PRMT5 inhibitors

Abstract

The invention provides a PRMT5 inhibitor as shown in a formula (I), or pharmaceutically acceptable salts, isotope variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates of the PRMT5 inhibitor, or pharmaceutically acceptable salts, isotope variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates of the PRMT5 inhibitor. The invention also provides a preparation method of the compound, a pharmaceutical composition containing the compound, and an effect of the compound in prevention and treatment of cancers. # imgabs0 #

Description

PRMT5 inhibitors

[0001] This application claims priority to Chinese application CN202210997380.5 filed on August 19, 2022, Chinese application CN202310576672.6 filed on May 19, 2023, and Chinese application CN202310997530.7 filed on August 9, 2023, all of 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 a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0011] in,

[0012] Ring A is

[0013] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0014] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0015] X3 for CR 2d or N;

[0016] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NRb R c ;

[0017] 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;

[0018] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0019] 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 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0020] 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;

[0021] R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0022] L1 is NH or CHR x ;

[0023] L2 is a chemical bond or CR x R y ;

[0024] L3 is -C(O)-, -S(O)- or -S(O)2-;

[0025] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or CR x R y Together to form C=O, C=S or C 3- 6-cycloalkylene;

[0026] 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;

[0027] Y1 is a chemical bond or (CR3R3) q ;

[0028] Y2 is a chemical bond, O, S, NR', S(O) or S(O)2;

[0029] q = 1, 2, or 3;

[0030] Z1 is N or CR;

[0031] Z2 is N or CR;

[0032] Z3 is N or CR;

[0033] R3 and R are independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0034] Or CR3R3 together to form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0035] R' is selected from H, D, C(O)R a 、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;

[0036] p = 0, 1, 2, 3, or 4;

[0037] One of Ar1 and Ar2 is phenyl or a 5-6 membered heteroaryl group substituted by n R1s; the other is H or D; or Ar1 and Ar2 are independently H or D;

[0038] 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)(OR a )2、P(OR a )2、P(O)(R a )2、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, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0039] or two adjacent ring atoms on Ar1 or Ar2 and their substituents together form a C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0040] n = 0, 1, 2, 3, 4 or 5;

[0041] R 1s Selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)R a 、C(O)OR a、C(O)NR b R c 、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, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0042] L is selected from chemical bonds, 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;

[0043] 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 3-10 membered heterocyclic group;

[0044] Among them, X1, X2, X3, R 2a 、R 2b 、R 2c 、R 2d 、R 2s , L1, L2, R x 、R y , Y1, Y2, Z1, Z2, Z3, R3, R, R', Ar1, Ar2, R1, R 1s , L, R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] definition

[0054] Chemical definition

[0055] Definitions of specific functional groups and chemical terms are described in more detail below.

[0056] 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.

[0057] “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, C 1-3Alkyl and C 1-2 Alkyl 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 by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), i-Bu(-CH2CH(CH3)2), or t-Bu(-C(CH3)3).

[0058] “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.

[0059] “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-"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). The alkynyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0060] “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.

[0061] “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.

[0062] “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.

[0063] “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".

[0064] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0065] 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 1-3 Halogenated alkyl, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CH2CH2CF3, -C(CH3)2CF3, -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.

[0066] “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 a ring system in which the above-mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such a case, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Cycloalkyl also includes the above-mentioned cycloalkyl ring, wherein the substituents on any non-adjacent carbon atoms are connected to form a bridge ring, together forming a polycycloalkane sharing two or more carbon atoms. Cycloalkyl also includes the above-mentioned cycloalkyl ring, wherein the substituents on the same carbon atom are connected to form a ring, together forming a polycycloalkane sharing one carbon atom. Exemplary cycloalkyls 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), etc. The cycloalkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0067] “C 3-10 "Cycloalkylene" refers to the removal of C 3-10 In some embodiments, C 3-6 Cycloalkylene, C 3-5 Cycloalkylene and C 3-4 Cycloalkylene is particularly preferred, preferably cyclopentylene, and especially preferably cyclopropylene.

[0068] "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; 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; a 5-membered heterocyclyl is more preferred. 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, tetrahydrothienyl, dihydrothienyl, 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, dihydropyranyl, 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.

[0069] “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.

[0070] "5-14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., with 6, 10, or 14 π electrons shared in a cyclic arrangement) having annular carbon atoms and 1-4 annular heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. "5-10 membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., with 6 or 10 π electrons shared in a cyclic arrangement) having annular carbon atoms and 1-4 annular 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 systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl ring is 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 heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-membered heteroaryl is particularly preferred. In other embodiments, 6-membered heteroaryl is particularly preferred. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl or pyridonyl. Exemplary 6-membered heteroaryl groups 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, oxacycloheptatrienyl, and thiacycloheptatrienyl. 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.

[0071] 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".

[0072] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0073] 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(=NRbb )N(R bb )2, -C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2, -SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2, -C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(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 Rdd group substitution;

[0074] 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;

[0075] 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;

[0076] 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 bbThe 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;

[0077] R cc Each 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;

[0078] 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;

[0079] 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;

[0080] 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;

[0081] 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 1-6Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -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, 3-7 membered heterocyclic group, 5-10 membered heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0082] 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 cc 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 dd group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0083] Other definitions

[0084] The term "cancer" includes, but is not limited to, 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, enchondroma, 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, fibroma Tumors of the uterus and bladder include: kidney (adenocarcinoma, Wilms' tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma), choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: 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 exostoses of bone (osteocartilaginous exostoses), benign enchondroma, chondroblastoma, fibrochondroma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, and osteitis deformans), meninges (meningiomas, meningeal sarcomas, and gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, and 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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).

[0092] "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.

[0093] "Disease," "disorder," and "condition" are used interchangeably herein.

[0094] 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").

[0095] Generally, an "effective amount" of a compound is an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0096] 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.

[0097] 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.

[0098] "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. Specific implementation plan

[0099] Herein, "compounds of the present invention" refers to the following compounds of formula (I), formula (II), formula (III), etc., and pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof.

[0100] 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.

[0101] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0102] in,

[0103] Ring A is

[0104] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0105] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0106] X3 for CR 2d or N;

[0107] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0108] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b Rc 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0109] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0110] 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 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0111] 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;

[0112] R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0113] L1 is NH or CHR x ;

[0114] L2 is a chemical bond or CR x R y ;

[0115] L3 is -C(O)-, -S(O)- or -S(O)2-;

[0116] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or CR x R yTogether to form C=O, C=S or C 3- 6-cycloalkylene;

[0117] 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;

[0118] Y1 is a chemical bond or (CR3R3) q ;

[0119] Y2 is a chemical bond, O, S, NR', S(O) or S(O)2;

[0120] q = 1, 2, or 3;

[0121] Z1 is N or CR;

[0122] Z2 is N or CR;

[0123] Z3 is N or CR;

[0124] R3 and R are independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0125] Or CR3R3 together to form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0126] R' is selected from H, D, C(O)R a 、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;

[0127] p = 0, 1, 2, 3, or 4;

[0128] One of Ar1 and Ar2 is phenyl or a 5-6 membered heteroaryl group substituted by n R1s; the other is H or D; or Ar1 and Ar2 are independently H or D;

[0129] R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SRa 、-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)(OR a )2、P(OR a )2、P(O)(R a )2、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, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0130] or two adjacent ring atoms on Ar1 or Ar2 and their substituents together form a C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0131] n = 0, 1, 2, 3, 4 or 5;

[0132] R 1s Selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-10Cycloalkyl, -L-3-10 membered heterocyclic group, -LC 6-10 Aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0133] L is selected from chemical bonds, 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;

[0134] 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 3-10 membered heterocyclic group;

[0135] Among them, X1, X2, X3, R 2a 、R 2b 、R 2c 、R 2d 、R 2s , L1, L2, R x 、R y , Y1, Y2, Z1, Z2, Z3, R3, R, R', Ar1, Ar2, R1, R 1s , L, R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0136] X1, X2 and X3

[0137] 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 2cIn one embodiment, X3 is a C atom; in another embodiment, X3 is a N atom; in another embodiment, X3 is CR 2d In another embodiment, X3 is NR 2d .

[0138] In a more specific embodiment, Selected from 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

[0139] 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, preferably a 5-7 membered heterocyclic group, preferably a 5-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, preferably a 5-6 membered heteroaryl, preferably a 5 membered heteroaryl; In another more specific embodiment, X1, X2 and their substituents together form C 5-7 In another more specific embodiment, X1, X2 and their substituents together form C 5-7 cycloalkyl, 5-7 membered heterocyclyl or 5-6 membered heteroaryl; in another more specific embodiment, X1, X2 and their substituents together form a 5-7 membered heterocyclyl or 5-6 membered heteroaryl; in another more specific embodiment, X1, X2 and their substituents together form a 5-membered heterocyclyl or 5-membered heteroaryl; in another more specific embodiment, the ring formed by X1, X2 and their substituents is optionally substituted by 1, 2 or 3 R 2sSubstitution, such as forming In another more specific embodiment, the ring formed by X1, X2 and their substituents is not substituted.

[0140] In a more specific embodiment, X1, X2 and their substituents together form Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation Preferred Formation In another more specific embodiment, X1, X2 and their substituents together form

[0141] R 2a

[0142] In one embodiment, R 2a is H; in another embodiment, R 2a is D; in another embodiment, R 2a is CN; in another embodiment, R 2a OR a In another embodiment, R 2a NR b R c In another embodiment, R 2a C(O)OR a In another embodiment, R 2a C(O)NR b R c .

[0143] 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 OMe or NH2, preferably OMe, preferably NH2.

[0144] R 2b

[0145] In one embodiment, R2b 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 , such as C(O)NH2; 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.

[0146] In a more specific embodiment, R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl; in another more specific embodiment, R 2b Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 2b Selected from C 1-6 Alkyl or C 1-6 Haloalkyl, preferably Me; in another more specific embodiment, R 2b Selected from H, D, halogen, C(O)NR b R c 、C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 2b Selected from C(O)NR b R c 、C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 2b C(O)NR b R c or C 1-3 Alkyl; in another more specific embodiment, R 2b It is C(O)NH2 or Me.

[0147] R 2c

[0148] 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.

[0149] In a more specific embodiment, R 2c is selected from H, D or halogen, preferably H or D, preferably H.

[0150] R 2d

[0151] 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 3-10 Cycloalkyl, such as C 3-7 Cycloalkyl, such as C 5- 10 Cycloalkyl; in another embodiment, R 2d is a 3-10 membered heterocyclyl, such as a 3-7 membered heterocyclyl, such as a 5-10 membered heterocyclyl; in another embodiment, R 2d C 6-10 Aryl; In another embodiment, R 2d is a 5-10 membered heteroaryl; in another embodiment, R 2d C 5-7 Cycloalkyl; in another embodiment, R 2d It is a 5-7 membered heterocyclic group.

[0152] In a more specific embodiment, R 2d Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclyl; 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 It is H or D, preferably H.

[0153] In a more specific embodiment, 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 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; in a more specific embodiment, R 2d Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; in a more specific embodiment, R 2d Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0154] R 2s

[0155] 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 C2-6 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.

[0156] In a more specific embodiment, R 2s Selected from H, D, halogen, =O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1- 6 haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; in another more specific embodiment, R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 2s Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, H, D, C 1-6 Alkyl and C 1-6 In another more specific embodiment, R 2s is selected from H, D or Me; in another more specific embodiment, R 2s Selected from H, D and C 1-3 Alkyl, preferably C 1-3 Alkyl, preferably Me.

[0157] L1, L2, and L3

[0158] In one embodiment, L1 is NH; in another embodiment, L1 is CHR x In another embodiment, L1 is NH and L2 is CR x R y , L1-L2 is preferably In another embodiment, L1-L2 is preferably In another embodiment, L1-L2 is preferably In another embodiment, L1-L2 is preferably In another embodiment, L1 is NH and L2 is a chemical bond; in another embodiment, L1 is CHR x And L2 is CR x R y , preferably In another embodiment, L3 is -C(O)-; in another embodiment, L3 is -S(O)-; in another embodiment, L3 is -S(O)2-.

[0159] In a more specific embodiment, L1-L2-L3 is

[0160] R x and R y

[0161] 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, R x and R y One is H or D, the other is C 1-6 Alkyl; in another embodiment, R x and R y One is H or D, the other is C 1-6 Halogenated alkyl, preferably CF3.

[0162] 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.

[0163] Ring A

[0164] In one embodiment, Ring A is In another embodiment, Ring A is

[0165] In one embodiment, Y1 is a chemical bond; in another embodiment, Y1 is CR3R3; in another embodiment, Y1 is (CR3R3) q , for example (CR3R3)2, for example (CH2)2; in one embodiment, Y2 is a chemical bond; in another embodiment, Y2 is O; in another embodiment, Y2 is S; in another embodiment, Y2 is NR', preferably NH, preferably NMe; in another embodiment, Y2 is S(O); in another embodiment, Y2 is S(O)2.

[0166] In one embodiment, q=1; in another embodiment, q=2; in another embodiment, q=3.

[0167] In a more specific embodiment, Y1 is a chemical bond or CR3R3, and Y2 is selected from a chemical bond, O, S or NH; in a more specific embodiment, Y1 is a chemical bond or CR3R3, and Y2 is a chemical bond or O; in a more specific embodiment, Y1 is CR3R3; Y2 is selected from O, S or NH; in a more specific embodiment, Y1 is CR3R3; Y2 is O.

[0168] In a more specific embodiment, Y1 is (CR3R3) q , preferably -CH2-, -CH(CH3)-, -CH2CH2-, Preferably -CH2-, -CH(CH3)- or More preferably -CH2- or -CH(CH3)-; in a more specific embodiment, Y1 is

[0169] In a more specific embodiment, Y2 is selected from O, S, NR', S(O) or S(O)2; in another more specific embodiment, Y2 is selected from O, S, NR' or S(O)2; in another more specific embodiment, Y2 is selected from O, NR' or S(O)2, preferably O.

[0170] In a more specific embodiment, q=1, 2 or 3; in another more specific embodiment, q=1 or 2.

[0171] In one embodiment, Selected from In another embodiment, Selected from Preferably In another embodiment, for Preferably

[0172] In one embodiment, for

[0173] In one embodiment, for In another embodiment, for

[0174] In one embodiment, Z1 is a N atom; in another embodiment, Z1 is CR; in one embodiment, Z2 is a N atom; in another embodiment, Z2 is CR; in another embodiment, Z3 is a N atom; in another embodiment, Z3 is CR.

[0175] In a more specific embodiment, Z1, Z2 and Z3 are all CR.

[0176] R

[0177] In one embodiment, R is H; in another embodiment, R is D; in another embodiment, R is halogen; in another embodiment, R is C 1-6 Alkyl; in another embodiment, R is C 1-6 In another embodiment, R is C 2-6 In another embodiment, R is C 2-6 Alkynyl; in another embodiment, R is C 3-10 Cycloalkyl; in another embodiment, R is a 3-10 membered heterocyclyl; in another embodiment, R is C 6-10 Aryl; in another embodiment, R is a 5-10 membered heteroaryl.

[0178] In a more specific embodiment, R is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl; In a more specific embodiment, R is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, preferably H or D.

[0179] R3

[0180] In one embodiment, R3 is H; in another embodiment, R3 is D; in another embodiment, R3 is halogen; in another embodiment, R3 is C 1-6Alkyl; 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 Cycloalkyl, such as C 3-6 In another embodiment, R3 is a 3-10 membered heterocyclic group, such as a 3-6 membered heterocyclic group; In another embodiment, R3 is C 6-10 Aryl, such as phenyl; in another embodiment, R3 is a 5-10 membered heteroaryl, such as a 5-6 membered heteroaryl; in another embodiment, at least one of the two R3 in the geminal position is H or D, preferably at least one is H.

[0181] In a more specific embodiment, R3 is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl; In another more specific embodiment, R3 is independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R3 is independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl; In another more specific embodiment, R3 is independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, preferably selected from H, Me, Et, CF3 or cyclopropyl; in another more specific embodiment, R3 is independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably H, Me or Et, preferably H or Me.

[0182] In one embodiment, CR3R3 together form C 3-10 In another embodiment, CR3R3 together form a 3-10 membered heterocyclylene; In another embodiment, CR3R3 together form a C 3-6 In another embodiment, CR3R3 together form a 3-6 membered heterocyclylene; In another embodiment, CR3R3 together form a cyclopropylene; In another embodiment, In another embodiment, the adjacent N atoms in the CR3R3 do not form a ring.

[0183] In a more specific embodiment, CR3R3 together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; In another more specific embodiment, CR3R3 together form Preferred Formation Preferred Formation

[0184] R 3a 、R 3b 、R 3c and R 3d

[0185] 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 C 1-6 Alkyl; in another embodiment, R 3a C 1-6 haloalkyl; in another embodiment, R 3a C 3-6 Cycloalkyl; in another embodiment, R 3a It is a 3-6 membered heterocyclic group.

[0186] 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 C 1-6 Alkyl; in another embodiment, R 3b C 1-6 haloalkyl; in another embodiment, R 3b C 3-6 Cycloalkyl; in another embodiment, R 3b It is a 3-6 membered heterocyclic group.

[0187] In one embodiment, R 3c is H; in another embodiment, R 3c is D; in another embodiment, R 3c is halogen; in another embodiment, R 3c C 1-6 Alkyl; in another embodiment, R 3c C 1-6 haloalkyl; in another embodiment, R 3c C 3-6 Cycloalkyl; in another embodiment, R3c It is a 3-6 membered heterocyclic group.

[0188] In one embodiment, R 3d is H; in another embodiment, R 3d is D; in another embodiment, R 3d is halogen; in another embodiment, R 3d C 1-6 Alkyl; in another embodiment, R 3d C 1-6 haloalkyl; in another embodiment, R 3d C 3-6 Cycloalkyl; in another embodiment, R 3d It is a 3-6 membered heterocyclic group.

[0189] In one embodiment, CR 3a R 3b Together they form C 3-6 Cycloalkylene; in another embodiment, CR 3a R 3b together to form a 3-6 membered heterocyclylene; in another embodiment, CR 3a R 3b No ring is formed.

[0190] In one embodiment, CR 3c R 3d Together they form C 3-6 Cycloalkylene; in another embodiment CR 3c R 3d together to form a 3-6 membered heterocyclylene; in another embodiment, CR 3c R 3d No ring is formed.

[0191] In a more specific embodiment, R 3a Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl; in another more specific embodiment, R 3a Selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl; in another more specific embodiment, R 3a Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; in another more specific embodiment, R 3a Selected from H, D, C1-6 Alkyl or C 1-6 Haloalkyl, preferably H, Me, Et, CF3 or cyclopropyl, preferably H, Me or Et; in another more specific embodiment, R 3a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, preferably C 1-6 Alkyl or C 1-6 Haloalkyl, preferably Me, Et, CF3 or cyclopropyl, preferably Me or Et, preferably Me.

[0192] In a more specific embodiment, R 3b is H or D; in another more specific embodiment, R 3b For H.

[0193] In a more specific embodiment, R 3c Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl; in another more specific embodiment, R 3c Selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl; in another more specific embodiment, R 3c Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; in another more specific embodiment, R 3c Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably H or Me; in another more specific embodiment, R 3c It is H or D.

