PRMT5 inhibitors

Abstract

Provided are a class of PRMT5 inhibitors represented by formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof, as well as methods for preparing the compounds, pharmaceutical compositions comprising the compounds, and the effects of the compounds in preventing and treating cancer.

Description

PRMT5 inhibitors

[0001] The present invention claims priority to Chinese application CN202211003217.9 filed on August 19, 2022, Chinese application CN202310465126.5 filed on April 26, 2023, and Chinese application CN202310997144.8 filed on August 9, 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 (I) or (I'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0011] in,

[0012] L1 is NH or CHR x ;

[0013] L2 is CR x R y ;

[0014] where R x and R y Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0015] or CR x R y Together to form C=O, C=S or C 3-6 alkylene;

[0016] Or when L1 is CHRx 、L2 is CR x R y When two R x Groups can combine to form chemical bonds or C 1-4 alkylene;

[0017] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0018] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0019] 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;

[0020] X3 for CR 2d or N;

[0021] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0022] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0023] 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;

[0024] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0025] 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;

[0026] Ar1 is phenyl or a 5-6 membered heteroaryl group, which is substituted by m R1;

[0027] 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、P(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl (e.g. C 5-10 cycloalkyl), 4-10 membered heterocyclic group (e.g. 5-10 membered heterocyclic group), C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0028] Or two adjacent R1 and the atoms they are connected to 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 1s replace;

[0029] m = 0, 1, 2, 3, 4 or 5;

[0030] R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)OR a 、C(O)NRb 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 H, D, halogen, ═O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0031] or twin or two adjacent R 1s and the atoms they are connected to form C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0032] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0033] 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, 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] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)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;

[0035] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0036] 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;

[0037] Among them, L1, L2, R x 、R y 、Ar1、R1、R 2a 、R 2b 、R 2c 、R 2d 、R 1s , L, R 2s , R3, R 3a 、R 3b 、R a 、R b and R c The various groups defined in are optionally deuterated, up to fully deuterated;

[0038] Provided that, when L2 is C=O, X1, X2 and their substituents together form a group optionally substituted by 1, 2 or 3 R 2s Substituted C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] definition

[0048] Chemical definition

[0049] Definitions of specific functional groups and chemical terms are described in more detail below.

[0050] 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.

[0051] “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).

[0052] “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, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0053] “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.

[0054] “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.

[0055] “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.

[0056] “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.

[0057] “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".

[0058] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0059] 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.

[0060] “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.

[0061] “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.

[0062] "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.

[0063] “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 an aryl ring as described above 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.

[0064] "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.

[0065] 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".

[0066] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0067] 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;

[0068] 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;

[0069] 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;

[0070] 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;

[0071] 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;

[0072] 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;

[0073] 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;

[0074] 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;

[0075] 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.

[0076] 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.

[0077] Other definitions

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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).

[0086] "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.

[0087] "Disease," "disorder," and "condition" are used interchangeably herein.

[0088] 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 reduces the severity of, or delays or slows 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").

[0089] Generally, an "effective amount" of a compound is an amount sufficient to elicit a 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.

[0090] 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.

[0091] 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.

[0092] "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

[0093] Figures 1 and 2 show the results of in vivo pharmacodynamic studies in the LU99CDX model. Specific implementation plan

[0094] 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.

[0095] 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.

[0096] In one embodiment, the present invention relates to a compound of formula (I) or (I'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0097] in,

[0098] L1 is NH or CHR x ;

[0099] L2 is CR x R y ;

[0100] where R x and R y Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0101] or CR x R y Together to form C=O, C=S or C 3-6 alkylene;

[0102] Or when L1 is CHR x 、L2 is CR x R y When two Rx Groups can combine to form chemical bonds or C 1-4 alkylene;

[0103] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0104] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0105] 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;

[0106] X3 for CR 2d or N;

[0107] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0108] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0109] 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;

[0110] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0111] 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;

[0112] Ar1 is phenyl or a 5-6 membered heteroaryl group, which is substituted by m R1;

[0113] 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、P(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl (e.g. C 5-10 cycloalkyl), 4-10 membered heterocyclic group (e.g. 5-10 membered heterocyclic group), C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0114] Or two adjacent R1 and the atoms they are connected to 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 1s replace;

[0115] m = 0, 1, 2, 3, 4 or 5;

[0116] R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、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, -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 H, D, halogen, ═O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0117] or twin or two adjacent R 1s and the atoms they are connected to form C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0118] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0119] 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, 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;

[0120] R3, R 3a and R 3bIndependently selected from H, D, halogen, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)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;

[0121] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0122] 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;

[0123] Among them, L1, L2, R x 、R y 、Ar1、R1、R 2a 、R 2b 、R 2c 、R 2d 、R 1s , L, R 2s , R3, R 3a 、R 3b 、R a 、R b and R c The various groups defined in are optionally deuterated, up to fully deuterated;

[0124] Provided that, when L2 is C=O, X1, X2 and their substituents together form a group optionally substituted by 1, 2 or 3 R 2s Substituted C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0125] L1 and L2

[0126] 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 , preferably More preferably More preferably More preferably In another embodiment, L1 is CHR x And L2 is CR x R y , preferably More preferably More preferably

[0127] R x and R y

[0128] 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.

[0129] X1, X2 and X3

[0130] 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 CR 2d ; In another embodiment, X3 is N.

[0131] 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

[0132] 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 Preferably

[0133] R 2a

[0134] In one embodiment, R 2ais 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 .

[0135] 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 , preferably NH2.

[0136] R 2b

[0137] 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.

[0138] 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, C1-6 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, F, Cl, Br, Me, CH2CH3, C(O)NH2 or

[0139] R 2c

[0140] 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.

[0141] In a more specific embodiment, R 2c Selected from H or Me.

[0142] R 2d

[0143] 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, R2d C 6-10 Aryl; In another embodiment, R 2d It is a 5-10 membered heteroaryl group.

[0144] 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.

[0145] Ar1

[0146] In one embodiment, Ar1 is phenyl; in another embodiment, Ar1 is a 5-6 membered heteroaryl, preferably a 5 membered heteroaryl; in another embodiment, Ar1 is phenyl, pyridyl or thienyl.

[0147] In another embodiment, Ar1 is For example Preferred In one embodiment, Preferably In one embodiment, Preferably In one embodiment, Preferably In one embodiment, Preferably In one embodiment, Preferably In one embodiment, Preferably In one embodiment, Preferably In one embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably In another embodiment, Preferably

[0148] In another embodiment, Ar1 is Preferably R 1s H, Me, Et, iPr, Preferred H, In one embodiment, R 1s is H; in one embodiment, R 1s is Me; in one embodiment, R 1sis Et; in one embodiment, R 1s is iPr; in another embodiment, R 1s for In one embodiment, R 1s for In another embodiment, R 1s for In one embodiment, R 1s for In one embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for In another embodiment, R 1s for

[0149] In another embodiment, Ar1 is

[0150] R1

[0151] 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)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)(OR a )2; In another embodiment, R1 is P(OR 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 3-10 Cycloalkyl, such as -LC 3-7 Cycloalkyl; in another embodiment, R1 is -L-3-10 membered heterocyclyl, for example -L-3-7 membered heterocyclyl; in another embodiment, R1 is -LC 6-10 Aryl; in another embodiment, R1 is -L-5-10 membered heteroaryl; in another embodiment, two adjacent R1 and the atoms to which they are attached together form C5-6 In another embodiment, two adjacent R1 and the atoms to which they are attached together form a 5-6 membered heterocyclic group; In another embodiment, two adjacent R1 and the atoms to which they are attached together form a phenyl group; In another embodiment, two adjacent R1 and the atoms to which they are attached together form a 5-6 membered heteroaryl group; In another embodiment, R1 is optionally replaced by 1, 2 or 3 R 1s replace.

[0152] In a more specific embodiment, R1 is selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, 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; 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 In another more specific embodiment, two adjacent R1 and the atoms to which they are attached together form C 5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

[0153] m

[0154] 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; in another embodiment, m=5.

[0155] R 1s

[0156] In one embodiment, R 1s is H; in another embodiment, R 1s is D; in another embodiment, R 1s is halogen; in another embodiment, R 1s =0; in another embodiment, R 1s For-L-OR a In another embodiment, R 1s For-L-SRa In another embodiment, R 1s For-L-NR b R c 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 For-LC 3-10 Cycloalkyl; in another embodiment, R 1s is -L-3-10 membered heterocyclyl; in another embodiment, R 1s For-LC 6-10 Aryl; In another embodiment, R 1s is -L-5-10 membered heteroaryl; in another embodiment, the two R 1s and the atoms they are connected to form C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, preferably C 3-6 Cycloalkyl, preferably 4-6 membered heterocyclic group, preferably phenyl, preferably 5-6 membered heteroaryl; In another embodiment, the two R 1s and the atoms to which they are attached together to form a ring optionally substituted by 1, 2 or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 In another embodiment, two adjacent R 1s and the atoms they are connected to form C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, preferably C 3-6 Cycloalkyl, preferably 4-6 membered heterocyclic group, preferably phenyl, preferably 5-6 membered heteroaryl; In another embodiment, two adjacent R 1s and the atoms to which they are attached together to form a ring optionally substituted by 1, 2 or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 2-6 Alkenyl or C 2-6 In another embodiment, R 1s Optionally substituted by 1, 2 or 3 H, D, halogen, ═O, —C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 Haloalkyl substitution.

[0157] In a more specific embodiment, R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-10 Cycloalkyl, -L-5-10 membered heterocyclic group, -LC 6-10 Aryl or -L-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, two adjacent R 1s and the atoms they are connected to form C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

[0158] L

[0159] 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.

[0160] R 2s

[0161] 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, R 2s 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.

[0162] In a more specific embodiment, R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0163] R3, R 3a and R 3b

[0164] In one embodiment, R3 is H; in another embodiment, R3 is D; in another embodiment, R3 is halogen; in another embodiment, R3 is OR a In another embodiment, R3 is NR b R c In another embodiment, R3 is C(O)R a In another embodiment, R3 is C(O)OR a In another embodiment, R3 is C(O)NR b Rc In another embodiment, R3 is OC(O)R a In another embodiment, R3 is NR b C(O)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 C 3-10 In another embodiment, R3 is a 3-10 membered heterocyclyl; In another embodiment, R3 is C 6-10 Aryl; in another embodiment, R3 is a 5-10 membered heteroaryl.

[0165] In one embodiment, R 3a is H; in another embodiment, R 3a is D; in another embodiment, R 3a is halogen; in another embodiment, R 3a OR a In another embodiment, R 3a NR b R c In another embodiment, R 3a C(O)R a In another embodiment, R 3a C(O)OR a In another embodiment, R 3a C(O)NR b R c In another embodiment, R 3a OC(O)R a In another embodiment, R 3a NR b C(O)R c In another embodiment, R 3a C 1-6 Alkyl; in another embodiment, R 3a C 1-6 haloalkyl; in another embodiment, R 3a C 2-6 alkenyl; in another embodiment, R 3a C 2-6 Alkynyl; in another embodiment, R 3a C 3-10 Cycloalkyl; in another embodiment, R3a is a 3-10 membered heterocyclic group; in another embodiment, R 3a C 6-10 Aryl; In another embodiment, R 3a It is a 5-10 membered heteroaryl group.

[0166] In one embodiment, R 3b is H; in another embodiment, R 3b is D; in another embodiment, R 3b is halogen; in another embodiment, R 3b OR a In another embodiment, R 3b NR b R c In another embodiment, R 3b C(O)R a In another embodiment, R 3b C(O)OR a In another embodiment, R 3b C(O)NR b R c In another embodiment, R 3b OC(O)R a In another embodiment, R 3b NR b C(O)R c In another embodiment, R 3b C 1-6 Alkyl; in another embodiment, R 3b C 1-6 haloalkyl; in another embodiment, R 3b C 2-6 alkenyl; in another embodiment, R 3b C 2-6 Alkynyl; in another embodiment, R 3b C 3-10 Cycloalkyl; in another embodiment, R 3b is a 3-10 membered heterocyclic group; in another embodiment, R 3b C 6-10 Aryl; In another embodiment, R 3b It is a 5-10 membered heteroaryl group.

[0167] In a more specific embodiment, R3 is selected from H, D, halogen, OR a NR b R c 、C(O)R a 、C(O)ORa 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; In another more specific embodiment, R3 is selected from H, D, halogen, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、C 1-6 Alkyl or C 1-6 In another more specific embodiment, R3 is selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0168] In a more specific embodiment, R 3a and R 3b One of them is C 1-6 Alkyl or C 1-6 haloalkyl, the other is H; in another more specific embodiment, R 3a and R 3b One is Me and the other is H; in another more specific embodiment, R 3a H and R 3b For Me.

[0169] n

[0170] In one embodiment, n=0; in another embodiment, n=1; in another embodiment, n=2; in another embodiment, n=3; in another embodiment, n=4; in another embodiment, n=5; in another embodiment, n=6; in another embodiment, n=7.

[0171] R a 、R b and R c

[0172] In one embodiment, Ra 、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 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.

[0173] 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 L1 can be combined with L2, R x 、R y , X1, X2, X3, R 2a 、R 2b 、R 2c 、R 2d 、Ar1、R1、m、R 1s , L, R 2s , R3, R 3a 、R 3b 、n、R a 、R b and R c The present invention is intended to include all of these technical solutions, which are not listed one by one due to space limitations.

