intermediate 8-2

[0827] Compound 8-1 (90.0 mg), 1-propylphosphonic anhydride (50% ethyl acetate solution, 244.0 mg), and N,N-diisopropylethylamine (66.0 mg) were added to a solution of compound 1-4 (50.0 mg) in N,N-dimethylformamide (3 mL) and stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 8-2 (50.0 mg, yield 64.9%) as a yellow solid. LC-MS m / z (ESI): 610.0 [M+H] + .

[0828] 8.3 Synthesis of Compound 8

[0829] Under ice, trifluoroacetic acid (2 mL) was added to a dichloromethane solution (4 mL) of compound 8-2 (50.0 mg), and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated under pressure, water (10 mL) was added, and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: Gemini 5u C18 150 x 21.2 mm; mobile phase: ACN-H2O (0.1% FA); B%: 2%-30%, 12 min) to obtain the formate salt of 8 as a white solid (6.0 mg, yield 17.8%). LC-MS m / z (ESI): 410.0 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 8.82(s,1H),8.12-7.96(m,2H),7.67-7.46(m,2H),5.14-4.62(m,2H),4.51-4.13( m,1H),2.17-2.11(m,3H),1.74-1.54(m,2H),1.26-1.19(m,3H),0.93-0.88(m,3H).

[0830] 9. Synthesis of Example 9

[0831] 9.1 Synthesis of Intermediate 9-1

[0832] 5-Trifluoromethylpyridine-2-carboxaldehyde (200.0 mg) and acetic acid (137.0 mg) were added to a solution of (R)-1-methoxy-2-propylamine hydrochloride (166.0 mg) in 1,2-dichloroethane (5 mL) and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (485.0 mg) was added and stirred at room temperature for 30 minutes. Water (30 mL) was added and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 9-1 as a yellow oil (20.0 mg, yield 7.1%). LC-MS m / z (ESI): 249.1 [M+H] + .

[0833] 9.2 Synthesis of Intermediate 9-2

[0834] Compound 1-4 (50.0 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50.0 mg), and N,N-diisopropylethylamine (20.0 mg) were added to a solution of compound 9-1 (20.0 mg) in N,N-dimethylformamide (3 mL) and stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 9-2 (15.0 mg, 30.2% yield) as a yellow solid. LC-MS m / z (ESI): 626.3 [M+H] + .

[0835] 9.3 Synthesis of Compound 9

[0836] Under ice, trifluoroacetic acid (0.5 mL) was added to a dichloromethane solution (2 mL) of compound 9-2 (15.0 mg), and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated under pressure, water (10 mL) was added, and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: Gemini 5u C18 150 x 21.2 mm; mobile phase: ACN-H2O (0.1% FA); B%: 2%-40%, 12 min) to afford the formate salt of 9 as a white solid (3.0 mg, yield 29.4%). LC-MS m / z (ESI): 426.2 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 8.71(s,1H),8.02-7.84(m,2H),7.62-7.51(m,2H),4.95(s,1H),4.69(d,J=8.0Hz,1H),4.53-4. 43(m,1H),3.36-3.25(m,2H),3.09(d,J=3.6Hz,3H),2.03(d,J=224.8Hz,3H),1.18-1.07(m,3H).

[0837] 10. Synthesis of Example 10

[0838] 10.1 Synthesis of Intermediate 10-1

[0839] Tributyl(1-ethoxyethylene)tin (13.2 g) was added to a mixture of 3-bromo-2-chloro-4-methylpyridine (5.0 g), potassium carbonate (6.7 g), and bistriphenylphosphine palladium dichloride (850.0 mg) in tetrahydrofuran and water (50 mL, V / V = 3:1). The mixture was stirred at 90°C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, and saturated potassium fluoride solution (100 mL) and ethyl acetate (100 mL) were added. The mixture was filtered, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL). Hydrochloric acid (6 M, 10 mL) was added to the solution, and the mixture was stirred at room temperature for 16 hours under nitrogen. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 20 / 1) to obtain a yellow liquid 10-1 (2.2 g, yield 53.7%). LC-MS m / z (ESI): 170.0 [M+H] + .

[0840] 10.2 Synthesis of Intermediate 10-2

[0841] Sodium borohydride (980.0 mg) was added to a solution of 10-1 (2.2 g) in methanol (20 mL). The mixture was stirred at 25°C for 1 hour under nitrogen. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 10 / 1-5 / 1) to obtain a colorless liquid 10-2 (2.0 g, yield 80.8%). LC-MS m / z (ESI): 172.1 [M+H] + .

[0842] 10.3 Synthesis of Intermediate 10-3

[0843] Tert-butyldiphenylsilyl chloride (3.9 g) was added to a dichloromethane (20 mL) solution of 10-2 (2.0 g) and imidazole (1.2 g). The mixture was stirred at 25°C for 16 hours under nitrogen. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1-5 / 1) to obtain a colorless oil 79-3 (4.5 g, yield 93.2%). LC-MS m / z (ESI): 410.0 [M+H] + .

[0844] 10.4 Synthesis of Intermediate 10-4

[0845] N-Bromosuccinimide (2.4 g) was added to a solution of 10-3 (5.0 g) and azobisisobutyronitrile (0.1 g) in carbon tetrachloride (50 mL). The mixture was stirred at 90°C for 2 hours under nitrogen. The reaction solution was cooled to room temperature, and water (100 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1-10 / 1) to obtain 10-4 (4.5 g, yield 59.8%) as a colorless oil. LC-MS m / z (ESI): 488.2 [M+H] + .

[0846] 10.5 Synthesis of Intermediate 10-5

[0847] A solution of tetrabutylammonium fluoride (1M, 18.4 mL) in tetrahydrofuran was added to a solution of 10-4 (4.5 g) in tetrahydrofuran (50 mL). The mixture was stirred at 25°C for 1 hour under nitrogen. Water (100 mL) was added to the reaction solution, which was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1-5 / 1) to obtain 10-5 (600.0 mg, yield 38.0%) as a colorless oil. LC-MS m / z (ESI): 170.1 [M+H] + .

[0848] 10.6 Synthesis of Intermediate 10-6

[0849] 1,1'-Binaphthyl-2,2'-bisdiphenylphosphine (418.5 mg), tris(dibenzylideneacetone)dipalladium (193.2 mg), and sodium tert-butoxide (645.9 mg) were added to a toluene (1 mL) solution of 10-5 (570.0 mg) and 2,4-dimethoxybenzylamine (842.9 mg). The mixture was stirred at 100°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to obtain 10-6 (410 mg, 40.6% yield) as a white solid. LC-MS m / z(ESI):301.1[M+H] + .

[0850] 10.7 Synthesis of Intermediate 10-7

[0851] 10-6 (410 mg) was added to a trifluoroacetic acid solution (3 mL). The mixture was stirred at 25°C for 1 hour under nitrogen protection. Saturated sodium bicarbonate solution (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 10) to obtain 10-7 (150.0 mg, yield 73.2%) as a white solid. LC-MS m / z (ESI): 151.0 [M+H] + .

[0852] 10.8 Synthesis of Intermediate 10-8

[0853] N-Bromosuccinimide (213.3 mg) was added to a solution of 10-7 (150.0 mg) in acetonitrile (5 mL). The mixture was stirred at 25°C for 2 hours under nitrogen. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 1) to obtain 10-8 (130.0 mg, yield 56.8%) as a white solid. LC-MS m / z (ESI): 229.0 [M+H] + .

[0854] 10.9 Synthesis of Intermediate 10-9

[0855] Di-tert-butyl dicarbonate (309.6 mg) was added to a solution of 10-8 (130.0 mg), 4-dimethylaminopyridine (6.9 mg), and triethylamine (172.3 mg) in dichloromethane (5 mL). Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1-5 / 1) to afford 10-9 (150.0 mg, 61.3% yield) as a white solid. LC-MS m / z (ESI): 451 [M+Na] + .

[0856] 10.10 Synthesis of Intermediate 10-10

[0857] Tris(dibenzylideneacetone)dipalladium (66.2 mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (67.5 mg), and cesium carbonate (176.5 mg) were added to a solution of benzophenone imine (98.2 mg) and 10-9 (150.0 mg) in dioxane (5 mL). The mixture was stirred at 100°C under nitrogen for 8 hours. The reaction mixture was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain 10-10 (60.0 mg, 32.2% yield) as a white solid. LC-MS m / z (ESI): 530.1 [M+H] + .

[0858] 10.11 Synthesis of Intermediate 10-11

[0859] At 0°C, a solution of HCl in dioxane (0.6 mL, 4 M) was added to a solution of 10-10 (60.0 mg) in tetrahydrofuran (5 mL). The mixture was stirred at 0°C for 1 hour under nitrogen. Saturated sodium carbonate solution (20 mL) and water were added to the reaction solution, which was then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 2) to obtain 10-11 (25.0 mg, 60.4% yield) as a white solid. LC-MS m / z (ESI): 366.2 [M+H] + .

[0860] 10.12 Synthesis of Intermediate 10-12

[0861] Ethyl oxalyl chloride (70.6 mg) was added to a solution of 10-11 (100.0 mg) and triethylamine (87.1 mg) in dichloromethane (3 mL). The mixture was stirred at 25°C for 1 hour under nitrogen. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1-2 / 1) to obtain a brown oil 10-12 (140 mg, yield 97.8%). LC-MS m / z (ESI): 333.2 [M+H] + .

[0862] 10.13 Synthesis of Intermediate 10-13

[0863] Lithium hydroxide monohydrate (94.7 mg) was added to a mixture of methanol and water (6 mL, V / V = 5:1) containing 10-12 (150.0 mg). The mixture was stirred at 25°C for 1 hour under nitrogen. Water (10 mL) was added to the reaction solution, and 1M hydrochloric acid was added dropwise until the pH of the reaction solution reached 5-6. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100 / 1-5 / 1) to obtain a brown solid 10-13 (80.0 mg, yield 58.2%). LC-MS m / z (ESI): 305.2 [M+H] + .

[0864] 10.14 Synthesis of Intermediate 10-14

[0865] N,N,N',N'-Tetramethylchloroformamidine hexafluorophosphate (22.9 mg) was added to a solution of 10-13 (33.1 mg), 10-11 (20.0 mg), and methylimidazole (8.9 mg) in N,N-dimethylformamide (1 mL). The mixture was stirred at 25°C for 1 hour under nitrogen. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 1) to obtain 10-14 (10.0 mg, 28.1% yield) as a white solid. LC-MS m / z (ESI): 652.2 [M+H] + .

[0866] 10.15 Synthesis of Compound 10

[0867] A solution of HCl in dioxane (0.2 mL, 4 M) was added to a solution of 10-14 (10 mg) in dichloromethane (1 mL). The mixture was stirred at 25°C for 3 hours under nitrogen. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (eluent: dichloromethane / methanol = 10 / 1) to afford 10 (5.4 mg, 78.4% yield) as a white solid. LC-MS m / z (ESI): 452.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6, 80℃) δ10.50-10.25(m,1H),8.87(s,1H),8.15(d,J=8.0Hz,1H),7.89 (s,1H),7.70-7.60(m,1H),5.72(s,2H),5.25-5.20(m,1H),5.05-4.93(m,1H),4.85(m,1H) ,4.72(m,1H),4.62-4.52(m,1H),4.10-3.87(m,1H),1.67-1.48(m,2H),1.39(d,J=6.4Hz,2 H), 1.34-1.31 (m, 1H), 1.20 (d, J = 6.5Hz, 2H), 1.07 (d, J = 6.8Hz, 1H), 0.84 (t, J = 7.4Hz, 3H).

[0868] 11. Synthesis of Example 11

[0869] 11.1 Synthesis of Intermediate 11-1

[0870] Cyclopentylamine (486.3 mg) was added to a solution of 5-trifluoromethylpyridine-2-carboxaldehyde (500.0 mg) and acetic acid (343.0 mg) in 1,2-chloroethane (10 mL). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (1210.0 mg) was added and stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1 to 8 / 1) to obtain 11-1 as a yellow oil (540.0 mg, yield 69.7%). LC-MS m / z (ESI): 245.1 [M+H] + .