[0194] In a more specific embodiment, R 3d Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl; in another more specific embodiment, R 3d It is H or D, preferably H.

[0195] In a more specific embodiment, R 3a and R 3c At least one of them is H or D; in another more specific embodiment, R 3a and R3c At least one of them is H.

[0196] In a more specific embodiment, R 3a Not for H and D, R 3c It is H or D.

[0197] In a more specific embodiment, CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene, preferably forming C 3-6 Cycloalkylene, preferably cyclopropylene

[0198] In a more specific embodiment, CR 3c R 3d Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene, preferably forming C 3-6 Cycloalkylene, preferably cyclopropylene and cyclopentylene Preferably forming a cyclopropylene Preferably forming cyclopentylene

[0199] R'

[0200] In one embodiment, R' is H; in another embodiment, R' is D; in another embodiment, R' is C 1-6 Alkyl; in another embodiment, R' is C 1-6 In another embodiment, R' is C 2-6 In another embodiment, R' is C 2-6 Alkynyl; in another embodiment, R' is C 3-10 Cycloalkyl; in another embodiment, R' is a 3-10 membered heterocyclyl; in another embodiment, R' is C 6-10 Aryl; in another embodiment, R' is a 5-10 membered heteroaryl.

[0201] In a more specific embodiment, R' is selected from H, D, C(O)R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; In a more specific embodiment, R' is selected from H, D, C(O)R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, preferably H; in a more specific embodiment, R' is selected from H, D, C1-6 Alkyl and C 1-6 In a more specific embodiment, R' is selected from H, C 1-3 Alkyl or C 1-3 In a more specific embodiment, R' is C 1-3 Alkyl, preferably Me.

[0202] Ar1 and Ar2

[0203] In one embodiment, Ar1 is phenyl and Ar2 is H or D; in another embodiment, Ar2 is phenyl and Ar1 is H or D; in another embodiment, Ar1 is a 5-6 membered heteroaryl and Ar2 is H or D; in another embodiment, Ar2 is a 5-6 membered heteroaryl and Ar1 is H or D; in another embodiment, one of the rings Ar1 and Ar2 is phenyl, pyridyl or pyridazinyl and the other is H or D.

[0204] In one embodiment, Ar1 or Ar2 is substituted with n R1.

[0205] In one embodiment, Ar1 and Ar2 are independently H or D.

[0206] In a more specific embodiment, Ar1 is pyridinyl and Ar2 is H or D; in another more specific embodiment, Ar2 is pyridinyl and Ar1 is H or D; in a more specific embodiment, Ar1 is pyridazinyl and Ar2 is H or D; in another more specific embodiment, Ar2 is pyridazinyl and Ar1 is H or D.

[0207] In a more specific embodiment, Ar1 is phenyl or a 5-6 membered heteroaryl; in another more specific embodiment, Ar1 is phenyl or a 6 membered nitrogen heteroaryl; in another more specific embodiment, Ar1 is phenyl, pyridyl, pyrimidinyl or pyridazinyl, preferably phenyl, pyridyl or pyridazinyl, preferably phenyl or pyridyl.

[0208] In another embodiment, two adjacent ring atoms on Ar1 or Ar2 and their substituents together form a C 5-7 In another embodiment, two adjacent ring atoms on Ar1 or Ar2 and their substituents together form a 5-7 membered heterocyclic group; In another embodiment, two adjacent ring atoms on Ar1 or Ar2 and their substituents together form a phenyl group; In another embodiment, two adjacent ring atoms on Ar1 or Ar2 and their substituents together form a 5-6 membered heteroaryl group; In another embodiment, the ring formed by two adjacent ring atoms on Ar1 or Ar2 and their substituents is optionally substituted with 1, 2 or 3 R 1sIn another embodiment, the ring formed by two adjacent ring atoms on Ar1 or Ar2 and their substituents is not substituted; in another embodiment, the ring formed by two adjacent ring atoms on Ar1 or Ar2 and their substituents does not form a ring.

[0209] In a more specific embodiment, two adjacent ring atoms on Ar1 and their substituents together form a C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably forming a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, preferably forming a 5-membered heterocyclyl or a 5-membered heteroaryl; In another more specific embodiment, two adjacent ring atoms on Ar1 and their substituents together form a 5-7 membered heterocyclyl, preferably a 5-membered heterocyclyl, for example In another more specific embodiment, two adjacent ring atoms on Ar1 and their substituents together form a 5-6 membered heteroaryl, preferably a 5 membered heteroaryl, for example For example For example For example For example For example

[0210] In a more specific embodiment, Ar1 is

[0211] In a more specific embodiment, Ar1 is Z4, Z5, Z7 and Z8 are independently CR 1b or N.

[0212] In a more specific embodiment, Ar2 is

[0213] In a more specific embodiment, Z4 is CR 1b , such as CH; in a more specific embodiment, Z4 is N; in a more specific embodiment, Z5 is CR 1b , such as CH; in a more specific embodiment, Z5 is N.

[0214] In a more specific embodiment, Z6 is CR 1a In a more specific embodiment, Z6 is N; In a more specific embodiment, Z7 is CR 1b , such as CH; in a more specific embodiment, Z7 is N; in a more specific embodiment, Z8 is CR 1b , such as CH; in a more specific embodiment, Z8 is N.

[0215] In a more specific embodiment, among Z4, Z5, Z6, Z7 and Z8, at most 3 are N, preferably at most 2 are N, and preferably at most 1 is N.

[0216] In a more specific embodiment, Z6, Z5 and their substituents together form C 5-7 In a more specific embodiment, Z6, Z5 and their substituents together form a 5-7 membered heterocyclic group, preferably a 5-membered heterocyclic group, such as In a more specific embodiment, Z6, Z5 and their substituents together form a phenyl group; in a more specific embodiment, Z6, Z5 and their substituents together form a 5-6 membered heteroaryl group, preferably a 5 membered heteroaryl group, for example For example For example For example For example In a more specific embodiment, when Z6, Z5 and their substituents together form a heteroaryl group, Z5 is CR 1b In a more specific embodiment, the ring formed by Z6, Z5 and their substituents is optionally substituted by 1, 2 or 3 R 1s In a more specific embodiment, the ring formed by Z6, Z5 and their substituents is unsubstituted; In a more specific embodiment, Z6, Z5 and their substituents do not form a ring.

[0217] In a more specific embodiment, Z6, Z5 and their substituents together form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; in a more specific embodiment, Z6, Z5 and their substituents together form a 5-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably a 5 membered heterocyclyl or 5 membered heteroaryl; in a more specific embodiment, Z6, Z5 and their substituents together form: Preferred Formation Preferred Formation

[0218] In a more specific embodiment, Z4 and Z5 are not N at the same time.

[0219] In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is

[0220] In a more specific embodiment, Ar2 is In a more specific embodiment, Ar2 is In a more specific embodiment, Ar2 is

[0221] In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is In a more specific embodiment, Ar1 is

[0222] In a more specific embodiment, Ar1 is selected from: In a more specific embodiment, Ar1 is selected from:

[0223] In a more specific embodiment, Ar2 is In a more specific embodiment, Ar2 is In a more specific embodiment, Ar2 is In a more specific embodiment, Ar2 is In a more specific embodiment, Ar2 is In a more specific embodiment, Ar2 is In a more specific embodiment, Ar2 is In a more specific embodiment, Ar2 is In a more specific embodiment, Ar2 is In a more specific embodiment, Ar2 is In a more specific embodiment, Ar2 is

[0224] R1

[0225] In one embodiment, R1 is H; in another embodiment, R1 is D; in another embodiment, R1 is halogen, such as F, such as Cl, such as Br; in another embodiment, R1 is CN; in another embodiment, R1 is NO2; in another embodiment, R1 is -L-OR a , for example -OR a In another embodiment, R1 is -L-SR a , such as SR a In another embodiment, R1 is -L-NR b R c , such as NR b R cIn 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 P(O)(R a )2; In another embodiment, R1 is C 1-6 Alkyl; in another embodiment, R1 is C 1-6 In another embodiment, R1 is C 2-6 In another embodiment, R1 is C 2-6 Alkynyl groups, e.g. In another embodiment, R1 is C 3-10 Cycloalkyl, such as C 3-6 Cycloalkyl, such as cyclopropyl, for example In another embodiment, R1 is a 3-10 membered heterocyclyl, such as a 3-7 membered heterocyclyl, such as For example For example In another embodiment, R1 is C 6-10 Aryl, such as phenyl, for example In another embodiment, R1 is a 5-10 membered heteroaryl, such as a 5-6 membered heteroaryl, such as For example For example For example For example For example For example For example For example For example For example For example For example In another embodiment, R1 is C 5-7 In another embodiment, R1 is a 5-7 membered heterocyclyl; In another embodiment, R1 is optionally substituted by 1, 2 or 3 R 1s Substitution, for example, R1 is For example, R1 is For example, R1 is For example, R1 is For example, R1 is For example, R1 is For example, R1 is In another embodiment, R1 is unsubstituted.

[0226] In a more specific embodiment, R1 is independently selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclyl; In another more specific embodiment, R1 is independently selected from H, D, halogen, CN, SF5, OR a NR b R c 、C 1-6 Alkyl or C 1-6 In another more specific embodiment, R1 is independently selected from H, D, halogen, SF5, OR a 、C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0227] In a more specific embodiment, R1 is independently 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)Rc 、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 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; In another more specific embodiment, R1 is independently selected from H, D, halogen, CN, OR a SR a NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(OR a )2、P(OR a )2、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3- 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; In another more specific embodiment, R1 is independently selected from H, D, halogen, CN, SF5, OR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; In another more specific embodiment, R1 is independently selected from H, D, halogen, CN, SF5, OR a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; In another more specific embodiment, R1 is independently selected from H, D, halogen, CN, OR a 、C 1- 6 alkyl, C 1-6 Halogenated alkyl, C 3-7 In another more specific embodiment, R1 is independently selected from H, Cl, Br, CN, CF3, CF2CF3, SF5, OCH3, OCF3, OCHF2, OCH2CH3, OCH2CH2CF3, cyclopropyl, Preferably selected from H, Br, Cl, CN, CF3, OCF3, cyclopropyl, Preferred is CF3.

[0228] In a more specific embodiment, R1 is independently selected from H, D, halogen, CN, OR a SR a NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(OR a )2、P(OR a )2、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 3-10 membered heterocyclic group, C 6- 10 Aryl and 5-10 membered heteroaryl; In another more specific embodiment; In another more specific embodiment, R1 is such as R 1a or R 1b In another more specific embodiment, R1 is as R 1a In another more specific embodiment, R1 is as R 1b defined.

[0229] In a more specific embodiment, R1 is F; in another more specific embodiment, R1 is CF3; in another more specific embodiment, R1 is CF2CF3; in another more specific embodiment, R1 is SF5; in another more specific embodiment, R1 is OCH3; in another more specific embodiment, R1 is OCF3; in another more specific embodiment, R1 is OCHF2; in another more specific embodiment, R1 is OCH2CH3; in another more specific embodiment, R1 is OCH2CH2CF3.

[0230] In one embodiment, two adjacent R1 and the atoms to which they are attached together form C 3-6 In another embodiment, two adjacent R1 and the atoms to which they are attached together form a 3-7 membered heterocyclic group; In another embodiment, two adjacent R1 and the atoms to which they are attached together form a C 6-10 Aryl; in another embodiment, two adjacent R1 and the atoms to which they are attached together form a 5-10 membered heteroaryl; in another embodiment, two adjacent R1 and the atoms to which they are attached together form a C 5-6 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 thiazolyl group.

[0231] R 1a

[0232] In one embodiment, R 1a is H; in another embodiment, R 1a is D; in another embodiment, R 1a is halogen, such as F, such as Cl, such as Br; in another embodiment, R 1a is CN; in another embodiment, R 1a is NO2; in another embodiment, R 1a For-L-OR a , such as ORa , such as OCH3, such as OCH2CH3, such as OCF3, such as OCHF2, such as OCH2CH2CF3; In another embodiment, R 1a For-L-SR a , such as SR a In another embodiment, R 1a -L-NR b R c , such as NR b R c In another embodiment, R 1a is SF5; in another embodiment, R 1a C(O)R a In another embodiment, R 1a C(O)OR a In another embodiment, R 1a C(O)NR b R c In another embodiment, R 1a OC(O)R a In another embodiment, R 1a NR b C(O)R c In another embodiment, R 1a S(O)R a In another embodiment, R 1a is S(O)2R a ,For example In another embodiment, R 1a S(O)OR a In another embodiment, R 1a S(O)2OR a In another embodiment, R 1a S(O)NR b R c In another embodiment, R 1a S(O)2NR b R c In another embodiment, R 1a P(O)(OR a )2; In another embodiment, R 1a P(OR a )2; In another embodiment, R 1a P(O)(R a )2, for example In another embodiment, R 1a C 1-6Alkyl groups, e.g. In another embodiment, R 1a C 1-6 Haloalkyl, such as CF3, such as CF2CF3, such as In another embodiment, R 1a C 2-6 alkenyl; in another embodiment, R 1a C 2-6 Alkynyl groups, e.g. In another embodiment, R 1a C 3-7 Cycloalkyl, such as C 3-6 Cycloalkyl groups, e.g. For example, cyclopropyl; in another embodiment, R 1a is a 3-7 membered heterocyclic group, for example For example For example In another embodiment, R 1a C 6-10 Aryl, such as phenyl, for example In another embodiment, R 1a is a 5-10 membered heteroaryl group, for example a 5-6 membered heteroaryl group, for example For example For example For example For example For example For example For example For example For example For example For example For example In another embodiment, R 1a C 5-7 Cycloalkyl; in another embodiment, R 1a is a 5-7 membered heterocyclic group; in another embodiment, R 1a Optionally 1, 2 or 3 R 1s Substitution, such as R 1a for For example, R 1a for For example, R 1a for For example, R 1a for For example, R 1a for For example, R 1a for For example, R1a for In another embodiment, R 1a Not replaced.

[0233] In a more specific embodiment, R 1a Selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclyl; in another more specific embodiment, R 1a Selected from H, D, halogen, CN, SF5, OR a NR b R c 、C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 1a Selected from H, D, SF5, OR a 、C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0234] In a more specific embodiment, R 1a Selected from H, D, halogen, CN, SF5, OR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; in another more specific embodiment, R 1a Selected from H, D, halogen, CN, SF5, OR a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; in another more specific embodiment, R 1a Selected from H, D, halogen, CN, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C3-7 Cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; in another more specific embodiment, R 1a Selected from H, Cl, Br, CN, CF3, CF2CF3, SF5, OCH3, OCF3, OCHF2, OCH2CH3, OCH2CH2CF3, cyclopropyl, Preferably selected from H, Br, Cl, CN, CF3, OCF3, cyclopropyl, Preferred is CF3.

[0235] In a more specific embodiment, R 1a Selected from H, D, halogen, CN, SF5, OR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; in another more specific embodiment, R 1a Selected from H, D, halogen, CN, SF5, OR a 、S(O)2R a 、 P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; in another more specific embodiment, R 1a Not P(O)(R a )2; In another more specific embodiment, R 1a Not P(O)(R a )2 and heterocyclyl; in another more specific embodiment, R 1a Selected from SF5, Cl, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OC 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, phenyl, In another more specific embodiment, R 1a When it is a heterocyclic group, the heterocyclic group contains one double bond, and the connection point with Ar1 is preferably on the double bond; in another more specific embodiment, R 1a When it is a heterocyclic group, the heterocyclic group contains two double bonds, and the connection point with Ar1 is preferably on the double bond.

[0236] In a more specific embodiment, R 1a Selected from H, Cl, Br, CN, SF5, CF3, CF2CF3, OCH3, OCH2CH3, OCF3, OCHF2, OCH2CH2CF3, cyclopropyl, In another more specific embodiment, R 1a Not for In another more specific embodiment, R 1a Selected from H, Br, Cl, CN, SF5, CF3, CF2CF3, OCF3, OCHF2, cyclopropyl, In another more specific embodiment, R 1a Selected from SF5, Cl, CN, CF3, OCF3, cyclopropyl,

[0237] In a more specific embodiment, R 1a is CF3; in another more specific embodiment, R 1a is CF2CF3; in another more specific embodiment, R 1a is SF5; in another more specific embodiment, R 1a is OCH3; in another more specific embodiment, R 1a is OCF3; in another more specific embodiment, R 1a is OCHF2; in another more specific embodiment, R 1a is OCH2CH3; in another more specific embodiment, R 1a It is OCH2CH2CF3.

[0238] R 1b

[0239] In one embodiment, R 1b is H; in another embodiment, R 1b is D; in another embodiment, R 1b is halogen, such as F, such as Cl; in another embodiment, R 1b is CN; in another embodiment, R 1b OR a In another embodiment, R 1b SR a In another embodiment, R 1b NR b R c In another embodiment, R 1b is SF5; in another embodiment, R 1b C 1-6 Alkyl; in another embodiment, R 1b C 1-6 Haloalkyl, such as CF3; in another embodiment, R 1b Such as R 1a defined.

[0240] In a more specific embodiment, R 1b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In a more specific embodiment, R 1b are independently selected from H, D and halogen, preferably H, F or Cl, preferably H or F; in a more specific embodiment, R 1b Independently selected from H, D, C 1-6 Alkyl and C 1-6 Haloalkyl, more preferably H or D; in a more specific embodiment, R 1b Independently selected from H, F, Cl or CF3, preferably H or CF3, preferably H.

[0241] In a more specific embodiment, R 1b Independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclyl; in a more specific embodiment, R 1b Independently selected from H, D, halogen, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups.

[0242] R 1s

[0243] In one embodiment, R 1s is H; in another embodiment, R 1s is D; in another embodiment, R 1s is halogen, such as F; in another embodiment, R 1s is CN; in another embodiment, R 1s For-L-OR a In another embodiment, R 1s For-L-SR a In another embodiment, R 1s -L-NR b R c In another embodiment, R 1s C(O)R a 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, such as Me; in another embodiment, R 1s C 1-6 Haloalkyl, such as CF3; 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, such as C 3-7 Cycloalkyl, such as cyclopropyl; in another embodiment, R 1s is -L-3-10 membered heterocyclyl, such as 3-7 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, R 1s C 3-7 Cycloalkyl; in another embodiment, R 1s is a 3-7 membered heterocyclic group; in another embodiment, R 1sOptionally substituted by 1, 2 or 3 H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl substitution.

[0244] In a more specific embodiment, R 1s Selected from H, D, halogen, -L-OR a 、-L-NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; in a more specific embodiment, R 1s 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 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclyl; in a more specific embodiment, R 1s Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclic group, preferably 5-6 membered heterocyclic group, more preferably

[0245] In a more specific embodiment, R 1s Independently selected from H, D, halogen, CN, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7Cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl and C 1-6 In another more specific embodiment, R 1s Independently selected from H, D, CN, C 1-6 Alkyl and C 1-6 Haloalkyl is preferably selected from H, D, CN, Me and CF3; in another more specific embodiment, R 1s Independently selected from H, D, C 1-6 Alkyl and C 1-6 The haloalkyl group is preferably selected from H, D and Me, more preferably Me.

[0246] In a more specific embodiment, R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-7 Cycloalkyl; in another more specific embodiment, R 1s Independently selected from H, D, F, CN, Me, CF3 and cyclopropyl.