[0174] In a more specific embodiment, the present invention provides a compound of formula (I) or (I'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0175] in,

[0176] L1 is NH or CHR x ;

[0177] L2 is CR x R y ;

[0178] where R xand R y Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0179] or CR x R y Together to form C=O, C=S or C 3-6 alkylene;

[0180] 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;

[0181] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0182] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0183] 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;

[0184] X3 for CR 2d or N;

[0185] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0186] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0187] 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;

[0188] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C1-6 alkyl halide;

[0189] 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;

[0190] Ar1 is phenyl or a 5-6 membered heteroaryl group, which is substituted by m R1;

[0191] 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、P(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl (e.g. C 5-10 cycloalkyl), 4-10 membered heterocyclic group (e.g. 5-10 membered heterocyclic group), C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0192] Or two adjacent R1 and the atoms they are connected to 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 1s replace;

[0193] m = 0, 1, 2, 3, 4 or 5;

[0194] R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-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, -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 H, D, halogen, ═O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0195] or twin or two adjacent R 1s and the atoms they are connected to form C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0196] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0197] R 2s Selected from H, D, halogen, =O, C(O)ORa 、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;

[0198] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)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;

[0199] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0200] 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;

[0201] Among them, L1, L2, R x 、R y 、Ar1、R1、R 2a 、R 2b 、R 2c 、R 2d 、R 1s , L, R 2s , R3, R 3a 、R 3b 、R a 、R b and R cThe various groups defined in are optionally deuterated, up to fully deuterated;

[0202] Provided that, when L2 is C=O, X1, X2 and their substituents together form a group optionally substituted by 1, 2 or 3 R 2s Substituted C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0203] In another more specific embodiment, the present invention provides a compound of formula (I) or (I'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Ar1 is phenyl or a 5-membered heteroaryl group; or Ar1 is phenyl or a 6-membered heteroaryl group; Ar1 ​​is preferably phenyl, pyridyl or thienyl; Ar1 ​​is more preferably Ar1, for example For example Preferred More preferably Preferably R 1s H, Me, Et, iPr, Preferred H, More preferably

[0204] In another more specific embodiment, the present invention provides a compound of formula (I) or (I'), 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 ; preferably More preferred

[0205] In another more specific embodiment, the present invention provides a compound of formula (I) or (I'), 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 ; preferably More preferred

[0206] In another more specific embodiment, the present invention provides a compound of formula (I) or (I') above, 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(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 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s Substituted; preferably H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、S(O)R a 、S(O)2R a 、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; preferably H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, 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; 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 Preferably, two adjacent R1 and the atoms to which they are connected together form a C 5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

[0207] In another more specific embodiment, the present invention provides a compound of formula (I) or (I') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein, Selected from

[0208] In another more specific embodiment, the present invention provides a compound of formula (I) or (I') above, 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 NH2.

[0209] In another more specific embodiment, the present invention provides a compound of formula (I) or (I') above, 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)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl or 4-6 membered heterocyclic group; preferably selected from H, F, Cl, Br, Me, CH2CH3, C(O)NH2 or

[0210] In another more specific embodiment, the present invention provides a compound of formula (I) or (I') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2cSelected from H or Me.

[0211] In another more specific embodiment, the present invention provides a compound of formula (I) or (I'), 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 More preferably, the

[0212] In another more specific embodiment, the present invention provides a compound of formula (I) or (I') above, 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 H or D.

[0213] In another more specific embodiment, the present invention provides a compound of formula (I) or (I') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 3a and R 3b One of them is C 1-6 Alkyl or C 1-6 Haloalkyl, the other is H; R 3a and R 3b One is Me, the other is H; preferably, R 3a H and R 3b For Me.

[0214] In another more specific embodiment, the present invention provides a compound of formula (I) or (I'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R3 is selected from H, D, halogen, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR bC(O)R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; preferably selected from H, D, halogen, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0215] In another more specific embodiment, the present invention provides a compound of formula (I) or (I') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-10 Cycloalkyl, -L-5-10 membered heterocyclic group, -LC 6-10 Aryl or -L-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, two R 1s and the atoms they are connected to form C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

[0216] In another more specific embodiment, the present invention provides a compound of formula (I) or (I') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0217] In another more specific embodiment, the present invention provides a compound of formula (I) or (I') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the following structural formula:

[0218] wherein each group is as defined above.

[0219] In another 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,

[0220] L1 is NH or CHR x ;

[0221] L2 is CR x R y ;

[0222] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0223] or CR x R y Together they form C 3-6 alkylene;

[0224] 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;

[0225] The other groups are as defined above.

[0226] In another 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 -L1-L2- is selected from

[0227] In another 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,

[0228] L1 is NH or CHR x ;

[0229] L2 is CR x R y ;

[0230] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0231] or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene;

[0232] 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;

[0233] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0234] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0235] And 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;

[0236] X3 for CR 2d or N;

[0237] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0238] R 2a Selected from H, D, OR a or NR b R c ;

[0239] R 2dSelected 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;

[0240] R1, R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, 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, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0241] or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms they are connected to, together forming C 5-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0242] m = 0, 1, or 2;

[0243] R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-10 Cycloalkyl, -L-5-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, ═O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0244] or two R in geminal or vicinal positions 1s and the atoms they are connected to form C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0245] L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0246] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0247] R3, R 3a and R 3b Independently selected from H, D, halogen, 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 H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0248] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0249] R a 、R b and R c Independently selected from H, D, C1-6 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;

[0250] Among them, L1, L2, R x 、R y , R1, R 1a 、R 1b 、R 1c 、R 2a 、R 2d 、R 1s , L, R 2s , R3, R 3a 、R 3b 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0251] In another 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,

[0252] L1 is NH or CHR x ;

[0253] L2 is CR x R y ;

[0254] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0255] or CR x R y Together to form C=O or C 3-6 cycloalkylene;

[0256] 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;

[0257] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0258] X2 is a C atom or a N atom, which is optionally replaced by R 2creplace;

[0259] And 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;

[0260] X3 for CR 2d or N;

[0261] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0262] R 2a Selected from OR a or NR b R c ;

[0263] 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 5-7 Cycloalkyl or 5-7 membered heterocyclic group;

[0264] R1, R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-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;

[0265] or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms to which they are attached, together forming a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0266] m = 0, 1, or 2;

[0267] R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NRb R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-10 Cycloalkyl or -L-5-10 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 H, D, halogen, =O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0268] or two R in geminal or vicinal positions 1s and the atoms they are connected to form C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0269] L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0270] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0271] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0272] n = 0, 1, 2, 3, 4 or 5;

[0273] R a 、R b and Rc 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 5-6 membered heterocyclic group.

[0274] In another 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,

[0275] L1 is NH or CHR x ;

[0276] L2 is CR x R y ;

[0277] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0278] or CR x R y Together they form C=O or C2 cycloalkylene;

[0279] 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;

[0280] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0281] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0282] And 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;

[0283] X3 for CR 2d or N;

[0284] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0285] R 2a NR b Rc ;

[0286] 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;

[0287] R1, R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0288] or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms to which they are attached, together forming a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0289] m = 0, 1, or 2;

[0290] R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、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 H, D, halogen, =O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0291] or two R in geminal or vicinal positions 1s and the atoms they are connected to form C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0292] L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0293] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0294] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0295] n = 0, 1, 2 or 3;

[0296] 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 5-6 membered heterocyclic group.

[0297] In another 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,

[0298] -L1-L2-Selected Preferred

[0299] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0300] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0301] And 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;

[0302] X3 for CR 2d ;

[0303] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0304] R 2a is NH2;

[0305] R 2d Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0306] R1 is selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide;

[0307] R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclic group, preferably H, D, halogen, CN, -L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0308] or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms to which they are attached, together forming a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0309] m = 0, 1, or 2;

[0310] R 1s Selected from H, D, halogen, =O, -L-NR b R c 、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 H, D, halogen, =O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0311] or two R in geminal or vicinal positions 1s and the atoms they are connected to form C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0312] L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0313] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0314] R3 is selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0315] R 3a and R 3b One of them is C 1-6 Alkyl or C 1-6 haloalkyl, the other is H or D;

[0316] n = 0, 1, 2 or 3;

[0317] 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 5-6 membered heterocyclic group;

[0318] Preferably, X1, X2 and their substituents together form a group selected from the following: Preferably selected from Preferably

[0319] Preferably, Selected from the following groups: Preferably Preferably

[0320] In another 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,

[0321] L1 is NH;

[0322] L2 is C=O;

[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] And 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;

[0326] X3 for CR 2d or N;

[0327] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0328] R 2a Selected from OR a or NR bR c ;

[0329] 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;

[0330] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0331] R1, R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl or C 1-6 Haloalkyl, optionally substituted by 1, 2 or 3 R 1s replace;

[0332] or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms to which they are attached, together forming a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0333] R 1s Selected from H, D, halogen, =O, OR a SR a NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0334] m = 0, 1, or 2;

[0335] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6alkyl halide;

[0336] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0337] 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;

[0338] Among them, R1, R 1a 、R 1b 、R 1c 、R 2a 、R 2d 、R 1s 、R 2s , R3, R 3a 、R 3b 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0339] In another 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;

[0341] L2 is C=O;

[0342] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0343] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0344] And X1, X2 and their substituents together form

[0345] X3 for CR 2d ;

[0346] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0347] R 2a NR b R c ;

[0348] R 2dSelected from H, D, halogen, CN, NO2, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0349] Selected from the following groups: Preferred

[0350] R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide;

[0351] m = 0, 1, or 2;

[0352] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0353] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0354] 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.

[0355] In another 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

[0356] L1 is NH;

[0357] L2 is C=O;

[0358] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0359] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0360] And X1, X2 and their substituents together form

[0361] X3 for CR 2d ;

[0362] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0363] R 2a is NH2;

[0364] R 2d Selected from H or D;

[0365] Selected from the following groups: Preferred

[0366] R1 is selected from H, D, F or Me;

[0367] m = 0, 1, or 2;

[0368] R3, R 3a and R 3b are independently selected from H, D or Me, preferably, R 3b for Me;

[0369] n=0, 1, 2, 3, 4, 5, 6 or 7.

[0370] In another 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

[0371] L1 is NH;

[0372] L2 is C=O;

[0373] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0374] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0375] And 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;

[0376] X3 for CR 2d or N;

[0377] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0378] R 2a Selected from OR a or NR b R c ;

[0379] 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;

[0380] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0381] R1, R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide;

[0382] or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms to which they are attached, together forming a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl;

[0383] L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0384] m = 0, 1, or 2;

[0385] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C1-6 Alkyl or C 1-6 alkyl halide;

[0386] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0387] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0388] Among them, R1, R 1a 、R 1b 、R 1c 、R 2a 、R 2d 、R 2s , R3, R 3a 、R 3b 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0389] In another 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

[0390] L1 is NH;

[0391] L2 is C=O;

[0392] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

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

[0394] And X1, X2 and their substituents together form

[0395] X3 for CR 2d ;

[0396] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0397] R 2a NR b R c ;

[0398] R 2d Selected from H, D, halogen, CN, NO2, ORa NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0399] Selected from the following groups: Preferred

[0400] R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide;

[0401] m = 0, 1, or 2;

[0402] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0403] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0404] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0405] In another 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

[0406] L1 is NH;

[0407] L2 is C=O;

[0408] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0409] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0410] And X1, X2 and their substituents together form

[0411] X3 for CR 2d ;

[0412] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0413] R 2a is NH2;

[0414] R 2d Selected from H or D;

[0415] Selected from the following groups: Preferred

[0416] R1 is selected from H, D, F or Me;

[0417] m = 0, 1, or 2;

[0418] R3, R 3a and R 3b are independently selected from H, D or Me, preferably, R 3b for Me;

[0419] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0420] In another 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

[0421] L1 is NH;

[0422] L2 is C=O;

[0423] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0424] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0425] And X1, X2 and their substituents together form

[0426] X3 for CR 2d or N;

[0427] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0428] R 2a Selected from OR a or NR b R c;

[0429] 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;

[0430] R1, R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide;

[0431] or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms to which they are attached, together forming a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl;

[0432] L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

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

[0434] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0435] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0436] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0437] Among them, R1, R 1a 、R 1b 、R 1c 、R2a 、R 2d , R3, R 3a 、R 3b 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0438] In another 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

[0439] L1 is NH;

[0440] L2 is C=O;

[0441] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0442] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0443] And X1, X2 and their substituents together form

[0444] X3 for CR 2d ;

[0445] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0446] R 2a NR b R c ;

[0447] 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;

[0448] Selected from the following groups:

[0449] R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide;

[0450] m = 0, 1, or 2;

[0451] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0452] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0453] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0454] In another 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

[0455] L1 is NH;

[0456] L2 is C=O;

[0457] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0458] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0459] And X1, X2 and their substituents together form

[0460] X3 for CR 2d ;

[0461] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0462] R 2a is NH2;

[0463] R 2d Selected from H or D;

[0464] Selected from the following groups:

[0465] R1 is selected from H, D, F or Me;

[0466] m = 0, 1, or 2;

[0467] R3, R 3a and R 3b are independently selected from H, D or Me, preferably, R 3b for Me;

[0468] n=0, 1, 2, 3, 4, 5, 6 or 7.

[0469] In another 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

[0470] L1 is NH;

[0471] L2 is C=O;

[0472] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0473] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0474] And 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 substituted, preferably 5-7 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0475] X3 for CR 2d or N;

[0476] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0477] R 2a Selected from OR a or NR b R c ;

[0478] 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;

[0479] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0480] R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide;

[0481] m = 0, 1, 2, or 3;

[0482] R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-6 Cycloalkyl, -L-5-6 membered heterocyclic group, -LC 6-10 Aryl or -L-5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0483] L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0484] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0485] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0486] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0487] In another 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

[0488] L1 is NH;

[0489] L2 is C=O;

[0490] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0491] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0492] And X1, X2 and their substituents together form Preferred

[0493] X3 for CR 2d ;

[0494] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0495] R 2a NR b R c ;

[0496] 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;

[0497] R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide;

[0498] m = 0, 1, 2, or 3;

[0499] R 1s H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl,

[0500] R3, R 3a and R 3b Independently selected from H, D, halogen, ORa NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0501] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0502] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0503] In another 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

[0504] L1 is NH;

[0505] L2 is C=O;

[0506] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0507] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0508] And X1, X2 and their substituents together form Preferred

[0509] X3 for CR 2d ;

[0510] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0511] R 2a is NH2;

[0512] R 2d Selected from H or D;

[0513] R1 is selected from H, D, F or Me;

[0514] m = 0, 1, 2, or 3;

[0515] R 1s H, Me, Et, iPr,

[0516] R3, R 3a and R 3bare independently selected from H, D or Me, preferably, R 3b for Me;

[0517] n=0, 1, 2, 3, 4, 5, 6 or 7.