[0871] 11.2 Synthesis of Intermediate 11-2

[0872] 1-n-Propylphosphonic anhydride (483.0 mg, 50% ethyl acetate solution) was added to a solution of N,N-diisopropylethylamine (130.7 mg), 11-1 (148.3 mg), and 1-4 (200.0 mg) in dichloromethane (8 mL). The mixture was stirred at room temperature for 2 hours. Ice water (20 mL) was added and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1-10 / 1) to obtain 11-2 (150.0 mg, 43.0% yield) as a white solid. LC-MS m / z (ESI): 622.3 [M+H] + .

[0873] 11.3 Synthesis of Compound 11

[0874] Under ice-cooling, a 1,4-dioxane solution of HCl (4 mL, 4 M) was added to 11-2 (140.0 mg). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150×19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 10%-40%, 20 min) to afford the formate salt of 11 (15.1 mg, 15.8% yield) as a white solid. LC-MS m / z (ESI): 422.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.52-10.30(m,1H),8.93-8.88(m,1H),8.28-8.05(m,2H),7.87-7.30(m,2H),5.67-5.60(m,2H) ,4.88-4.66(m,2H),4.38-4.34(m,1H),2.06-1.95(m,3H),1.84-1.73(m,2H),1.63-1.49(m,6H).

[0875] 12. Synthesis of Example 12

[0876] 12.1 Synthesis of Intermediate 12-1

[0877] Cyclopropylamine (131.0 mg) was added to a solution of 5-trifluoromethylpyridine-2-carboxaldehyde (200.0 mg) in 1,2-chloroethane (2 mL) and acetic acid (1 mL). Under nitrogen, the mixture was stirred at room temperature for 1 hour, followed by the addition of sodium triacetoxyborohydride (485.0 mg) and stirring at room temperature for 1 hour. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a pale yellow liquid crude product 12-1 (10.0 mg). LC-MS m / z (ESI): 217.1 [M+H] + .

[0878] 12.2 Synthesis of Intermediate 12-2

[0879] 1-4 (20.0 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (35.0 mg), and N,N-diisopropylethylamine (10.0 mg) were added to a solution of 12-1 (10.0 mg) in N,N-dimethylformamide (1 mL). Under nitrogen protection, the mixture was stirred at room temperature for 2 hours. Water (1 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a pale yellow liquid crude product 12-2 (15.0 mg). LC-MS m / z (ESI): 594.0 [M+H] + .

[0880] 12.3 Synthesis of Compound 12

[0881] Under ice, trifluoroacetic acid (0.5 mL) was added to a solution of 12-2 (15.0 mg) in dichloromethane (1 mL). The mixture was stirred at room temperature for 1 hour, adjusted to pH 8 with saturated sodium carbonate solution, extracted with dichloromethane (5 mL x 3), and concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-10%, 20 min) to afford the formate salt of 12 (3.47 mg, 34.9% yield) as a yellow solid. LC-MS m / z (ESI): 394.1 [M+H] + . 1 H NMR(400MHz,CD3OD)δppm 8.87(s,1H),8.14-8.13(m,1H),8.10-8.09(m,1H),7.63-7.61(m,2H),4.87(s,2H),3.13-3.03(m,1H),2.18(s,3H),0.91-0.83(m,4H).

[0882] 13. Synthesis of Example 13

[0883] 13.1 Synthesis of Intermediate 13-1

[0884] 5-Trifluoromethylpyridine-2-carboxaldehyde (200.0 mg) and acetic acid (137.0 mg) were added to a solution of cyclobutylamine (162.0 mg) in 1,2-dichloroethane (5 mL) and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (485.0 mg) was added and stirred at room temperature for 30 minutes. Water (30 mL) was added and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 13-1 (250.0 mg, 95.0% yield) as a yellow oil. LC-MS m / z (ESI): 230.9 [M+H] + .

[0885] 13.2 Synthesis of Intermediate 13-2

[0886] Compound 13-1 (100.0 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (216.0 mg), and N,N-diisopropylethylamine (98.0 mg) were added to a solution of compound 1-4 (150.0 mg) in N,N-dimethylformamide (5 mL) and stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 13-2 (40.0 mg, yield 17.4%) as a yellow solid. LC-MS m / z (ESI): 608.2 [M+H] + .

[0887] 13.3 Synthesis of Compound 13

[0888] Under ice-cooling, trifluoroacetic acid (2 mL) was added to a solution of compound 13-2 (40.0 mg) in dichloromethane (4 mL), and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, water (10 mL) was added, and the pH was adjusted to weak alkalinity with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain a light yellow solid 13 (10.0 mg, yield 37.3%). LC-MS m / z (ESI): 408.0 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 8.84-8.82(m,1H),8.11-7.95(m,2H),7.64-7.47(m,2H),5.10-4.93(m,2H),4.75-4.65(m,1H),2.27-2.06(m,7H),1.72-1.63(m,2H).

[0889] 14. Synthesis of Examples 14-P1 and 14-P2

[0890] 14.1 Synthesis of Intermediate 14-1

[0891] 5-Trifluoromethylpyridine-2-carboxaldehyde (200.0 mg) and acetic acid (102.0 mg) were added to a solution of 3-aminotetrahydropyran (229.7 mg) in 1,2-dichloroethane (5 mL) and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (418.6 mg) was added and stirred at room temperature for 30 minutes. Water (30 mL) was added and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to obtain 14-1 as a yellow oil (210.0 mg, yield 67.9%). LC-MS m / z (ESI): 261.0 [M+H] + .

[0892] 14.2 Synthesis of Intermediate 14-2

[0893] 1-Propylphosphonic anhydride (216.0 mg) and N,N-diisopropylethylamine (98.0 mg) were added to a solution of compound 14-1 (100.0 mg) and 1-4 (150.0 mg) in N,N-dimethylformamide (5 mL) and stirred at room temperature for 2 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to obtain a yellow solid 14-2 (210.0 mg, yield 85.6%). LC-MS m / z (ESI): 638.1 [M+H] + .

[0894] 14.3 Synthesis of Compounds 14-P1 and 14-P2

[0895] Under ice, trifluoroacetic acid (2 mL) was added to a dichloromethane solution (6 mL) of compound 14-2 (210.0 mg), and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and water (30 mL) was added. The pH was adjusted to a weakly alkaline state with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: Gemini 5u C18 150 x 21.2 mm; mobile phase: [water (FA)-ACN]; B%: 2%-10%, 16 min) to afford the formate salt of 14-3 as a white solid (82.0 mg, yield 67.3%). Separation by SFC (column: CHIRALPAK IC 250 mm × 20 mm, 5 μm; mobile phase: ETOH (NH4OH 0.2%); B%: 40% EtOH, 15 min) gave 14-P1 (30.0 mg) as a white solid. LC-MS m / z (ESI): 438.0 [M+H] + . 1 H NMR(400 MHz,MeOD-d4)δppm 8.83(s,1H),8.13-7.90(m,2H),7.68-7.40(m,2H),5.11-4.83(m,2H),4.43-4.12(m,2H),4. 03-3.75(m,2H),3.45-3.41(m,1H),2.16-2.09(m,3H),2.04-1.79(m,2H),1.75-1.65(m,2H);

[0896] A white solid 14-P2 (37.0 mg) was obtained. LC-MS m / z (ESI): 438.0 [M+H] + . 1H NMR(400MHz,MeOD-d4)δppm8.83(s,1H),8.11-7.90(m,2H),7.68-7.39(m,2H),5.12-4.81(m,2H),4.43-4. 09(m,2H),4.03-3.74(m,2H),3.50-3.39(m,1H),2.18-2.06(m,3H),2.03-1.80(m,2H),1.75-1.65(m,2H).

[0897] 15. Synthesis of Example 15

[0898] 15.1 Synthesis of Intermediate 15-1

[0899] 5-Trifluoromethylpyridine-2-carboxaldehyde (100.0 mg) and acetic acid (65.0 mg) were added to a solution of cyclopropylmethylamine (41.0 mg) in anhydrous dichloroethane (2 mL). The mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (363.0 mg) was added and stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution (30 mL) was added and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 15-1 as a yellow oil (20.0 mg, yield 15.2%). LC-MS m / z (ESI): 231.1 [M+H] + .

[0900] 15.2 Synthesis of Intermediate 15-2

[0901] 1-4 (34.0 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (66.0 mg), and N,N-diisopropylethylamine (23.0 mg) were added to 15-1 in N,N-dimethylformamide (2 mL) and stirred at room temperature for 3 hours. Ice water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 15-2 (20.0 mg). The crude product was used directly in the next reaction. LC-MS m / z (ESI): 608.3 [M+H] + .

[0902] 15.3 Synthesis of Compound 15

[0903] Trifluoroacetic acid (1 mL) was added to a solution of 15-2 (20.0 mg) in dichloromethane (3 mL) and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 15 (4.4 mg, 32.8% yield) as a white solid. LC-MS m / z (ESI): 408.2 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 8.61(s,1H),8.00-7.92(m,2H),7.54-7.44(m,2H),5.04-4.85(m,2H),3.41-3.28( m,2H),2.09-2.03(m,3H),1.00-0.82(m,1H),0.26-0.21(m,2H),0.13-0.11(m,2H).

[0904] 16. Synthesis of Example 16

[0905] 16.1 Synthesis of Intermediate 16-1

[0906] Cyclobutylmethylamine (300.0 mg) was added to a solution of 5-trifluoromethylpyridine-2-carboxaldehyde (300.0 mg) in 1,2-chloroethane (2 mL) and acetic acid (1 mL). Under nitrogen, the mixture was stirred at room temperature for 1 hour, followed by the addition of sodium triacetoxyborohydride (727.0 mg) and stirring at room temperature for 1 hour. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 16-1 (300.0 mg, 71.7% yield) as a pale yellow oil. LC-MS m / z (ESI): 245.0 [M+H] + .

[0907] 16.2 Synthesis of Intermediate 16-2

[0908] 1-4 (453.0 mg), 1-propylphosphonic anhydride (782.1 mg), and N,N-diisopropylethylamine (318.0 mg) were added to a solution of 16-1 (280.0 mg) in N,N-dimethylformamide (3 mL). The mixture was stirred at room temperature for 12 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 16-2 (240.0 mg, yield 33.7%) as a white solid. LC-MS m / z (ESI): 622.0 [M+H]+ .

[0909] 16.3 Synthesis of Compound 16

[0910] Under ice, trifluoroacetic acid (1 mL) was added to a solution of 16-2 (240.0 mg) in dichloromethane (2 mL). The mixture was stirred at room temperature for 2 hours, adjusted to pH 8 with saturated sodium carbonate solution, extracted with dichloromethane (5 mL x 3), and concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-10%, 20 min) to afford the formate salt of 16 (145.6 mg, 89.5% yield) as a white solid. LC-MS m / z (ESI): 422.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.54-10.39(m,1H),8.95-8.90(m,1H),8.25-8.21(m,1H),8.06-7.95(m,1H),7.62-7.42(m,2H),5.86-5. 66(m,2H),4.91-4.73(m,2H),3.57-3.34(m,2H),2.61-2.56(m,1H),2.05-1.99(m,3H),1.95-1.63(m,6H).

[0911] 17. Synthesis of Example 17

[0912] 17.1 Synthesis of Intermediate 17-1

[0913] 5-Trifluoromethylpyridine-2-carboxaldehyde (200.0 mg) and acetic acid (137.0 mg) were added to a solution of cyclopentylmethylamine (225.0 mg) in 1,2-dichloroethane (5 mL) and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (485.0 mg) was added and stirred at room temperature for 30 minutes. Water (30 mL) was added and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 17-1 (200.0 mg, yield 67.8%) as a yellow oil. LC-MS m / z (ESI): 259.2 [M+H] + .

[0914] 17.2 Synthesis of Intermediate 17-2

[0915] Compound 17-1 (100.0 mg), 1-propylphosphonic anhydride (244.0 mg, 50% ethyl acetate solution), and N,N-diisopropylethylamine (66.0 mg) were added to a solution of compound 1-4 (50.0 mg) in N,N-dimethylformamide (3 mL) and stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 17-2 (55.0 mg, yield 68.4%) as a yellow solid. LC-MS m / z (ESI): 636.1 [M+H] + .