[0247] L

[0248] 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 by 1, 2 or 3 H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl radical substitution.

[0249] p

[0250] In one embodiment, p=0; in another embodiment, p=1; in another embodiment, p=2; in another embodiment, p=3; in another embodiment, p=4.

[0251] In a more specific embodiment, p=0, 1 or 2; in another more specific embodiment, p=0 or 1.

[0252] n

[0253] 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.

[0254] m

[0255] In one embodiment, m=0; in another embodiment, m=1; in another embodiment, m=2.

[0256] R a 、R b and R c

[0257] In one embodiment, R a 、R b and R c are independently H; in another embodiment, R a 、R b and R c is independently D; in another embodiment, R a 、R b and R c Independently C 1-6 Alkyl; in another embodiment, R a 、R b and R c Independently C 1-6 haloalkyl; in another embodiment, R b 、R c and the atoms to which they are attached together form a 5-10 membered heterocyclic group, preferably a 5-7 membered heterocyclic group; in another embodiment, R b 、R c Together with the atoms to which they are attached, they form a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group.

[0258] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of Ring A can be combined with X1, X2, X3, R 2a 、R 2b 、R 2c 、R 2d 、R 2s , L1, L2, L3, R x 、R y , Y1, Y2, Z1, Z2, Z3, R3, R, R', Ar1, Ar2, R1, R 1a 、R 1b 、R 1s ,L,n,m,p,Ra 、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.

[0259] In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0260] in,

[0261] Ring A is

[0262] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0263] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0264] X3 for CR 2d or N;

[0265] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0266] 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;

[0267] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0268] 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 3-10Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0269] 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;

[0270] R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0271] L1 is NH or CHR x ;

[0272] L2 is a chemical bond or CR x R y ;

[0273] L3 is -C(O)-, -S(O)- or -S(O)2-;

[0274] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or CR x R y Together to form C=O, C=S or C 3-6 cycloalkylene;

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

[0276] Y1 is a chemical bond or (CR3R3) q ;

[0277] Y2 is a chemical bond, O, S, NR', S(O) or S(O)2;

[0278] q = 1, 2, or 3;

[0279] Z1 is N or CR;

[0280] Z2 is N or CR;

[0281] Z3 is N or CR;

[0282] R3 and R are independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0283] Or CR3R3 together to form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0284] R' is selected from H, D, C(O)R a 、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;

[0285] p = 0, 1, 2, 3, or 4;

[0286] One of Ar1 and Ar2 is phenyl or a 5-6 membered heteroaryl group substituted by n R1s; the other is H or D; or Ar1 and Ar2 are independently H or D;

[0287] 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)2NRb R c 、P(O)(OR a )2、P(OR a )2、P(O)(R a )2、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, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0288] or two adjacent ring atoms on Ar1 or Ar2 and their substituents together form a C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0289] n = 0, 1, 2, 3, 4 or 5;

[0290] R 1s Selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、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, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0291] L is selected from chemical bonds, 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;

[0292] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 3-10 membered heterocyclic group;

[0293] Among them, X1, X2, X3, R 2a 、R 2b 、R 2c 、R 2d 、R 2s , L1, L2, R x 、R y , Y1, Y2, Z1, Z2, Z3, R3, R, R', Ar1, Ar2, R1, R 1s , L, R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0294] In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0295] in,

[0296] Ring A is

[0297] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0298] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0299] X3 for CR 2d or N;

[0300] R 2a Selected from H, D, CN, OR a NR b R c 、C(O)OR a or C(O)NR b R c ;

[0301] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NRb R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0302] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0303] 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;

[0304] 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;

[0305] R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0306] L1 is NH or CHR x ;

[0307] L2 is a chemical bond or CR x R y ;

[0308] L3 is -C(O)-, -S(O)- or -S(O)2-;

[0309] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or CR xR y Together to form C=O, C=S or C 3-6 cycloalkylene;

[0310] 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;

[0311] Y1 is a chemical bond or CR3R3;

[0312] Y2 is a chemical bond, O, S, NR', S(O) or S(O)2;

[0313] Z1 is N or CR;

[0314] Z2 is N or CR;

[0315] Z3 is N or CR;

[0316] R3 and R are independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0317] Or CR3R3 together to form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0318] R' is selected from H, D, C(O)R a 、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;

[0319] p = 0, 1, 2, 3, or 4;

[0320] One of Ar1 and Ar2 is phenyl or 5-6 membered heteroaryl, which is substituted by n R1; the other is H or D;

[0321] R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)Ra 、C(O)OR a 、C(O)NR b R c 、OC(O)R a NR b C(O)R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、P(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0322] 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;

[0323] n = 0, 1, 2, 3, 4 or 5;

[0324] R 1s Selected from H, D, halogen, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、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, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0325] L is selected from chemical bonds, 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;

[0326] 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;

[0327] Among them, X1, X2, X3, R 2a 、R 2b 、R 2c 、R 2d 、R 2s , L1, L2, R x 、R y , Y1, Y2, Z1, Z2, Z3, R3, R, R', Ar1, Ar2, R1, R 1s , L, R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0328] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0329] Selected from Preferably selected from

[0330] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2a Selected from H, D, CN, OR a or NR b R c ; preferably OR a or NRb R c ; preferably NH2.

[0331] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Me.

[0332] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2c is selected from H, D or halogen; preferably H or D.

[0333] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2d Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably H or D.

[0334] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein 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 Substitution; preferably forming

[0335] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2s Selected from H, D, halogen, =O, C 1- 6 alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D or Me.

[0336] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH; L2 is a chemical bond or CR x R y ; L3 is -C(O)- or -S(O)2-;

[0337] Preferably, L1-L2 are selected from L3 is -C(O)-; or L1-L2-L3 is

[0338] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Y1 is a chemical bond or CR3R3; Y2 is selected from a chemical bond, O, S, NR';

[0339] Preferably, Y1 is a chemical bond or CR3R3; Y2 is selected from a chemical bond, O, S or NH, preferably a chemical bond or O;

[0340] Preferably, Y1 is CR3R3; Y2 is selected from O, S or NH, preferably O;

[0341] Preferably, Selected from

[0342] Preferably, Selected from

[0343] Preferably, for More preferably

[0344] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein, for Preferably

[0345] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Z1, Z2 and Z3 are all CR.

[0346] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 more preferably H or D.

[0347] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R3 is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, or CR3R3 together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, or CR3R3 together to form C 3-6 Cycloalkylene; preferably selected from H or Me, or CR3R3 together form cyclopropylene.

[0348] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R' is selected from H, D, C(O)R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, C(O)R a 、C 1-6 Alkyl, C 1-6 The haloalkyl group is more preferably H or D.

[0349] In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein one of Ar1 and Ar2 is phenyl, pyridyl or pyridazinyl, which is substituted by n R1; the other is H or D;

[0350] Preferably, Ar1 is phenyl, pyridyl or pyridazinyl, which is substituted by n R1; Ar2 is H or D; or Ar2 is phenyl, which is substituted by n R1; Ar1 ​​is H or D;

[0351] Preferably, one of Ar1 and Ar2 is Among them, Z4 is CR 1b or N, Z5 is CR 1b or N, m=0, 1 or 2; the other is H or D;

[0352] Preferably, one of Ar1 and Ar2 is selected from The other is H or D; more preferably one of Ar1 and Ar2 is selected from The other is H or D.

[0353] In a more specific embodiment, the present invention provides a compound of formula (I) as described 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 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0354] Preferably selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0355] Preferably selected from H, D, halogen, CN, SF5, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0356] Preferably selected from H, D, halogen, SF5, OR a 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0357] Preferably selected from F, CF3, CF2CF3, SF5, OCH3, OCF3, OCHF2, OCH2CH3 or OCH2CH2CF3, preferably F or CF3;

[0358] 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, preferably forming phenyl or 5-6 membered heteroaryl, more preferably forming thiazolyl, which is optionally substituted by 1, 2 or 3 R 1s replace.

[0359] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1a Selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s Substituted; preferably selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s Substituted; preferably selected from H, D, halogen, CN, SF5, OR a NR b Rc 、C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, SF5, OR a 、C 1-6 Alkyl or C 1-6 preferably selected from CF3, CF2CF3, SF5, OCH3, OCF3, OCHF2, OCH2CH3 or OCH2CH2CF3, more preferably CF3.

[0360] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1b Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably selected from H, D or halogen; preferably H or F.

[0361] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1s Selected from H, D, halogen, -L-OR a 、-L-NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl substituted; 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 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclic group; preferably 5-6 membered heterocyclic group, more preferably

[0362] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein 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 The haloalkyl group is substituted; preferably by a chemical bond.

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

[0364] Among them, R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0365] Preferably, R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0366] Preferably, R 3a 、R 3b 、R 3c and R 3dIndependently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, or CR 3a R 3b Together they form C 3-6 cycloalkylene;

[0367] Preferably, R 3a 、R 3b 、R 3c and R 3d are independently H or Me, or CR 3a R 3b Together they form a cyclopropylene group;

[0368] The remaining groups are as defined herein.

[0369] In a more specific embodiment, the present invention provides a compound of formula (II) or formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0370] L1 is NH;

[0371] L2 is CR x R y ;

[0372] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0373] or CR x R y Together to form C=O, C=S or C 3-4 cycloalkylene;

[0374] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0375] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0376] X3 for CR 2d or N;

[0377] R 2a Selected from H, D, CN, OR a or NR b R c ;

[0378] R 2b Selected from H, D, halogen, C(O)OR a、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0379] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0380] 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, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group;

[0381] Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0382] R 2s Independently selected from H, D, halogen, ═O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0383] Y1 is selected from a chemical bond or CR3R3;

[0384] Y2 is selected from a chemical bond, O, S, NR', S(O) or S(O)2;

[0385] R3 is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, or CR3R3 together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0386] R' is selected from H, D, C(O)R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0387] Ar1 and Ar2 are independently phenyl or 5-6 membered heteroaryl, preferably phenyl, pyridyl or pyridazinyl, which are substituted by n R1;

[0388] R1 is independently 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;

[0389] R 1s 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 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclic group;

[0390] p = 0, 1, 2, 3, or 4;

[0391] n = 0, 1, 2, 3, 4 or 5;

[0392] 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 5-7 membered heterocyclic group;

[0393] Among them, L1, L2, X1, X2, X3, R 2a 、R 2b 、R 2c 、R 2d 、R 2s , Y1, Y2, R3, R', Ar1, Ar2, R1, R 1s 、R a 、Rb and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0394] In a more specific embodiment, the present invention provides a compound of formula (II) or formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0395] L1 is NH;

[0396] L2 is CR x R y ;

[0397] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0398] or CR x R y Together to form C=O or C 3-4 cycloalkylene;

[0399] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0400] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0401] X3 for CR 2d or N;

[0402] R 2a OR a or NR b R c ;

[0403] R 2b 、R 2c and R 2d Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0404] Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0405] R 2s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0406] Y1 is selected from a chemical bond or CR3R3;

[0407] Y2 is selected from a chemical bond, O, S or NR', preferably selected from a chemical bond, O, S or NH;

[0408] R3 is independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, or CR3R3 together to form C 3-6 cycloalkylene;

[0409] R' is selected from H, D, C(O)R a 、C 1-6 Alkyl, C 1-6 alkyl halide;

[0410] Ar1 and Ar2 are independently

[0411] Z4 for CR 1b or N;

[0412] Z5 is CR 1b or N;

[0413] R 1a Selected from H, D, halogen, CN, SF5, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0414] R 1b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0415] p = 0, 1, 2, 3, or 4;

[0416] m=0, 1 or 2, preferably m=0;

[0417] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0418] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0419] L1-L2 is

[0420] Y1 is CR3R3;

[0421] Y2 is selected from O, S or NH, preferably O.

[0422] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[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] X3 for CR 2d ;

[0426] R 2a is NH2;

[0427] R 2b Selected from C 1-6 Alkyl or C 1-6 alkyl halide;

[0428] R 2c Selected from H, D or halogen; preferably H or D;

[0429] R 2d H or D;

[0430] Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0431] R 2s independently selected from H, D or Me;

[0432] R3 is independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, or CR3R3 together to form C 3-6 cycloalkylene;

[0433] Ar1 is

[0434] Z4 for CR 1b or N;

[0435] Z5 is CR 1b or N;

[0436] R1a Selected from H, D, SF5, OR a 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0437] R 1b independently selected from H, D or halogen;

[0438] p = 0, 1, or 2;

[0439] m=0, 1 or 2, preferably m=0;

[0440] R a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0441] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0442] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0443] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0444] X3 is CH;

[0445] R 2a is NH2;

[0446] R 2b for Me;

[0447] R 2c is H;

[0448] Or X1, X2 and their substituents together form:

[0449] R3 is independently selected from H or Me, or CR3R3 together form cyclopropylene;

[0450] Ar1 is Preferably selected from More preferably selected from

[0451] Z4 for CR 1b or N;

[0452] Z5 is CR 1b or N;

[0453] R 1a Selected from CF3, CF2CF3, SF5, OCH3, OCF3, OCHF2, OCH2CH3 or OCH2CH2CF3, preferably CF3;

[0454] R 1b Selected from H or F;

[0455] p = 0, 1, or 2;

[0456] m=0, 1 or 2, preferably m=0.

[0457] In a more specific embodiment, the present invention provides a compound of formula (II) or formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0458] L1 is NH;

[0459] L2 is CR x R y ;

[0460] where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide;

[0461] or CR x R y Together they form C 3-4 cycloalkylene;

[0462] Preferably, L1-L2 is Preferably

[0463] In a more specific embodiment, the present invention provides a compound of formula (II) or formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0464] X1 for CR 2b ;

[0465] X2 is CR 2c ;

[0466] X3 for CR 2d ;

[0467] R 2a is NH2;

[0468] R 2b Selected from C1-6 Alkyl or C 1-6 alkyl halide;

[0469] R 2c Selected from H, D or halogen; preferably H or D;

[0470] R 2d Selected from H or D;

[0471] Y1 is selected from a chemical bond or CR3R3;

[0472] Y2 is selected from a chemical bond, O, S or NH, preferably a chemical bond or O;

[0473] R3 is independently selected from H, D or Me, or CR3R3 together form cyclopropylene; preferably H or D;

[0474] Ar1 and Ar2 are independently

[0475] Z4 for CR 1b ;

[0476] Z5 is CR 1b ;

[0477] R 1a Selected from H, D, SF5, OR a 、C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0478] R 1b Independently selected from H, D or halogen; preferably H or D;

[0479] p = 0, 1, or 2;

[0480] m=0, 1 or 2, preferably m=0;

[0481] R a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0482] In a more specific embodiment, the present invention provides a compound of formula (II) or formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0483] X1 for CR 2b ;

[0484] X2 is CH;

[0485] X3 is CH;

[0486] R 2a is NH2;

[0487] R 2b C 1-6 Alkyl or C 1-6 Haloalkyl, preferably Me;

[0488] Y1 is selected from a chemical bond or CR3R3, preferably CR3R3;

[0489] Y2 is a chemical bond or O;

[0490] R3 is H;

[0491] Ar1 and Ar2 are independently

[0492] R 1a C 1-6 Alkyl or C 1-6 Haloalkyl, preferably CF3;

[0493] p=0.

[0494] In a 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,

[0495] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0496] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0497] 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;

[0498] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0499] X3 for CR 2d or N;

[0500] R 2a Selected from H, D, CN, OR a or NR b Rc ;

[0501] 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, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group;

[0502] R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0503] or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0504] Ar1 is phenyl or a 5-6 membered heteroaryl, preferably phenyl, pyridyl or pyridazinyl, which is substituted by n R1;

[0505] 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;

[0506] R 1s 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 、C 1-6Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclic group;

[0507] n = 0, 1, 2, 3, 4 or 5;

[0508] 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 5-7 membered heterocyclic group;

[0509] Among them, X1, X2, R1, R 2d 、Ar1、R 1s 、R 2s 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

[0510] In a 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,

[0511] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0512] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0513] 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;

[0514] R 2s Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0515] X3 for CR 2d ;

[0516] R 2a OR a or NRb R c ;

[0517] R 2d H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0518] R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0519] or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0520] Ar1 is

[0521] Z4 for CR 1b or N;

[0522] Z5 is CR 1b or N;

[0523] R 1a Selected from H, D, halogen, CN, SF5, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0524] R 1b Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0525] m = 0, 1, or 2;

[0526] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0527] In a 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,

[0528] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0529] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0530] 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;

[0531] R 2s Selected from H, D or Me;

[0532] X3 for CR 2d ;

[0533] R 2a is NH2;

[0534] R 2d is H or D;

[0535] R 3a 、R 3b and R 3c Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0536] or CR 3a R 3b Together they form C 3-6 cycloalkylene;

[0537] R 3d Selected from H or D;

[0538] Ar1 is

[0539] Z4 for CR 1b or N;

[0540] Z5 is CR 1b or N;

[0541] R 1a Selected from H, D, SF5, OR a 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0542] R 1b is selected from H, D or halogen;

[0543] m=0, 1 or 2, preferably m=0;

[0544] R a Selected from H, D, C 1-6 Alkyl or C 1-6Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0545] In a 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,

[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:

[0549] X3 is CH;

[0550] R 2a is NH2;

[0551] R 3a is H or Me;

[0552] R 3b is H or Me;

[0553] or CR 3a R 3b Together they form a cyclopropylene group;

[0554] R 3c is H or Me;

[0555] R 3d is H;

[0556] Ar1 is Preferably selected from More preferably selected from

[0557] Z4 for CR 1b or N;

[0558] Z5 is CR 1b or N;

[0559] R 1a Selected from CF3, CF2CF3, SF5, OCH3, OCF3, OCHF2, OCH2CH3 or OCH2CH2CF3, preferably CF3;

[0560] R 1b H or F;

[0561] m=0, 1 or 2, preferably m=0.

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

[0563] Among them, L1-L2 is

[0564] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0565] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0566] X3 for CR 2d or N;

[0567] R 2a Selected from H, D, CN, OR a or NR b R c ;

[0568] R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0569] R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0570] 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 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0571] Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0572] R 2s Independently selected from H, D, halogen, ═O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0573] Y1 is selected from (CR3R3) q ;

[0574] Y2 is selected from O, S, NR', S(O) or S(O)2;

[0575] q = 1 or 2;

[0576] R' is selected from H, D, C(O)R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0577] R3 is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, and at least one of the two R3 in the geminal position is H or D; or CR3R3 together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0578] Ar1 is phenyl or a 5-6 membered heteroaryl, preferably a phenyl or a 6 membered nitrogen heteroaryl, preferably a phenyl, pyridyl, pyrimidinyl or pyridazinyl group, which is substituted by n R1, or Ar1 is H or D;

[0579] R1 is independently selected from H, D, halogen, CN, OR a SR a NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c、P(O)(OR a )2、P(OR a )2、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace;

[0580] Or the two adjacent ring atoms on Ar1 and their substituents together form a C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0581] R 1s Independently selected from H, D, halogen, CN, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1- 6 haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3- 7-membered cycloalkyl or 3-7-membered heterocyclic group;

[0582] p = 0, 1, 2, 3, or 4;

[0583] n = 0, 1, 2, 3, 4 or 5;

[0584] 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 3-7 membered heterocyclic group;

[0585] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0586] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0587] L1-L2 is

[0588] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0589] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0590] X3 for CR 2d or N;

[0591] R 2a OR a or NR b R c ;

[0592] R 2b Selected from H, D, halogen, C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0593] R 2c and R 2d Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0594] Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

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

[0596] Y1 is selected from (CR3R3) q ;

[0597] Y2 is selected from O, S, NR' or S(O)2;

[0598] q = 1 or 2;

[0599] R' is selected from H, D, C 1-6 Alkyl and C 1-6 alkyl halide;

[0600] R3 is independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, and at least one of the two R3 in the geminal position is H or D; or CR3R3 together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0601] Ar1 is or Ar1 is H or D;

[0602] Z4, Z5, Z7 and Z8 are independently CR 1b or N;

[0603] Z6 is CR 1a or N;

[0604] Or Z6, Z5 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 1s replace;

[0605] R 1a Selected from H, D, halogen, CN, SF5, OR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace;

[0606] R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl and C 1-6 alkyl halide;

[0607] R 1b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0608] p = 0, 1, or 2;

[0609] R a 、R b and R c Independently selected from H, D, C1-6 Alkyl or C 1-6 Halogenated alkyl.