[0518] In another 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,

[0519] L1 is NH or CHR x ;

[0520] L2 is CR x R y ;

[0521] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0522] or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene;

[0523] 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;

[0524] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0525] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0526] And 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;

[0527] X3 for CR 2d or N;

[0528] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0529] R 2a Selected from H, D, OR a or NRb R c ;

[0530] 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;

[0531] 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;

[0532] m = 0, 1, 2, or 3;

[0533] R 1s Selected from H, D, halogen, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-10 Cycloalkyl, -L-5-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, ═O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0534] L is a chemical bond, C 1-6 Alkylene, C2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0535] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0536] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0537] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0538] 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;

[0539] Among them, L1, L2, R x 、R y , R1, R 2a 、R 2d 、R 1s , L, R 2s , R3, R 3a 、R 3b 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0540] In another 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,

[0541] L1 is NH or CHR x ;

[0542] L2 is CRx R y ;

[0543] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0544] or CR x R y Together to form C=O or C 3-6 cycloalkylene;

[0545] 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;

[0546] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0547] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0548] And 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;

[0549] X3 for CR 2d or N;

[0550] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0551] R 2a Selected from OR a or NR b R c ;

[0552] 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 5-7 Cycloalkyl or 5-7 membered heterocyclic group;

[0553] R1 is selected from H, D, halogen, CN, OR a SR a NR b Rc , 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;

[0554] m = 0, 1, or 2;

[0555] R 1s Selected from H, D, halogen, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-10 Cycloalkyl, -L-5-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, ═O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0556] L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0557] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0558] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0559] n = 0, 1, 2, 3, 4 or 5;

[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 5-6 membered heterocyclic group.

[0561] In another 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,

[0562] L1 is NH or CHR x ;

[0563] L2 is CR x R y ;

[0564] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0565] or CR x R y Together they form C=O or C2 cycloalkylene;

[0566] 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;

[0567] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0568] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0569] And 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;

[0570] X3 for CR 2d or N;

[0571] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0572] R 2a NR b R c ;

[0573] 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;

[0574] 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;

[0575] m = 0, 1, or 2;

[0576] R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-7 Cycloalkyl, -L-5-7 membered heterocyclyl or -L-5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, ═O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0577] L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0578] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0579] R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0580] n = 0, 1, 2 or 3;

[0581] 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 5-6 membered heterocyclic group.

[0582] In another 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,

[0583] -L1-L2-Selected Preferred

[0584] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0585] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0586] And 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;

[0587] X3 for CR 2d ;

[0588] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0589] R 2a is NH2;

[0590] R2d Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0591] R1 is selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 Haloalkyl, optionally substituted by 1, 2 or 3 R 1s replace;

[0592] m = 0, 1, or 2;

[0593] R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-7 Cycloalkyl, -L-5-7 membered heterocyclyl or -L-5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, ═O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0594] L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0595] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0596] R3 is selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0597] R 3a and R 3b One of them is C 1-6 Alkyl or C 1-6haloalkyl, the other is H or D;

[0598] n = 0, 1, 2 or 3;

[0599] 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 5-6 membered heterocyclic group;

[0600] Preferably, X1, X2 and their substituents together form a group selected from the following: Preferably selected from

[0601] Preferably, R 1s Selected from H, Preferably

[0602] In another more specific embodiment, the present invention provides a compound of formula (IV) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0603] L1 is NH or CHR x ;

[0604] L2 is CR x R y ;

[0605] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0606] or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene;

[0607] 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;

[0608] X1 is a C atom or a N atom, which is optionally replaced by R2b replace;

[0609] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0610] And 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;

[0611] X3 for CR 2d or N;

[0612] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0613] R 2a Selected from H, D, OR a or NR b R c ;

[0614] 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;

[0615] 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;

[0616] m = 0, 1, 2, or 3;

[0617] m′=0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;

[0618] 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 5-7Cycloalkyl or 5-7 membered heterocyclic group;

[0619] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0620] R3 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0621] n = 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0622] 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;

[0623] Among them, L1, L2, R x 、R y , R1, R 2a 、R 2d 、R 1s 、R 2s , R3, R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0624] In another more specific embodiment, the present invention provides a compound of formula (IV) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0625] L1 is NH or CHR x ;

[0626] L2 is CR x R y ;

[0627] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0628] or CR x R y Together to form C=O or C 3-6 cycloalkylene;

[0629] 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;

[0630] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0631] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0632] And 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;

[0633] X3 for CR 2d or N;

[0634] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0635] R 2a Selected from OR a or NR b R c ;

[0636] 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 5-7 Cycloalkyl or 5-7 membered heterocyclic group;

[0637] 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;

[0638] m = 0, 1, 2, or 3;

[0639] m' = 0, 1, 2, 3, 4 or 5;

[0640] R 1sSelected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 haloalkyl;

[0641] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0642] R3 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0643] n = 0, 1, 2, 3, 4 or 5;

[0644] 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 5-6 membered heterocyclic group.

[0645] In another more specific embodiment, the present invention provides a compound of formula (IV) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0646] -L1-L2-Selected Preferred

[0647] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0648] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0649] And 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;

[0650] X3 for CR 2d ;

[0651] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0652] R 2a is NH2;

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

[0654] R1 is selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 Haloalkyl, optionally substituted by 1, 2 or 3 R 1s replace;

[0655] m = 0, 1, or 2;

[0656] m' = 0, 1, 2, or 3;

[0657] 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 haloalkyl;

[0658] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0659] R3 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0660] n = 0, 1, 2 or 3;

[0661] 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 5-6 membered heterocyclic group;

[0662] Preferably, X1, X2 and their substituents together form a group selected from the following: Preferably selected from

[0663] In another more specific embodiment, the present invention provides a compound of formula (Va) or (Vb), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0664] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0665] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0666] And 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;

[0667] X3 for CR 2d or N;

[0668] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0669] R 2a Selected from OR a or NR b R c ;

[0670] 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;

[0671] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0672] Ar1 is a 5-6 membered heteroaryl group, which is substituted by m R1;

[0673] 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)NRb 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 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0674] m = 0, 1, 2, 3, 4 or 5;

[0675] Or two adjacent R1 and the atoms they are connected to 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 1s replace;

[0676] R 1s Selected from H, D, halogen, =O, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0677] R3 and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0678] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0679] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0680] Among them, R1, R 1s 、R 2a 、R 2d , R3, R 3b 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0681] In another more specific embodiment, the present invention provides a compound of formula (Va) or (Vb) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0682] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0683] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0684] And X1, X2 and their substituents together form

[0685] X3 for CR 2d ;

[0686] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0687] R 2a NR b R c ;

[0688] 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;

[0689] Ar1 is a 5-6 membered heteroaryl group, which is substituted by m R1;

[0690] R1 is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0691] m = 0, 1, 2, or 3;

[0692] Or two adjacent R1 and the atoms they are connected to 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 1s replace;

[0693] R 1s Selected from H, D, halogen, =O, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0694] R3 and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0695] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0696] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0697] In another more specific embodiment, the present invention provides a compound of formula (Va) or (Vb) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0698] X1 is a C atom, which is optionally replaced by R 2b replace;

[0699] X2 is a C atom, which is optionally replaced by R 2c replace;

[0700] And X1, X2 and their substituents together form Preferred

[0701] X3 for CR 2d ;

[0702] and the ring where X1, X2 and X3 are located is an aromatic ring;

[0703] R 2a is NH2;

[0704] R 2d Selected from H or D;

[0705] Ar1 is a 5-6 membered heteroaryl group, which is substituted by m R1s; preferably, Ar1 is selected from:

[0706] R1 is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0707] m = 0, 1, or 2;

[0708] Or two adjacent R1 and the atoms to which they are attached together form a phenyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0709] R 1s Selected from H, D, halogen, =O, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0710] R3 and R 3b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0711] n = 0, 1, 2, 3, 4, 5, 6 or 7;

[0712] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

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

[0716] 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.

[0717] 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.

[0718] 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.

[0719] 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.

[0720] 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)).

[0721] 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.

[0722] 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 14C) can be used in drug and / or substrate tissue distribution assays. 3 H 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.

[0723] 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.

[0724] 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.

[0725] 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.

[0726] Pharmaceutical compositions and kits

[0727] 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.

[0728] 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.

[0729] 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.

[0730] 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.

[0731] Drug administration

[0732] 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.

[0733] 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.

[0734] 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.

[0735] 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.

[0736] 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.

[0737] 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.

[0738] 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.

[0739] 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.

[0740] 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.

[0741] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier as well as 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.

[0742] 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.

[0743] 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.

[0744] 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.

[0745] 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.

[0746] 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.

[0747] 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%).

[0748] Indications

[0749] 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.

[0750] 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.

[0751] 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.;

[0752] Combination therapy

[0753] 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.

[0754] Example

[0755] The starting materials and reagents used herein are either commercially available or prepared by synthetic methods generally known in the art.

[0756] 1. Synthesis of Example 1

[0757] 1.1 Synthesis of Intermediate 1-1

[0758] At -78°C, a 1M solution of lithium bistrimethylsilylamide in tetrahydrofuran (35 mL) was added to a solution of (S)-tert-butyl 5-methyl-2-oxopiperidine-1-carboxylate (5.0 g) in tetrahydrofuran (100 mL). Under nitrogen, the mixture was stirred at -78°C for 1.5 hours before the addition of N-phenylbis(trifluoromethanesulfonyl)imide (10.5 g). The mixture was stirred at room temperature for 12 hours. Saturated ammonium chloride solution (100 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 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 = 2 / 1) to obtain 1-1 (5.0 g, 61.7% yield) as a pale yellow liquid. LC-MS m / z (ESI): 289.9 [M-56+H]. + .

[0759] 1.2 Synthesis of intermediate 1-2

[0760] Di-tert-butyl dicarbonate (565.0 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 silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-2 / 1) to obtain compound 1-2 as a white solid (160.0 mg, yield 65.6%). LC-MS m / z (ESI): 437.1, 439.1 [M+Na] + .

[0761] 1.3 Synthesis of intermediate 1-3

[0762] 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 1-2 (100.0 mg) in dioxane (5 mL). The mixture was stirred at 110°C under nitrogen for 16 hours, 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 silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 5 / 1 to 1 / 1) to obtain 1-3 as a white solid (34.0 mg, 38.7% yield). LC-MS m / z (ESI): 352.0 [M+H] + .

[0763] 1.4 Synthesis of Intermediates 1-4

[0764] 2-Amino-4-bromothiophenol (1.0 g), tetrahydrofuran-4-carboxylic acid (960.0 mg), and phosphorus pentoxide (1.9 g) were added to a polyphosphoric acid solution (6 mL) and stirred at 100°C for 16 hours under nitrogen. Aqueous sodium hydroxide was added to adjust the pH to a weak base, and the mixture was extracted with dichloromethane (160 mL). 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: petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain 1-4 (680.0 mg, 46.0% yield) as a pale yellow liquid. LC-MS m / z (ESI): 297.9, 299.9 [M+H] + .

[0765] 1.5 Synthesis of intermediate 1-5

[0766] 1-4 (250.0 mg), pinacol diboronate (255.0 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride·dichloromethane complex (137.0 mg), and potassium acetate (123.0 mg) were added to a dioxane (15 mL) solution. Under nitrogen, the mixture was stirred at 90°C for 16 hours. The mixture was concentrated under reduced pressure to afford a brown solid crude product 1-5 (400.0 mg), which was used directly in the next reaction. LC-MS m / z (ESI): 346.1 [M+H] + .

[0767] 1.6 Synthesis of intermediate 1-6

[0768] 1-5 (23.0 g), 1-1 (10.5 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium·dichloromethane complex (4.5 g), and sodium carbonate (5.9 g) were added to a 100 mL solution of dioxane and water (V:V = 3:1). Under nitrogen, the mixture was stirred at 90°C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) was added, and the mixture was extracted with dichloromethane (150 mL × 3). The organic phase was washed with saturated sodium chloride (150 mL). The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1-10 / 1) to obtain 1-6 (6.4 g, 55.0% yield) as a white solid. LC-MS m / z (ESI): 415.0 [M+H] + .

[0769] 1.7 Synthesis of Intermediate 1-7

[0770] Under ice bath, trifluoroacetic acid (15 mL) was added to a solution of 1-6 (6.4 g) in dichloromethane (15 mL). Stir at room temperature for 1 hour and concentrate under reduced pressure. Adjust the pH to weak alkaline with saturated sodium bicarbonate, extract with dichloromethane (100 mL × 3), wash the organic phase with saturated sodium chloride solution (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a brown solid crude product 1-7 (4.8 g). The crude product was used directly in the next reaction. LC-MS m / z (ESI): 315.0 [M+H] + .

[0771] 1.8 Synthesis of intermediate 1-8

[0772] Sodium borohydride (0.6 g) was added to a solution of 1-7 (4.8 g) in methanol (20 mL) under an ice bath and stirred at 25°C for 2 hours under nitrogen. The mixture was quenched with water and concentrated under reduced pressure. The mixture was extracted with dichloromethane (50 mL x 3), and the organic phase was washed with saturated sodium chloride (50 mL). The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1-3 / 1) to obtain 1-8 (3.0 g, 63.0% yield) as a yellow solid. LC-MS m / z (ESI): 317.2 [M+H] + .