[0916] 17.3 Synthesis of Compound 17

[0917] Under ice bath, trifluoroacetic acid (2 mL) was added to a dichloromethane (4 mL) solution of compound 17-2 (40.0 mg), and the mixture was heated to room temperature and stirred for 2 hours. Water (10 mL) was added, and the pH was adjusted to weak alkalinity with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Gemini 5u C18 150 x 21.2 mm

[0918] The formate salt of 17 (18.0 mg, 27.5% yield) was purified using ACN-H2O (0.1% FA) as a mobile phase (B%: 2%-40%, 12 min). LC-MS m / z (ESI): 436.1 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 8.84(s,1H),8.13-8.0(m,2H),7.63-7.52(m,2H),5.08-4.86(m,2H),3.62-3.43(m ,2H),2.31-2.29(m,1H),2.16-2.11(m,3H),1.75-1.55(m,6H),1.29-1.25(m,2H).

[0919] 18. Synthesis of Example 18

[0920] 18.1 Synthesis of Intermediate 18-1

[0921] 1-Methyl-1H-pyrazol-4-amine (270.0 mg) was added to a solution of 5-trifluoromethylpyridine-2-carboxaldehyde (200.0 mg) in dichloromethane (2 mL) and trifluoroacetic acid (1 mL). Under nitrogen, the mixture was stirred at room temperature for 1 hour, followed by the addition of triethylsilane (1 mL) and stirring at room temperature for 2 hours. Saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 18-1 (240.0 mg, 82.0% yield), a yellow liquid. LC-MS m / z (ESI): 257.2 [M+H] + .

[0922] 18.2 Synthesis of Intermediate 18-2

[0923] 1-4 (53.0 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120.0 mg), and N,N-diisopropylethylamine (40.0 mg) were added to a solution of 18-1 (40.0 mg) in N,N-dimethylformamide (1 mL) and stirred at room temperature for 2 hours. Water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 18-2 (50.0 mg) as a light yellow oil. The crude product was used directly in the next reaction without purification. LC-MS m / z (ESI): 634.0 [M+H] + .

[0924] 18.3 Synthesis of Compound 18

[0925] Under ice-cooling, trifluoroacetic acid (0.5 mL) was added to a solution of 18-2 (50.0 mg) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-10%, 20 min) to afford the formate salt of 18 as a yellow solid (9.4 mg, 27.5% yield). LC-MS m / z (ESI): 434.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 10.77-10.59(m,1H),8.94-8.90(m,1H),8.26-8.23(m,1H),8.06-8.04(m,1H),7.78(s,1H),7.64 -7.57(m,2H),7.41-7.38(m,1H),6.21(s,2H),5.29-5.02(m,2H),3.79-3.71(m,3H),2.05(s,3H).

[0926] 19. Synthesis of Examples 19-P1 and 19-P2

[0927] 19.1 Synthesis of Intermediate 19-1

[0928] Triethylamine (239.0 mg) was added to a solution of 5-(trifluoromethyl)-2-pyridinemethylamine hydrochloride (334.0 mg) in 1,2-dichloroethane (5 mL), and the mixture was stirred at room temperature for 3 hours. 4-Acetylthiazole (200.0 mg) was added, and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (667.0 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Water (30 mL) was added, and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 19-1 as a yellow oil (150.0 mg, yield 33.2%). LC-MS m / z (ESI): 288.0 [M+H] + .

[0929] 19.2 Synthesis of Intermediate 19-2

[0930] Compound 19-1 (130.0 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (258.0 mg), and N,N-diisopropylethylamine (117.0 mg) were added to a solution of compound 1-4 (180.0 mg) in N,N-dimethylformamide (5 mL) and stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 19-2 (75.0 mg, yield 24.9%) as a yellow solid. LC-MS m / z (ESI): 665.2 [M+H] + .

[0931] 19.3 Synthesis of Compounds 19-P1 and 19-P2

[0932] Trifluoroacetic acid (2 mL) was added to a solution of compound 19-2 (75 mg) in dichloromethane (4 mL) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction solution was concentrated under pressure, and water (10 mL) was added. The pH was adjusted to a weakly alkaline state with saturated sodium carbonate solution, and the mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to afford 19-3 (30.0 mg, 57.3% yield) as a pale yellow solid. Compound 19-3 was purified by high performance liquid chromatography (column: SFC Thar prep 80, CHIRALPAK AD-H 250 mm x 20 mm, 5 μm; mobile phase: 40% IPA (NH 4 OH 0.2%)) to give a white solid 19-P1 (12.0 mg, 40% yield). LC-MS m / z (ESI): 464.9 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 8.88-8.87(m,1H),8.70-8.68(m,1H),8.14-7.89(m,2H),7.68-7.60(m,1H),7.54-7.3 6(m,2H),6.09-5.81(m,1H),5.01-4.60(m,2H),2.16-2.09(m,3H),1.75-1.61(m,3H);

[0933] A white solid 19-P2 (11.8 mg, yield 39.3%) was obtained. LC-MS m / z (ESI): 465.0 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 8.88-8.87(m,1H),8.70-8.68(m,1H),8.14-7.89(m,2H),7.68-7.60(m,1H),7.55-7.3 6(m,2H),6.09-5.81(m,1H),5.01-4.60(m,2H),2.16-2.10(m,3H),1.75-1.61(m,3H).

[0934] 20. Synthesis of Example 20

[0935] 20.1 Synthesis of Intermediate 20-1

[0936] 5-Trifluoromethylpyridine-2-carboxaldehyde (200.0 mg) was added to a solution of 4-aminomethyl-7-azaindole (167.0 mg) and acetic acid (136.0 mg) in 1,2-dichloroethane (5 mL). The mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (481.0 mg) was added and stirred for 30 minutes. Water (20 mL) was added, and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (30 mL x 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 20-1 as a yellow oil (250.0 mg, yield 71.4%). LC-MS m / z (ESI): 307.1 [M+H] + .

[0937] 20.2 Synthesis of Intermediate 20-2

[0938] Compound 20-1 (36.5 mg), 1-propylphosphonic anhydride (121.0 mg, 50% ethyl acetate solution), and N,N-diisopropylethylamine (33.0 mg) were added to a solution of compound 1-4 (50.0 mg) in N,N-dimethylformamide (2 mL) and stirred at room temperature for 16 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-2 / 1) to obtain 20-2 (40.0 mg, 46.3% yield) as a yellow solid. LC-MS m / z (ESI): 684.0 [M+H] + .

[0939] 20.3 Synthesis of Compound 20

[0940] Under an ice bath, trifluoroacetic acid (2 mL) was added to a solution of compound 20-2 (40.0 mg) in dichloromethane (4 mL), and the mixture was heated to room temperature and stirred for 2 hours. The reaction solution was concentrated under pressure, water (10 mL) was added, and the pH was adjusted to weak alkalinity with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3), and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1-10 / 1) to obtain a white solid 20 (10.0 mg, yield 35.3%). LC-MS m / z (ESI): 484.0 [M+H] + . 1H NMR(400MHz,MeOD-d4)δppm 8.76(s,1H),8.16-8.11(m,1H),8.05-7.93(m,2H),7.58-7.47(m,2H),7.39-7.38(m,1H),7. 13-7.03(m,1H),6.58-6.57(m,1H),5.32-5.06(m,2H),5.04-4.8(m,2H),2.12-2.16(m,3H).

[0941] 21. Synthesis of Example 21

[0942] 21.1 Synthesis of Intermediate 21-1

[0943] Di-tert-butyl dicarbonate (12.5 g), 4-dimethylaminopyridine (1.4 g), and triethylamine (4.7 g) were added to a solution of 3-bromo-5-nitropyridin-2-amine (5.0 g) in dichloromethane (50 mL) and stirred at room temperature for 12 hours. The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain a pale yellow solid 21-1 (8.0 g, yield 83.3%). LC-MS m / z (ESI): 440.1, 442.1 [M+Na] + .

[0944] 21.2 Synthesis of Intermediate 21-2

[0945] Potassium ethylene trifluoroborate (540.0 mg), potassium carbonate (1.3 g), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (150.0 mg), and 21-1 (1.0 g) were added to a mixture of 1,4-dioxane (12 mL) and water (4 mL). The mixture was stirred at 100°C for 12 hours under nitrogen. After cooling to room temperature, water (30 mL) was added and the mixture was extracted with dichloromethane (30 mL x 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain 21-2 as a light yellow solid (500.0 mg, yield 57.1%). LC-MS m / z (ESI): 753.0 [2M+Na] + .

[0946] 21.3 Synthesis of Intermediate 21-3

[0947] Under nitrogen protection, palladium carbon (500.0 mg) was added to a solution of 21-2 (500.0 mg) in methanol (10 mL). Hydrogen was introduced and replaced three times. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1-1 / 1) to obtain a light yellow solid 21-3 (400.0 mg, yield 86.6%). LC-MS m / z (ESI): 338.1 [M+H] + .

[0948] 21.4 Synthesis of Intermediate 21-4

[0949] Ethyl oxalyl chloride (410.0 mg) was added to a solution of 21-3 (1.0 g) and N,N-diisopropylethylamine (390.0 mg) in dichloromethane (14 mL) under ice-cooling and stirred at room temperature for 3 hours. Water (10 mL) was added and the mixture was extracted with dichloromethane (15 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 1) to obtain a light yellow solid 21-4 (1.0 g, yield 76.9%). LC-MS m / z (ESI): 438.1 [M+H] + .

[0950] 21.5 Synthesis of Intermediate 21-5

[0951] Lithium hydroxide (110.0 mg) was added to a solution of 21-4 (1.0 g) in methanol (9 mL) and water (3 mL). The mixture was stirred at room temperature for 2 hours. 2M hydrochloric acid was added to adjust the pH to 6, and the mixture was filtered to obtain a light yellow solid 21-5 (800.0 mg, 85.5% yield). LC-MS m / z (ESI): 410.0 [M+H] + .

[0952] 21.6 Synthesis of Intermediate 21-6

[0953] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (134.2 mg) and N,N-diisopropylethylamine (45.6 mg) were added to a solution of 21-5 (87.2 mg) and 1-5 (50.0 mg) in N,N-dimethylformamide (5 mL) and stirred at room temperature for 5 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 21-6 (40.0 mg, 40.7%) as a yellow oil. LC-MS m / z (ESI): 674.0 [M+H] + .

[0954] 21.7 Synthesis of Compound 21

[0955] Under ice-cooling, trifluoroacetic acid (2 mL) was added to a solution of 21-6 (40.0 mg) in dichloromethane (2 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150×19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-10%, 20 min) to afford the formate salt of 21 (2.0 mg, 7.1% yield) as a white solid. LC-MS m / z (ESI): 474.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.71-8.68(m,3H),8.02-7.95(m,2H),7.65-7.63(m,1H),7.54-7.46(m,1H),7.3 1-7.28(m,1H),5.88-5.80(m,1H),4.59(s,2H),2.51-2.44(m,2H),1.75-1.61(m,3H),1.26-1.17(m,3H).

[0956] 22. Synthesis of Example 22

[0957] 22.1 Synthesis of Intermediate 22-1

[0958] Di-tert-butyl dicarbonate (14.3 g), triethylamine (10.6 g), and 4-dimethylaminopyridine (0.6 g) were added to a dichloromethane solution (50 mL) of 5-bromo-3-fluoro-pyridin-2-amine (5.0 g) and stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to obtain compound 22-1 (8.8 g, yield 95.3%) as a white solid. LC-MS m / z (ESI): 804.9 [2M+Na] + .

[0959] 22.2 Synthesis of Intermediate 22-2

[0960] Ethyl oxalamide (134.1 mg), cuprous iodide (15.0 mg), cesium carbonate (497.0 mg), and N,N'-dimethylethylenediamine (19.4 mg) were added to a solution of compound 22-1 (300 mg) in 1,4-dioxane (5 mL). The mixture was stirred at 100°C for 2 hours under nitrogen. After cooling to room temperature, water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to obtain compound 22-2 (200.0 mg, 49.4% yield) as a yellow solid. LC-MS m / z (ESI): 677.3 [2M+Na] + .