[0610] In a more specific embodiment, among Z4, Z5, Z6, Z7 and Z8, at most 3 are N, preferably at most 2 are N, and preferably at most 1 is N.

[0611] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0612] L1-L2 is

[0613] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0614] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0615] X3 for CR 2d ;

[0616] R 2a is OMe or NH2, preferably OMe, preferably NH2;

[0617] R 2b Selected from C(O)NR b R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C(O)NR b R c or C 1-3 Alkyl, preferably C(O)NH2 or Me, preferably C(O)NH2;

[0618] R 2c Selected from H, D or halogen; preferably H or D;

[0619] R 2d is H or D;

[0620] Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably forming a 5-7 membered heterocyclyl or 5-6 membered heteroaryl, more preferably forming a 5 membered heterocyclyl or 5 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0621] R 2s Independently selected from H, D and C 1-3 Alkyl, preferably selected from H, D and Me;

[0622] Y1 is (CR3R3) q , preferably -CH2-, -CH(CH3)-, -CH2CH2-, Preferably -CH2-, -CH(CH3)- or More preferably -CH2- or -CH(CH3)-;

[0623] Y2 is selected from O, NR' or S(O)2, preferably O;

[0624] q=1 or 2, preferably 1;

[0625] R' is H, C 1-3 Alkyl or C 1-3 Halogenated alkyl, preferably C 1-3 Alkyl, preferably Me;

[0626] R3 is independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, preferably H, D, C 1-6 Alkyl or C 1-6 A haloalkyl group, wherein at least one of the two R3 groups in the geminal position is H or D; preferably, R3 is independently selected from H, Me, Et, CF3 or cyclopropyl, preferably H, Me or Et;

[0627] Or CR3R3 together to form C 3-6 Cycloalkylene, preferably forming Preferred Formation Preferably, CR3R3 does not form a ring;

[0628] Ar1 is Or Ar1 is H; preferably Ar1 is

[0629] Z4, Z5 and Z7 are independently CR 1b or N, preferably Z7 is CR 1b ;

[0630] Z6 is CR 1a or N, preferably CR 1a ;

[0631] Z8 is CR 1b ;

[0632] Or Z6, Z5 and their substituents together form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group, more preferably a 5 membered heterocyclic group or a 5 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0633] R 1a Selected from H, D, halogen, CN, SF5, OR a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl, preferably selected from H, D, halogen, CN, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3- 7-membered cycloalkyl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace;

[0634] R 1s Independently selected from H, D, CN, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D, CN, Me and CF3, preferably selected from H, D and Me;

[0635] R 1b Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably selected from H, D, C 1-6 Alkyl and C 1-6 alkyl halide;

[0636] p=0, 1 or 2, preferably p=0 or 1;

[0637] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0638] In a 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,

[0639] in,

[0640] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0641] X2 is a C atom or a N atom, which is optionally replaced by R 2creplace;

[0642] 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;

[0643] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0644] X3 for CR 2d or N;

[0645] R 2a Selected from H, D, CN, OR a or NR b R c ;

[0646] 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 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0647] R 3a 、R 3c and R 3d Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0648] R 3b H or D;

[0649] or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0650] Ar1 is phenyl or 5-6 membered heteroaryl, preferably phenyl or 6 membered nitrogen heteroaryl, which is substituted by n R1;

[0651] R1 is independently selected from H, D, halogen, CN, OR a SR a NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(OR a )2、P(OR a )2、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace;

[0652] Or the two adjacent ring atoms on Ar1 and their substituents together form a C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0653] R 1s Independently selected from H, D, halogen, CN, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1- 6 haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3- 7-membered cycloalkyl or 3-7-membered heterocyclic group;

[0654] n = 0, 1, 2, 3, 4 or 5;

[0655] 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 3-7 membered heterocyclic group;

[0656] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0657] In a 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,

[0658] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0659] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0660] 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;

[0661] R 2s Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0662] X3 for CR 2d ;

[0663] R 2a OR a or NR b R c , preferably OMe or NH2;

[0664] R 2d H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0665] R 3a and R 3c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6Cycloalkyl or 3-6 membered heterocyclic group;

[0666] R 3b and R 3d independently H or D;

[0667] or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0668] Ar1 is

[0669] Z4, Z5, Z7 and Z8 are independently CR 1b or N;

[0670] Z6 is CR 1a or N;

[0671] Or Z6, Z5 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 1s replace;

[0672] R 1a Selected from H, D, halogen, CN, SF5, OR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace;

[0673] R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl and C 1-6 alkyl halide;

[0674] R 1b Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0675] R a 、Rb and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0676] In a more specific embodiment, among Z4, Z5, Z6, Z7 and Z8, at most 3 are N, preferably at most 2 are N, and preferably at most 1 is N.

[0677] In a 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,

[0678] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0679] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0680] And X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably forming a 5-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably forming a 5-6 membered heteroaryl, preferably forming a 5 membered heterocyclyl or 5 membered heteroaryl, more preferably forming a 5 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace;

[0681] R 2s Selected from H, D and C 1-3 Alkyl, preferably selected from H, D and Me;

[0682] X3 for CR 2d ;

[0683] R 2a is NH2;

[0684] R 2d is H or D;

[0685] R 3a and R 3c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, preferably H, D, C 1-6 Alkyl or C 1- 6 haloalkyl;

[0686] R 3b and R 3d independently H or D;

[0687] or CR 3a R 3b Together they form C 3-6 Cycloalkylene; or CR 3c R 3d Together they form C 3-6 cycloalkylene;

[0688] Ar1 is

[0689] Z4, Z5 and Z7 are independently CR 1b or N, preferably Z7 is CR 1b ;

[0690] Z6 is CR 1a or N, preferably CR 1a ;

[0691] Z8 is CR 1b ;

[0692] Or Z6, Z5 and their substituents together form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group, preferably a 5 membered heterocyclic group or a 5 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0693] R 1a Selected from H, D, halogen, CN, SF5, OR a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl, preferably selected from H, D, halogen, CN, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3- 7-membered cycloalkyl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace;

[0694] R 1s Independently selected from H, D, CN, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D, CN, Me and CF3, preferably selected from H, D and Me;

[0695] R 1b Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably selected from H, D, C 1-6 Alkyl and C 1-6Haloalkyl, more preferably H or D;

[0696] R a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0697] In a more specific embodiment, R 3a and R 3c At least one of them is H or D.

[0698] In a more specific embodiment, R 3a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, preferably C 1-6 Alkyl or C 1-6 Haloalkyl; R 3c It is H or D.

[0699] In more specific embodiments, when X1, X2 and their substituents together form a cycloalkyl group (e.g. For example ) or a heterocyclic group (e.g. For example ), Z6, Z5 and their substituents do not together form a phenyl or heteroaryl group (e.g. For example For example For example For example For example ).

[0700] In a 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,

[0701] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0702] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0703] And X1, X2 and their substituents together form:

[0704] Preferred Formation Preferred Formation

[0705] X3 is CH;

[0706] R 2a is NH2;

[0707] R 3a is H, Me, Et, CF3 or cyclopropyl, preferably H, Me or Et;

[0708] R 3b is H;

[0709] R 3c is H or Me;

[0710] R 3d is H;

[0711] or CR 3a R 3b Formed together or CR 3c R 3d Formed together

[0712] Ar1 is

[0713] Z4, Z5 and Z7 are independently CR 1b or N, preferably Z7 is CH or N, preferably Z7 is CH;

[0714] Z6 is CR 1a or N, preferably CR 1a ;

[0715] Z8 is CH;

[0716] Or Z6, Z5 and their substituents together form: Preferred Formation

[0717] R 1a Selected from H, Cl, Br, CN, CF3, CF2CF3, SF5, OCH3, OCF3, OCHF2, OCH2CH3, OCH2CH2CF3, cyclopropyl, Preferably selected from H, Br, Cl, CN, CF3, OCF3, cyclopropyl, Preferably CF3;

[0718] R 1b is independently H, F, Cl or CF3, preferably H or CF3, preferably H.

[0719] In a more specific embodiment, R 3a and R 3cAt least one of them is H.

[0720] In a more specific embodiment, R 3a is Me, Et, CF3 or cyclopropyl, preferably Me or Et; R 3c For H.

[0721] In more specific embodiments, Ar1 is selected from the group consisting of:

[0722] In more specific embodiments, Ar1 is selected from the group consisting of:

[0723] In a 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,

[0724] in,

[0725] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0726] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0727] 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;

[0728] R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide;

[0729] X3 for CR 2d or N;

[0730] R 2a Selected from H, D, CN, OR a or NR b R c ;

[0731] 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 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C6-10 Aryl or 5-10 membered heteroaryl, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0732] R 3a 、R 3c and R 3d Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0733] R 3b is H or D;

[0734] or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0735] Ar1 is phenyl or 5-6 membered heteroaryl, preferably phenyl or 6 membered nitrogen heteroaryl, which is substituted by n R1;

[0736] R1 is independently selected from H, D, halogen, CN, OR a SR a NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(OR a )2、P(OR a )2、P(O)(R a )2、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, C6-10 Aryl and 5-10 membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace;

[0737] Or the two adjacent ring atoms on Ar1 and their substituents together form a C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace;

[0738] R 1s Independently selected from H, D, halogen, CN, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1- 6 haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups;

[0739] n = 0, 1, 2, 3, 4 or 5;

[0740] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl and C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 3-7 membered heterocyclic group;

[0741] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0742] In a 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,

[0743] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0744] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0745] 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;

[0746] R 2s Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0747] X3 for CR 2d ;

[0748] R 2a OR a or NR b R c , preferably OMe or NH2;

[0749] R 2d H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0750] R 3a and R 3c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0751] R 3b and R 3d independently H or D;

[0752] or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene;

[0753] Ar1 is

[0754] Z4, Z5, Z7 and Z8 are independently CR 1b or N;

[0755] Z6 is CR 1a or N;

[0756] Or Z6, Z5 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 1s replace;

[0757] R 1a Selected from H, D, halogen, CN, SF5, OR a NR b R c、C(O)R a 、S(O)R a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace;

[0758] R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups;

[0759] R 1b Independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups;

[0760] R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0761] Preferably, among Z4, Z5, Z6, Z7 and Z8, at most 3 are N, preferably at most 2 are N, and preferably at most 1 is N.

[0762] In a 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,

[0763] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0764] X2 is a C atom or a N atom, which is optionally replaced by R2c replace;

[0765] and X1, X2 and their substituents together form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group, preferably a 5-6 membered heteroaryl group, preferably a 5 membered heterocyclic group or a 5 membered heteroaryl group, more preferably a 5 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 2s Substituted; preferably, X1, X2 and their substituents together form

[0766] R 2s Selected from H, D, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D and Me;

[0767] X3 for CR 2d ;

[0768] R 2a is NH2;

[0769] R 2d is H or D;

[0770] R 3a and R 3c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, preferably H, D, C 1-6 Alkyl or C 1- 6 haloalkyl; preferably, R 3a and R 3c At least one of them is H or D, preferably R 3a Not for H and D, R 3c is H or D;

[0771] R 3b and R 3d independently H or D;

[0772] or CR 3a R 3b Together they form C 3-6 Cycloalkylene, preferably CR 3a R 3b No ring formation; or CR 3c R 3d Together they form C 3-6 Cycloalkylene, preferably CR 3c R 3d No ring formation;

[0773] Ar1 is

[0774] Z4, Z5 and Z7 are independently CR 1b or N;

[0775] Z6 is CR 1a or N, preferably CR 1a ;

[0776] Z8 is CR 1b ;

[0777] Or Z6, Z5 and their substituents together form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group, preferably a 5-7 membered heterocyclic group, preferably a 5 membered heterocyclic group or a 5 membered heteroaryl group, preferably a 5 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s Preferably, when Z6, Z5 and their substituents together form a heteroaryl group, Z5 is CR 1b ; Preferably, Z4 and Z5 are not N at the same time; Preferably, Z6, Z5 and their substituents do not form a ring;

[0778] R 1a Selected from H, D, halogen, CN, SF5, OR a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, preferably not P(O)(R a ) 2, preferably selected from SF5, Cl, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OC 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, phenyl, It is optionally replaced by 1, 2 or 3 R 1s replace;

[0779] R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-7 Cycloalkyl, preferably selected from H, D, F, CN, Me, CF3 and cyclopropyl;

[0780] R 1b Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D and halogen, more preferably H or D;

[0781] R a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Haloalkyl;.

[0782] In more specific embodiments, when X1, X2 and their substituents together form a cycloalkyl or heterocyclyl group, Z6, Z5 and their substituents together do not form a phenyl or heteroaryl group.

[0783] In a 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,

[0784] X1 is a C atom or a N atom, which is optionally replaced by R 2b replace;

[0785] X2 is a C atom or a N atom, which is optionally replaced by R 2c replace;

[0786] And X1, X2 and their substituents together form:

[0787] Preferred Formation Preferred Formation

[0788] X3 is CH;

[0789] R 2a is NH2;

[0790] R 3a is H, Me, Et, CF3 or cyclopropyl, preferably Me, Et, CF3 or cyclopropyl, preferably Me;

[0791] R 3b is H;

[0792] R 3c is H or Me, preferably H;

[0793] R 3d is H;

[0794] or CR 3a R 3b Formed together or CR 3c R 3d Formed together

[0795] Ar1 is

[0796] Z4, Z5 and Z7 are independently CR 1b Or N, preferably Z7 is CH or N;

[0797] Z6 is CR 1a or N, preferably CR 1a ;

[0798] Z8 is CH;

[0799] Or Z6, Z5 and their substituents together form: Preferred Formation Preferred Formation

[0800] R 1a Selected from H, Cl, Br, CN, SF5, CF3, CF2CF3, OCH3, OCH2CH3, OCF3, OCHF2, OCH2CH2CF3, cyclopropyl, Preferably not Preferably selected from H, Br, Cl, CN, SF5, CF3, CF2CF3, OCF3, OCHF2, cyclopropyl, Preferably selected from SF5, Cl, CN, CF3, OCF3, cyclopropyl, Preferably CF3;

[0801] R 1b are independently H, F, Cl or CF3, preferably H, F or Cl, preferably H;

[0802] Preferably, R 3a and R 3c At least one of them is H;

[0803] Preferably,

[0804] R 3a is Me, Et, CF3 or cyclopropyl, preferably Me or Et;

[0805] R 3c For H.

[0806] In more specific embodiments, Ar1 is selected from the group consisting of:

[0807] In a more specific embodiment, Ar1 is not

[0808] In more specific embodiments, Ar1 is selected from the group consisting of:

[0809] In more specific embodiments, Ar1 is selected from the group consisting of:

[0810] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,

[0811] wherein L1, L2, R3, Y1, Y2 and p are each as defined herein;

[0812] X1, X2, X3, R 2a and Ar1 are each as defined in any one of the present invention.

[0813] In a more specific embodiment, the present invention provides a compound of formula (IV-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,

[0814] Among them, X1, X2, R 2a 、R 3a and Ar1 are each as defined herein.

[0815] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the compound is selected from the following:

[0816] 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.

[0817] 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.

[0818] 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.

[0819] 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.

[0820] 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·0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0821] 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.

[0822] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I) but for which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 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 (I) of the present invention and their prodrugs 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.

[0823] 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.

[0824] 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 be cleaved 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 (I). Additionally, 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 its salt.

[0825] The present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present invention.

[0826] Pharmaceutical compositions and kits

[0827] 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.

[0828] 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.

[0829] 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.

[0830] 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.

[0831] Drug administration

[0832] 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.

[0833] 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.

[0834] 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.

[0835] 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.

[0836] 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.

[0837] 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.

[0838] 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.

[0839] 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.

[0840] 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.

[0841] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0842] 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.

[0843] 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.

[0844] 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.

[0845] 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.

[0846] 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.

[0847] 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%).

[0848] Indications

[0849] 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.

[0850] 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.

[0851] 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 (tumors, lymphoma, leiomyosarcoma, etc.) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma, etc.), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, etc.), Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, etc.), large intestine (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.), testicle (seminoma, teratoma, etc.) Tumor, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, mesenchymal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma, etc.); Liver: hepatoma, bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer, etc.; Bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma, etc.), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilage exostosis), benign enchondroma, Chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor of bone; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans, etc.), meninges (meningiomas, meningeal sarcomas, gliomas, etc.), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas, etc.), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, 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: Hematology (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, 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.;

[0852] Combination therapy

[0853] 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.

[0854] Example

[0855] The starting materials and reagents used herein are either commercially available or prepared by synthetic methods generally known in the art.

[0856] 1. Synthesis of Example 1

[0857] 1.1 Synthesis of Intermediate 1-1

[0858] 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 1-1 as a white solid (10.0 g, yield 86.9%). LC-MS m / z (ESI): 376.1 [M+Na] + .

[0859] 1.2 Synthesis of intermediate 1-2

[0860] 10% palladium on carbon (2.0 g) was added to a solution of compound 1-1 (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 light yellow solid 1-2 (9.2 g), which was used directly in the next reaction. LC-MS m / z (ESI): 324.2 [M+H] + .

[0861] 1.3 Synthesis of intermediates 1-3

[0862] At 0°C under a nitrogen atmosphere, ethyl oxalyl chloride (830.0 mg) and triethylamine (620.0 mg) were added to a solution of 1-2 (2.0 g) in dichloromethane (20 mL) and stirred at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 1-3 (2.5 g, yield 95.7%) as a white solid. LC-MS m / z (ESI): 424.0 [M+H] + .

[0863] 1.4 Synthesis of Intermediates 1-4

[0864] Lithium hydroxide (240.0 mg) was added to a solution of 1-3 (3.0 g) in methanol (10 mL) and water (10 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, diluted with water (20 mL), and 1 M hydrochloric acid was added dropwise to a pH of 5-6. The mixture was filtered and the filter cake dried to obtain a white solid 1-4 (1.0 g), which was used directly in the next reaction. LC-MS m / z (ESI): 396.2 [M+H] + .