[0773] 1.9 Synthesis of Intermediate 1-9

[0774] Under ice-cooling, ethyl oxalyl chloride (140 mg) was added to a solution of triethylamine (160 mg) and 1-8 (250 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 silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-2 / 1) to obtain 1-9 (250.0 mg, 80.0% yield) as a white solid. LC-MS m / z (ESI): 417.2 [M+H] + .

[0775] 1.10 Synthesis of Intermediate 1-10

[0776] Lithium hydroxide (23.0 mg) was added to a solution of 1-9 (200.0 mg) in methanol (3 mL) and water (1 mL). The mixture was stirred at room temperature for 2 hours, and water (5 mL) was added. The pH was adjusted to 6 with 2M hydrochloric acid. 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 and lyophilized to obtain 1-10 as a white solid (180.0 mg, 86.8% yield). LC-MS m / z (ESI): 389.1 [M+H] + .

[0777] 1.11 Synthesis of intermediate 1-11

[0778] T3P (123.0 mg) was added to a solution of N,N-diisopropylethylamine (33.0 mg), 1-10 (50.0 mg), and 1-3 (45.0 mg) in dichloromethane (2 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 silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain 1-11 (60.0 mg, 58.1% yield) as a white solid. LC-MS m / z (ESI): 722.0 [M+H] + .

[0779] 1.12 Synthesis of Intermediate 1

[0780] Under ice-cooling, trifluoroacetic acid (1 mL) was added to a solution of 1-11 (60.0 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 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-10%, 20 min) to obtain the formate salt of 1 as a white solid (20.9 mg, 48.0% yield). LC-MS m / z (ESI): 522.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.58-10.49(m,1H),8.1(d,J=8.4Hz,1H),7.93-7.73(m,1H),7.46-7.35(m,1H),6.01-5.95(m,1H),4.92-4.68(m,3H),3.97-3 .94(m,2H),3.52-3.48(m,1H),2.32-2.30(m,1H),2.04-2.02(m,3H),1.88-1.71(m,5H),1.35-1.33(m,1H),1.05-1.04(m,1H).

[0781] 2. Synthesis of Example 2

[0782] 2.1 Synthesis of Intermediate 2-1

[0783] Add pinacol diboronate (2.2 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.7 g), and potassium acetate (1.5 g) to a solution of 1-(3-bromophenyl)-4-methyl-piperazine (2.0 g) in dioxane (20 mL). Stir at 90°C under nitrogen for 16 hours. Cool to room temperature and concentrate under reduced pressure to obtain crude brown solid 2-1 (4.0 g). The product was directly used in the next step without purification. LC-MS m / z (ESI): 303.1 [M+H] + .

[0784] 2.2 Synthesis of intermediate 2-2

[0785] 1-1 (1.0 g), sodium carbonate (0.6 g), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.5 g) were added to a solution of crude 2-1 (2.0 g) in dioxane (10 mL). The mixture was stirred at 90°C under nitrogen for 16 hours. After cooling to room temperature, water (50 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were 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 = 10 / 1–5 / 1) to obtain 2-2 as a clear oil (600.0 mg, 60% yield). LC-MS m / z (ESI): 372.2 [M+H] + .

[0786] 2.3 Synthesis of intermediate 2-3

[0787] Under a nitrogen atmosphere, trifluoroacetic acid (2 mL) was added to a solution of 2-2 (600 mg) in dichloromethane (6 mL). The mixture was stirred at room temperature for 1 hour. Aqueous sodium bicarbonate (10 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude yellow oil 2-3 (550.0 mg). The product was directly used in the next reaction without purification. LC-MS m / z (ESI): 272.3 [M+H] + .

[0788] 2.4 Synthesis of Intermediate 2-4

[0789] Under a nitrogen atmosphere, sodium borohydride (100.0 mg) was added portionwise to a solution of 2-3 (550 mg) in methanol (10 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 combined organic phases were 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 = 10 / 1–1 / 1) to obtain 2-4 as a clear oil (170.0 mg, 34.0% yield). LC-MS m / z (ESI): 274.2 [M+H] + .

[0790] 2.5 Synthesis of Intermediate 2-5

[0791] Under a nitrogen atmosphere at 0°C, sodium hydride (2.0 g) 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 = 10 / 1–2 / 1) to obtain compound 2-5 (1.9 g, 61.9% yield) as a white solid. LC-MS m / z (ESI): 245.9, 247.8 [M+H] + .

[0792] 2.6 Synthesis of intermediate 2-6

[0793] Under a nitrogen atmosphere, sodium carbonate (1.6 g) and p-anisidine (1.6 g) were added to a solution of 2-5 (1.9 g) in N-methylpyrrolidone (20 mL). The mixture was stirred at 130°C for 2 hours, followed by addition of water (60 mL) and extraction 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 (petroleum ether / ethyl acetate = 10 / 1–2 / 1) to afford 2-6 as a white solid (1.6 g, 60.4% yield). LC-MS m / z (ESI): 346.9, 348.9 [M+H] + .

[0794] 2.7 Synthesis of Intermediate 2-7

[0795] Under a nitrogen atmosphere, 2-6 (1.6 g) was added to trifluoroacetic acid (20 mL) and stirred at 60°C for 16 hours. Aqueous sodium bicarbonate (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 = 10 / 1–1 / 1) to obtain 2-7 as a white solid (800.0 mg, yield 76.9%). LC-MS m / z (ESI): 227.0, 229.1 [M+H] + .

[0796] 2.8 Synthesis of Intermediate 2-8

[0797] 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 2-7 (800.0 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 × 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 = 10 / 1–3 / 1) to obtain 2-8 as a white solid (900.0 mg, 59.6% yield). LC-MS m / z (ESI): 449.0, 451.0 [M+Na] + .

[0798] 2.9 Synthesis of Intermediate 2-9

[0799] 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 2-8 (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: dichloromethane / methanol = 20 / 1) to obtain 2-9 (120.0 mg, 56.3% yield) as a yellow solid. LC-MS m / z (ESI): 364.2 [M+H] + .

[0800] 2.10 Synthesis of Intermediate 2-10

[0801] 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 2-9 (110.0 mg) in anhydrous dichloromethane (5 mL) and stirred for 1 hour. The mixture was warmed to room temperature, water (20 mL) was added, and extraction with dichloromethane (10 mL x 3) was performed. 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 2-10 (110.0 mg, 72.3% yield) as a yellow solid. LC-MS m / z (ESI): 464.0 [M+H] + .

[0802] 2.11 Synthesis of Intermediate 2-11

[0803] At 0°C under a nitrogen atmosphere, trimethylaluminum (0.1 mL, 2 M n-hexane solution) was added dropwise to a solution of 2-4 (20.0 mg) in chloroform (1 mL). The mixture was stirred for 0.5 hours, and 2-10 (30.0 mg) was added. The mixture was stirred at 80°C for 16 hours. After cooling to room temperature, 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 to give a crude yellow solid 2-11 (20.0 mg). The product was directly used in the next step without purification. LC-MS m / z (ESI): 591.4 [M-100+H]. + .

[0804] 2.12 Synthesis of Intermediate 2

[0805] Under a nitrogen atmosphere, trifluoroacetic acid (1 mL) was added to a solution of crude product 2-11 (20.0 mg) in dichloromethane (1 mL) and stirred 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: [water (0.05% NH3)-ACN]; B%: 2%-10%, 10 min) to afford 2 as a white solid (7.0 mg, 22.5% yield over two steps). LC-MS m / z (ESI): 491.1 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 8.15-8.04(m,1H),7.90-7.73(m,1H),7.34(t,J=7.8Hz,1H),7.08-6.90(m,3H),5.70-5.30(m,1H),4.43-4.32(m,3H) ,3.65-3.08(m,9H),2.95(s,3H),2.27(s,2H),1.93(d,J=48.8Hz,3H),1.45(d,J=13.4Hz,1H),1.16(d,J=7.2Hz,3H).

[0806] 3. Synthesis of Example 3

[0807] 3.1 Synthesis of Intermediate 3-1

[0808] 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 3-1 as a white solid (830.0 mg, yield 72.5%). LC-MS m / z (ESI): 412.0 [M+Na] + .

[0809] 3.2 Synthesis of Intermediate 3-2

[0810] Under nitrogen, palladium on carbon (88.5 mg) was added to a solution of 3-1 (810.0 mg) in methanol (10 mL). A hydrogen balloon was passed through the mixture and stirred at 25°C for 4 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give crude 3-2 (600.0 mg) as an off-white solid. LC-MS m / z (ESI): 360.0 [M+H] + .

[0811] 3.3 Synthesis of Intermediate 3-3

[0812] Under nitrogen, platinum dioxide (73.3 mg) was added to a solution of 3-2 (580.0 mg) and acetic acid (48.5 mg) in methanol (8 mL). Hydrogen was passed through a hydrogen balloon and stirred at 25°C 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 3-3 as an off-white solid (500.0 mg, yield 76.7%). LC-MS m / z (ESI): 364.1 [M+H] + .

[0813] 3.4 Synthesis of Intermediate 3-4

[0814] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (75.3 mg) was added to a solution of N,N-diisopropylethylamine (42.7 mg), 3-3 (60.0 mg), and 1-10 (70.6 mg) in N,N-dimethylformamide (2 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 (10 x 3 mL). 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 / 1-8 / 1) to obtain 3-4 (35.0 mg, 30.0% yield) as a pale white semi-solid. LC-MS m / z (ESI): 734.1 [M+H] + .

[0815] 3.5 Synthesis of compound 3

[0816] Under ice-cooling, a 4M solution of HCl in 1,4-dioxane (2 mL) was added to 3-4 (30.0 mg). The mixture was stirred at room temperature for 4 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 3 as a white solid (9.0 mg, 39.1% yield). LC-MS m / z (ESI): 534.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.11-9.98(m,1H),8.08(d,J=8.4Hz,1H),7.96-7.86(m,1H),7.69-7. 58(m,1H),7.54-7.35(m,1H),5.65(t,J=26.8Hz,3H),3.95(d,J=11.8H z,2H),3.56-3.46(m,3H),2.40-2.28(m,3H),2.27-2.15(m,2H),2.09- 1.99(m,3H),1.98-1.53(m,9H),1.49-1.32(m,2H),1.11-1.02(m,3H).

[0817] 4. Synthesis of Example 4

[0818] 4.1 Synthesis of Intermediate 4-1

[0819] Di-tert-butyl dicarbonate (11.5 g), triethylamine (5.5 g), and 4-dimethylaminopyridine (0.6 g) were added to a solution of methyl 6-methyl-1H-indole-5-carboxylate (3.0 g) in dichloromethane (30 mL) and stirred at room temperature for 2 hours. Water (200 mL) was added, and the mixture was extracted with dichloromethane (100 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: petroleum ether / ethyl acetate = 5 / 1) to obtain 4-1 as a colorless oil (5.5 g, yield 89.2%). LC-MS m / z (ESI): 449.0 [2M+H] + .

[0820] 4.2 Synthesis of intermediate 4-2

[0821] Under a nitrogen atmosphere, a solution of lithium bistrimethylsilylamide (30 mL, 1 M) in tetrahydrofuran was added to a solution of 4-1 (5.5 g) in tetrahydrofuran (60 mL) at -78°C. The mixture was stirred for 1.5 hours at -78°C, and N-phenylbis(trifluoromethanesulfonyl)imide (13.5 g) was added. The mixture was stirred at room temperature for 12 hours. Saturated ammonium chloride solution (5 mL) was added to quench the mixture. Water (100 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: petroleum ether / ethyl acetate = 20 / 1) to obtain 4-2 (6.5 g, 70.2% yield) as a colorless oil. LC-MS m / z (ESI): 289.9 [M-56+H]. + .

[0822] 4.3 Synthesis of Intermediate 4-3

[0823] [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (2.3 g), sodium carbonate (3.3 g), and 4-2 (6.5 g) were added to a solution of 5-benzothiazolylpinacol borate (4.0 g) in dioxane and water (60 mL, v / v = 3:1). The mixture was stirred at 90°C for 16 hours under nitrogen. The mixture was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) was added and the mixture was extracted with ethyl acetate (50 × 3 mL). The organic phase was washed with saturated sodium chloride (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 4-3 (2.4 g, 45.5% yield) as a white solid. LC-MS m / z (ESI): 331.0 [M+H] + .

[0824] 4.4 Synthesis of Intermediate 4-4

[0825] Under ice-cooling, trifluoroacetic acid (5 mL) was added to a solution of 4-3 (2.4 g) in dichloromethane (15 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the pH was adjusted to a weak base with sodium bicarbonate. The mixture was extracted with dichloromethane (50 × 3 mL). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-4 (1.5 g). The crude product was used directly in the next reaction. LC-MS m / z (ESI): 231.0 [M+H] + .

[0826] 4.5 Synthesis of intermediate 4-5

[0827] Under ice-cooling, sodium borohydride (600.0 mg) was added to a solution of 4-4 (1.5 g) in methanol (20 mL). The mixture was stirred at 0°C for 2 hours, and then water (100 mL) was added. The mixture was extracted with dichloromethane (3 × 80 mL). The organic phase was washed with saturated sodium chloride solution (50 mL). The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 4-5 (1.4 g, 83.3% yield for two steps) as a white solid. LC-MS m / z (ESI): 233.1 [M+H] + .

[0828] 4.6 Synthesis of intermediate 4-6

[0829] Under ice-cooling, monomethyl oxalyl chloride (630.0 mg) was added dropwise to a solution of triethylamine (440.0 mg) and compound 4-5 (1.0 g) in dichloromethane (15 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 (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 compound 4-6 (1.1 g, yield 75.4%) as a colorless oil. LC-MS m / z (ESI): 319.0 [M+H] + .