[0961] 22.3 Synthesis of Intermediate 22-3

[0962] Under an ice-bath nitrogen atmosphere, ethyl oxalyl chloride (82.9 mg) was added to a solution of triethylamine (61.4 mg) and compound 22-2 (200.0 mg) in dichloromethane (5 mL) and stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 40 / 1) to obtain a yellow oil 22-3 (200.0 mg, yield 71.4%). LC-MS m / z (ESI): 877.0 [2M+Na] + .

[0963] 22.4 Synthesis of Intermediate 22-4

[0964] Trimethyltin hydroxide (252.6 mg) was added to a solution of compound 22-3 (200.0 mg) in 1,2-dichloroethane (5 mL) and stirred at 70°C for 2 hours. After cooling to room temperature, water (50 mL) was added and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid crude product 22-4 (180 mg). LC-MS m / z (ESI): 821.0 [2M+Na] + .

[0965] 22.5 Synthesis of Intermediate 22-5

[0966] Compound 1-5 (140.6 mg), 1-propylphosphonic anhydride (317.6 mg), and N,N-diisopropylethylamine (128.8 mg) were added to a solution of compound 22-4 (180.0 mg) in N,N-dimethylformamide (3 mL) and stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to obtain 22-5 as a yellow oil (80.0 mg, yield 23.2%). LC-MS m / z (ESI): 664.0 [M+H] + .

[0967] 22.6 Synthesis of Intermediate 22

[0968] Trifluoroacetic acid (2 mL) was added to a solution of compound 22-5 (80.0 mg) in dichloromethane (6 mL) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, water (10 mL) was added, and the pH was adjusted to weak alkalinity with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain a light yellow solid 22 (30.0 mg, yield 53.7%). LC-MS m / z (ESI): 464.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.77-10.69(m,1H),8.86-8.71(m,3H),8.17-8.10(m,1H),8.09-7.92(m,1H),7.75-7.64(m,1H),7.50-7. 39(m,1H),7.41-7.34(m,1H),6.12-6.10(m,2H),5.75-5.72(m,1H),5.17-4.56(m,2H),1.67-1.52(m,3H).

[0969] 23. Synthesis of Example 23

[0970] 23.1 Synthesis of Intermediate 23-1

[0971] 2-Amino-3-chloro-5-nitropyridine (1.0 g) and di-tert-butyl dicarbonate (3.2 g) were added to a solution of 4-dimethylaminopyridine (140.0 mg) and triethylamine (2.4 g) in dichloromethane (20 mL) and stirred at room temperature for 3 hours. Water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 5 / 1) to obtain compound 23-1 (1.5 g, yield 69.4%) as a white solid. LC-MS m / z (ESI): 396.0 [M+Na] + .

[0972] 23.2 Synthesis of Intermediate 23-2

[0973] Iron powder (743.2 mg) and ammonium chloride (711.2 mg) were added to a mixture of 23-1 (500.0 mg) in ethanol (10 mL) and water (10 mL) at 0°C and stirred for 16 hours. The mixture was filtered, and the filtrate was added with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 23-2 (220.0 mg, 47.8% yield) as a white solid. LC-MS m / z (ESI): 244.0 [M-100+H] + .

[0974] 23.3 Synthesis of Intermediate 23-3

[0975] At 0°C, ethyl oxalyl chloride (48.0 mg) was added to a solution of triethylamine (40.0 mg) and 23-2 (100.0 mg) in dichloromethane (5 mL) and stirred at room temperature for 2 hours. The organic phase was washed with saturated sodium chloride solution (3 mL). It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1-1 / 1) to obtain a white solid 23-3 (100.0 mg, yield 77.4%). LC-MS m / z (ESI): 288.0 [M-156+H] + .

[0976] 23.4 Synthesis of Intermediate 23-4

[0977] Lithium hydroxide (20.0 mg) was added to a solution of 23-3 (100.0 mg) in methanol (3 mL) and water (1 mL) and stirred at room temperature for 2 hours. The mixture was acidified with 1 M hydrochloric acid and filtered to obtain crude 23-4 (100.0 mg) as a white solid. The crude product was used directly in the next reaction without purification. LC-MS m / z (ESI): 437.9 [M+Na] + .

[0978] 23.5 Synthesis of Intermediate 23-5

[0979] 1-5 (70.0 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (142.0 mg), and N,N-diisopropylethylamine (65.0 mg) were added to a solution of 23-4 (100.0 mg) in N,N-dimethylformamide (1 mL). Under nitrogen protection, the mixture was stirred at room temperature for 12 hours. Water (1 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude yellow solid 23-5 (50.0 mg). LC-MS m / z (ESI): 680.0 [M+H] + .

[0980] 23.6 Synthesis of Intermediate 23

[0981] Under ice, trifluoroacetic acid (1 mL) was added to a solution of 23-5 (50.0 mg) in dichloromethane (2 mL). The mixture was stirred at room temperature for 2 hours, adjusted to pH 8 with saturated sodium carbonate solution, extracted with dichloromethane (10 mL x 3), and concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-10%, 20 min) to afford the formate salt of 23 as a yellow solid (19.0 mg, 53.8% yield). LC-MS m / z (ESI): 480.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.77-10.60(m,1H),8.83-8.74(m,3H),8.20-8.06(m,2H),7.92-7.34(m,3H) ,6.24-6.18(m,2H),5.77-5.70(m,1H),5.21-4.56(m,2H),1.65-1.47(m,3H).

[0982] 24. Synthesis of Example 24

[0983] 24.1 Synthesis of Intermediate 24-1

[0984] Di-tert-butyl dicarbonate (12.5 g), triethylamine (9.3 g), and 4-dimethylaminopyridine (0.6 g) were added to a dichloromethane solution (50 mL) of 5-nitro-3-bromopyridin-2-amine (5 g) and stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain compound 24-1 (9.0 g, yield 97%) as a white solid. LC-MS m / z (ESI): 859.0 [2M+Na] + .

[0985] 24.2 Synthesis of Intermediate 24-2

[0986] Iron powder (664.5 mg) and ammonium chloride (636.4 mg) were added to a solution of compound 24-1 (500 mg) in ethanol (5 mL) and stirred at 50°C for 2 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain a yellow solid 24-2 (360.0 mg, yield 72.4%). LC-MS m / z (ESI): 799.0 [2M+Na] + .

[0987] 24.3 Synthesis of Intermediate 24-3

[0988] Ethyl oxalyl chloride (82.9 mg) and triethylamine (61.4 mg) were added to a solution of compound 24-2 (200.0 mg) in dichloromethane (5 mL) and stirred at room temperature for 2 hours. Water (50 mL) was added and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain a yellow solid 24-3 (240 mg, yield 81.4%). LC-MS m / z (ESI): 998.8 [2M+Na] + .

[0989] 24.4 Synthesis of Intermediate 24-4

[0990] Trimethyltin hydroxide (276.6 mg) was added to a solution of compound 24-3 (240 mg) in 1,2-dichloroethane (5 mL) and stirred at room temperature for 2 hours. Water (50 mL) was added and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid 24-4 (100 mg, yield 76.2%). LC-MS m / z (ESI): 942.8 [2M+Na] + .

[0991] 24.5 Synthesis of Intermediate 24-5

[0992] Compound 1-5 (62.6 mg), 1-propylphosphonic anhydride (55.9 mg), and N,N-diisopropylethylamine (55.8 mg) were added to a solution of compound 24-4 (100 mg) in N,N-dimethylformamide (3 mL) and stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 24-5 as a yellow oil (80 mg, yield 23.2%). LC-MS m / z (ESI): 723.9 [M+H] + .

[0993] 24.6 Synthesis of Compound 24

[0994] Trifluoroacetic acid (2 mL) was added to a dichloromethane solution (6 mL) of compound 24-5 (80.0 mg) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, water (10 mL) was added, and the pH was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain a light yellow solid 24 (9.0 mg, yield 22.3%). LC-MS m / z (ESI): 524.0, 526.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.75-10.25(m,1H),8.86-8.73(m,3H),8.15-8.10(m,2H),7.68-7.35(m,3H) ,6.17-6.11(m,2H),5.71-5.70(m,1H),5.19-4.56(s,2H),1.59-1.52(m,3H).

[0995] 25. Synthesis of Example 25

[0996] 25.1 Synthesis of Intermediate 25-1

[0997] 2-Chloro-5-nitronicotinic acid (3.2 g) was added to a solution of sodium methoxide (4.3 g) in methanol (40 mL) and stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure and the residue was diluted with water (20 mL). The pH was adjusted to 7 with 1 M hydrochloric acid and filtered to obtain 25-1 (1.8 g) as a light yellow solid. The crude product was used directly in the next reaction without purification. LC-MS m / z (ESI): 197.0 [MH] + .

[0998] 25.2 Synthesis of Intermediate 25-2

[0999] 25-1 (1.8 g) was added to a solution of thionyl chloride (20 mL) and stirred at 80°C for 4 hours. The mixture was concentrated under reduced pressure. The residue was added to tetrahydrofuran (20 mL) and added dropwise to aqueous ammonia (9 mL) under an ice bath. The mixture was stirred at 0°C for 1 hour. The mixture was warmed to room temperature, diluted with water (50 mL), and filtered to obtain a crude white solid 25-2 (1.1 g). The crude product was used directly in the next reaction without purification. LC-MS m / z (ESI): 198.1 [M+H] + .

[1000] 25.3 Synthesis of Intermediate 25-3

[1001] Under nitrogen, palladium on carbon (0.1 g) was added to a solution of 25-2 (1.0 g) in methanol (12 mL). Hydrogen was introduced three times and the mixture was stirred at 25°C for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude off-white solid 25-3 (0.8 g). The crude product was used directly in the next reaction without purification. LC-MS m / z (ESI): 168.1 [M+H] + .

[1002] 25.4 Synthesis of Intermediate 25-4

[1003] Ethyl oxalyl chloride (270.0 mg) was added dropwise to a solution of crude product 25-3 (300.0 mg) and triethylamine (272.0 mg) in dichloromethane (8 mL) under ice-cooling. The mixture was stirred at room temperature for 1 hour. Dichloromethane (30 mL) was added, and the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-4 / 1) to obtain 25-4 as a white solid (340.0 mg, yield 63.8%). LC-MS m / z (ESI): 268.0 [M+H] + .

[1004] 25.5 Synthesis of Intermediate 25-5

[1005] Lithium hydroxide (34.4 mg) was added to a mixture of 25-5 (320.0 mg) in 8 mL of methanol and water (V / V = 3:1). The mixture was stirred at room temperature for 1 hour. 1 M hydrochloric acid was added to adjust the pH to 7, and the mixture was filtered to obtain a crude white solid 25-5 (200.0 mg). The crude product was used directly in the next reaction without purification. LC-MS m / z (ESI): 239.9 [M+H] + .

[1006] 25.6 Synthesis of Compound 25

[1007] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (254.4 mg) was added to a solution of N,N-diisopropylethylamine (108.1 mg), 25-5 (80.0 mg), and 1-5 (113.3 mg) in N,N-dimethylformamide (4 mL). The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 × 19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 10%-60%, 20 min) to obtain the formate salt of 25 as a white solid (27.8 mg, yield 15.7%). LC-MS m / z(ESI):504.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 11.10-10.82(m,1H),8.87-8.71(m,3H),8.54(dd,J=14.8,2.6Hz,1H),8.48-8.39(m,1H),8.21-8.07(m,1H),7.80-7.45( m,3H),7.45-7.34(m,1H),5.78-5.66(m,1H),5.22-4.91(m,1H),4.90-4.49(m,1H),3.97-3.91(m,3H),1.67-1.52(m,3H).

[1008] 26. Synthesis of Example 26

[1009] 26.1 Synthesis of Intermediate 26-1

[1010] Under an ice bath, ethyl oxalyl chloride (1.1 g) was slowly added dropwise to a dichloromethane solution (20 mL) of compound 1-5 (2.0 g) and triethylamine (0.9 g). The mixture was warmed to room temperature and stirred for 16 hours. Water (20 mL) and dichloromethane (15 mL x 3) were added, and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain a yellow oil 26-1 (1.9 g, yield 70.1%). LC-MS m / z (ESI): 393.1 [M+H] + .