[0865] 1.5 Synthesis of intermediate 1-5

[0866] At 0°C under a nitrogen atmosphere, phosphorus oxychloride (29.0 mg) was added dropwise to a solution of 1-4 (50.0 mg) and 3-(4-trifluoromethylphenyl)morpholine (30.0 mg) in pyridine (5 mL). The mixture was stirred for 1 hour, and water (50 mL) was added. 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: dichloromethane / methanol = 20 / 1) to obtain 1-5 (50.0 mg, yield 64.9%) as a yellow solid. LC-MS m / z (ESI): 609.2 [M+H] + .

[0867] 1.6 Synthesis of Compound 1

[0868] Under a nitrogen atmosphere, trifluoroacetic acid (2 mL) was added to a solution of 1-5 (50.0 mg) in dichloromethane (6 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 (NH3)-ACN]; B%: 2%-10%, 10 min) to give 1 (10.0 mg, 29.8% yield) as a white solid. LC-MS m / z (ESI): 409.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.77-10.74(m,1H),8.12-8.07(m,1H),7.78(t,J=8Hz,2H),7.68(t,J=8.8Hz,2H),7.60(d,J=13.6Hz,1H),6.25(s,2H),5.52- 5.26(m,1H),4.52-4.15(m,1H),3.91-3.73(m,2H),3.59-3.50(m,1H),3.30-3.20(m,1H),2.90-2.64(m,1H),2.07-2.05(m,3H).

[0869] 2. Synthesis of Example 2

[0870] 2.1 Synthesis of Intermediate 2-1

[0871] At 0°C under nitrogen, 2-bromobenzenesulfonyl chloride (177.0 mg) was added to a solution of 1-2 (150.0 mg) and triethylamine (93.0 mg) in pyridine (10 mL). The mixture was heated to 25°C and stirred 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 = 5 / 1 to 1 / 5) to obtain 2-1 as a white solid (120.0 mg, 47.0% yield). LC-MS m / z (ESI): 542.1, 544.1 [M+H] + .

[0872] 2.2 Synthesis of intermediate 2-2

[0873] 2-Amino-4-bromobenzenethiol (1.0 g), tetrahydrofuran-4-carboxylic acid (960.0 mg), and phosphorus pentoxide (1.9 g) were added to polyphosphoric acid (6 mL) and stirred at 100°C for 16 hours under nitrogen. Aqueous sodium hydroxide solution 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 a light yellow liquid 2-2 (680.0 mg, 46.0% yield). LC-MS m / z (ESI): 297.9, 299.9 [M+H] + .

[0874] 2.3 Synthesis of intermediate 2-3

[0875] 2-2 (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 dioxane (15 mL). Under nitrogen, the mixture was stirred at 90°C for 16 hours. The mixture was concentrated under reduced pressure to afford 2-3 (400.0 mg), which was used directly in the next reaction. LC-MS m / z (ESI): 346.1 [M+H] + .

[0876] 2.4 Synthesis of Intermediate 2-4

[0877] 2-3 (400.0 mg), 2-1 (250.0 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium·dichloromethane complex (75.0 mg), and sodium carbonate (98.0 mg) were added to a 15 mL mixture of dioxane and water (v:v = 4:1). Under nitrogen, the mixture was stirred at 100°C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Extraction was performed with dichloromethane (150 mL), and the organic phase was washed with saturated sodium chloride (50 mL). The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1-10 / 1) to obtain 2-4 (80.0 mg, 25.4% yield) as a white solid. LC-MS m / z (ESI): 680.2 [M+H] + .

[0878] 2.5 Synthesis of compound 2

[0879] Under ice-cooling, trifluoroacetic acid (3 mL) was added to a solution of 2-4 (80.0 mg) in dichloromethane (3 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.05% NH3); B%: 2%-10%, 20 min) to give 2 as a white solid (2.2 mg, 8.1% yield). LC-MS m / z (ESI): 414.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.39(s,1H),8.02(m,2H),7.98(dd,J=1.2,8.0Hz,1H),7.75(d,J=1.2Hz,1H),7.67-7.58(m,2H),7.36-7.33(m,2H),7.20(dd,J=1.2,8.4Hz,1H ),6.83-6.80(m,1H),5.63(s,1H),3.99-3.94(m,2H),3.54-3.49(m,2H) ,3.47-3.41(m,1H),2.12-2.06(m,2H),1.91(s,3H),1.87-1.83(m,2H).

[0880] 3. Synthesis of Example 3

[0881] 3.1 Synthesis of Intermediate 3-1

[0882] Under ice-cooling, phosphorus oxychloride (45.0 mg) was added to a solution of 3-(4-trifluoromethylphenyl)pyrrolidine hydrochloride (50.0 mg) and 1-4 (80.0 mg) in pyridine (2 mL) and stirred at room temperature for 1 hour. Saturated sodium bicarbonate (1 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 1) to obtain 3-1 (50.0 mg, yield 42.3%) as a white solid. LC-MS m / z (ESI): 593.0 [M+H] + .

[0883] 3.2 Synthesis of compound 3

[0884] Under ice-cooling, trifluoroacetic acid (1 mL) was added to a solution of 3-1 (50.0 mg) in dichloromethane (3 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.05% NH3); B%: 2%-10%, 20 min) to afford 3 as a white solid (8.6 mg, 26.1% yield). LC-MS m / z (ESI): 393.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δppm 10.36(s,1H),8.11(dd,J=5.2,2.4Hz,1H),7.70(dd,J=8.0,4.0Hz,2H),7.58-7.55(m,3H),5.63(d,J=5.2Hz,2H),4.29(d d,J=10.8,7.2Hz,1H),4.05-3.95(m,1H),3.81-3.64(m,2H),3.56-3.48(m,1H),2.40-2.27(m,2H),2.03(d,J=6.8Hz,3H).

[0885] 4. Synthesis of Example 4

[0886] 4.1 Synthesis of Intermediate 4-1

[0887] At 0°C under a nitrogen atmosphere, phosphorus oxychloride (58.0 mg) was added dropwise to a solution of 1-4 (50.0 mg) and 3-(4-(trifluoromethyl)phenyl)azetidine hydrochloride (30.0 mg) in pyridine (2 mL). The mixture was stirred for 1 hour, and water (50 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 4-1 (30.0 mg, yield 60.1%) as a yellow solid. LC-MS m / z (ESI): 579.0 [M+H] + .

[0888] 4.2 Synthesis of compound 4

[0889] Under a nitrogen atmosphere, trifluoroacetic acid (2 mL) was added to a solution of 4-1 (30.0 mg) in dichloromethane (6 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by HPLC (column: Gemini 5u C18 150 x 21.2 mm; mobile phase: [water (NH3)-ACN]; B%: 2%-10%, 6 min) to give 4 (8.0 mg, 40.8% yield) as a white solid. LC-MS m / z (ESI): 379.0 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 8.14(d,J=2.0Hz,1H),7.68(d,J=8.4Hz,2H),7.64(d,J=1.6Hz,1H),7.60(d,J=8.4Hz,2H),5.14-5.07(m,1H), 4.69(dd,J=11.2,6.4Hz,1H),4.63-4.54(m,1H),4.18(dd,J=11.2,6.4Hz,1H),4.13-4.07(m,1H),2.14(s,3H).

[0890] 5. Synthesis of Example 5

[0891] 5.1 Synthesis of Intermediate 5-1

[0892] Ethyl 3,3,3-trifluoropyruvate (780.0 mg) and anhydrous p-toluenesulfonic acid (54.0 mg) were added to a solution of 1-2 (1.0 g) in anhydrous toluene (20 mL). Stir at 100°C under nitrogen for 15 hours. Cool to room temperature and concentrate under reduced pressure to obtain a light yellow solid 5-1 (1.8 g), which was used directly in the next reaction. LC-MS m / z (ESI): 476.0 [M+H] + .

[0893] 5.2 Synthesis of Intermediate 5-2

[0894] Under a nitrogen atmosphere, sodium cyanoborohydride (125.0 mg) was added to a solution of crude product 5-1 (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 × 3). The organic phase was washed with saturated sodium chloride (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 5-2 as a white solid (300.0 mg, yield 20.4%). LC-MS m / z (ESI): 478.3 [M+H] + .

[0895] 5.3 Synthesis of Intermediate 5-3

[0896] Trimethyltin hydroxide (342.0 mg) was added to a solution of 5-2 (300.0 mg) in 1,2-dichloroethane (10 mL). Under nitrogen protection, the mixture was stirred at 50°C for 3 hours. 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 (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid 5-3 (200.0 mg). LC-MS m / z (ESI): 450.0 [M+H] + .

[0897] 5.4 Synthesis of Intermediate 5-4

[0898] 3-(4-Trifluoromethylphenyl)pyrrolidine (30.0 mg) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (80.0 mg) were added to a solution of 5-3 (50.0 mg) in N,N'-dimethylformamide (5 mL). The mixture was stirred at room temperature for 3 hours under nitrogen. Water (5 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride (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 = 2 / 1-1 / 2) to obtain 5-4 as a white solid (40.0 mg, yield 55.9%). LC-MS m / z (ESI): 647.2 [M+H] + .

[0899] 5.5 Synthesis of compound 5

[0900] Under ice-cooling, trifluoroacetic acid (1 mL) was added to a solution of 5-4 (40.0 mg) in dichloromethane (3 mL), and the mixture was 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 obtain the formate salt of 5 as a white solid (7.0 mg, 25.8% yield). LC-MS m / z (ESI): 447.1 [M+H] + . 1H NMR(400MHz,MeOD-d4)δppm 7.57-7.46(m,2H),7.45-7.25(m,3H),7.26-7.14(m,1H),5.03-4.86(m,1H),4.18-3.9 8(m,1H),3.90-3.75(m,1H),3.68-3.40(m,3H),2.38-2.24(m,1H),2.10-1.92(m,4H).

[0901] 6. Synthesis of Example 6

[0902] 6.1 Synthesis of Intermediate 6-1

[0903] At 0°C under a nitrogen atmosphere, trimethylaluminum (0.2 mL, 2 M in hexanes) was added to a solution of 3-(4-(trifluoromethyl)phenyl)azetidine hydrochloride (30.0 mg) in toluene (5 mL). The mixture was stirred for 30 minutes, and 5-2 (50.0 mg) was added. The mixture was stirred at 80°C for 5 hours. Water (5 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride (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 = 2 / 1-1 / 2) to obtain 6-1 (15.0 mg, 22.1% yield) as a white solid. LC-MS m / z (ESI): 655.2 [M+Na] + .

[0904] 6.2 Synthesis of compound 6

[0905] Under ice-cooling, trifluoroacetic acid (0.5 mL) was added to a solution of 6-1 (15.0 mg) in dichloromethane (2 mL), and the mixture was 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 obtain the formate salt of 6 as a white solid (3.0 mg, 28.9% yield). LC-MS m / z (ESI): 433 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δppm 7.56(dd,J=12.4,8.4Hz,2H),7.45-7.28(m,3H),7.10(s,1H),4.72-4.63(m,2H), 4.45-4.35(m,1H),4.25-4.17(m,1H),3.98-3.89(m,2H),2.04(d,J=11.2Hz,3H).

[0906] 7. Synthesis of Example 7

[0907] 7.1 Synthesis of Intermediate 7-1

[0908] 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 (120.0 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 7-1 (160.0 mg, 65.6% yield) as a white solid. LC-MS m / z (ESI): 437.1, 439.1 [M+Na] + .

[0909] 7.2 Synthesis of Intermediate 7-2

[0910] Cuprous iodide (18.1 mg), cesium carbonate (200.0 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 7-1 (100.0 mg) in dioxane (5 mL). Under nitrogen, the mixture was stirred at 110°C for 16 hours, cooled to room temperature, and extracted with water (10 mL). 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 7-2 (34.0 mg, 38.7% yield) as a white solid. LC-MS m / z (ESI): 352.0 [M+1] + .

[0911] 7.3 Synthesis of Intermediate 7-3

[0912] Under ice-cooling, ethyl oxalyl chloride (139.8 mg) was added to a solution of triethylamine (121.2 mg) and 7-2 (240.0 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 7-3 (230.0 mg, yield 74.6%) as a white solid. LCMS m / z (ESI): 451.9 [M+H] + .

[0913] 7.4 Synthesis of Intermediate 7-4

[0914] Lithium hydroxide (38.2 mg) was added to a solution of 7-3 (230.0 mg) in methanol (5 mL) and water (1 mL). The mixture was stirred at room temperature for 1 hour, adjusted to pH 6 with dilute acid, and 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 7-4 as a white solid (170.0 mg, yield 71.9%). LCMS m / z (ESI): 424.2 [M+H] + .

[0915] 7.5 Synthesis of Intermediate 7-5

[0916] 7-4 (50.0 mg) and 3-[4-(trifluoromethylphenyl)]-morpholine (48.0 mg) were added to pyridine (10 mL), and phosphorus oxychloride (0.1 mL) was added dropwise under nitrogen. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 - 1 / 5) to obtain 7-5 as a light yellow oil (15.0 mg, yield 18.75%). LC-MS m / z (ESI): 637.1 [M+H] + .

[0917] 7.6 Synthesis of Compound 7

[0918] Under ice-cooling, trifluoroacetic acid (3 mL) was added to a solution of 7-5 (15.0 mg) in dichloromethane (3 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.05% NH3); B%: 2%-10%, 20 min) to obtain 7 (5.0 mg, 49.0% yield) as a white solid. LC-MS m / z (ESI): 437.1 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.99-7.55(m,1H),7.75-7.69(m,4H),5.62-5.47(m,1H),5.07-4.98(m,3H) ,4.58-4.28(m,2H),4.01-3.88(m,2H),3.73-3.65(m,1H),3.44-3.36(m,1H),3.08-2.98(m,1H).

[0919] 8. Synthesis of Example 8

[0920] 8.1 Synthesis of Intermediate 8-1

[0921] Di-tert-butyl dicarbonate (14.6 g), triethylamine (10.8 g), and 4-dimethylaminopyridine (0.7 g) were added to a solution of 2-amino-3-methyl-5-bromopyridine (5.0 g) in dichloromethane (50 mL). The mixture was stirred at room temperature for 2 hours, diluted with dichloromethane (100 mL), and the organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 8-1 (9.3 g, yield 85.0%) as a white solid. LC-MS m / z (ESI): 387.0 [M+H] + .

[0922] 8.2 Synthesis of Intermediate 8-2

[0923] 8-1 (100.0 mg), sodium tert-butoxide (80.0 mg), and (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl) palladium(II) methanesulfonate (70.0 mg) were added to a solution of methyl 1-aminocyclopropanecarboxylate (50.0 mg) in dioxane (5 mL). Under nitrogen, the mixture was stirred at 100°C for 3 hours. After cooling to room temperature, water (5 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1 to 5 / 1) to obtain 8-2 (50.0 mg, 62.5% yield) as a pale yellow solid. LC-MS m / z(ESI):308.0[M+H] + .

[0924] 8.3 Synthesis of Intermediate 8-3

[0925] Under ice-cooling, 8-2 (50.0 mg), phosphorus oxychloride (50.0 mg), and 3-[4-(trifluoromethylphenyl)]-morpholine (48.0 mg) were added to pyridine (10 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 5) to obtain 8-3 as a light yellow oil (15.0 mg, yield 17.8%). LC-MS m / z (ESI): 521.1 [M+H] + .

[0926] 8.4 Synthesis of Compound 8

[0927] Under ice-cooling, trifluoroacetic acid (3 mL) was added to a solution of 8-3 (15.0 mg) in dichloromethane (3 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: ACN-H2O (0.05% NH3); B%: 2%-10%, 20 min) to obtain a brown solid 8 (1.5 mg, 12.5% ​​yield). LC-MS m / z (ESI): 421.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.52-7.28(m,4H),6.75(s,1H),5.84(s,1H),5.41(s,1H),4. 90(s,2H),4.42-4.20(m,1H),3.77-3.14(m,2H),1.96(s,3H),1.2-1.21(m,2H),0.93-0.81(m,2H).

[0928] 9. Synthesis of Example 9

[0929] 9.1 Synthesis of Intermediate 9-1

[0930] Under ice-cooling, ethyl oxalyl chloride (95.0 mg) was added to a solution of triethylamine (95.0 mg) and 3-(4-(trifluoromethyl)phenyl)pyrrolidine hydrochloride (100.0 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 (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 9-1 (120.0 mg) as a colorless oil. The crude product was used directly in the next reaction. LC-MS m / z (ESI): 316.0 [M+H] + .

[0931] 9.2 Synthesis of Intermediate 9-2

[0932] Lithium hydroxide (18.2 mg) was added to a solution of 9-1 (120.0 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 × 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 9-2 (50.0 mg, 50.4% yield) as a yellow solid. LC-MS m / z (ESI): 288.0 [M+H] + .

[0933] 9.3 Synthesis of Intermediate 9-3

[0934] HATU (132.4 mg) was added to a solution of N,N'-diisopropylethylamine (45.0 mg), 9-2 (50.0 mg), and 7-2 (67.8 mg) in N,N'-dimethylformamide (3 mL). The mixture was stirred at room temperature for 1 hour, then water (6 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 to obtain a brown solid 9-3 (80.0 mg, 74.1% yield). LC-MS m / z (ESI): 621.0 [M+H] + .

[0935] 9.4 Synthesis of Compound 9

[0936] Under ice-cooling, trifluoroacetic acid (3 mL) was added to a solution of 9-3 (80.0 mg) in dichloromethane (3 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge-C18 150×19 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); B%: 5%-10%, 20 min) to afford the formate salt of 9 as a white solid (6.6 mg, 12.2% yield). LC-MS m / z (ESI): 420.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.33-10.33(m,1H),8.21(s,1H),7.83-7.826(m,1H),7.72-7.68(m,2H),7.58-7.55(m,2H) ,5.96-5.95(m,2H),4.89-4.82(m,4H),4.28-4.23(m,1H),4.01-3.96(m,1H),3.64-3.45(m,4H),2.08-1.97(m,1H).

[0937] 10. Synthesis of Example 10

[0938] 10.1 Synthesis of Intermediate 10-1

[0939] Under ice bath, ethyl oxalyl chloride (114.0 mg) was added to a solution of triethylamine (106.0 mg) and 3-(4-(trifluoromethyl)phenyl)azetidine (140.0 mg) in dichloromethane (3 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 to obtain a yellow oil 10-1 (180.0 mg). The crude product was used directly in the next reaction. LC-MS m / z (ESI): 302.0 [M+H] + .

[0940] 10.2 Synthesis of Intermediate 10-2

[0941] Lithium hydroxide (28.6 mg) was added to a solution of 10-1 (180.0 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 × 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 a yellow solid 10-2 (120.0 mg, yield 66.6%). LC-MS m / z (ESI): 274.0 [M+H] + .

[0942] 10.3 Synthesis of Intermediate 10-3

[0943] HATU (83.2 mg) was added to a solution of N,N'-diisopropylethylamine (37.7 mg), 10-2 (40.0 mg), and 7-2 (56.2 mg) in N,N'-dimethylformamide (2 mL). The mixture was stirred at room temperature for 1 hour, then water (6 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 to obtain a brown solid 10-3 (80.0 mg, yield 72.1%). LC-MS m / z (ESI): 607.2 [M+H] + .