[0830] 4.7 Synthesis of intermediate 4-7

[0831] Lithium hydroxide (170.0 mg) was added to a mixture of methanol and water (20 mL, v / v = 1:1) of 4-6 (1.1 g) and stirred at room temperature for 2 hours. The mixture was acidified with hydrochloric acid (1 M) and extracted with dichloromethane (30 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 a white solid 4-7 (950.0 mg). The crude product was used directly in the next reaction. LC-MS m / z (ESI): 305.0 [M+H] + .

[0832] 4.8 Synthesis of intermediate 4-8

[0833] N,N,N,N-Tetramethylchloroformamidine hexafluorophosphate (370.0 mg) and N-methylimidazole (110.0 mg) were added to a solution of 4-7 (200.0 mg) and 2-9 (240.0 mg) in acetonitrile (6 mL) and stirred at room temperature for 5 hours. Water (40 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 3 mL). 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 / 1-10 / 1) to obtain 4-8 (300.0 mg, 56.6% yield) as a yellow solid. LC-MS m / z (ESI): 650.0 [M+H] + .

[0834] 4.9 Synthesis of compound 4

[0835] Compound 4-8 (300.0 mg) was added to a solution of 1,4-dioxane in hydrochloric acid (6 mL, 4 M), and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water (10 mL) was added, and the pH was adjusted to weak alkaline with saturated sodium bicarbonate solution. The product was extracted with dichloromethane (10 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 / 1-10 / 1) to give a yellow solid (250.0 mg). The product was separated by SFC (column: CHIRALPAK AS-H 250 mm × 20 mm, 5 μm; mobile phase: 40% IPA (0.2% NH4OH)) to give a white solid (ee = 80%, 65.0 mg, RT = 6.08 min). The product was further purified by HPLC (column: Gemini 5u C18 150 x 21.2 mm; mobile phase: [water (FA)-ACN]; B%: 2%-20%, 15 min) to give a white solid 4 (ee=100%, 56.0 mg, yield 33.1%). LC-MS m / z (ESI): 449.9 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92-10.74(m,1H),9.48-9.36(m,1H),8.25-8.16(m,1H),8.15-8.03(m ,1H),7.99-7.85(m,1H),7.86-7.72(m,1H),7.60-7.43(m,1H),6.36-6.1 6(m,2H),5.89-5.22(m,1H),4.32-4.22(m,3H),3.54-3.36(m,2H),2.47- 2.03(m,2H),1.99-1.66(m,2H),1.40-1.30(m,1H),1.08(d,J=4.0Hz,3H).

[0836] 5. Synthesis of Example 5

[0837] 5.1 Synthesis of Intermediate 5-1

[0838] 3-1 (2.6 g), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] methanesulfonate palladium(II) methanesulfonate (469.4 mg), and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (138.8 mg) were added to a solution of methyl 1-aminocyclopropane-1-carboxylate (357.4 mg) in 1,4-dioxane (50 mL). The mixture was stirred at 100°C for 8 hours under nitrogen protection. After cooling to room temperature, water (50 mL) was added to the reaction solution, and the mixture was 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: petroleum ether / ethyl acetate = 1 / 1) to obtain a light yellow solid 5-1 (220.0 mg, yield 20.1%). LC-MS m / z (ESI): 422.1 [M+H] + .

[0839] 5.2 Synthesis of Intermediate 5-2

[0840] Lithium hydroxide (65.8 mg) was added to a solution of 5-1 (220.0 mg) in tetrahydrofuran and water (10 mL, V / V = 5 / 1). The mixture was 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 5-2 (120.0 mg, 74.6% yield) as a pale yellow solid. LC-MS m / z (ESI): 308.2 [M+H] + .

[0841] 5.3 Synthesis of Intermediate 5-3

[0842] 5-2 (40.0 mg), N,N-diisopropylethylamine (50.4 mg), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (99.1 mg) were added to a solution of 1-8 (41.2 mg) in N,N-dimethylformamide (5 mL). Under nitrogen protection, 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 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 silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to obtain a light yellow solid 5-3 (42.7 mg, yield 54.2%). LC-MS m / z (ESI): 606.2 [M+H] + .

[0843] 5.4 Synthesis of compound 5

[0844] Under ice-cooling, trifluoroacetic acid (2 mL) was added to a solution of 5-4 (42.7 mg) in dichloromethane (6 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 5 as a white solid (14.0 mg, 29.3% yield). LC-MS m / z (ESI): 506.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 7.89-7.73(m,1H),7.66-7.53(m,1H),7.22(s,1H),7.05-6.94(m,1H), 6.20-5.66(m,5H),4.08(d,J=12.6Hz,1H),3.96-3.94(m,2H),3.52-3.4 7(m,3H),2.29-2.19(m,1H),2.02-1.97(m,6H),1.84-1.75(m,3H),1.64 -1.57(m,1H),1.38-1.23(m,3H),1.19-1.14(m,1H),0.98-0.77(m,5H).

[0845] 6. Synthesis of Example 6

[0846] 6.1 Synthesis of Intermediate 6-1

[0847] Di-tert-butyl dicarbonate (18.0 g), triethylamine (13.0 g), and 4-dimethylaminopyridine (0.8 g) were added to a solution of 2-amino-3-methyl-5-nitropyridine (5.0 g) in dichloromethane (50 mL). The mixture was stirred at room temperature for 3 hours 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 compound 6-1 (10.0 g, yield 86.9%) as a white solid. LC-MS m / z (ESI): 376.1 [M+Na] + .

[0848] 6.2 Synthesis of Intermediate 6-2

[0849] 10% palladium on carbon (2.0 g) was added to a solution of compound 6-1 (10.0 g) in methanol (100 mL). The mixture was replaced with hydrogen three times and stirred at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a pale yellow solid 6-2 (9.2 g), which was used directly in the next reaction without purification. LC-MS m / z (ESI): 324.2 [M+H] + .

[0850] 6.3 Synthesis of Intermediate 6-3

[0851] Ethyl 3,3,3-trifluoropyruvate (780.0 mg) and anhydrous p-toluenesulfonic acid (54.0 mg) were added to a solution of 6-2 (1.0 g) in anhydrous toluene (20 mL). The mixture was stirred at 100°C under nitrogen for 15 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain a pale yellow solid 6-3 (1.8 g), which was used directly in the next reaction without purification. LC-MS m / z (ESI): 476.0 [M+H] + .

[0852] 6.4 Synthesis of Intermediate 6-4

[0853] Under a nitrogen atmosphere, sodium cyanoborohydride (125.0 mg) was added to a solution of crude product 6-3 (1.8 g) in acetic acid (20 mL) and stirred at room temperature for 1 hour. Water (20 mL) was added for dilution, 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 = 3 / 1-1 / 1) to obtain a white solid 6-4 (300 mg, yield 20.4%). LC-MS m / z (ESI): 478.3 [M+H] + .

[0854] 6.5 Synthesis of Intermediate 6-5

[0855] Trimethyltin hydroxide (342.0 mg) was added to a solution of 6-4 (300 mg) in 1,2-dichloroethane (10 mL). Stir at 50°C for 3 hours under nitrogen. Water (10 mL) was added for dilution, 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 to obtain a yellow solid 6-5 (200 mg, yield 70.8%). LC-MS m / z (ESI): 450.0 [M+H] + .

[0856] 6.6 Synthesis of Intermediate 6-6

[0857] Compound 1-8 (50.0 mg) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (80.0 mg) were added to a solution of 6-5 (50 mg) in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature for 3 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 (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 a white solid 6-6 (12.0 mg, yield 14%). LC-MS m / z (ESI): 748.2 [M+H] + .

[0858] 6.7 Synthesis of Compound 6

[0859] Under ice, trifluoroacetic acid (0.5 mL) was added to a solution of 6-6 (14.0 mg) in dichloromethane (2 mL) and stirred at room temperature for 2 hours. 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 (0.05% FA); B%: 5%-60%, 35 min) to afford the formate salt of 6 as a white solid (1.4 mg, yield 14.1%). LC-MS m / z (ESI): 548.2 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 7.72-7.60(m,2H),7.45(d,J=2.8Hz,1H),7.10(s,1H),6.61(s,1H),5.74(s,1H),4.50(s,2H),4.02-3.89(m,2H),3.63 (s,1H),3.59-3.45(m,2H),3.39-3.24(m,1H),2.16(s,2H),2.07-1.88(m,7H),1.68(s,2H),1.28(s,1H),1.01(s,3H).

[0860] 7. Synthesis of Example 7

[0861] 7.1 Synthesis of Intermediate 7-1

[0862] At 0°C, a solution of lithium bistrimethylsilylamide 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 solution (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 7-1 (6.0 g, 60.7% yield) as a white solid. LC-MS m / z (ESI): 173.0 [M-56+H]. + .

[0863] 7.2 Synthesis of Intermediate 7-2

[0864] At -78°C, a solution of n-butyllithium in tetrahydrofuran (4.4 mL, 2.4 M) was added to a solution of 7-1 (1.0 g) in tetrahydrofuran (10 mL). 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 7-2 (270.0 mg, 20.5% yield) as a yellow solid. LC-MS m / z (ESI): 156.9 [M-100+H] + .

[0865] 7.3 Synthesis of Intermediate 7-3

[0866] Under ice, trifluoroacetic acid (600.0 mg) was added to a solution of 7-2 (270.0 mg) in dichloromethane (3 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The pH was adjusted to a weak base with saturated sodium bicarbonate 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 obtain a yellow solid crude product 7-3 (180.0 mg). The crude product was used directly in the next reaction. LC-MS m / z (ESI): 157.0 [M+H] + .

[0867] 7.4 Synthesis of Intermediate 7-4

[0868] N-Bromobutyric acid diamide (187.5 mg) was added to a solution of 7-3 (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 solution (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid 7-4 (180.0 mg). The crude product was used directly in the next reaction. LC-MS m / z (ESI): 235.0, 237.0 [M+H] + .

[0869] 7.5 Synthesis of Intermediate 7-5

[0870] Hydrazine hydrate (171.9 mg) was added to a solution of 7-4 (160.0 mg) in dimethyl sulfoxide (2 mL). The mixture was stirred at 120°C for 2 hours, cooled to room temperature, and extracted with water (5 mL). The organic phase was washed with saturated sodium chloride solution (5 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then added with dichloromethane (2 mL). The mixture was filtered to obtain a yellow solid 7-5 (60.0 mg, 35.2% yield). LC-MS m / z (ESI): 213.0, 215.0 [M+H] + .

[0871] 7.6 Synthesis of Intermediate 7-6

[0872] Under nitrogen, diisopropyl azodicarboxylate (142.3 mg) was added to a solution of 7-5 (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 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: dichloromethane / ethyl acetate = 1 / 2) to obtain 7-6 (70.0 mg, 59.1% yield) as a white solid. LC-MS m / z (ESI): 226.9, 228.9 [M+H] + .

[0873] 7.7 Synthesis of Intermediate 7-7

[0874] Di-tert-Butyl dicarbonate (148.0 mg) was added to a solution of 7-6 (70 mg), triethylamine (62.3 mg), and 4-dimethylaminopyridine (3.7 mg) in dichloromethane (2 mL) and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to afford 7-7 (100.0 mg, 89.2% yield) as a white solid. LC-MS m / z (ESI): 427.0, 429.0 [M+H] +.

[0875] 7.8 Synthesis of Intermediate 7-8

[0876] 7-7 (150.0 mg), benzophenone imine (127.2 mg), tris(dibenzylideneacetone)dipalladium (32.1 mg), 1,1'-biphenyl-2,2'-bis(diphenylphosphine) (32.7 mg), and cesium carbonate (228.7 mg) were added to a toluene (10 mL) solution. Under nitrogen, the mixture was stirred at 110°C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 3) to afford 7-8 (100.0 mg, 48.6% yield) as a yellow solid. LC-MS m / z (ESI): 528.3 [M+H] + .

[0877] 7.9 Synthesis of Intermediate 7-9

[0878] At 0°C, a solution of hydrochloric acid (1 mL, 2 M) was added to a solution of 7-8 (90.0 mg) in tetrahydrofuran (2 mL). The mixture was stirred at 0°C for 1 hour. The mixture was concentrated under reduced pressure and lyophilized to obtain a yellow solid 7-9 (20.0 mg). The crude product was used directly in the next reaction without purification. LC-MS m / z (ESI): 264.1 [M+H] + .

[0879] 7.10 Synthesis of Intermediate 7-10

[0880] N-Methylimidazole (123.0 mg) was added to a solution of 7-9 (20.0 mg), 1-10 (32.4 mg), and tetramethyluronium chloride hexafluorophosphate (42.6 mg) in acetonitrile (2 mL). The mixture was stirred at room temperature for 2 hours, then water (5 mL) was added and extracted with ethyl acetate (5 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 silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1) to obtain 7-10 (15.0 mg, 15.5% yield) as a yellow solid. LC-MS m / z (ESI): 634.2 [M+H] + .

[0881] 7.11 Synthesis of Compound 7-11

[0882] Under ice, a solution of HCl in dioxane (2 mL, 4 M) was added to a solution of 7-10 (15.0 mg) in dioxane (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 150×19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-10%, 20 min) to afford the formate salt of 7 (4.3 mg, 42.8% yield) as a white solid. LC-MS m / z (ESI): 534.0 [M+H] + . 1 H NMR(400MHz,CD3OD)δppm 8.18-8.12(m,1H),7.98-7.73(m,2H),7.53-7.31(m,2H),5.85-5.75(m,1H),4.16-4.08(m,2H),4.05-4.02(m,2H),3.96-3.9 4(m,1H),3.62-3.55(m,2H),3.43-3.36(m,1H),2.35-2.26(m,2H),2.20-1.90(m,6H),1.49-1.26(m,3H),1.18-1.13(m,3H).