[1011] 26.2 Synthesis of Intermediate 26-2

[1012] Under ice, lithium hydroxide (238.0 mg) was added to a mixture of compound 26-1 (1.9 g) in ethanol and water (100 mL, V / V = 1:1), and the mixture was warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and water (10 mL) was added. The pH was adjusted to weak acidity with 2M hydrochloric acid. The mixture was extracted with dichloromethane (15 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 26-2 (1.5 g, 85.2%). LC-MS m / z (ESI): 355.1 [M+H] + .

[1013] 26.3 Synthesis of Intermediate 26-3

[1014] Sodium hydride (200.0 mg) was added to a solution of 2-amino-5-nitro-4-methylpyridine (500.0 mg) in tetrahydrofuran (20 mL). The mixture was stirred at room temperature for 0.5 hours, and di-tert-butyl carbonic anhydride (900.0 mg) was added, followed by stirring at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 26-3 as a yellow solid (800.0 mg, yield 96.9%). LC-MS m / z (ESI): 198.1 [M-56+H] + .

[1015] 26.4 Synthesis of Intermediate 26-4

[1016] Under nitrogen, 26-3 (800.0 mg) was added to a solution of palladium on carbon (200.0 mg) in ethanol (20 mL). Hydrogen was introduced three times and the mixture was stirred at room temperature for 5 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to obtain a yellow solid 26-4 (300.0 mg, yield 40.8%). LC-MS m / z (ESI): 224.1 [M+H] + .

[1017] 26.5 Synthesis of Intermediate 26-5

[1018] 26-4 (100.0 mg), N,N-diisopropylethylamine (173.5 mg), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (300.0 mg) were added to a solution of 26-2 (250.0 mg) in N,N-dimethylformamide (5 mL) and stirred at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to obtain 26-5 (35.0 mg, yield 14.8%) as a yellow solid. LC-MS m / z (ESI): 560.1 [M+H] + .

[1019] 26.6 Synthesis of Compound 26

[1020] Under ice-cooling, trifluoroacetic acid (1 mL) was added to a solution of 26-5 (35.0 mg) in dichloromethane (3 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-10%, 20 min) to afford the formate salt of 26 (12.0 mg, 41.8% yield) as a white solid. LC-MS m / z (ESI): 460.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.10-9.96(m,1H),8.83-8.74(m,3H),8.14-8.10(m,1H),7.70-7.63(m,1H),7.46-7.35(m,2H),6.32-6. 25(m,1H),5.95-5.88(m,3H),5.25-4.97(m,1H),4.92-4.59(m,1H),2.01-1.82(m,3H),1.66-1.52(m,3H).

[1021] 27. Synthesis of Example 27

[1022] 27.1 Synthesis of Intermediate 27-1

[1023] Di-tert-butyl dicarbonate (2.9 g) was added to a solution of 4-dimethylaminopyridine (0.1 g), triethylamine (1.6 g), and 2-amino-5-bromo-3-methylpyrazine (1.0 g) in dichloromethane (20 mL) and stirred at room temperature for 1 hour. The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8 / 1 to 6 / 1) to obtain compound 27-1 (1.9 g, 83.0% yield) as a white solid. LC-MS m / z (ESI): 410.0, 411.9 [M+Na] + .

[1024] 27.2 Synthesis of Intermediate 27-2

[1025] Cuprous iodide (0.1 g) was added to a 1,4-dioxane solution (10 mL) of 27-1 (1.0 g), ethyl oxamate (0.5 g), N,N'-dimethylethylenediamine (0.1 g), and cesium carbonate (2.5 g). The mixture was stirred at 100°C for 3 hours under nitrogen. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1-2 / 3) to obtain 27-2 as a white solid (600.0 mg, yield 65.4%). LC-MS m / z (ESI): 325.0 [M+H] + .

[1026] 27.3 Synthesis of Intermediate 27-3

[1027] Ethyl oxalyl chloride (269.0 mg) was added dropwise to a solution of 27-2 (580.0 mg) and triethylamine (271.0 mg) in dichloromethane (8 mL) under ice-cooling. The mixture was stirred at room temperature for 1 hour. Dichloromethane (10 mL) was added, and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1-3 / 1) to obtain 27-3 as a white solid (520.0 mg, yield 61.7%). LC-MS m / z (ESI): 425.0 [M+H] + .

[1028] 27.4 Synthesis of Intermediate 27-4

[1029] Lithium hydroxide (33.9 mg) was added to a mixture of 27-3 (500.0 mg) in methanol and water (5 mL, V / V = 3:1). The mixture was stirred at room temperature for 1 hour. Water (8 mL) was added, and the pH was adjusted to 7 with 1M hydrochloric acid. The mixture was filtered to obtain a crude white solid 27-4 (240.0 mg). The crude product was used directly in the next reaction without purification. LC-MS m / z (ESI): 397.0 [M+H] + .

[1030] 27.5 Synthesis of Intermediate 27-5

[1031] 1-n-Propylphosphonic anhydride (722.0 mg, 50% ethyl acetate solution) was added to a solution of N,N-diisopropylethylamine (244.5 mg), 27-4 (150.0 mg), and 1-5 (128.2 mg) in dichloromethane (4 mL). The mixture was stirred at room temperature for 2 hours. Ice-water (20 mL) was added and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1-10 / 1) to obtain 27-5 (80.0 mg, yield 28.8%) as a white solid. LC-MS m / z (ESI): 661.0 [M+H] + .

[1032] 27.6 Synthesis of Compound 27

[1033] Under ice-cooling, a solution of HCl in dioxane (2 mL, 4 M) was added to a solution of 27-5 (70.0 mg) in dioxane (1 mL) and stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC (column: Xbridge-C18 150×19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 10%-50%, 20 min) to afford the formate salt of 27 (25.4 mg, 51.6% yield) as a white solid. LC-MS m / z (ESI): 461.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 11.03-10.58(m,1H),8.80-8.71(m,3H),8.41-8.06(m,2H),7.69-7.54(m,1H),7.39-7.33(m,1H) ,6.15-6.11(m,2H),5.71-5.47(m,1H),5.12-4.65(m,2H),2.28-2.22(m,3H),1.64-1.53(m,3H).

[1034] 28. Synthesis of Example 28

[1035] 28.1 Synthesis of Intermediate 28-1

[1036] Triethylamine (153.0 mg) was added to a solution of (R)-1-(pyrimidin-2-yl)ethanamine hydrochloride (146.0 mg) in 1,2-dichloroethane / methanol (5 mL, V / V = 1:1) and stirred at room temperature for 2 hours. Acetic acid (91.0 mg) and 5-cyanopyridine-2-carboxaldehyde (100.0 mg) were added and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (321.0 mg) was added and stirred at room temperature for 2 hours. Water (30 mL) was added and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (30 mL x 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 28-1 as a yellow oil (70.0 mg, yield 38.7%). LC-MS m / z(ESI):240.0[M+H] + .

[1037] 28.2 Synthesis of Intermediate 28-2

[1038] Compound 28-1 (45.0 mg), 1-propylphosphonic anhydride (121.0 mg, 50% ethyl acetate solution), and N,N-diisopropylethylamine (33.0 mg) were added to a solution of compound 1-4 (50.0 mg) in N,N-dimethylformamide (3 mL) and stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to obtain 28-2 (30.0 mg, 38.2% yield) as a yellow solid. LC-MS m / z (ESI): 617.3 [M+H] + .

[1039] 28.3 Synthesis of Compound 28

[1040] Under an ice bath, trifluoroacetic acid (1 mL) was added to a solution of compound 28-2 (30.0 mg) in dichloromethane (4 mL), and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added, and the pH was adjusted to a weakly alkaline state with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: Gemini 5u C18 150 x 21.2 mm; mobile phase: ACN-H2O (0.1% FA); B%: 2%-35%, 14 min) to afford the formate salt of compound 28 as a white solid (1.9 mg, 9.3% yield). LC-MS m / z (ESI): 417.2 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 8.75-8.69(m,3H),8.08-8.03(m,2H),7.65-7.61(m,1H),7.51-7.49(m,1H),7.34-7.3 0(m,1H),5.86-5.81(m,1H),5.33-4.69(m,2H),2.16-2.12(m,3H),1.74-1.59(m,3H).

[1041] 29. Synthesis of Example 29

[1042] 29.1 Synthesis of Intermediate 29-1

[1043] Triethylamine (367.0 mg) was added to a solution of (R)-1-(pyrimidin-2-yl)ethanamine hydrochloride (558.0 mg) in 1,2-dichloroethane (10 mL), and the mixture was stirred at room temperature for 2 hours. Acetic acid (323.0 mg) and 5-bromopyridine-2-carboxaldehyde (500.0 mg) were added, and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (1140.0 mg) was added, and the mixture was stirred at room temperature for 2 hours. Water (100 mL) was added, and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 29-1 as a yellow oil (250.0 mg, yield 31.7%). LC-MS m / z(ESI):293.1,295.1[M+H] + .

[1044] 29.2 Synthesis of Intermediate 29-2

[1045] Di-tert-butyl dicarbonate (280.0 mg) was added to a solution of compound 29-1 (250.0 mg) and triethylamine (175.0 mg) in dichloromethane (5 mL) and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain a yellow solid 29-2 (240 mg, yield 71.6%). LC-MS m / z (ESI): 392.9, 394.9 [M+H] + .

[1046] 29.3 Synthesis of Intermediate 29-3

[1047] 3,3-Difluoropyrrolidine hydrochloride (168.0 mg), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (98.0 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (109.0 mg), and cesium carbonate (760.0 mg) were added to a solution of compound 29-2 (230.0 mg) in 1,4-dioxane (10 mL). The mixture was stirred at 90°C for 16 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 29-3 (150.0 mg, 56.2% yield) as a yellow oil. LC-MS m / z(ESI):420.0[M+H] + .

[1048] 29.4 Synthesis of Intermediate 29-4

[1049] Under ice-cooling, trifluoroacetic acid (2 mL) was added to a solution of compound 29-3 (150.0 mg) in dichloromethane (5 mL), and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and water (20 mL) was added. The pH was adjusted to a weak base with saturated sodium carbonate solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain a yellow oil 29-4 (90.0 mg, yield 78.9%). LC-MS m / z (ESI): 320.2 [M+H] + .

[1050] 29.5 Synthesis of Intermediate 29-5

[1051] Compound 29-4 (90.0 mg), 1-propylphosphonic anhydride (359.0 mg, 50% ethyl acetate solution), and N,N-diisopropylethylamine (110.0 mg) were added to a solution of compound 1-4 (167.0 mg) in N,N-dimethylformamide (5 mL) and stirred at room temperature for 16 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 29-5 (90.0 mg, 45.9% yield) as a yellow solid. LC-MS m / z (ESI): 697.3 [M+H] + .

[1052] 29.6 Synthesis of Compound 29

[1053] Under an ice bath, trifluoroacetic acid (1 mL) was added to a solution of compound 29-5 (90.0 mg) in dichloromethane (3 mL), and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added, and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: Gemini 5u C18 150 x 21.2 mm; mobile phase: ACN-H2O (0.1% FA); B%: 2%-30%, 15 min) to obtain the formate salt of compound 29 (11.0 mg, 17.2% yield) as a white solid. LC-MS m / z (ESI): 497.2 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 8.71-8.69(m,2H),8.08-7.96(m,1H),7.82-7.72(m,1H),7.62-7.52(m,1H),7.34-7.21(m,2H),7.00-6.94(m,1H),5.72-5.6 2(m,1H),4.96-4.49(m,2H),3.71-3.63(m,2H),3.55-3.50(m,2H),2.54-2.49(m,2H),2.14-2.11(m,3H),1.68-1.60(m,3H).