[0944] 10.4 Synthesis of Compound 10

[0945] Under ice, a 4M solution of hydrogen chloride in dioxane (2 mL) was added to a solution of 10-3 (70.0 mg) in 1,4-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 obtain the formate salt of 10 as a white solid (5.6 mg, 10.5% yield). LC-MS m / z (ESI): 407.1 [M+H] + . 1H NMR(400MHz,CD3OD)δppm 7.79(s,1H),7.59(d,J=8.0Hz,2H),7.50(d,J=12.0Hz,2H),4.99-4.95(m,1H),4.94-4.92(m,2H) ,4.87-4.85(m,2H),4.58-4.54(m,1H),4.51-4.46(m,1H),4.11-4.06(m,1H),4.03-3.95(m,1H).

[0946] Example 15

[0947] 11.1 Synthesis of Intermediate 15-1

[0948] Di-tert-butyl dicarbonate (1.9 g) and 4-dimethylaminopyridine (530.6 mg) were added to a tetrahydrofuran solution (20 mL) of 6-methylmorpholin-3-one (500.0 mg) and stirred at room temperature under nitrogen for 3 hours. Saturated ammonium chloride solution (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (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. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 15-1 as a white oil (762.0 mg, yield 81.5%). LC-MS m / z (ESI): 238.1 [M+Na] + .

[0949] 11.2 Synthesis of Intermediate 15-2

[0950] Under nitrogen protection, a solution of n-butyllithium in n-hexane (2.2 mL, 1 M) was added dropwise to a solution of para-bromotrifluorotoluene (378.0 mg) in tetrahydrofuran (10 mL) at -78°C. The mixture was stirred at -78°C for 0.5 hours. A solution of 15-1 (300.0 mg) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture. The mixture was stirred at -78°C for 1 hour. Saturated ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture 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. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 15-2 (223.0 mg, 42.1% yield) as a light yellow oil. LC-MS m / z (ESI): 384.1 [M+Na] + .

[0951] 11.3 Synthesis of Intermediate 15-3

[0952] 15-2 (212.0 mg) was added to a mixture of trifluoroacetic acid and dichloromethane (9 mL, v / v = 2:1). The mixture was stirred at room temperature for 2 hours under nitrogen. The reaction mixture was concentrated to give crude product 15-3 (140.0 mg), which was directly used in the next step without purification. LC-MS m / z (ESI): 244.0 [M+H] + .

[0953] 11.4 Synthesis of Intermediate 15-4

[0954] Under nitrogen protection, sodium triacetoxyborohydride (4.9 g) was added to a solution of 15-3 (140.0 mg) in dichloromethane (19.0 mL) at 0°C. The reaction solution was warmed to room temperature and stirred for 10 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain a white solid 15-4 (100.0 mg, yield 63.8%). LC-MS m / z (ESI): 246.1 [M+H] + .

[0955] 11.5 Synthesis of Intermediate 15-5

[0956] At 0°C, ethyl oxalyl chloride (111.4 mg) was added to a solution of triethylamine (74.3 mg) and 15-4 (50.0 mg) in dichloromethane (1.0 mL). The reaction solution was warmed to room temperature and stirred under nitrogen for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 15-5 (45.0 mg, yield 57.5%) as a white oil. LC-MS m / z (ESI): 346.0 [M+H] + .

[0957] 11.6 Synthesis of Intermediate 15-6

[0958] Lithium hydroxide monohydrate (28.0 mg) was added to a mixed solvent of methanol and water (5.3 mL, v / v = 3:1) of 15-5 (40.0 mg). Stir at room temperature for 1 hour under nitrogen protection. Water (10 mL) was added to the reaction solution, and hydrochloric acid (1 M) was added dropwise until the pH of the reaction solution was 5-6. The mixture was extracted with ethyl acetate (10 mL × 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 and lyophilized to obtain a white solid 15-6 (24.0 mg, yield 58.8%). LC-MS m / z (ESI): 360.3 [M+CH3CN+H] + .

[0959] 11.7 Synthesis of Intermediate 15-7

[0960] N-Methylimidazole (33.7 mg) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (69.0 mg) were added to a solution of 15-6 (26.0 mg) and 7-2 (31.7 mg) in N,N-dimethylformamide (3 mL) and 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 thin-layer chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1) to afford 15-7 (30.0 mg, 53.0% yield) as a white solid. LC-MS m / z (ESI): 651.2 [M+H] + .

[0961] 11.8 Synthesis of Compound 15

[0962] 15-7 (31.0 mg) was added to a solution of HCl in dioxane (3 mL, 4.0 M) and stirred at room temperature for 2 hours under nitrogen. The mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (mobile phase: dichloromethane / methanol = 10 / 1) to afford 15 (10.5 mg, 48.6% yield) as a white solid. LC-MS m / z (ESI): 451.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6, 80℃) δ10.23(s,1H),7.83(s,1H),7.73(d,J=8.3Hz,2H),7.66(d,J=8.3Hz,2H),5.72(s,2H),5.34(s,1H),4.85(s,4H),4 .16(dd,J=12.5,4.5Hz,1H),4.11-4.05(m,1H),4.03(dd,J=12.5,4.2Hz,1H),3.59-3.65(m,2H),1.27(d,J=6.5Hz,3H).

[0963] Example 16

[0964] 12.1 Synthesis of Intermediate 16-1

[0965] A solution of potassium carbonate (110.4 g) in water (40 mL) was added to a solution of 2-aminopropan-1-ol (20.0 g) in tetrahydrofuran (100 mL). Chloroacetyl chloride (33.1 g) was added dropwise to the solution under nitrogen at 0°C, and the mixture was stirred at 0°C for 2 hours under nitrogen. The reaction mixture was warmed to room temperature, and water (300 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford crude product 16-1 (40.0 g, 94.1% yield) as a pale yellow oil. The product was directly used in the next step without purification. LC-MS m / z (ESI): 152.1 [M+H] + .

[0966] 12.2 Synthesis of Intermediate 16-2

[0967] At 0°C, a solution of potassium tert-butoxide (59.2 g) in isopropanol (200 mL) was added dropwise to a solution of 16-1 (20.0 g) in dichloromethane (200 mL). The mixture was stirred at room temperature for 2 hours under nitrogen. Water (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford crude product 16-2 (10.1 g, 65.8% yield) as a pale yellow oil. LC-MS m / z (ESI): 116.2 [M+H] + .

[0968] 12.3 Synthesis of Intermediate 16-3

[0969] Triethylamine (21.9 g), di-tert-butyl dicarbonate (28.4 g), and 4-dimethylaminopyridine (530.0 mg) were added to a tetrahydrofuran solution (100 mL) of the crude product 16-2 (5.0 g). The mixture was stirred at room temperature for 3 hours under nitrogen. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain the yellow oily product 16-3 (7.1 g, yield 75.4%). LC-MS m / z (ESI): 238.1 [M+Na] + .

[0970] 12.4 Synthesis of Intermediate 16-4

[0971] Under nitrogen, p-bromobenzotrifluoride (100.0 mg) was added dropwise to a suspension of magnesium (106.7 mg) and iodine (11.0 mg) in tetrahydrofuran (10 mL). The mixture was stirred at 80°C until the solution became transparent. The remaining p-bromobenzotrifluoride (900.0 mg) was then added dropwise to the solution at room temperature and stirred at 40°C for 2 hours. Under nitrogen at -15°C, the solution was added dropwise to a solution of 16-3 (956.6 mg) in tetrahydrofuran (10 mL) and stirred at -15°C for 1 hour. The reaction mixture was warmed to room temperature, and saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to afford 16-4 (410.0 mg, 20.4% yield) as a white solid. LC-MS m / z(ESI):384.1[M+H] + .

[0972] 12.6 Synthesis of Intermediate 16-5

[0973] 16-4 (400.0 mg) was added to a mixture of trifluoroacetic acid and dichloromethane (3 mL, v / v = 2:1). The mixture was stirred at room temperature for 2 hours under nitrogen. The reaction solution was concentrated to obtain crude product 16-5 (280.0 mg), which was directly used for the next step without purification. LC-MS m / z (ESI): 244.1 [M+H] + .

[0974] 12.6 Synthesis of Intermediate 16-6

[0975] Sodium triacetylborohydride (31.1 mg) was added to a solution of crude product 16-5 (280.0 mg) in dichloromethane (10 mL) at 0°C and stirred at room temperature under nitrogen for 14 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 16-6 (180.0 mg, yield 63.8%) as a white solid. LC-MS m / z (ESI): 246.2 [M+H] + .

[0976] 12.7 Synthesis of Intermediate 16-7

[0977] Under ice-cooling, ethyl oxalyl chloride (125.3 mg) was added to a solution of triethylamine (123.8 mg) and 16-6 (150.0 mg) in dichloromethane (5 mL). The mixture was stirred at room temperature under nitrogen for 1 hour. The organic phase was washed with saturated sodium chloride solution (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 16-7 (149.0 mg, yield 70.6%) as a colorless oil. LC-MS m / z (ESI): 346.1 [M+H] + .

[0978] 12.8 Synthesis of Intermediate 16-8

[0979] Lithium hydroxide (24.6 mg) was added to a mixture of 16-7 (71.0 mg) in methanol and water (4 mL, v / v = 1:1). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure until one-third of the solution remained. Dichloromethane (3 mL) was added for extraction. The aqueous phase was adjusted to a pH of 5-6 with hydrochloric acid (1 M). The mixture was purified on a C18 column (eluent: 0.1% FA / 50% acetonitrile) to afford 16-8 (45.0 mg, 81.6% yield) as a white solid. LC-MS m / z (ESI): 318.1 [M+H] + .

[0980] 12.9 Synthesis of Intermediate 16-9

[0981] N-Methylimidazole (41.4 mg) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (84.9 mg) were added to a solution of 16-8 (32.0 mg) and 7-2 (39.0 mg) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 2 hours under nitrogen. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1) to obtain 16-9 (40.0 mg, 60.8% yield) as a white solid. LC-MS m / z (ESI): 651.3 [M+H] + .

[0982] 12.10 Synthesis of Compound 16

[0983] Under nitrogen, 16-9 (35.0 mg) was added to a solution of HCl in dioxane (5 mL, 4.0 M). The mixture was stirred at room temperature for 2 hours under nitrogen. The mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (mobile phase: dichloromethane / methanol = 10 / 1) to afford 16 (17.4 mg, 72.0% yield) as a white solid. LC-MS m / z (ESI): 451.1 [M+H]+ . 1 H NMR (400MHz, DMSO-d6, 80℃) δ10.29(s,1H),7.89(s,1H),7.78(d,J=8.2Hz,2H),7.72(d,J=8.2Hz,2H),5.73(s,2H),4.8 9-4.86(m,4H),4.69(d,J=12.6Hz,1H),3.82(dd,J=12.6,3.8Hz,1H),3.74(s,2H),1.26(s,2H),0.91(d,J=7.0Hz,3H).

[0984] Example 17

[0985] 13.1 Synthesis of Intermediate 17-1

[0986] Tributyl(1-ethoxyethylene)tin (13.2 g) was added to a mixture of 3-bromo-2-chloro-4-methylpyridine (5.0 g), potassium carbonate (6.7 g), and bistriphenylphosphine palladium dichloride (850.0 mg) in tetrahydrofuran and water (50 mL, v / v = 3:1). The mixture was stirred at 90°C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, and saturated potassium fluoride solution (100 mL) and ethyl acetate (100 mL) were added. The mixture was filtered, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL). Hydrochloric acid (10 mL, 6 M) was added to the solution, and the mixture was stirred at room temperature for 16 hours under nitrogen. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1-20 / 1) to obtain a yellow liquid 17-1 (2.2 g, yield 53.7%). LC-MS m / z (ESI): 170.1 [M+H] + .

[0987] 13.2 Synthesis of Intermediate 17-2

[0988] Sodium borohydride (980.0 mg) was added to a solution of 17-1 (2.2 mg) in methanol (20 mL). The mixture was stirred at 25°C for 1 hour under nitrogen. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 10 / 1-5 / 1) to obtain a colorless liquid 17-2 (2.0 g, yield 80.8%). LC-MS m / z (ESI): 172.1 [M+H] + .

[0989] 13.3 Synthesis of Intermediate 17-3

[0990] Tert-butyldiphenylsilyl chloride (3.9 g) was added to a dichloromethane (20 mL) solution of 17-2 (2.0 g) and imidazole (1.2 g). The mixture was stirred at 25°C for 16 hours under nitrogen. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1-5 / 1) to obtain a colorless oil 17-3 (4.5 g, yield 93.2%). LC-MS m / z (ESI): 410.1 [M+H] + .

[0991] 13.4 Synthesis of Intermediate 17-4

[0992] N-Bromosuccinimide (2.4 g) was added to a solution of 17-3 (5.0 g) and azobisisobutyronitrile (0.1 g) in carbon tetrachloride (50 mL). The mixture was stirred at 90°C for 2 hours under nitrogen. The reaction solution was cooled to room temperature, and water (100 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1-10 / 1) to obtain 17-4 as a colorless oil (4.5 g, yield 59.8%). LC-MS m / z (ESI): 488.0 [M+H] + ,490.1[M+H] + .

[0993] 13.5 Synthesis of Intermediate 17-5

[0994] A solution of tetrabutylammonium fluoride (18.4 mL, 1 M) in tetrahydrofuran was added to a solution of 17-4 (4.5 g) in tetrahydrofuran (50 mL). The mixture was stirred at 25°C for 1 hour under nitrogen. Water (100 mL) was added to the reaction solution, which was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1-5 / 1) to obtain 17-5 (600.0 mg, yield 38.0%) as a colorless oil. LC-MS m / z (ESI): 170.1 [M+H] + .

[0995] 13.6 Synthesis of Intermediate 17-6

[0996] 1,1'-Binaphthyl-2,2'-bisdiphenylphosphine (418.5 mg), tris(dibenzylideneacetone)dipalladium (193.2 mg), and sodium tert-butoxide (645.9 mg) were added to a toluene (1 mL) solution of 17-5 (570.0 mg) and 2,4-dimethoxybenzylamine (842.9 mg). The mixture was stirred at 100°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to obtain 17-6 (410 mg, 40.6% yield) as a white solid. LC-MS m / z(ESI):301.2[M+H] + .

[0997] 13.7 Synthesis of Intermediate 17-7

[0998] 17-6 (410 mg) was added to a trifluoroacetic acid solution (3 mL). The mixture was stirred at 25°C for 1 hour under nitrogen protection. Saturated sodium bicarbonate solution (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 10) to obtain a white solid 17-7 (150.0 mg, yield 73.2%). LC-MS m / z (ESI): 151.1 [M+H] + .

[0999] 13.8 Synthesis of Intermediate 17-8

[1000] N-Bromosuccinimide (213.3 mg) was added to a solution of 17-7 (150.0 mg) in acetonitrile (5 mL). The mixture was stirred at 25°C for 2 hours under nitrogen. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 1) to obtain 17-8 (130.0 mg, yield 56.8%) as a white solid. LC-MS m / z (ESI): 229.1 [M+H] + ,231.1[M+H] + .

[1001] 13.9 Synthesis of Intermediate 17-9

[1002] Di-tert-butyl dicarbonate (309.6 mg) was added to a solution of 17-8 (130.0 mg), 4-dimethylaminopyridine (6.9 mg), and triethylamine (172.3 mg) in dichloromethane (5 mL). Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1-5 / 1) to afford 17-9 (150.0 mg, 61.3% yield) as a white solid. LC-MS m / z (ESI): 451.1 [M+Na] + ,453.1[M+Na] + .

[1003] 13.10 Synthesis of Intermediate 17-10

[1004] Tris(dibenzylideneacetone)dipalladium (66.2 mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (67.5 mg), and cesium carbonate (176.5 mg) were added to a solution of benzophenone imine (98.2 mg) and 17-9 (150.0 mg) in dioxane (5 mL). The mixture was stirred at 100°C under nitrogen for 8 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain 17-10 (60.0 mg, 32.2% yield) as a white solid. LC-MS m / z (ESI): 530.3 [M+H] + .

[1005] 13.11 Synthesis of Intermediate 17-11

[1006] At 0°C, a solution of HCl in dioxane (0.6 mL, 4 M) was added to a solution of 17-10 (60.0 mg) in tetrahydrofuran (5 mL). The mixture was stirred at 0°C for 1 hour under nitrogen. Saturated sodium carbonate solution (20 mL) and water were added to the reaction solution, which was then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 2) to obtain 17-11 (25.0 mg, yield 60.4%). LC-MS m / z (ESI): 366.2 [M+H] + .

[1007] 13.12 Synthesis of Intermediate 17-12

[1008] N,N,N',N'-Tetramethylchloroformamidine hexafluorophosphate (69.1 mg) was added to a solution of 16-8 (30.0 mg), 17-11 (39.1 mg), and N-methylimidazole (33.7 mg) in N,N-dimethylformamide (1 mL). The mixture was stirred at 25°C for 1 hour under nitrogen. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 5) to obtain 17-12 (30.0 mg, yield 66.1%) as a white solid. LC-MS m / z (ESI): 665.3 [M+H] + .

[1009] 13.13 Synthesis of Compound 17

[1010] A solution of HCl in dioxane (0.6 mL, 4 M) was added to a solution of 17-12 (30.0 mg) in dichloromethane (2 mL). The mixture was stirred at 25°C for 1 hour under nitrogen. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100 / 1-10 / 1) to afford 17 (13.2 mg, 63.1% yield) as a white solid. LC-MS m / z (ESI): 465.2 [M+H] + . 1H NMR (400MHz, DMSO-d6, 80℃) δ10.25(s,1H),7.88(s,1H),7.77(d,J=8.4Hz,2H),7.70(d,J=8.4Hz,2H),5.63(s,2H),5.43(s,1H),5.25(s,1H),4.8 7-4.93(m,1H),4.75-4.80(m,1H),4.65-4.69(m,1H),4.10(s,1H),3.85 -3.77(m,1H),3.72(s,2H),1.36(d,J=6.2Hz,3H),0.90(d,J=7.0Hz,3H).

[1011] Example 24

[1012] 14.1 Synthesis of Intermediate 24-1

[1013] A 20 mL solution of potassium carbonate (27.6 g) was added to a mixture of (R)-(-)-1-amino-2-propanol (5.0 g) in tetrahydrofuran and water (40 mL, v / v = 1:1). Chloroacetyl chloride (8.3 g) was added dropwise to the solution under nitrogen at 0°C. The mixture was stirred at 0°C for 1.5 hours under nitrogen. The reaction mixture was warmed to room temperature and filtered. The filtrate was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 24-1 as a light yellow oil (8.2 g, 81.7% yield). LC-MS m / z (ESI): 152.2 [M+H] + .

[1014] 14.2 Synthesis of Intermediate 24-2

[1015] Under nitrogen at 0°C, a solution of potassium tert-butoxide (24.4 g) in isopropanol (80 mL) was added dropwise to a solution of 24-1 (8.2 g) in dichloromethane (80 mL). The mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a yellow oil. Tetrahydrofuran (40 mL) was added and the turbid liquid was filtered. The filter cake was washed with dichloromethane (80 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a light yellow oil 24-2 (3.2 g, 51.1% yield). LC-MS m / z (ESI): 231.1 [M+H] + .