[0883] 8. Synthesis of Example 8

[0884] 8.1 Synthesis of Intermediate 8-1

[0885] 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 a saturated sodium bicarbonate solution and the pH was adjusted to 8. The mixture was filtered and the filter cake dried to afford a yellow solid 8-1 (1.0 g, 75.75% yield). LC-MS m / z (ESI): 191.1 [M+H] + .

[0886] 8.2 Synthesis of Intermediate 8-2

[0887] Sodium hydride (336.8 mg, 60% wt) was added to a tetrahydrofuran solution (500 mL) of 8-1 (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 8-2 (1.0 g, 65.5% yield) as a yellow solid. LC-MS m / z (ESI): 291.1 [M+H] + .

[0888] 8.3 Synthesis of Intermediate 8-3

[0889] Reduced iron powder (1.9 g) was added to a mixture of 8-2 (1.0 g) and ammonium chloride (900.0 mg) in ethanol and water (30 mL, V / V = 1:9). The mixture was stirred at 50°C for 8 hours, then water (20 mL) was added and 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 8-3 as a yellow oil (600.0 mg, yield 66.9%). LC-MS m / z (ESI): 261.2 [M+H] + .

[0890] 8.4 Synthesis of Intermediate 8-4

[0891] N-Methylimidazole (50.4 mg) was added to a solution of 8-3 (80.0 mg), 1-10 (131.3 mg), and tetramethyluronium chloride hexafluorophosphate (258.6 mg) in acetonitrile (2 mL). The mixture was stirred at room temperature for 2 hours, then water (5 mL) was added and extracted with ethyl acetate (5 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 silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 8-4 as a yellow oil (150.0 mg, yield 69.6%). LC-MS m / z (ESI): 631.0 [M+H] + .

[0892] 8.5 Synthesis of Compound 8

[0893] Under ice, trifluoroacetic acid (1 mL) was added to a solution of 8-4 (130.0 mg) in dichloromethane (2 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 8 as a yellow solid (60 mg, 52.1% yield). LC-MS m / z (ESI): 531.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δppm10.77-10.70(m,1H),8.63-8.29(m,2H),8.12-8.06(m,2H),7.97-7.84(m,2H),7.50-7.40(m,1H),7.29-7.24(m ,2H),5.80-5.76(m,1H),3.96-3.94(m,2H),3.59-3.47(m,4H),2.06- 1.94(m,4H),1.87-1.75(m,4H),1.46-1.37(m,2H),1.15-1.08(m,3H),

[0894] 9. Synthesis of Example 9

[0895] 9.1 Synthesis of Intermediate 9-1

[0896] 2-Chloro-4-bromopyrimidine (100.0 mg) was added to a solution of 1-8 (196.9 mg) in ethylene glycol monomethyl ether (5 mL) and stirred at 125°C for 3 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 9-1 (60.0 mg, yield 25.7%) as a white solid. LC-MS m / z (ESI): 429.0 [M+H] + .

[0897] 9.2 Synthesis of Intermediate 9-2

[0898] Pinacol diboronate (235.0 mg) and potassium acetate (298.2 mg) were added to a solution of 3-1 (300.0 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (126.2 mg) in 1,4-dioxane (15 mL). The mixture was stirred at 90°C for 16 hours. 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 (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 (250.0 mg, 74.2% yield) as a white solid. LC-MS m / z (ESI): 435.2 [M+H] + .

[0899] 9.3 Synthesis of Compound 9

[0900] [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (22.8 mg) and cesium carbonate (91.2 mg) were added to a mixture of 9-1 (21.0 mg) and 9-2 (72.9 mg) in 1,4-dioxane (5 mL) and water (1 mL). The mixture was stirred at 90°C for 16 hours. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with dichloromethane (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 HPLC (column: Xbridge-C18 150 × 19 mm, 5 μm; mobile phase: ACN-H2O (0.1% TFA); B%: 5%-10%, 20 min) to afford the trifluoroacetate salt of 9 as a white solid (1.4 mg, 5.6% yield). LC-MS m / z(ESI):501.2[M+H] + . 1 H NMR(400MHz,CD3OD)δppm 8.62(d,J=4.0Hz,1H),8.11(d,J=8.0Hz,1H),8.03(s,1H),7.94(d,J=8.0Hz,1H),7. 81(s,1H),7.40(dd,J=4.0,8.0Hz,1H),6.57(d,J=8.0Hz,1H),5.80-5.77(m,1H),4. 20-4.17(m,1H),4.05-4.02(m,2H),3.59-3.55(m,3H),3.39-3.35(m,1H),2.38-2.3 2(m,2H),2.14(s,3H),1.99-1.96(m,2H),1.93-1.90(m,4H),1.11(d,J=8.0Hz,3H).

[0901] 10. Synthesis of Example 10

[0902] 10.1 Synthesis of Intermediate 10-1

[0903] At 0°C, under a nitrogen atmosphere, a solution of 2-bromo-5-hydroxypyrazine (10.0 g) in N,N-dimethylformamide (30 mL) and tetrahydrofuran (30 mL) was slowly added dropwise to a solution of sodium hydride (2.7 g, 60% wt) in N,N-dimethylformamide (30 mL). The mixture was stirred at 0°C for 30 minutes. A solution of 4-methoxybenzyl chloride (10.0 g) in tetrahydrofuran (30 mL) was added, and the mixture was slowly warmed to room temperature and stirred for 16 hours. The mixture was cooled to 0°C and quenched by the dropwise addition of saturated ammonium chloride solution (10 mL). The mixture was diluted with water (500 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 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: petroleum ether / ethyl acetate = 3 / 1-2 / 1) to give a white solid 10-1 (11.0 g, yield 65.5%). LC-MS m / z (ESI): 316.9, 318.9 [M+Na] + .

[0904] 10.2 Synthesis of Intermediate 10-2

[0905] At 0°C, under a nitrogen atmosphere, a solution of p-toluenesulfonylmethyl isocyanide (8.9 g) and 10-1 (12.2 g) in tetrahydrofuran (60 mL) was slowly added dropwise to a solution of sodium hydride (2.3 g, 60% wt) in tetrahydrofuran (60 mL). The mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for 1 hour. The mixture was cooled to 0°C and quenched by the addition of saturated ammonium chloride solution (5 mL). The mixture was diluted with water (500 mL) and extracted with ethyl acetate (100 mL × 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 = 2 / 3-1 / 4) to obtain 10-2 (10.0 g, 72.4% yield) as a white solid. LC-MS m / z (ESI): 333.9, 335.9 [M+H] + .

[0906] 10.3 Synthesis of Intermediate 10-3

[0907] At 0°C, under a nitrogen atmosphere, trifluoromethanesulfonic acid (25 mL) was added to a solution of 10-2 (10.0 g) in trifluoroacetic acid (100 mL) and anisole (45 mL). The mixture was heated to room temperature and stirred for 30 minutes, then at 40°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was slowly poured into a mixture of sodium bicarbonate and ice water. The mixture was concentrated under reduced pressure at 60°C, and the residue was slurried with dichloromethane and methanol (200 mL, V / V = 10:1), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100 / 5-100 / 6) to obtain 10-3 (4.5 g, yield 71.4%) as a white solid. LC-MS m / z (ESI): 213.9, 215.9 [M+H] + .

[0908] 10.4 Synthesis of Intermediate 10-4

[0909] 4-Methoxybenzylamine (4.6 g), 1,8-diazacyclo[5,4,0]undecene-7 (6.8 g), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14.8 g) were added to a solution of 10-3 (4.5 g) in anhydrous acetonitrile (80 mL) and stirred at 80°C for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, diluted with water (100 mL), and 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: petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain 10-4 (6.0 g, 85.7% yield) as a pale yellow solid. LC-MS m / z (ESI): 333.1, 335.0 [M+H] + .

[0910] 10.5 Synthesis of Intermediate 10-5

[0911] 10-4 (5.0 g) was added to trifluoroacetic acid (50 mL) and stirred at 80°C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to a weakly alkaline state with sodium bicarbonate solution and 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 = 100 / 3) to obtain 10-5 (2.3 g, yield 71.8%) as a yellow solid. LC-MS m / z (ESI): 213.0, 214.9 [M+H] + .

[0912] 10.6 Synthesis of Intermediate 10-6

[0913] Di-tert-butyl dicarbonate (5.9 g), triethylamine (3.2 g), and 4-dimethylaminopyridine (0.3 g) were added to a solution of 10-5 (2.3 g) in dichloromethane (30 mL) and stirred at room temperature for 16 hours. Dichloromethane (100 mL) was added, and the mixture was washed with saturated sodium chloride solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain 10-6 (2.5 g, 54.3% yield) as a yellow solid. LC-MS m / z (ESI): 412.9, 414.9 [M+H] + .

[0914] 10.7 Synthesis of Intermediate 10-7

[0915] Benzophenone imine (440.0 mg), cesium carbonate (790.0 mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (150.0 mg), and tris(dibenzylideneacetone)dipalladium (110.0 mg) were added to a solution of 10-6 (500.0 mg) in anhydrous toluene (20 mL). The mixture was stirred at 100°C under nitrogen for 16 hours. The mixture was cooled to room temperature, diluted with water (50 mL), and 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: petroleum ether / ethyl acetate = 4 / 1-3 / 1) to obtain 10-7 (500.0 mg, 80.3% yield) as a yellow solid. LC-MS m / z (ESI): 514.1 [M+H] + .

[0916] 10.8 Synthesis of Intermediate 10-8

[0917] Hydrochloric acid (5 mL, 2 M) was added to a solution of 10-7 (500.0 mg) in methanol (5 mL) and stirred at room temperature for 30 minutes. The pH was adjusted to a weak base with saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL × 3), and 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 = 100 / 31-100 / 3) to obtain an off-white solid 10-8 (300.0 mg, yield 88.3%). LC-MS m / z (ESI): 350.2 [M+H] + .

[0918] 10.9 Synthesis of Intermediate 10-9

[0919] Methyl oxalyl chloride (83.0 mg) and triethylamine (80.0 mg) were added to a solution of 10-8 (200.0 mg) in dichloromethane (5 mL) and stirred at room temperature for 3 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 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: petroleum ether / ethyl acetate = 1 / 1) to obtain an off-white solid 10-9 (100.0 mg, yield 40.2%). LC-MS m / z (ESI): 436.1 [M+H] + .

[0920] 10.10 Synthesis of Compound 10

[0921] At 0°C under a nitrogen atmosphere, trimethylaluminum (0.25 mL, 1 M n-hexane solution) was added dropwise to a solution of 1-8 (28.0 mg) in anhydrous toluene (2 mL). The mixture was stirred at 0°C for 0.5 h, and 10-9 (30.0 mg) was added. The mixture was stirred at 100°C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. Saturated sodium bicarbonate solution (10 mL) and water (20 mL) were 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 HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-30%, 14 min) to afford the formate salt of 10 (1.0 mg, 2.8% yield) as a white solid. LC-MS m / z(ESI):520.2[M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 8.28-8.22(m,1H),8.03-7.99(m,1H),7.96(s,1H),7.92-7.85(m,1H),7.51-7. 42(m,1H),7.07-7.01(m,1H),5.37-5.32(m,1H),4.08-4.01(m,2H),3.66-3.56( m,2H),2.41-2.33(m,1H),2.22-2.16(m,1H),2.15-2.07(m,2H),2.06-1.92(m,4 H),1.64-1.56(m,1H),1.53-1.46(m,1H),1.31-1.26(m,3H),1.21-1.14(m,2H).

[0922] 11. Synthesis of Example 98

[0923] 11.1 Synthesis of Intermediate 98-1

[0924] Triphenylphosphine (22.3 mg) and potassium carbonate (718.3 mg) were added to a dioxane solution (20 mL) of bistriphenylphosphine palladium dichloride (36.5 mg), pinacol diboron (659.9 mg), and 1-1 (600.0 mg). The mixture was stirred at 90°C under nitrogen for 3 hours. The reaction 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 = 20 / 1-2 / 1) to afford 98-1 as a white oil (525.0 mg, 93.5% yield). LC-MS m / z (ESI): 346.2 [M+Na] + .

[0925] 11.2 Synthesis of Intermediate 98-2

[0926] 98-1 (813.8 mg), tetrakistriphenylphosphine palladium (241.7 mg), and potassium hydroxide (352.1 mg) were added to a mixture of 1-bromo-4-[(difluoromethyl)sulfanyl]benzene (500.0 mg) in 1,4-dioxane and water (22 mL, v / v = 10:1). The mixture was stirred at 70°C for 1 hour under nitrogen. Water (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (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 = 10 / 1) to afford 98-2 (330.0 mg, 44.3% yield) as a white solid. LC-MS m / z (ESI): 300.0 [M-55]. + .

[0927] 11.3 Synthesis of Intermediate 98-3

[0928] Add 98-2 (330.0 mg) to a mixture of trifluoroacetic acid and dichloromethane (6 mL, v / v = 2:1). Stir at room temperature under nitrogen for 1 hour. The reaction mixture was directly carried out to the next step without purification. LC-MS m / z (ESI): 256.2 [M+H] + .

[0929] 11.4 Synthesis of Intermediate 98-4

[0930] Under nitrogen, sodium borohydride (170.4 mg) was added to a methanol solution (5 mL) of 98-3 (230.0 mg) at 0°C and stirred for 1 hour. Water (50 mL) was added to the reaction solution, which was extracted with dichloromethane (50 mL x 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 to give the crude yellow oil 98-4 (230.0 mg, 99.2% yield). The product was directly used in the next step without purification. LC-MS m / z (ESI): 258.1 [M+H] + .

[0931] 11.5 Synthesis of Intermediate 98-5

[0932] At 0°C, ethyl oxalyl chloride (305.1 mg) was added to a dichloromethane solution (1.0 mL) of triethylamine (271.3 mg) and 98-4 (230.0 mg). The reaction mixture was warmed to room temperature and stirred under nitrogen for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (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 to obtain the crude yellow oil 98-5 (100.0 mg, yield 93.9%). LC-MS m / z (ESI): 358.1 [M+H] + .