[1054] 30. Synthesis of Example 30

[1055] 30.1 Synthesis of Intermediate 30-1

[1056] Under a nitrogen atmosphere at 0°C, sodium hydride (2.0 g, 60%) was added to a solution of 4-bromo-7-chloro-1H-pyrazolo[3,4-c]pyridine (3.0 g) in N,N-dimethylformamide (30 mL). The mixture was stirred for 1 hour. Iodomethane (375.0 mg) was added dropwise to the reaction solution, which was warmed to room temperature and stirred for 2 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 30-1 (1.9 g, yield 61.9%) as a white solid. LC-MS m / z (ESI): 245.9, 247.8 [M+H] + .

[1057] 30.2 Synthesis of Intermediate 30-2

[1058] Under a nitrogen atmosphere, sodium carbonate (1.6 g) and p-anisidine (1.6 g) were added to a solution of 30-1 (1.9 g) in N-methylpyrrolidone (20 mL). The mixture was stirred at 130°C for 2 hours, and water (60 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 30-2 (1.6 g, yield 60.4%) as a white solid. LC-MS m / z (ESI): 346.9, 348.9 [M+H] + .

[1059] 30.3 Synthesis of Intermediate 30-3

[1060] Under a nitrogen atmosphere, 30-2 (1.6 g) was added to trifluoroacetic acid (20 mL) and stirred at 60°C for 16 hours. Saturated sodium bicarbonate solution (60 mL) was added and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 30-3 as a white solid (800.0 mg, yield 76.9%). LC-MS m / z (ESI): 227.0, 229.1 [M+H] + .

[1061] 30.4 Synthesis of Intermediate 30-4

[1062] Under a nitrogen atmosphere, triethylamine (1.5 g), 4-dimethylaminopyridine (80.0 mg), and di-tert-butyl dicarbonate (1.9 g) were added to a dichloromethane solution (20 mL) of 30-3 (800 mg). The mixture was stirred at room temperature for 2 hours, and then water (60 mL) was added. The mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain 30-4 as a white solid (900.0 mg, yield 59.6%). LC-MS m / z (ESI): 449.0, 451.0 [M+Na] + .

[1063] 30.5 Synthesis of Intermediate 30-5

[1064] Trifluoroacetamide (250.0 mg), cesium carbonate (380.0 mg), cuprous iodide (30.0 mg), and trans-N,N'-dimethyl-1,2-cyclohexanediamine (16.0 mg) were added to a solution of 30-4 (50.0 mg) in anhydrous dioxane (8 mL). The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. After cooling to room temperature, water (50 mL) was added and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to afford 30-5 (120.0 mg, 56.3% yield) as a yellow solid. LC-MS m / z (ESI): 364.2 [M+H] + .

[1065] 30.6 Synthesis of Intermediate 30-6

[1066] At 0°C under a nitrogen atmosphere, ethyl oxalyl chloride (45.0 mg) was added dropwise to a solution of triethylamine (35.0 mg) and 30-5 (110.0 mg) in anhydrous dichloromethane (5 mL). The mixture was stirred at 0°C for 1 hour. The mixture was warmed to room temperature, and water (20 mL) was added. The mixture was extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50 / 1) to give 30-6 (110 mg, 72.3% yield) as a yellow solid. LC-MS m / z (ESI): 464.0 [M+H] + .

[1067] 30.7 Synthesis of Intermediate 30-7

[1068] At room temperature, trimethyltin hydroxide (78.0 mg) was added to a solution of 30-6 (40.0 mg) in 1,2-dichloroethane (6 mL) and stirred at 50°C for 2 hours. After cooling to room temperature, dichloromethane (20 mL) and water (20 mL) were added, and the pH was adjusted to 4-5 with 1M hydrochloric acid. The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain an off-white solid crude product 30-7 (40.0 mg), which was used directly in the next reaction. LC-MS m / z (ESI): 436.2 [M+H] + .

[1069] 30.8 Synthesis of Intermediate 30-8

[1070] Under nitrogen atmosphere, 1-propylphosphonic anhydride (102.0 mg, 50% ethyl acetate solution) was added to a solution of triethylamine (32.0 mg), 1-5 (27.0 mg), and 30-7 (35.0 mg) in N,N-dimethylformamide (2 mL) at room temperature and stirred at room temperature for 16 hours. Ethyl acetate (30 mL) was added to dilute the mixture and washed with saturated sodium chloride solution (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain 30-8 (30.0 mg, 53.5% yield) as an off-white solid. LC-MS m / z (ESI): 700.0 [M+H] + .

[1071] 30.9 Synthesis of Compound 30

[1072] Under an ice-bath nitrogen atmosphere, trifluoroacetic acid (1 mL) was added to a solution of 30-8 (30.0 mg) in dichloromethane (2 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150×19 mm, 5 μm; mobile phase: ACN-H2O (0.05% NH4OH); B%: 20%-50%, 15 min) to afford 30 (4.0 mg, 18.7% yield) as a white solid. LC-MS m / z (ESI): 500.0 [M+H] + . 1H NMR(400MHz,MeOD-d4)δppm 8.73-8.69(m,3H),8.05-7.82(m,2H),7.75-7.66(m,1H),7.64-7.55(m,1H),7.33-7.29(m,1H), 5.91-5.82(m,1H),5.35-5.12(m,1H),5.05-4.78(m,1H),4.34-4.30(m,3H),1.76-1.63(m,3H).

[1073] 31. Synthesis of Example 31

[1074] 31.1 Synthesis of Intermediate 31-1

[1075] Di-tert-butyl dicarbonate (1442.1 mg) was added to a solution of 4-dimethylaminopyridine (64.6 mg), triethylamine (802.4 mg), and 4-nitroisoquinolin-1-amine (500.0 mg) in dichloromethane (8 mL) and stirred at room temperature for 1 hour. The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1-2 / 3) to obtain compound 31-1 (830.0 mg, yield 72.5%) as a white solid. LC-MS m / z (ESI): 412.0 [M+Na] + .

[1076] 31.2 Synthesis of Intermediate 31-2

[1077] Under nitrogen protection, palladium carbon (88.5 mg) was added to a solution of 31-1 (810.0 mg) in methanol (10 mL). The mixture was replaced with hydrogen three times and stirred at 25°C under a hydrogen atmosphere for 4 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude 31-2 (600 mg) as an off-white solid. LC-MS m / z (ESI): 360.0 [M+H] + .

[1078] 31.3 Synthesis of Intermediate 31-3

[1079] Under nitrogen protection, platinum dioxide (73.3 mg) was added to a solution of 31-2 (580.0 mg) and acetic acid (48.5 mg) in methanol (8 mL). The mixture was replaced with hydrogen three times and stirred at 25°C under a hydrogen atmosphere for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 12 / 1-10 / 1) to obtain an off-white solid 31-3 (500.0 mg, yield 76.7%). LC-MS m / z (ESI): 364.1 [M+H] + .

[1080] 31.4 Synthesis of Intermediate 31-4

[1081] Under ice-cooling, ethyl oxalyl chloride (83.0 mg) was added to a solution of 31-3 (200.0 mg) and triethylamine (83.5 mg) in dichloromethane (4 mL) and stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane (20 mL), and the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1-3 / 1) to afford 31-4 as a white solid (240.0 mg, yield 84.7%). LC-MS m / z (ESI): 464.0 [M+H] + .

[1082] 31.5 Synthesis of Intermediate 31-5

[1083] Lithium hydroxide (13.6 mg) was added to a solution of 31-4 (220.0 mg) in methanol and water (5 mL, V / V = 4:1). The mixture was stirred at room temperature for 1 hour. 1 M hydrochloric acid was added to adjust the pH to 7, and the mixture was filtered to obtain a crude white solid 31-5 (150.0 mg). The crude product was used directly in the next reaction without purification. LC-MS m / z (ESI): 336.0 [M+H] + .

[1084] 31.6 Synthesis of Compound 31

[1085] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (170.1 mg) was added to a solution of N,N-diisopropylethylamine (77.1 mg), 31-5 (100.0 mg), and 1-5 (101.0 mg) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 1 hour. Ice water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 10%-40%, 20 min) to afford the formate salt of 31 as a white solid (5.5 mg, 3.0% yield). LC-MS m / z(ESI):500.0[M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 10.00-9.89(m,1H),8.85-8.73 (m,3H),8.14-8.11(m,1H),7.65-7.59(m,1H),7.47-7.35(m,2H),5.69 -5.64(m,2H),5.26-4.59(m,2H),2.49-2.05(m,4H),1.70-1.45(m,8H).

[1086] 32. Synthesis of Example 32

[1087] 32.1 Synthesis of Intermediate 32-1

[1088] Concentrated nitric acid (1.0 mL) was added to a solution of [2,6]naphthyridine-1-amino (1.0 g) in concentrated sulfuric acid (20 mL) at 0°C and stirred for 16 hours. The reaction mixture was slowly poured into saturated sodium bicarbonate solution and the pH was adjusted to 8. The mixture was filtered and the filter cake dried to afford compound 32-1 as a yellow solid (1.0 g, 75.8% yield). LC-MS m / z (ESI): 191.1 [M+H] + .

[1089] 32.2 Synthesis of Intermediate 32-2

[1090] Sodium hydride (336.8 mg, 60%) was added to a tetrahydrofuran solution (500 mL) of 32-1 (1.0 g) at 0°C and stirred for 0.5 hours. Di-tert-butyl dicarbonate (10.2 g) was then added and stirred at room temperature for 1 hour. Saturated ammonium chloride solution (10 mL) was added, the mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to afford 32-2 (1.0 g, 65.5% yield) as a yellow solid. LC-MS m / z (ESI): 291.1 [M+H] + .

[1091] 32.3 Synthesis of Intermediate 32-3

[1092] Reduced iron powder (1.9 g) was added to a mixture of 32-2 (1.0 g) and ammonium chloride (900.0 mg) in ethanol and water (30 mL, V / V = 1:9) at 50°C and stirred for 8 hours. Water (20 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 32-3 as a yellow oil (600.0 mg, yield 66.9%). LC-MS m / z (ESI): 261.2 [M+H]+ .

[1093] 32.4 Synthesis of Intermediate 32-4

[1094] At 0°C, ethyl oxalyl chloride (130.0 mg) was added to a solution of triethylamine (230.0 mg) and 32-3 (200.0 mg) in dichloromethane (10 mL). The mixture was stirred at room temperature for 2 hours. The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 32-4 (120.0 mg, 60.3% yield) as a pale yellow solid. LC-MS m / z (ESI): 233.0 [M-56+H] + .

[1095] 32.5 Synthesis of Intermediate 32-5

[1096] Lithium hydroxide (65.8 mg) was added to a mixture of 32-4 (120.0 mg) in tetrahydrofuran and water (10 mL, V / V = 5:1) and stirred at 40°C for 5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC (column: Daisogel-C18 30 x 250 mm, 10 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-60%, 80 min) to afford the formate salt of 32-5 as a pale yellow solid (60.0 mg, yield 54.6%). LC-MS m / z (ESI): 333.0 [M+H] + .

[1097] 32.6 Synthesis of Compound 32-6

[1098] 32-5 (60.0 mg), N,N-diisopropylethylamine (69.9 mg), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (137.3 mg) were added to a solution of 1-5 (50.9 mg) in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain a light yellow solid 32-6 (42.7 mg, yield 11.9%). LC-MS m / z (ESI): 597.1 [M+H] + .

[1099] 32.7 Synthesis of Compound 32

[1100] Under ice-cooling, trifluoroacetic acid (1 mL) was added to a solution of 32-6 (42.7 mg) in dichloromethane (1 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-10%, 20 min) to afford the formate salt of 32 as a white solid (1.2 mg, 3.4% yield). LC-MS m / z (ESI): 497.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δppm 9.23-8.98(m,1H),8.69-8.60(m,3H),8.49-8.31(m,3H),7.97-7.89(m,3H),7.52-7.44(m,1H), 7.27-7.20(m,1H),5.83-5.81(m,1H),5.31-5.11(m,1H),4.93-4.89(m,1H),1.67-1.53(m,3H).