[1016] 14.3 Synthesis of Intermediate 24-3

[1017] Triethylamine (14.1 g), di-tert-butyl dicarbonate (18.2 g), and 4-dimethylaminopyridine (340.0 mg) were added to a tetrahydrofuran solution (100 mL) of 24-2 (3.2 g). The mixture was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain the yellow oily product 24-3 (4.0 g, yield 67.3%). LC-MS m / z (ESI): 453.2 [2M+Na] + .

[1018] 14.4 Synthesis of Intermediate 24-4

[1019] Under nitrogen, p-bromobenzotrifluoride (1.0 g) was added dropwise to a suspension of magnesium (400.0 mg) and iodine (20.0 mg) in tetrahydrofuran (10 mL). The mixture was stirred at 80°C until the solution became transparent. The remaining p-bromobenzotrifluoride (2.1 g) was then added dropwise to the solution at room temperature and stirred at 50°C for 2 hours. Under nitrogen at -15°C, the reaction solution was added to a solution of 24-3 (2.0 g) in tetrahydrofuran (10 mL) and stirred at -15°C for 1 hour. After the reaction solution was warmed to room temperature, saturated ammonium chloride solution (10 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to afford the white solid product 24-4 (2.5 g, 70.9% yield). LC-MS m / z(ESI):384.2[M+H] + .

[1020] 14.5 Synthesis of Intermediate 24-5

[1021] Under nitrogen, 24-4 (700.0 mg) was dissolved in a mixture of trifluoroacetic acid and dichloromethane (9 mL, v / v = 2:1) and stirred at room temperature for 1 hour. The reaction solution was concentrated to give a brown crude product 24-5 (500.0 mg), which was directly used in the next reaction without purification. LC-MS m / z (ESI): 244.1 [M+H] + .

[1022] 14.6 Synthesis of Intermediate 24-6

[1023] Under nitrogen at 0°C, sodium triacetylborohydride (8.7 g) was added to a solution of crude product 24-5 (500.0 mg) in dichloromethane (20 mL) and stirred at room temperature for 1 hour. Water (5 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain the white solid product 24-6 (450.0 mg, yield 89.3%). LC-MS m / z (ESI): 246.1 [M+H] + .

[1024] 14.7 Synthesis of Intermediate 24-7

[1025] Under ice-cooling, ethyl oxalyl chloride (125.3 mg) was added to a solution of triethylamine (123.8 mg) and 24-6 (150 mg) in dichloromethane (5 mL). The mixture was stirred at room temperature for 1 hour. The organic phase was washed with water (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 24-7 (186.0 mg, 88.1% yield) as a colorless oil. LC-MS m / z (ESI): 346.1 [M+H] + .

[1026] 14.8 Synthesis of Intermediate 24-8

[1027] Lithium hydroxide (64.5 mg) was added to a mixture of 24-7 (186.0 mg) in methanol and water (4 mL, v / v = 3:1). The mixture was stirred at room temperature for 2 hours, and the solution was concentrated under reduced pressure to approximately one-quarter of the remaining solution. Dichloromethane (3 mL) was added, and the aqueous phase was adjusted to a pH of 6-7 with hydrochloric acid (1 M). The mixture was purified on a C18 column (eluent: 0.1% FA / 50% acetonitrile) and lyophilized to obtain 24-8 as a white solid (150.0 mg, yield 87.8%). LC-MS m / z (ESI): 318.1 [M+H] + .

[1028] 14.9 Synthesis of Intermediate 24-9

[1029] 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 then added dropwise to the reaction solution. The mixture was warmed to room temperature and stirred for 2 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain compound 24-9 (1.9 g, yield 61.9%) as a white solid. LC-MS m / z (ESI): 245.9, 247.8 [M+H]. + .

[1030] 14.10 Synthesis of Intermediate 24-10

[1031] Under a nitrogen atmosphere, sodium carbonate (1.6 g) and p-anisidine (1.6 g) were added to a solution of 24-9 (1.9 g) in N-methylpyrrolidone (20 mL). The mixture was stirred at 130°C for 2 hours, and water (60 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 24-10 (1.6 g, yield 60.4%) as a white solid. LC-MS m / z (ESI): 346.9, 348.9 [M+H] + .

[1032] 14.11 Synthesis of Intermediate 24-11

[1033] Under a nitrogen atmosphere, 24-10 (1.62 g) was added to trifluoroacetic acid (20 mL) and stirred at 60°C for 16 hours. Saturated sodium bicarbonate solution (60 mL) was added and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 24-11 as a white solid (800.0 mg, yield 76.9%). LC-MS m / z (ESI): 227.0, 229.1 [M+H] + .

[1034] 14.12 Synthesis of Intermediate 24-12

[1035] 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 24-11 (800.0 mg). The mixture was stirred at room temperature for 2 hours, and 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 = 3 / 1) to obtain 24-12 as a white solid (900.0 mg, yield 59.6%). LC-MS m / z (ESI): 449.0, 451.0 [M+H] + .

[1036] 14.13 Synthesis of Intermediate 24-13

[1037] 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 24-12 (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 afford 24-13 (120.0 mg, 56.3% yield) as a yellow solid. LC-MS m / z (ESI): 364.2 [M+H] + .

[1038] 14.14 Synthesis of Intermediate 24-14

[1039] N-Methylimidazole (56.2 mg) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (115.2 mg) were added to a solution of 24-8 (56.4 mg) and 24-13 (50.0 mg) in N,N-dimethylformamide (3 mL). The mixture was stirred at room temperature for 2 hours. The organic phase was washed sequentially with water (3 mL), saturated sodium bicarbonate (3 mL), and saturated sodium chloride solution (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (mobile phase: dichloromethane / methanol = 10 / 1) to afford 24-14 (20.0 mg, 22.0% yield) as a white solid. LC-MS m / z (ESI): 651.3 [M+H] + .

[1040] 14.15 Synthesis of Compound 24

[1041] Under nitrogen, a solution of 24-14 (20.0 mg) in HCl in dioxane (5 mL, 4 M) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (mobile phase: dichloromethane / methanol / aqueous ammonia = 10 / 1 / 1%) to afford 24 (7.8 mg, 56.2% yield) as a white solid. LC-MS m / z (ESI): 463.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6, 80℃) δ10.45(s,1H),7.85(s,1H),7.81-7.52(m,5H),5.98(s,2H),5.39-5.31(m,1H),4. 25(s,3H),4.19-4.14(m,1H),4.10-3.99(m,2H),3.78-3.66(m,1H),3.63-3.46(m,1H),1.28(d,J=6.8Hz,3H).

[1042] Example 27

[1043] 15.1 Synthesis of Intermediate 27-1

[1044] A solution of potassium carbonate (27.6 g) in water (20 mL) was added to a solution of D-aminopropanol (5.0 g) in tetrahydrofuran (40 mL). Chloroacetyl chloride (8.3 g) was added dropwise to the solution and stirred at 0°C under nitrogen for 1 hour. The reaction mixture was warmed to room temperature and filtered. The filtrate was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford product 27-1 (8.1 g, 80.2% yield) as a pale yellow oil. LC-MS m / z (ESI): 152.1 [M+H] + .

[1045] 15.2 Synthesis of Intermediate 27-2

[1046] Under nitrogen at 0°C, a solution of potassium tert-butoxide (23.9 g) in isopropanol (80 mL) was added dropwise to a solution of 27-1 (8.1 g) in dichloromethane (80 mL) and stirred at room temperature for 1 hour. Water (200 mL) was added to the reaction solution, which was then extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 27-2 as a light yellow oil (4.7 g, 76.4% yield). LC-MS m / z (ESI): 116.2 [M+H] + .

[1047] 15.3 Synthesis of Intermediate 27-3

[1048] Triethylamine (20.6 g), di-tert-butyl dicarbonate (26.7 g), and 4-dimethylaminopyridine (500.0 mg) were added to a tetrahydrofuran solution (100 mL) of 27-2 (4.7 g). The mixture was stirred at room temperature for 1 hour under nitrogen. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain the yellow oily product 27-3 (5.4 g, yield 61.5%). LC-MS m / z (ESI): 453.2 [2M+Na] + .

[1049] 15.4 Synthesis of Intermediate 27-4

[1050] Under nitrogen, magnesium sticks (0.74 g) and iodine (40 mg) were added to a solution of para-bromobenzotrifluoride (2.0 g) in tetrahydrofuran (10 mL) and stirred at 25°C for 0.5 hours. The remaining para-bromobenzotrifluoride (4.3 g) was added to the reaction mixture. Stirred at 40°C for 1 hour under nitrogen. The reaction mixture was cooled to room temperature and added to a solution of 27-3 (3.0 g) in tetrahydrofuran (10 mL) at 0°C. Stirred at 25°C for 1 hour under nitrogen. Saturated ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture 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. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain a colorless liquid 27-4 (900.0 mg, yield 18.0%). LC-MS m / z(ESI):384.1[M+Na] + .

[1051] 15.5 Synthesis of Intermediate 27-5

[1052] 27-4 (450.0 mg) was added to a mixture of trifluoroacetic acid and dichloromethane (9 mL, v / v = 2:1). The mixture was stirred at room temperature under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid crude product 27-5 (300.0 mg). The reaction solution was directly used in the next reaction without purification. LC-MS m / z (ESI): 244.1 [M+H] + .

[1053] 15.6 Synthesis of Intermediate 27-6

[1054] Under nitrogen protection, sodium triacetoxyborohydride (10.5 g) was added to a dichloromethane solution (15 mL) of 27-5 (300.0 mg) at 0°C. The mixture was stirred at room temperature for 10 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain a white solid 27-6 (183.0 mg, yield 60.5%). LC-MS m / z (ESI): 246.2 [M+H] + .

[1055] 15.7 Synthesis of Intermediate 27-7

[1056] At 0°C, ethyl oxalyl chloride (222.7 mg) was added to a solution of triethylamine (148.6 mg) and 27-6 (100.0 mg) in dichloromethane (2 mL). The mixture was stirred at room temperature for 1 hour under nitrogen. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 27-7 (116.0 mg, yield 82.4%) as a white oil. LC-MS m / z (ESI): 346.2 [M+H] + .

[1057] 15.8 Synthesis of Intermediate 27-8

[1058] Lithium hydroxide monohydrate (48.6 mg) was added to a mixture of 27-7 (80.0 mg) in methanol and water (4 mL, v / v = 3:1). Stirring was performed at room temperature under nitrogen for 1 hour. The solution was then concentrated under reduced pressure until one-third of the solution remained. The pH was adjusted to 5-6 with hydrochloric acid (1 M). The solution was purified on a C18 column (eluent: 0.1% FA / 50% acetonitrile) and lyophilized to obtain the formate salt of 27-8 as a white solid (12.0 mg, 16.3% yield). LC-MS m / z (ESI): 318.0 [M+H] + .

[1059] 15.9 Synthesis of Intermediate 27-9

[1060] N-Methylimidazole (15.5 mg) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (31.8 mg) were added to a solution of 27-8 (12.0 mg) and 24-13 (18.0 mg) in N,N-dimethylformamide (3 mL) and 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 thin-layer chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1) to afford 27-9 (19.0 mg, 75.7% yield) as a white solid. LC-MS m / z (ESI): 663.2 [M+H] + .

[1061] 15.10 Synthesis of Compound 27

[1062] 27-9 (19.0 mg) was added to a solution of HCl in dioxane (3 mL, 4.0 M) and stirred at room temperature for 2 hours under nitrogen. The mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (mobile phase: dichloromethane / methanol = 10 / 1) to afford 27 (4.0 mg, 30.4% yield) as a white solid. LC-MS m / z (ESI): 463.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6, 80℃) δ10.55(s,1H),7.91(s,1H),7.80-7.82(m,3H),7.71-7.73(m,2H),6.01 (s,2H),5.49(s,1H),4.71(d,J=12.6Hz,1H),4.28(s,3H),3.92-3.67(m,4H),0.94(d,J=6.9Hz,3H).

[1063] The following compounds were synthesized using the same synthesis strategy as in Examples 3, 5, 6, 8, 15, 16, 17, 24, and 27:

[1064] 16. Synthesis of Example 49

[1065] 16.1 Synthesis of Intermediate 49-1

[1066] Under nitrogen at -15°C, a solution of diphenyl chlorophosphate (686.4 mg) in tetrahydrofuran (3 mL) was added dropwise to a mixture of 27-3 (500.0 mg) in tetrahydrofuran and toluene (9 mL, v / v = 2 / 1). Then, under nitrogen at -15°C, a solution of lithium bistrimethylsilylamide in tetrahydrofuran (2.8 mL, 1.0 M) was added dropwise to the above solution. After stirring at -15°C for 2 hours, the reaction solution was warmed to room temperature, and saturated ammonium chloride solution (5 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain the product 49-1 as a light yellow oil (830.0 mg, yield 79.9%). LC-MS m / z (ESI): 470.1 [M+Na] + .

[1067] 16.2 Synthesis of Intermediate 49-2

[1068] Tetrakis(triphenylphosphine)palladium (103.1 mg) and potassium hydroxide (125.1 mg) were added to a mixture of 4-(sulfur pentafluoride)phenylboronic acid pinacol ester (353.4 mg) and 49-1 (400.0 mg) in dioxane and water (11 mL, v / v = 10:1). The mixture was stirred at 70°C for 3 hours under nitrogen. The reaction solution was cooled to room temperature, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1-5 / 1) to obtain 49-2 (310.0 mg, 82.1% yield) as a white solid. LC-MS m / z (ESI): 346.0 [M-55]. + .

[1069] 16.3 Synthesis of Intermediate 49-3

[1070] Trifluoroacetic acid (1 mL) was added to a dichloromethane solution (1 mL) of 49-2 (380.0 mg). The mixture was stirred at 25°C for 1 hour under nitrogen protection. Sodium triacetoxyborohydride (2.0 g) was added to the above solution. The mixture was stirred at 0°C for 1 hour under nitrogen protection. The reaction solution was added dropwise to a saturated sodium bicarbonate solution and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude yellow solid 49-3 (300.0 mg). The product was used directly in the next reaction without purification. LC-MS m / z (ESI): 304.0 [M+H] + .

[1071] 16.4 Synthesis of Intermediate 49-4

[1072] Under ice bath, ethyl oxalyl chloride (256.6 mg) was added to a dichloromethane solution (5 mL) of triethylamine (380.3 mg) and crude product 49-3 (380.0 mg). Stir at 0°C for 1 hour under nitrogen protection. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, 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 crude product 49-4 (300.0 mg) as a yellow solid. The product was used directly in the next reaction without purification. LC-MS m / z (ESI): 404.1 [M+H] + .

[1073] 16.5 Synthesis of Intermediate 49-5

[1074] Lithium hydroxide monohydrate (312.1 mg) was added to a mixture of methanol and water (4.5 mL, v / v = 2:1) containing 49-4 (300.0 mg). After stirring at room temperature for 0.5 h, the reaction solution was concentrated under reduced pressure until approximately one-third of the solution remained. The reaction mixture was washed with dichloromethane (3 mL). The aqueous phase was adjusted to a pH of 5-6 with hydrochloric acid (1 M). The reaction mixture was then purified on a C18 column (eluent: water (0.1% formic acid) / methanol = 100 / 1 to 1 / 1) to afford the formate salt of 49-5 as a white solid (100.0 mg, 34.0% yield). LC-MS m / z (ESI): 376.0 [M+H] + .

[1075] 16.6 Synthesis of Intermediate 49-6

[1076] N-Methylimidazole (26.3 mg) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (44.9 mg) were added to a solution of 49-5 (40.0 mg) and 24-13 (39.0 mg) in N,N-dimethylformamide (0.5 mL). The mixture was stirred at 25°C under nitrogen for 0.5 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain 49-6 (40.0 mg, 49.3% yield) as a white solid. LC-MS m / z (ESI): 721.2 [M+H] + .

[1077] 16.7 Synthesis of Compound 49

[1078] 49-6 (40.0 mg) was added to a solution of HCl in dioxane (5 mL, 4 M). The mixture was stirred at 25°C under nitrogen for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (eluent: dichloromethane / methanol = 10 / 1) to afford 49 (24.8 mg, 82.3% yield) as a yellow solid. LC-MS m / z (ESI): 521.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6, 80℃) δ10.54(s,1H),7.94-7.85(m,3H),7.78-7.81(m,3H),6.08(s,2H),5.46(s,1H),4.6 8(d,J=12.8Hz,1H),4.27(s,3H),3.84(d,J=12.0Hz,1H),3.79-3.70(m,2H),3.16(s,1H),0.94(d,J=6.8Hz,1H).

[1079] 17. Synthesis of Example 58

[1080] 17.1 Synthesis of Intermediate 58-1

[1081] Under nitrogen, 1,4-dibromobenzene (1.1 g) was added dropwise to a suspension of magnesium (210.0 mg) and iodine (20.0 mg) in tetrahydrofuran (10 mL). The solution was stirred until transparent, and the remaining para-bromotrifluorobenzoate (3.0 g) was added dropwise to the solution. The mixture was stirred at 60°C under nitrogen for 2 hours. Under nitrogen at -15°C, the solution was added dropwise to a solution of 27-3 (1.7 g) in tetrahydrofuran (15 mL) and stirred at -15°C for 0.5 hours. The reaction mixture was warmed to room temperature and quenched by the addition of saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to afford 58-1 (820.0 mg, 27.9% yield) as a white solid. LC-MS m / z(ESI):394.0, 396.0[M+Na] + .

[1082] 17.2 Synthesis of Intermediate 58-2

[1083] 58-1 (720.0 mg) was added to a mixed solution of trifluoroacetic acid and dichloromethane (10 mL, v / v = 2:1). The mixture was stirred at room temperature for 1 hour under nitrogen protection. Sodium triacetylborohydride (8.2 g) was added to the above solution under ice bath and stirred at room temperature for 12 hours under nitrogen protection. The reaction solution was added dropwise to a saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain the white solid product 58-2 (220.0 mg, yield 44.4%). LC-MS m / z (ESI): 256.0, 258.0 [M+H] + .

[1084] 17.3 Synthesis of Intermediate 58-3

[1085] Under ice-cooling, ethyl oxalyl chloride (234.5 mg) was added to a dichloromethane solution (10 mL) of triethylamine (260.7 mg) and 58-2 (220.0 mg). The mixture was stirred at room temperature under nitrogen for 1 hour. The organic phase was washed with saturated sodium chloride solution (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 58-3 as a colorless oil (300.0 mg, 98.1% yield). LC-MS m / z (ESI): 356.1, 358.1 [M+H] + .

[1086] 17.4 Synthesis of Intermediate 58-4

[1087] Lithium hydroxide (16.8 mg) was added to a mixture of 58-3 (50.0 mg) in methanol and water (4 mL, v / v = 3:1). The mixture was stirred at room temperature for 0.5 h. The mixture was purified by C18 column (eluent: 0.1% FA / 50% acetonitrile) and lyophilized to obtain the formate salt of 58-4 as a white solid (40.0 mg, 86.8% yield). LC-MS m / z (ESI): 328.0, 330.0 [M+H] + .