[0933] 11.6 Synthesis of Intermediate 98-6

[0934] Lithium hydroxide monohydrate (352.2 mg) was added to a solution of 98-5 (300.0 mg) in methanol and water (4.0 mL, v / v = 3:1). The mixture was stirred at room temperature for 1 hour under nitrogen. Water (10 mL) was added to the reaction solution, and hydrochloric acid (1 M) was added dropwise until the pH of the reaction solution reached 5-6. The aqueous phase was purified by reverse phase chromatography on a C18 column (eluent: 0.1% FA / 50% acetonitrile) and lyophilized to obtain the formate salt of 98-6 as a white solid (180.0 mg, yield 65.1%). LC-MS m / z (ESI): 330.0 [M+H] + .

[0935] 11.7 Synthesis of Intermediate 98-7

[0936] N-Methylimidazole (56.2 mg) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (191.9 mg) were added to a solution of 2-9 (50.0 mg) and 98-6 (67.6 mg) in N,N-dimethylformamide (1 mL) and stirred at room temperature for 1 hour. The reaction solution was added dropwise to ice water, and a solid precipitated. The solid was filtered under reduced pressure and the filter cake was collected to obtain the crude yellow solid 98-7 (50.0 mg, 54.0% yield). LC-MS m / z (ESI): 675.2 [M+H] + .

[0937] 11-8 Synthesis of Compound 98

[0938] 98-7 (50.0 mg) was added to a solution of HCl in dioxane (2 mL, 4 M) and stirred at room temperature under nitrogen for 1 hour. The reaction 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%: 20%-95%, 9.5 min) to afford the formate salt of 98 as a white solid (14.1 mg, 40.2% yield). LC-MS m / z (ESI): 475.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6, 80℃) δ10.48(s,1H),7.79-7.90(m,2H),7.63-7.61(m,2H),7.54-7.40(m,3H),5.99(s,2H),5.55(s,1H) ,4.27(s,3H),3.14-3.10(m,2H),2.25-2.06(m,2H),1.72(s,1H),1.68-1.65(m,1H),1.26-1.24(m,1H),1.05(d,J=7.0Hz,3H).

[0939] The following compounds were synthesized using the same synthesis strategy as in Examples 1, 2, and 98:

[0940] Experimental Example 1: Cell Anti-Proliferation Experimental Method

[0941] 1.1 Materials and cells

[0942] HCT116MTAP Deletion cells were from Pharmaron (China); HCT116 cells were from ATCC (USA); McCoy's 5A medium was purchased from Invitrogen (USA); penicillin-streptomycin and fetal bovine serum were purchased from Gibco (USA); 384-well plates were purchased from PerkinElmer (USA); and Cell-Titer Glo reagent was purchased from Promega (USA).

[0943] 1.2 Compound Storage

[0944] Compound Dissolution: All compounds were dissolved in dimethyl sulfoxide (DMSO) and stored in a dry place at room temperature for short-term storage for 3 months or at -20°C for long-term storage.

[0945] 1.3 Cell culture and passaging

[0946] Cells were cultured in strict accordance with ATCC guidelines. Cell culture medium (McCoy's 5A medium + 10% fetal bovine serum + 1% penicillin + streptomycin) was transferred to a 15 mL centrifuge tube and centrifuged at 1000 rpm for 5 minutes. The supernatant was removed, and the cells were resuspended in complete culture medium. The cells were seeded into culture dishes at the desired density and cultured in an incubator at 37°C in a humidified atmosphere of 95% air and 5% carbon dioxide. Depending on cell growth, the culture medium was replenished or the cells were passaged every 2-3 days.

[0947] 1.4 Cell proliferation activity detection

[0948] When cells reached approximately 90% confluency in the culture dish, they were washed twice with PBS and trypsinized to single cells. Cells were counted and plated in 384-well plates (50 cells / well) at 40 μl per well. The plates were equilibrated at 37°C and 5% CO2 for 10-15 minutes. Compounds were injected into the 384-well plates using an Echo550. A three-fold dilution gradient of 10 was set up for each compound, with duplicate wells containing 0.1% DMSO. The 384-well plates were incubated in a cell culture incubator for 10 days.

[0949] Then, 40 μl of cell proliferation detection reagent (CTG) was added to the 384-well plate and shaken to mix. The 384-well plate was then incubated in the dark at 37°C and 5% carbon dioxide for 30 minutes. The reading was performed using the Envision multifunctional microplate reader. The formula for calculating the percentage of compound inhibition is as follows: Percentage inhibition = 100-(Signal value 药物处理组 -Signal value day0_cell ) / (Signal value 阴性对照组 -Signal value day0_cell ) × 100. GraphPad 8.0 software was used to analyze the GI tract according to different drug concentrations and their corresponding inhibition rates. 50 Draw curves, analyze data, and get the final GI 50 The results are shown in Table 1, where GI 50 ≤0.1μM is A, 0.1μM<GI 50 ≤1μM is B, 1μM<GI 50 ≤10μM is C, 10μM<GI 50 It is D.

[0950] Table 1 Test results of the compounds of the present invention

[0951] In addition, the compounds of the present invention also have selectivity for mutant HCT116 cells, for example, compounds 33 and 34 have a selective effect on HCT116 cells. MTAP Deletion GI 50 ≤0.1μM, but the GI of HCT116 50 The selectivity of the representative compounds is shown in Table 2:

[0952] Table 2 Selectivity data of representative compounds

[0953] Experimental Example 2: Cell SDMA In-cell Western blotting assay

[0954] 2.1 Materials and cells

[0955] HCT116MTAP Deletion cells were from Horizon; HCT116 cells were from ATCC; RPMI-1640 medium was purchased from ATCC (USA); penicillin-streptomycin was purchased from Gibco (USA); fetal bovine serum was purchased from ExCell; 96-well plates were purchased from Corning (USA); Symmetric Di-Methyl Arginine Motif [sdme-RG] antibody was purchased from CST (USA); IRDye 800CW Goat anti-Rabbit IgG secondary antibody was purchased from LI-COR (USA), and CellTag 700 stain was purchased from LI-COR (USA).

[0956] 2.2 Compound Storage

[0957] Compound Dissolution: All compounds were dissolved in dimethyl sulfoxide (DMSO) and stored at -20°C for long-term storage.

[0958] 2.3 Cell culture and passaging

[0959] Cells were cultured in strict accordance with ATCC guidelines. Cell culture medium (RPMI-1640 medium + 10% serum + 1% penicillin + streptomycin) was transferred to a 15 mL centrifuge tube and centrifuged at 1000 rpm for 5 minutes. The supernatant was removed and the cells were resuspended in complete culture medium. The cells were seeded into culture dishes at the desired density and cultured in an incubator at 37°C in a humidified atmosphere of 95% air and 5% carbon dioxide. The culture medium was replenished or passaged every 2-3 days, depending on cell growth.

[0960] 2.4 SDMA in-cell western blot

[0961] When the cells reached approximately 90% confluence in the culture dish, they were washed twice with PBS, trypsinized, and 100 μL per well was seeded into a 96-well plate (800 cells / well). The cells were cultured overnight at 37°C in a 5% CO2 incubator. 50 μL of the compound at 3x the final concentration was added to the cell culture plate. Each compound was diluted 10 times in a 3-fold series in duplicate wells. The final DMSO concentration was 0.5%. The cells were cultured in a 37°C, 5% CO2 incubator for 96 hours.

[0962] Add 150 μL of 8% paraformaldehyde to each well and incubate at room temperature for 15 minutes. Discard the supernatant, wash the plate with PBS, and add 200 μL of freshly prepared 1x Permeabilization buffer to each well and incubate at room temperature for 30 minutes. Discard the supernatant, add 200 μL of 1x Blocking buffer to each well and incubate at room temperature for 2 hours. Discard the supernatant, add 50 μL of primary antibody (CST, diluted 1:500 in 1x Incubation buffer) to each well and incubate at 4°C overnight. Discard the supernatant, add 250 μL of 1x Washing buffer to each well and wash three times. Add 50 μL of secondary antibody (IRDye 800CW Goat anti-Rabbit IgG and CellTag 700 dye, diluted 1:800 and 1:500 in Incubation buffer) to each well and incubate at room temperature for 1 hour. Discard the supernatant and wash the plate with 1x Washing buffer. Signal detection was performed using a Licor Odyssey CLX. The formula for calculating the percentage of compound inhibition rate is as follows: Inhibition rate percentage = 100-(signal value 药物处理组 -Signal value 背景值 ) / (signal value 0.5% DMSO treatment group - signal value 背景值 ) × 100. According to different drug concentrations and their corresponding inhibition rates, IC was calculated using GraphPad 8.0 software. 50 Draw curves, analyze data, and obtain the final IC 50 The results are shown in Table 3, where IC 50 ≤0.1μM is A, 0.1μM<IC 50 ≤1μM is B, 1μM<IC 50 C is ≤10μM.

[0963] Table 3 Cellular SDMA inhibitory activity

[0964] Experimental Example 3 In vivo pharmacodynamic study in LU99 CDX model

[0965] 3.1 Experimental materials: LU99 cells were obtained from JCRB (Japan); RPMI-1640 and 0.25% trypsin-EDTA were purchased from Gibco (USA); fetal bovine serum was purchased from Dongling (China); PBS was purchased from Hyclone (USA); penicillin-streptomycin was purchased from Meilun Biotechnology (China); and Matrigel was purchased from Corning (USA).

[0966] 3.2 Animal Information: Female BALB / c Nude mice, 6–8 weeks old, weighing 18–22 g, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. The mice were housed in an SPF-grade environment with individual ventilation in each cage. All animals had free access to a standard certified commercial laboratory diet and free drinking water.

[0967] 3.3 Experimental methods:

[0968] 3.3.1 Cell Culture: Human large cell lung cancer LU99 cells were cultured as monolayers in RPMI-1640 medium supplemented with 10% fetal bovine serum in a 37°C, 5% CO2 incubator. Cells were routinely digested and passaged twice weekly using trypsin-EDTA. When the desired cell number was reached, cells were harvested and counted.

[0969] 3.3.2 Cell inoculation: 0.2 mL (5 × 10 6 LU99 cells (with Matrigel, volume ratio of 1:1) were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached approximately 150 mm 3 At 4 hr, the patients were randomly divided into groups according to the tumor volume and animal body weight and began to receive the drugs.

[0970] 3.3.3 Administration: Compound 14 was administered at a dose of 30 mpk, PO, once daily (QD) for 3 weeks, with 6 mice per group.

[0971] 3.3.4 Tumor Measurement and Experimental Indicators:

[0972] Tumor diameter was measured twice a week using a vernier caliper. Tumor volume was calculated using the formula: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively. The body weight of mice was measured twice a week.

[0973] The antitumor efficacy of the compound was evaluated by tumor growth inhibition rate (TGI).

[0974] TGI (%) = [(1-(average tumor volume of a treatment group at the end of drug administration - average tumor volume of the treatment group at the beginning of drug administration)) / (average tumor volume of the solvent control group at the end of treatment - average tumor volume of the solvent control group at the beginning of treatment)] × 100%.

[0975] The experimental results are shown in Figures 1 and 2. No mice became ill or died during the experiment.

Claims

1. A compound of formula (I) or (I'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof: in, L1 is NH or CHR x ; L2 is CR x R y ; where R x and R y Independently selected from H, D, C 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 alkylene; 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; 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; 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; X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; 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; 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; Ar1 is phenyl or a 5-6 membered heteroaryl group, which is substituted by m R1; 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、P(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl (e.g. C 5-10 cycloalkyl), 4-10 membered heterocyclic group (e.g. 5-10 membered heterocyclic group), C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; Or two adjacent R1 and the atoms they are connected to 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 1s replace; m = 0, 1, 2, 3, 4 or 5; R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-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, -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 H, D, halogen, =O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution; or twin or two adjacent R 1s and the atoms they are connected to form C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkyne Substitution of radicals; L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups; 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, 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; R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)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; n = 0, 1, 2, 3, 4, 5, 6 or 7; 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 、Ar1、R1、R 2a 、R 2b 、R 2c 、R 2d 、R 1s , L, R 2s , R3, R 3a 、R 3b 、R a 、R b and R c The various groups defined in are optionally deuterated, up to fully deuterated; Provided that, when L2 is C=O, X1, X2 and their substituents together form a group optionally substituted by 1, 2 or 3 R 2s Substituted C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

2. The compound of formula (I) or (I') according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: Ar1 is phenyl or 5-membered heteroaryl; or Ar1 is phenyl or 6-membered heteroaryl; Ar1 ​​is preferably phenyl, pyridyl or thienyl; Ar1 ​​is more preferably Ar1, for example For example Preferred More preferably Preferably R 1s H, Me, Et, iPr, Preferred H, More preferably 3. The compound of formula (I) or (I') according to claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L1 and L2 are 4. The compound of formula (I) or (I') according to any one of claims 1 to 3, 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(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 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s Substituted; preferably H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、S(O)R a 、S(O)2R a 、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; preferably H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, 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; 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 Preferably, two adjacent R1 and the atoms to which they are connected together form a C 5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

5. The compound of formula (I) or (I') according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: Selected from 6. The compound of formula (I) or (I') according to any one of claims 1 to 5, 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 NH2.

7. A compound of formula (I) or (I') according to any one of claims 1 to 6, 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 More preferably, the 8. A compound of formula (I) or (I') according to any one of claims 1 to 7, 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 H or D.

9. The compound of formula (I) or (I') according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 3a and R 3b One of them is C 1-6 Alkyl or C 1-6 Haloalkyl, the other is H; R 3a and R 3b One is Me, the other is H; preferably, R 3a H and R 3b For Me.