[1101] 33. Synthesis of Example 33

[1102] 33.1 Synthesis of Intermediate 33-1

[1103] 5-Trifluoromethylpyridine-2-carboxaldehyde (200.0 mg) and acetic acid (102.0 mg) were added to a solution of tert-butylamine (249.7 mg) in 1,2-dichloroethane (5 mL) and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (721.6 mg) was added and stirred at room temperature for 30 minutes. Water (30 mL) was added and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 40 / 1) to obtain 33-1 as a yellow oil (220.0 mg, yield 72.3%). LC-MS m / z (ESI): 233.1 [M+H] + .

[1104] 33.2 Synthesis of Intermediate 33-2

[1105] 1-Propylphosphonic anhydride (226.0 mg) and N,N-diisopropylethylamine (98.0 mg) were added to a solution of compound 33-1 (100.0 mg) and 1-4 (150.0 mg) in N,N-dimethylformamide (5 mL) and stirred at room temperature for 5 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to obtain a yellow solid 33-2 (50.0 mg, yield 25.6%). LC-MS m / z (ESI): 610.2 [M+H] + .

[1106] 33.3 Synthesis of compound 33

[1107] Under ice, trifluoroacetic acid (1 mL) was added to a dichloromethane solution (3 mL) of compound 33-2 (50.0 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added, and the pH was adjusted to a weak base with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: Gemini 5u C18 150 x 21.2 mm; mobile phase: [water (FA)-ACN]; B%: 2%-10%, 6 min) to obtain the formate salt of 33 as a white solid (2.0 mg, yield 10.3%). LC-MS m / z (ESI): 410.1 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 8.85(s,1H),8.25(s,1H), 8.10(d,J=8.0,1H),8.01(s,1H),7.71(d,J=8.0Hz,1H),7.53(s,1H),4.96(s,2H),2.12(s,3H),1.46(s,9H).

[1108] 34. Synthesis of Example 34

[1109] 34.1 Synthesis of Intermediate 34-1

[1110] At 0°C, lithium bis(trimethylsilyl)amide in tetrahydrofuran (77.8 mL, 1 M) was added to a solution of 2-amino-4-chloro-pyridine (5.0 g) in tetrahydrofuran (50 mL). The mixture was stirred for 0.5 hours. Di-tert-butyl dicarbonate (10.2 g) was slowly added, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (60 mL x 3). The organic phase was washed with saturated sodium chloride (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to obtain 34-1 (6.0 g, 60.7% yield) as a white solid. LC-MS m / z (ESI): 173.0 [M-56+H]. + .

[1111] 34.2 Synthesis of Intermediate 34-2

[1112] At -78°C, n-butyllithium in tetrahydrofuran (4.4 mL, 2.4 M) was added to a tetrahydrofuran solution (10 mL) of 34-1 (1.0 g). Under nitrogen, the mixture was stirred at -78°C for 0.5 hour, followed by the addition of N,N-dimethylformamide (1.6 g). The mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to afford 34-2 (270.0 mg, 20.5% yield) as a yellow solid. LC-MS m / z (ESI): 156.9 [M-100+H]. + .

[1113] 34.3 Synthesis of Intermediate 34-3

[1114] Under ice-cooling, trifluoroacetic acid (600.0 mg) was added to a solution of 34-2 (270.0 mg) in dichloromethane (3 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The pH was adjusted to a weak base with saturated sodium bicarbonate solution, extracted with dichloromethane (10 mL × 3), and the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid crude product 34-3 (180.0 mg). The crude product was used directly in the next reaction. LC-MS m / z (ESI): 157.0 [M+H] + .

[1115] 34.4 Synthesis of Intermediate 34-4

[1116] N-Bromobutyric acid diamide (187.5 mg) was added to a solution of 34-3 (150.0 mg) in 1,2-dichloroethane (3 mL). The mixture was stirred at 50°C for 2 hours, cooled to room temperature, and the organic phase was washed with saturated sodium sulfite (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid 34-4 (180.0 mg). The crude product was used directly in the next reaction. LC-MS m / z (ESI): 235.0, 237.0 [M+H] + .

[1117] 34.5 Synthesis of Intermediate 34-5

[1118] Hydrazine hydrate (171.9 mg) was added to a solution of 34-4 (160.0 mg) in dimethyl sulfoxide (2 mL) and stirred at 120°C for 2 hours. The mixture was cooled to room temperature, and water (5 mL) was added. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and dichloromethane (2 mL) was added. The mixture was filtered to obtain a yellow solid 34-5 (60.0 mg, 35.2% yield). LC-MS m / z (ESI): 213.0, 215.0 [M+H] + .

[1119] 34.6 Synthesis of Intermediate 34-6

[1120] Under nitrogen, diisopropyl azodicarboxylate (142.3 mg) was added to a solution of 34-5 (100.0 mg), triphenylphosphine (160.0 mg), and methanol (30.0 mg) in tetrahydrofuran (2 mL) at 0°C. The mixture was stirred at room temperature for 16 hours, then water (5 mL) was added and extracted with ethyl acetate (5 mL x 3). The organic phase was washed...

Claims

1. A compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof: in, Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; L1 is NH or CHR x ; L2 is CR x R y ; L3 is -C(O)-, -S(O)- or -S(O)2-; where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide; or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene; Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-4 alkylene; R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)(=NR a )R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, 2, 3, or 4; R4 is selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; Or an R1 is connected to R4 to form -(CR ss R ss ) q1 -X-(CR ss R ss ) q2 -(preferably -(CH2) q1 -X-(CH2) q2 -); wherein X is O, S, NH or CH2, q1=0, 1 or 2, q2=1, 2 or 3, R ss Independently selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R ss and the carbon atoms to which they are attached together to form C 3-10 Cycloalkyl; X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom or a N atom, which is optionally replaced by R 2d replace; R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ; R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R3 is selected from -C 1-6 Alkylene-OR a 、-C 1-6 Alkylene-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s1 and 1 R 3s2 replace; L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R; R 1s and R 2s Independently selected from H, D, halogen, CN, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or two R 1s and the atoms they are connected to form C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace; Or, R 3s1 、R 3s2 and the carbon atoms to which they are attached together to form C 3-10 Cycloalkyl; R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; wherein the above rings A, L1, L2, R x 、R y , R1, R 2a 、R 2b 、R 2c 、R 2d , R3, R4, L, R, R 1s 、R 2s 、R 3s 、R 3s1 、R 3s2 、R a 、R b and R c The various groups defined in are optionally deuterated, up to fully deuterated; The condition is that when L2 is CR x R y 、When L3 is -S(O)- or -S(O)2-, R y With R 2d Combined to form vinylidene.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Ring A is phenyl or a 5- to 6-membered heteroaryl group; preferably phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.

3. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH, L2 is CR x R y ;-L1-L2- is preferably -L1-L2- is preferably 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L3 is -C(O)-.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R1 and R4 are connected to form -(CH2) q1 -X-(CH2) q2 -; wherein X is O, S, NH or CH2, q1 = 0 or 1, q2 = 1 or 2; preferably, R1 and R4 are connected to form -(CH2) q1 -X-(CH2) q2 -; wherein X is O, S or NH, q1=0 or 1, q2=1 or 2.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Selected from Preferably 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2a Selected from H, D, CN, OR a or NR b R c ; preferably selected from OR a or NR b R c ; preferably selected from OMe or NH2; preferably NH2.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably forming C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; preferably formed Preferred Formation Preferred Formation Preferred Formation 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; preferably selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-10 Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl; preferably selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; preferably selected from Me, Et, iPr, cyclopropyl, cyclobutyl, 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, having the following structural formula: wherein each group is as defined in claims 1 to 9.

11. The compound of claim 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is a compound of formula (II), wherein L1 is NH or CHR x ; L2 is CR x R y ; where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide; or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene; Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-4 alkylene; Z1 is CH or N; R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace; m=0, 1, 2 or 3, preferably m=0; X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom or a N atom, which is optionally replaced by R 2d replace; R 2a Selected from H, D, OR a or NR b R c ; R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 1s Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl, 5-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace; L is a chemical bond or C 1-6 Alkylene, optionally substituted with 1, 2 or 3 R; R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; Among them, L1, L2, R x 、R y , Z1, R1, R 2a 、R 2b 、R 2c 、R 2d 、R 1s 、R 2s 、R 3s1 、R 3s2 ,L,R,R 3s 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

12. The compound of claim 11, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH or CHR x ; L2 is CR x R y ; where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide; or CR x R y Together to form C=O, C=S or C 3-4 cycloalkylene; Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-3 alkylene; Z1 is CH or N; R1 is selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 haloalkyl or 5-6 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1, 2 or 3 R 1s replace; m=0, 1, 2 or 3, preferably m=0; X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom or a N atom, which is optionally replaced by R 2d replace; R 2a is NH2; R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2d Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; R 1s Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 2s Selected from H, D, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R 3s1 Selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl, 5-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace; L is a chemical bond or C 1-3 Alkylene, optionally substituted with 1, 2 or 3 R; R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

13. The compound of claim 11, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH or CHR x ; L2 is CR x R y ; where R x and R y H, D, C independently 1-3 Alkyl or C 1-3 alkyl halide; or CR x R y Together they form C=O or cyclopropylene; Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-2 alkylene; Z1 is CH or N; R1 is selected from H, D, CN, OR a 、C 1-6 Alkyl, C 1-6 A haloalkyl group or a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace; m=0, 1, 2 or 3, preferably m=0; X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom or a N atom, which is optionally replaced by R 2d replace; R 2a is NH2; R 2b Selected from H, D, halogen, C(O)NR b R c 、C 1-6 Alkyl, C 1-6 a haloalkyl group or a 4-6 membered heterocyclic group; R 2c Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s Replacement; Preferred R 2d Selected from H or D; R 1s Selected from H, D, halogen, C(O)OR a 、C 1-6 Alkyl or C 1-6 Haloalkyl, preferably halogen or C(O)OCH3; R 2s is selected from H, D, ═O or Me; R 3s1 Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R 3s2 Selected from H, D, -L-OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl, phenyl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s substituted; preferably, R 3s2 Selected from H, D, Me, CF3, CH2OCH3, cyclopropyl, L is a chemical bond or C 1-3 Alkylene, preferably methylene, optionally substituted with 1, 2 or 3 R; R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

14. The compound of claim 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is a compound of formula (II), wherein L1 is NH; L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S; R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, 2, 3, or 4; X1 is a C atom, which is R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom, which is R 2d replace; R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ; R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl (preferably ), which is optionally replaced by 1, 2 or 3 R 2s replace; R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Z1 is CH; L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R; R 1s and R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace; R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

15. The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S; R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, 2, 3, or 4; X1 is a C atom, which is R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom, which is R 2d replace; R 2a Selected from H, D, CN, OR a or NR b R c ; R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl (preferably ), which is optionally replaced by 1, 2 or 3 R 2s replace; R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; Z1 is CH; L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene; R 1s and R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace; R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, preferably H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

16. The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S; R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, 2, 3, or 4; X1 is a C atom, which is R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom, which is R 2d replace; R 2a Selected from H, D, CN, OR a or NR b R c ; R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl (preferably ), which is optionally replaced by 1, 2 or 3 R 2s replace; R 2d Selected from H, D, halogen, CN, NO2, C 1-6 Alkyl or C 1-6 alkyl halide; Z1 is CH; L is a chemical bond or C 1-6 alkylene; R 1s and R 2s Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; R 3s1 Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace; R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, preferably H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

17. The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S; R1 is selected from H, D, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, 2, 3, or 4; X1 is a C atom, which is R 2b replace; X2 is a C atom, which is R 2c replace; X3 is a C atom, which is R 2d replace; R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ; R 2b Selected from C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 alkyl halide; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form a 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl (preferably ), which is optionally replaced by 1, 2 or 3 R 2s replace; R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Z1 is CH; L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R; R 1s and R 2s Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace; R and R 3s Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, preferably H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

18. The compound of claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S; R1 is selected from H, D, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, 2, 3, or 4; X1 is a C atom, which is R 2b replace; X2 is a C atom, which is R 2c replace; X3 is a C atom, which is R 2d replace; R 2a Selected from H, D, CN, OR a or NR b R c ; R 2b Selected from C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 alkyl halide; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form a 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl (preferably ), which is optionally replaced by 1, 2 or 3 R 2s replace; R 2d is selected from H, D, halogen or CN; Z1 is CH; L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene; R 1s and R 2s Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, preferably H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

19. The compound of claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S; R1 is selected from H, D, OR a SR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, 2, 3, or 4; X1 is a C atom, which is R 2b replace; X2 is a C atom, which is R 2c replace; X3 is a C atom, which is R 2d replace; R 2a Selected from OR a or NR b R c ; R 2b Selected from C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 alkyl halide; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form a 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl (preferably ), which is optionally replaced by 1, 2 or 3 R 2s replace; R 2d is selected from H, D, halogen or CN; Z1 is CH; L is a chemical bond or C 1-6 alkylene; R 1s and R 2s Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; R 3s1 Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 alkyl halide; R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, preferably H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

20. The compound of claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S; R1 is selected from H, D, OR a SR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, 2, 3, or 4; X1 is a C atom, which is R 2b replace; X2 is a C atom, which is R 2c replace; X3 is a C atom, which is R 2d replace; R 2a Selected from OR a or NR b R c ; R 2b Selected from C(O)OR a 、C(O)NR b R c or C 1-6 alkyl; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form a 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl (preferably ), which is optionally replaced by 1, 2 or 3 R 2s replace; R 2d is selected from H, D, halogen or CN; Z1 is CH; L is a chemical bond or C 1-6 alkylene; R 1s and R 2s Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; R 3s1 Selected from Me; R 3s2 Selected from Et; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, preferably H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

21. The compound of claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S; R1 is selected from H, D, OR a SR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, 2, 3, or 4; X3 is a C atom, which is R 2d replace; R 2a Selected from OR a or NR b R c ; X1, X2 and their substituents together form a 5-6 membered heteroaryl group (preferably ), which is optionally replaced by 1, 2 or 3 R 2s replace; R 2d is selected from H, D, halogen or CN; Z1 is CH; R 1s and R 2s Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; R 3s1 Selected from H or D; R 3s2 Selected from C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

22. The compound of claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is CR x R y ; Among them CR x R y Together they form C=O or C=S; R1 is selected from H, D, OR a SR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, 2, 3, or 4; X3 is a C atom, which is R 2d replace; R 2a Selected from OR a or NR b R c ; X1, X2 and their substituents together form a 5-6 membered heteroaryl group (preferably ), which is optionally replaced by 1, 2 or 3 R 2s replace; R 2d is selected from H, D, halogen or CN; Z1 is CH; L is a chemical bond or C 1-6 alkylene; R 1s and R 2s Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; R 3s1 Selected from C 1-4 Alkyl or C 1-4 alkyl halide; R 3s2 Selected from -L-OR a 、-L-NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

23. The compound of claim 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is a compound of formula (III), wherein L1 is NH or CHR x ; L2 is CR x R y ; where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide; or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene; Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-4 alkylene; Z1 is CH or N; R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace; m=0, 1, 2 or 3, preferably m=0; X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom or a N atom, which is optionally replaced by R 2d replace; R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2d Selected from H or D; R 1s Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 3s Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; p=0, 1, 2 or 3, preferably p=0; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; Among them, L1, L2, R x 、R y , Z1, R1, R 2b 、R 2c 、R 1s 、R 2s 、R 3s1 、R 3s 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

24. The compound of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH or CHR x ; L2 is CR x R y ; where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide; or CR x R y Together to form C=O, C=S or C 3-4 cycloalkylene; Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-3 alkylene; Z1 is CH or N; R1 is selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 haloalkyl or 5-6 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1, 2 or 3 R 1s replace; m=0, 1, 2 or 3, preferably m=0; X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom or a N atom, which is optionally replaced by R 2d replace; R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered hetero Cyclic group; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2d Selected from H or D; R 1s Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 2s Selected from H, D, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R 3s1 Selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 3s Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; p=0, 1, 2 or 3, preferably p=0; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

25. The compound of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH or CHR x ; L2 is CR x R y ; where R x and R y H, D, C independently 1-3 Alkyl or C 1-3 alkyl halide; or CR x R y Together they form C=O or cyclopropylene; Or when L1 is CHR x 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-2 alkylene; Z1 is CH or N; R1 is selected from H, D, CN, OR a 、C 1-6 Alkyl, C 1-6 A haloalkyl group or a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace; m=0, 1, 2 or 3, preferably m=0; X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom or a N atom, which is optionally replaced by R 2d replace; R 2b Selected from H, D, halogen, C(O)NR b R c 、C 1-6 Alkyl, C 1-6 a haloalkyl group or a 4-6 membered heterocyclic group; R 2c Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2d Selected from H or D; R 1s Selected from H, D, halogen, C(O)OR a 、C 1-6 Alkyl or C 1-6 Haloalkyl, preferably halogen or C(O)OCH3; R 2s is selected from H, D, ═O or Me; R 3s1 Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R 3s Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; p=0, 1, 2 or 3, preferably p=0; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

26. The compound of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1-L2 is: Z1 is CH or N; R1 is CF3, CN, OCF3, OCH2CH3, Preferably CF3; m＝0； X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom or a N atom, which is optionally replaced by R 2d replace; R 2b H, F, Cl, Br, Me, CH2CH3, C(O)NH2 or R 2c is H or Me; Or X1, X2 and their substituents together form: R 2d is H; R 3s1 is H, Me or cyclopropyl; R 3s is H; p＝0。 27. The compound of claim 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is a compound of formula (IV), (IV-1), (IV-1a), (IV-1b), (IV-2), (IV-2a) or (IV-2b), wherein R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3-7 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, or 2; R4 is selected from H or D; X1 is a C atom, which is R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom, which is R 2d replace; R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ; R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl (preferably ), which is optionally replaced by 1, 2 or 3 R 2s replace; R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Z1 is CH; Z2 is CR1 or N; Z3 is CR1 or N; When Z2 or Z3 is CR1, any R1 is connected with R4 to form -(CR ss R ss ) q1 -X-(CR ss R ss ) q2 -(preferably -(CH2) q1 -X-(CH2) q2 -); wherein X is O, S, NH or CH2, q1=0, 1 or 2, q2=1, 2 or 3, R ss Independently selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R ss and the carbon atoms to which they are attached together to form C 3-10 Cycloalkyl; L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R; R 1s and R 2s Independently selected from H, D, halogen, CN, ═O, OR a NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or two R 1s and the atoms they are connected to form C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, halogen, CN, =O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace; Or, R 3s1 、R 3s2 and the carbon atoms to which they are attached together to form C 3-10 Cycloalkyl; R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

28. The compound of claim 27, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R1 is selected from H, D, halogen, CN, NO2, OR a SR a NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, or 2; R4 is selected from H or D; X1 is a C atom, which is R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom, which is R 2d replace; R 2a Selected from H, D, CN, OR a or NR b R c ; R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-6 Cycloalkyl, 5-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl (preferably ), which is optionally replaced by 1, 2 or 3 R 2s replace; R 2d Selected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; Z1 is CH; Z2 is CR1, and R1 and R4 are connected to form -(CR ss R ss ) q1 -X-(CR ss R ss ) q2 -(preferably -(CH2) q1 -X-(CH2) q2 -); wherein X is O, S, NH or CH2, q1=0 or 1, q2=1 or 2, R ss Independently selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R ss and the carbon atoms to which they are attached together to form C 3-10 Cycloalkyl; Z3 is CR1 or N; L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, optionally substituted with 1, 2 or 3 R; R 1s and R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or two R 1s and the atoms they are connected to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace; Or, R 3s1 、R 3s2 and the carbon atoms to which they are attached together to form C 3-10 Cycloalkyl; R and R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

29. The compound of claim 27, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R1 is selected from H, D, halogen, CN, NO2, OR a SR a NR b R c 、SF5、C(O)R a 、S(O)R a 、S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 4-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, or 2; R4 is selected from H or D; X1 is a C atom, which is R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 is a C atom, which is R 2d replace; R 2a Selected from OR a or NR b R c ; R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-6 Cycloalkyl, 5-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl (preferably ), which is optionally replaced by 1, 2 or 3 R 2s replace; R 2d Selected from H, D, halogen, CN, NO2, C 1-6 Alkyl or C 1-6 alkyl halide; Z1 is CH; Z2 is CR1, and R1 and R4 are connected to form -(CR ss R ss ) q1 -X-(CR ss R ss ) q2 -(preferably -(CH2) q1 -X-(CH2) q2 -); wherein X is O, S or NH, q1=0 or 1, q2=1 or 2, R ss Independently selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R ss and the carbon atoms to which they are attached together to form C 3-6 Cycloalkyl; Z3 is CR1 or N; L is a chemical bond or C 1-6 alkylene; R 1s and R 2s Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; or two R 1s and the atoms they are connected to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 3s1 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; R 3s2 Selected from H, D, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3s replace; Or, R 3s1 、R 3s2 and the carbon atoms to which they are attached together to form C 3-6 Cycloalkyl; R 3s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

30. The compound of formula (X) according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein The compound is selected from Compound 1 to Compound 245.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, optionally with another therapeutic agent.

32. The pharmaceutical composition of claim 31, wherein the additional therapeutic agent is selected from the following target drugs / cell activity modulators, including CDK4 / 6 inhibitors, MAT2A inhibitors, MAPK1 / MAPK3 inhibitors, Type I PRMT inhibitors, EGFR inhibitors, SHP2 inhibitors, pan-KRAS inhibitors, KRASG12C inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, MALT1 inhibitors, MALT2 inhibitors, BTK inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, DNA methyltransferase (DNMT) inhibitors, EZH1 / 2 inhibitors, EZH2 inhibitors, Menin-MLL inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1 / 2 inhibitors, chemotherapeutic drugs, radiotherapy, STING agonists or immune checkpoint inhibitors / modulators.

33. Use of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in the preparation of a medicament for treating or preventing a PRMT5-mediated disease.

34. A method for treating or preventing a PRMT5-mediated disease in a subject, comprising administering to the subject a compound of any one of claims 1-30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutical composition of claim 31 or 32.

35. A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutical composition according to claim 31 or 32, for use in treating or preventing a PRMT5-mediated disease.

36. The use of claim 33 or the method of claim 34 or the use of a compound or pharmaceutical composition of claim 35, wherein the disease is cancer.

37. The use of claim 33 or the method of claim 34 or the use of the compound or pharmaceutical composition of claim 35, wherein the PRMT5-mediated disease is selected from the group consisting of cancers: cardiac: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondroma, hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor), Kaposi's sarcoma, leiomyomas, hemangiomas, lipomas, neurofibromas, fibromas), large intestine (adenocarcinoma, tubular adenomas, villous adenomas, hamartomas, leiomyomas); genitourinary tract: kidney (adenocarcinoma, Wilms' Tumors (Wilms tumor), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma), choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary carcinoma, bile duct cancer; Bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, chronic exostosis of bone (osteocartilaginous exostoses), benign enchondromas, chondroblastomas, fibrochondromas, chondromyxofibromas, osteoid osteomas, and giant cell tumors; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, and osteitis deformans); meninges (meningiomas, meningiosarcomas, and gliomas); brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastomas multiforme, oligodendrogliomas, neurothecomas, retinoblastomas, and congenital tumors); spinal neurofibromas, meningiomas, gliomas, and sarcomas; gynecological: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia, etc.), ovary (ovarian cancer, serous cystadenocarcinomas, mucinous cystadenocarcinomas, and unclassified carcinomas); granulosa cell tumors and Sertoli-Leydig cell tumors. , dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); hematology: blood (myeloid leukemias (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

38. The use of claim 33 or the method of claim 34 or the compound or pharmaceutical composition of claim 35, wherein the PRMT5-mediated disease is selected from the group consisting of malignant peripheral nerve sheath tumor, mesothelioma, glioblastoma multiforme, pancreatic cancer, bile duct cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer, astrocytoma, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, thymoma, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, squamous cell carcinoma of the lung, lung adenocarcinoma, oral cancer, ovarian cancer, kidney cancer and thyroid cancer, and sarcoma.

39. The use of claim 33 or the method of claim 34 or the use of the compound or pharmaceutical composition of claim 35, wherein the PRMT5-mediated disease is selected from MTAP-associated cancers, such as hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer or head and neck cancer.

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