10. The compound of formula (I) or (I') according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-10 Cycloalkyl (preferably -LC 5-10 Cycloalkyl), -L-5-10 membered heterocyclic group, -LC 6-10 Aryl or -L-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, two R 1s and the atoms they are connected to form C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

11. A compound of formula (I) or (I') according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

12. A compound of formula (I) or (I') according to any one of claims 1 to 11, 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 11.

13. The compound of formula (II) according to claim 12, 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 3-6 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; 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; And 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; X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a Selected from H, D, OR a or NR b R c ; 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; R1, R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、S(O)R a 、S(O)2R a 、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, preferably H, D. Halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, 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, which is optionally substituted by 1, 2 or 3 R 1s replace; or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms they are connected to, together forming C 5-6 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; R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-10 Cycloalkyl, -L-5-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, =O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution; or two R in geminal or vicinal positions 1s and the atoms they are connected to form C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups; L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R3, R 3a and R 3b Independently selected from H, D, halogen, 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 H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6 or 7; 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 , R1, R 1a 、R 1b 、R 1c 、R 2a 、R 2d 、R 1s , L, R 2s , R3, R 3a 、R 3b 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

14. The compound of formula (II) according to claim 13, 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 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 1-3 alkylene; 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; And 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; X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a Selected from OR a or NR b R c ; 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 5-7 Cycloalkyl or 5-7 membered heterocyclic group; R1, R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-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; or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms to which they are attached, together forming a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, or 2; R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-10 Cycloalkyl or -L-5-10 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 H, D, halogen, =O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution; or two R in geminal or vicinal positions 1s and the atoms they are connected to form C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups; L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4 or 5; 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 5-6 membered heterocyclic group.

15. The compound of formula (II) according to claim 13, 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 they form C=O or C2 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 1-2 alkylene; 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; And 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; X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a NR b R c ; 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; R1, R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace; or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms to which they are attached, together forming a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, or 2; R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、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 H, D, halogen, =O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution; or two R in geminal or vicinal positions 1s and the atoms they are connected to form C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups; L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2 or 3; 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 5-6 membered heterocyclic group.

16. The compound of formula (II) according to claim 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein -L1-L2-Selected Preferred 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; And 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; X3 for CR 2d ; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a is NH2; R 2d Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R1 is selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 alkyl halide; R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclic group, preferably H, D, halogen, CN, -L-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace; or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms to which they are attached, together forming a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, or 2; R 1s Selected from H, D, halogen, =O, -L-NR b R c 、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 H, D, halogen, =O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution; or two R in geminal or vicinal positions 1s and the atoms they are connected to form C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups; L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R3 is selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 3a and R 3b One of them is C 1-6 Alkyl or C 1-6 haloalkyl, the other is H or D; n = 0, 1, 2 or 3; 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 5-6 membered heterocyclic group; Preferably, X1, X2 and their substituents together form a group selected from the following: Preferably selected from Preferably Preferably, Selected from the following groups: Preferably Preferably 17. The compound of formula (II) according to claim 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is C=O; 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; And 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; X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a Selected from OR a or NR b R c ; 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; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R1, R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl or C 1-6 Haloalkyl, optionally substituted by 1, 2 or 3 R 1s replace; or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms to which they are attached, together forming a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; R 1s Selected from H, D, halogen, =O, OR a SR a NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; m = 0, 1, or 2; R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6 or 7; 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, R1, R 1a 、R 1b 、R 1c 、R 2a 、R 2d 、R 1s 、R 2s , R3, R 3a 、R 3b 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

18. The compound of formula (II) according to claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is C=O; 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; And X1, X2 and their substituents together form X3 for CR 2d ; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a NR b R c ; 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; Selected from the following groups: Preferred R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide; m = 0, 1, or 2; R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6 or 7; 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.

19. The compound of formula (II) according to claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is C=O; 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; And X1, X2 and their substituents together form X3 for CR 2d ; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a is NH2; R 2d Selected from H or D; Selected from the following groups: Preferred R1 is selected from H, D, F or Me; m = 0, 1, or 2; R3, R 3a and R 3b are independently selected from H, D or Me, preferably, R 3b for Me; n=0, 1, 2, 3, 4, 5, 6 or 7.

20. The compound of formula (II) according to claim 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is C=O; 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; And 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; X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a Selected from OR a or NR b R c ; 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; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R1, R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide; or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms to which they are attached, together forming a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl; L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; m = 0, 1, or 2; R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6 or 7; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; Among them, R1, R 1a 、R 1b 、R 1c 、R 2a 、R 2d 、R 2s , R3, R 3a 、R 3b 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

21. The compound of formula (II) according to claim 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is C=O; 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; And X1, X2 and their substituents together form X3 for CR 2d ; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a NR b R c ; 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; Selected from the following groups: Preferred R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide; m = 0, 1, or 2; R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6 or 7; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

22. The compound of formula (II) of claim 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is C=O; 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; And X1, X2 and their substituents together form X3 for CR 2d ; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a is NH2; R 2d Selected from H or D; Selected from the following groups: Preferred R1 is selected from H, D, F or Me; m = 0, 1, or 2; R3, R 3a and R 3b are independently selected from H, D or Me, preferably, R 3b for Me; n=0, 1, 2, 3, 4, 5, 6 or 7.

23. The compound of formula (II) according to claim 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is C=O; 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; And X1, X2 and their substituents together form X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a Selected from OR a or NR b R c ; 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; R1, R 1a 、R 1b and R 1c Independently selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide; or R 1a 、R 1b and the atoms they are connected to, or R 1b 、R 1c and the atoms to which they are attached, together forming a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl; L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; m = 0, 1, or 2; R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6 or 7; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; Among them, R1, R 1a 、R 1b 、R 1c 、R 2a 、R 2d , R3, R 3a 、R 3b 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

24. The compound of formula (II) according to claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is C=O; 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; And X1, X2 and their substituents together form X3 for CR 2d ; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a NR b R c ; 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; Selected from the following groups: R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide; m = 0, 1, or 2; R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6 or 7; 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 formula (II) of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is C=O; 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; And X1, X2 and their substituents together form X3 for CR 2d ; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a is NH2; R 2d Selected from H or D; Selected from the following groups: R1 is selected from H, D, F or Me; m = 0, 1, or 2; R3, R 3a and R 3b are independently selected from H, D or Me, preferably, R 3b for Me; n=0, 1, 2, 3, 4, 5, 6 or 7.

26. The compound of formula (III) of claim 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is C=O; 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; And 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 substituted, preferably 5-7 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a Selected from OR a or NR b R c ; 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; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide; m = 0, 1, 2, or 3; R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 3-6 Cycloalkyl, -L-5-6 membered heterocyclic group, -LC 6-10 Aryl or -L-5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6 or 7; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

27. The compound of formula (III) of claim 26, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is C=O; 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; And X1, X2 and their substituents together form Preferred X3 for CR 2d ; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a NR b R c ; 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; R1 is selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl or C 1-6 alkyl halide; m = 0, 1, 2, or 3; R 1s H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6 or 7; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

28. The compound of formula (III) of claim 26, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is C=O; 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; And X1, X2 and their substituents together form Preferred X3 for CR 2d ; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a is NH2; R 2d Selected from H or D; R1 is selected from H, D, F or Me; m = 0, 1, 2, or 3; R 1s H, Me, Et, iPr, R3, R 3a and R 3b are independently selected from H, D or Me, preferably, R 3b for Me; n=0, 1, 2, 3, 4, 5, 6 or 7.

29. The compound of formula (III) according to claim 12, 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 3-6 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; 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; And 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; X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a Selected from H, D, OR a or NR b R c ; 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; 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; R 1s Selected from H, D, halogen, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-10 Cycloalkyl, -L-5-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, =O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution; L is a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6 or 7; 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 , R1, R 2a 、R 2d 、R 1s , L, R 2s , R3, R 3a 、R 3b 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

30. The compound of formula (III) according to claim 29, 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 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 1-3 alkylene; 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; And 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; X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a Selected from OR a or NR b R c ; 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 5-7 Cycloalkyl or 5-7 membered heterocyclic group; 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, or 2; R 1s Selected from H, D, halogen, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-10 Cycloalkyl, -L-5-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, =O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution; L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4 or 5; 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 5-6 membered heterocyclic group.

31. The compound of formula (III) of claim 29, 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 they form C=O or C2 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 1-2 alkylene; 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; And 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; X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a NR b R c ; 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; 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, or 2; R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-SR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-7 Cycloalkyl, -L-5-7 membered heterocyclyl or -L-5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, ═O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution; L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R3, R 3a and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2 or 3; 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 5-6 membered heterocyclic group.

32. The compound of formula (III) of claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein -L1-L2-Selected Preferred 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; And 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; X3 for CR 2d ; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a is NH2; R 2d Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R1 is selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 Haloalkyl, optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, or 2; R 1s Selected from H, D, halogen, =O, -L-OR a 、-L-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 5-7 Cycloalkyl, -L-5-7 membered heterocyclyl or -L-5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, ═O, -C 0-6 Alkylene-NH2, -C 0-6 Alkylene-NH(C 1-6 Alkyl), -C 0-6 Alkylene-N(C 1-6 Alkyl)2, -C 0-6 Alkylene-OH, -C 0-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 haloalkyl substitution; L is a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R3 is selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 3a and R 3b One of them is C 1-6 Alkyl or C 1-6 haloalkyl, the other is H or D; n = 0, 1, 2 or 3; 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 5-6 membered heterocyclic group; Preferably, X1, X2 and their substituents together form a group selected from the following: Preferably selected from Preferably, R 1s Selected from H, Preferably 33. The compound of formula (IV) of claim 12, 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 3-6 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; 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; And 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; X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a Selected from H, D, OR a or NR b R c ; 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; 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; m′=0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; 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; R3 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6, 7 or 8; 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 , R1, R 2a 、R 2d 、R 1s 、R 2s , R3, R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

34. The compound of formula (IV) of claim 33, 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 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 1-3 alkylene; 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; And 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; X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a Selected from OR a or NR b R c ; 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 5-7 Cycloalkyl or 5-7 membered heterocyclic group; 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; m' = 0, 1, 2, 3, 4 or 5; 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 haloalkyl; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R3 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4 or 5; 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 5-6 membered heterocyclic group.

35. The compound of formula (IV) of claim 33, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein -L1-L2-Selected Preferred 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; And X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, any of which Choose 1, 2 or 3 R 2s replace; X3 for CR 2d ; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a is NH2; R 2d Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R1 is selected from H, D, halogen, CN, C 1-6 Alkyl or C 1-6 Haloalkyl, optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, or 2; m' = 0, 1, 2, or 3; 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 haloalkyl; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; R3 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2 or 3; 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 5-6 membered heterocyclic group; Preferably, X1, X2 and their substituents together form a group selected from the following: Preferably selected from 36. The compound of formula (Va) or (Vb) of claim 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein 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; And 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; X3 for CR 2d or N; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a Selected from OR a or NR b R c ; 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; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; Ar1 is a 5-6 membered heteroaryl group, which is substituted by m R1; 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, C 3-6 Cycloalkyl, 4-6 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, 2, 3, 4 or 5; Or two adjacent R1 and the atoms they are connected to form C 5-6 Cycloalkyl, 5-6 membered heterocyclic group, phenyl group or 5-6 membered heteroaryl group group, which is optionally substituted by 1, 2 or 3 R 1s replace; R 1s Selected from H, D, halogen, =O, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R3 and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6 or 7; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; Among them, R1, R 1s 、R 2a 、R 2d , R3, R 3b 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

37. The compound of formula (Va) or (Vb) of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein 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; And X1, X2 and their substituents together form X3 for CR 2d ; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a NR b R c ; 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; Ar1 is a 5-6 membered heteroaryl group, which is substituted by m R1; R1 is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 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, 2, or 3; Or two adjacent R1 and the atoms they are connected to 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 1s replace; R 1s Selected from H, D, halogen, =O, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R3 and R 3b Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6 or 7; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

38. The compound of formula (Va) or (Vb) of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein X1 is a C atom, which is optionally replaced by R 2b replace; X2 is a C atom, which is optionally replaced by R 2c replace; And X1, X2 and their substituents together form Preferred X3 for CR 2d ; and the ring where X1, X2 and X3 are located is an aromatic ring; R 2a is NH2; R 2d Selected from H or D; Ar1 is a 5-6 membered heteroaryl group, which is substituted by m R1s; preferably, Ar1 is selected from: R1 is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace; m = 0, 1, or 2; Or two adjacent R1 and the atoms to which they are attached together form a phenyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 1s replace; R 1s Selected from H, D, halogen, =O, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R3 and R 3b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; n = 0, 1, 2, 3, 4, 5, 6 or 7; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

39. The compound of formula (I) or (I') of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: The compound is selected from the compounds of Examples 1-104.

40. A pharmaceutical composition comprising a compound according to any one of claims 1 to 39, 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.

41. The pharmaceutical composition of claim 40, 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.

42. Use of a compound according to any one of claims 1 to 39, 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.

43. 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 1-39, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutical composition of claim 40 or 41.

44. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutical composition according to claim 40 or 41, for use in treating or preventing a PRMT5-mediated disease.

45. The use of claim 42 or the method of claim 43 or the use of a compound or pharmaceutical composition of claim 44, wherein the disease is cancer.

46. ​​The use of claim 42 or the method of claim 43 or the use of the compound or pharmaceutical composition of claim 44, 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, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Weil's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma); Tumors (including 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 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.

47. The use of claim 42 or the method of claim 43 or the compound or pharmaceutical composition of claim 44, 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.

48. The use of claim 42 or the method of claim 43 or the use of the compound or pharmaceutical composition of claim 44, 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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