[1088] 17.5 Synthesis of Intermediate 58-5

[1089] N-Methylimidazole (33.7 mg) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (69.1 mg) were added to a solution of 58-4 (35.1 mg) and compound 24-13 (30.0 mg) in N,N-dimethylformamide (3 mL). The mixture was stirred at room temperature for 1 hour, and the reaction solution was added dropwise to ice water. A solid precipitated and was filtered under reduced pressure to obtain a yellow filter cake of product 58-5 (50.0 mg, 90.1% yield). LC-MS m / z (ESI): 673.2, 675.2 [M+H]+ .

[1090] 17.6 Synthesis of Intermediate 58-6

[1091] 58-5 (50.0 mg) and sodium methanesulfinate (11.3 mg) were added to a dimethyl sulfoxide solution (1 mL) of (2S,4R)-N-(2,6-dimethylphenyl)-4-hydroxypyrrolidine-2-carboxamide (4.3 mg), cuprous iodide (3.5 mg), and potassium phosphate (78.5 mg). The mixture was stirred at 100°C under nitrogen for 8 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: dichloromethane / methanol = 100 / 1-10 / 1) to obtain 58-6 (30.0 mg, 57.0% yield) as a yellow solid. LC-MS m / z (ESI): 673.2 [M+H] + .

[1092] 17.7 Synthesis of Compound 58

[1093] 58-6 (30.0 mg) was added to a solution of HCl in dioxane (1 mL, 4 M). The mixture was stirred at 25°C for 1 hour under nitrogen. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (eluent: dichloromethane / methanol = 10 / 1) to afford 58 (11.6 mg, 53.0% yield) as a white solid. LC-MS m / z (ESI): 473.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6, 80℃) δ10.55(s,1H),7.93-7.90(m,3H),7.86-7.76(m,3H),6.05(s,2H),5.48(s,1H),4.70(d, J=12.8Hz,1H),4.27(s,3H),4.14(s,1H),3.86-3.82(m,1H),3.80-3.69(m,2H),3.17(s,3H),0.94(d,J=6.8Hz,3H).

[1094] The following compounds were synthesized using the same synthesis strategy as in Examples 3, 5, 6, 8, 15, 16, 17, 24, 27, 49, and 58:

[1095] Experimental Example 1: Determination of PRMT5:MEP50 enzyme inhibitory activity of the compounds of the present invention using radioisotope Flash Plate technology in the presence of MTA

[1096] 1.1 Reagents and consumables

[1097] Table 1

[1098] 1.2 Instruments

[1099] Centrifuge (manufacturer: Kubota, model: 2420).

[1100] Scintillation counter (manufacturer: Perkin Elmer, model: MicroBeta2).

[1101] 1.3 Reaction process

[1102] (1) Prepare 1×Assay buffer (50mM Tris 8.0 (Sigma, Cat. No. 93362), 0.01% Tween-20 (Sigma, Cat. No. P9416), 1mM DTT (Sigma, Cat. No. D9779), 50mM NaCl (Sigma, Cat. No. S9888).

[1103] (2) The test compound concentration starts at 10 μM and is diluted 3-fold to 10 concentrations. The positive control compound concentration starts at 1 μM and is diluted 3-fold to 10 concentrations. The compound and the positive control are diluted with DMSO to 100× the test concentration. The test compound is then diluted 3-fold to 10 concentrations, while the positive control is diluted 3-fold to 10 concentrations. Next, the test compound is diluted 20-fold with 1× reaction solution (DMSO concentration is 5%). Finally, 5 μL of each is added to a 384-well reaction plate for testing. Each compound is tested in duplicate. 5 μL of 5% DMSO is transferred to the Max well and Min well.

[1104] (3) Prepare an enzyme solution with a final concentration of 2.5 times using 1× Assay buffer.

[1105] (4) Add 10 μL of enzyme solution at 2.5 times the final concentration to the compound wells and positive control wells respectively; add 10 μL of 1× Assay buffer to the negative control wells.

[1106] (5) Centrifuge at 1000 rpm for 60 seconds, shake to mix, and incubate at room temperature for 15 minutes.

[1107] (6) Prepare a mixed solution of 3H-SAM, MTA, and H4 peptide at 2.5 times the final concentration using 1× Assay buffer.

[1108] (7) Add 10 μL of a mixed solution of 3H-SAM, MTA, and H4 peptide at 2.5 times the final concentration to start the reaction.

[1109] (8) Centrifuge the 384-well plate at 1000 rpm for 60 seconds, shake to mix, and incubate at room temperature for 60 minutes.

[1110] (9) Prepare stop solution (200 μM SAM (Sigma, Cat. No. A7007)) in 1× Assay buffer.

[1111] (10) 5 μL of stop solution was added to terminate the reaction. After centrifugation at 1000 rpm for 60 seconds, all the solutions in each well were transferred to the FlashPlate and incubated at room temperature for 60 minutes.

[1112] (11) Readings were made using MicroBeta2.

[1113] 1.4 Data Analysis

[1114] Calculation formula

[1115] Fitting dose-effect curve

[1116] The log value of the concentration was used as the X-axis and the percentage inhibition rate was used as the Y-axis. The log (inhibitor) vs. response-Variable slope of the analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the IC50 value of the compound's inhibition of enzyme activity. The results are shown in Table 2, where IC 50 ≤0.1μM is A, 0.1μM<IC 50 ≤1μM is B, 1μM<IC 50 ≤10μM is C, 10μM<IC 50 It is D.

[1117] Experimental Example 2: Cell Anti-Proliferation Experimental Method

[1118] 2.1 Materials and cells

[1119] HCT116MTAP Deletion cells were from Pharmaron (China); 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).

[1120] 2.2 Compound Storage

[1121] 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.

[1122] 2.3 Cell culture and passaging

[1123] 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.

[1124] 2.4 Cell proliferation activity detection

[1125] 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.

[1126] 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 2-4, where GI 50 ≤0.01μM is AA, 0.01μM <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.

[1127] Table 2 Test results of the anti-proliferative activity of the compounds of the present invention

[1128] Table 3 Test results of the anti-proliferative activity of the compounds of the present invention

[1129] Table 4 Test results of the anti-proliferative activity of the compounds of the present invention

[1130] Experimental Example 3 Investigation of brain permeability in CD1 mice after oral administration

[1131] 3.1 Experimental design

[1132] 3.1.1 Dosage Information

[1133] Table 5

[1134] 3.1.2 Collection time:

[1135] Table 6

[1136] 3.1.3 Blood sample collection and processing

[1137] Table 7

[1138] 3.1.4 In vivo evaluation

[1139] Table 8

[1140] 3.1.5 Testing System

[1141] Table 9

[1142] 3.2 Test sample and preparation

[1143] 3.2.1 Test product information

[1144] Table 10

[1145] 3.2.2 Preparation

[1146] Table 11

[1147] 3.3 Sample analysis

[1148] All samples were analyzed by LC-MS / MS, and the concentration of the drug to be tested in the samples was determined by the standard curve method.

[1149] The plasma test results were analyzed using WinNonlin (Phoenix TM ) or other similar software to calculate pharmacokinetic parameters.

[1150] 3.4 Experimental Results

[1151] Table 12 Brain penetration data of the compounds of the present invention

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof: in, Ring A is X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 for CR 2d or N; 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 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; L1 is NH or CHR x ; L2 is a chemical bond or CR x R y ; L3 is -C(O)-, -S(O)- or -S(O)2-; where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, 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; Y1 is a chemical bond or (CR3R3) q ; Y2 is a chemical bond, O, S, NR', S(O) or S(O)2; q = 1, 2, or 3; Z1 is N or CR; Z2 is N or CR; Z3 is N or CR; R3 and R are independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Or CR3R3 together to form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; R' is selected from H, D, C(O)R a 、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; p = 0, 1, 2, 3, or 4; One of Ar1 and Ar2 is phenyl or a 5-6 membered heteroaryl group substituted by n R1s; the other is H or D; or Ar1 and Ar2 are independently H or D; 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)(OR a )2、P(OR a )2、P(O)(R a )2、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, which is optionally substituted by 1, 2 or 3 R 1s replace; or two adjacent ring atoms on Ar1 or Ar2 and their substituents together form a C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; n = 0, 1, 2, 3, 4 or 5; R 1s Selected from H, D, halogen, CN, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、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, C 1-6 Alkyl or C 1-6 haloalkyl substitution; L is selected from chemical bonds, 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 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 3-10 membered heterocyclic group; Among them, X1, X2, X3, R 2a 、R 2b 、R 2c 、R 2d 、R 2s , L1, L2, R x 、R y , Y1, Y2, Z1, Z2, Z3, R3, R, R', Ar1, Ar2, R1, R 1s , L, R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof: in, Ring A is X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 for CR 2d or N; 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; Or X1, X2 and their substituents together form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2s Independently selected from H, D, halogen, ═O, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; L1 is NH or CHR x ; L2 is a chemical bond or CR x R y ; L3 is -C(O)-, -S(O)- or -S(O)2-; where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, 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; Y1 is a chemical bond or CR3R3; Y2 is a chemical bond, O, S, NR', S(O) or S(O)2; Z1 is N or CR; Z2 is N or CR; Z3 is N or CR; R3 and R are independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Or CR3R3 together to form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; R' is selected from H, D, C(O)R a 、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; p = 0, 1, 2, 3, or 4; One of Ar1 and Ar2 is phenyl or 5-6 membered heteroaryl, which is substituted by n R1; the other is H or D; 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 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; 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; n = 0, 1, 2, 3, 4 or 5; R 1s Selected from H, D, halogen, -L-OR a 、-L-SR a 、-L-NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、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, C 1-6 Alkyl or C 1-6 haloalkyl substitution; L is selected from chemical bonds, 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 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, X1, X2, X3, R 2a 、R 2b 、R 2c 、R 2d 、R 2s , L1, L2, R x 、R y , Y1, Y2, Z1, Z2, Z3, R3, R, R', Ar1, Ar2, R1, R 1s , L, R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Selected from 4. A compound of formula (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: R 2a Selected from H, D, CN, OR a or NR b R c ; preferably OR a or NR b R c ; preferably NH2.

5. A compound of formula (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 R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Me.

6. A compound of formula (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 2c is selected from H, D or halogen; preferably H or D.

7. A compound of formula (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: R 2d Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably H or D.

8. A compound of formula (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 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 Substitution; preferably forming 9. A compound of formula (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 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably selected from H, D or Me.

10. A compound of formula (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: L1 is NH; L2 is a chemical bond or CR x R y ; L3 is -C(O)- or -S(O)2-; Preferably, L1-L2 are selected from L3 is -C(O)-; or L1-L2-L3 is 11. A compound of formula (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: Y1 is a chemical bond or CR3R3; Y2 is selected from a chemical bond, O, S, NR'; Preferably, Y1 is a chemical bond or CR3R3; Y2 is selected from a chemical bond, O, S or NH, preferably a chemical bond or O; Preferably, Y1 is CR3R3; Y2 is selected from O, S or NH, preferably O; Preferably, Selected from Preferably, Selected from Preferably, for More preferably 12. A compound of formula (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, wherein: for Preferably 13. A compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: Z1, Z2 and Z3 are all CR.

14. A compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 more preferably H or D.

15. A compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R3 is independently selected from H, D, halogen, C 1-6 Alkyl, C 1- 6 haloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, or CR3R3 together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, or CR3R3 together to form C 3-6 Cycloalkylene; preferably selected from H or Me, or CR3R3 together form cyclopropylene.

16. A compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R' is selected from H, D, C(O)R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, C(O)R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl.

17. A compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: One of Ar1 and Ar2 is phenyl, pyridyl or pyridazinyl, which is substituted by n R1; the other is H or D; Preferably, Ar1 is phenyl, pyridyl or pyridazinyl, which is substituted by n R1; Ar2 is H or D; or Ar2 is phenyl, which is substituted by n R1; Ar1 ​​is H or D; Preferably, one of Ar1 and Ar2 is Among them, Z4 is CR 1b or N, Z5 is CR 1b or N, m=0, 1 or 2; the other is H or D; Preferably, one of Ar1 and Ar2 is selected from The other is H or D; more preferably one of Ar1 and Ar2 is selected from The other is H or D.

18. A compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R1 is selected from H, D, halogen, CN, NO2, -L-OR a 、 -L-SR a 、-L-NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; Preferably selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s replace; Preferably selected from H, D, halogen, CN, SF5, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; Preferably selected from H, D, halogen, SF5, OR a 、C 1-6 Alkyl or C 1-6 alkyl halide; Preferably selected from F, CF3, CF2CF3, SF5, OCH3, OCF3, OCHF2, OCH2CH3 or OCH2CH2CF3, preferably F or CF3; 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, preferably forming phenyl or 5-6 membered heteroaryl, more preferably forming thiazolyl, which is optionally substituted by 1, 2 or 3 R 1s replace.

19. A compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1a Selected from H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s Substituted; preferably selected from H, D, halogen, CN, OR a SR a NR b R c , SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s Substituted; preferably selected from H, D, halogen, CN, SF5, OR a NR b R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, SF5, OR a 、C 1-6 Alkyl or C 1-6 preferably selected from CF3, CF2CF3, SF5, OCH3, OCF3, OCHF2, OCH2CH3 or OCH2CH2CF3, more preferably CF3.

20. A compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1b Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably selected from H, D or halogen; preferably H or F.

21. A compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1s Selected from H, D, halogen, -L-OR a 、-L-NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl substituted; 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 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclic group; preferably 5-6 membered heterocyclic group, more preferably 22. A compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: 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 The haloalkyl group is substituted; preferably by a chemical bond.

23. A compound of formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, having the following structural formula: in, R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; Preferably, R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; Preferably, R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, or CR 3a R 3b Together they form C 3-6 cycloalkylene; Preferably, R 3a 、R 3b 、R 3c and R 3d are independently H or Me, or CR 3a R 3b Together they form a cyclopropylene group; The remaining groups are as defined in claims 1-21.

24. A compound of formula (II) or formula (III) according to claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, L1 is NH; L2 is CR x R y ; where R x and R y H, D, C independently 1-6 Alkyl or C 1-6 alkyl halide; or CR x R y Together to form C=O, C=S or C 3-4 cycloalkylene; X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 for CR 2d or N; R 2a Selected from H, D, CN, OR a or NR b R c ; R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered hetero Cyclic group; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; 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, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group; Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2s Independently selected from H, D, halogen, ═O, C 1-6 Alkyl or C 1-6 alkyl halide; Y1 is selected from a chemical bond or CR3R3; Y2 is selected from a chemical bond, O, S, NR', S(O) or S(O)2; R3 is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, or CR3R3 together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; R' is selected from H, D, C(O)R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; Ar1 and Ar2 are independently phenyl or 5-6 membered heteroaryl, preferably phenyl, pyridyl or pyridazinyl, which are substituted by n R1; R1 is independently 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; R 1s 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 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclic group; p = 0, 1, 2, 3, or 4; 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 5-7 membered heterocyclic group; Among them, L1, L2, X1, X2, X3, R 2a 、R 2b 、R 2c 、R 2d 、R 2s , Y1, Y2, R3, R', Ar1, Ar2, R1, R 1s 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

25. The compound of formula (II) or formula (III) according to claim 24, 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 ; 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 3-4 cycloalkylene; X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 for CR 2d or N; R 2a OR a or NR b R c ; R 2b 、R 2c and R 2d Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Y1 is selected from a chemical bond or CR3R3; Y2 is selected from a chemical bond, O, S or NR', preferably selected from a chemical bond, O, S or NH; R3 is independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, or CR3R3 together to form C 3-6 cycloalkylene; R' is selected from H, D, C(O)R a 、C 1-6 Alkyl, C 1-6 alkyl halide; Ar1 and Ar2 are independently Z4 for CR 1b or N; Z5 is CR 1b or N; R 1a Selected from H, D, halogen, CN, SF5, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 1b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; p = 0, 1, 2, 3, or 4; m=0, 1 or 2, preferably m=0; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

26. The compound of formula (II) according to claim 24 or 25, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1-L2 is Y1 is CR3R3; Y2 is selected from O, S or NH, preferably O.

27. The compound of formula (II) according to claim 26, 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; X3 for CR 2d ; R 2a is NH2; R 2b Selected from C 1-6 Alkyl or C 1-6 alkyl halide; R 2c Selected from H, D or halogen; preferably H or D; R 2d H or D; Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2s independently selected from H, D or Me; R3 is independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, or CR3R3 together to form C 3-6 cycloalkylene; Ar1 is Z4 for CR 1b or N; Z5 is CR 1b or N; R 1a Selected from H, D, SF5, OR a 、C 1-6 Alkyl or C 1-6 alkyl halide; R 1b independently selected from H, D or halogen; p = 0, 1, or 2; m=0, 1 or 2, preferably m=0; R a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

28. The compound of formula (II) according to claim 27, 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; X3 is CH; R 2a is NH2; R 2b for Me; R 2c is H; Or X1, X2 and their substituents together form: R3 is independently selected from H or Me, or CR3R3 together form cyclopropylene; Ar1 is Preferably selected from More preferably selected from Z4 for CR 1b or N; Z5 is CR 1b or N; R 1a Selected from CF3, CF2CF3, SF5, OCH3, OCF3, OCHF2, OCH2CH3 or OCH2CH2CF3, preferably CF3; R 1b Selected from H or F; p = 0, 1, or 2; m=0, 1 or 2, preferably m=0.

29. The compound of formula (II) or formula (III) according to claim 24 or 25, 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 ; 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 3-4 cycloalkylene; Preferably, L1-L2 is Preferably 30. The compound of formula (II) or formula (III) of claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: X1 for CR 2b ; X2 is CR 2c ; X3 for CR 2d ; R 2a is NH2; R 2b Selected from C 1-6 Alkyl or C 1-6 alkyl halide; R 2c Selected from H, D or halogen; preferably H or D; R 2d Selected from H or D; Y1 is selected from a chemical bond or CR3R3; Y2 is selected from a chemical bond, O, S or NH, preferably a chemical bond or O; R3 is independently selected from H, D or Me, or CR3R3 together form cyclopropylene; preferably H or D; Ar1 and Ar2 are independently Z4 for CR 1b ; Z5 is CR 1b ; R 1a Selected from H, D, SF5, OR a 、C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; R 1b Independently selected from H, D or halogen; preferably H or D; p = 0, 1, or 2; m=0, 1 or 2, preferably m=0; R a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

31. The compound of formula (II) or formula (III) of claim 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: X1 for CR 2b ; X2 is CH; X3 is CH; R 2a is NH2; R 2b C 1-6 Alkyl or C 1-6 Haloalkyl, preferably Me; Y1 is selected from a chemical bond or CR3R3, preferably CR3R3; Y2 is a chemical bond or O; R3 is H; Ar1 and Ar2 are independently R 1a C 1-6 Alkyl or C 1-6 Haloalkyl, preferably CF3; p＝0。 32. The compound of formula (IV) of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, 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; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; X3 for CR 2d or N; R 2a Selected from H, D, CN, 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, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group; R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; Ar1 is phenyl or a 5-6 membered heteroaryl, preferably phenyl, pyridyl or pyridazinyl, which is substituted by n R1; 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; R 1s 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 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-7 Cycloalkyl or 5-7 membered heterocyclic group, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclic group; 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 5-7 membered heterocyclic group; Among them, X1, X2, R1, R 2d 、Ar1、R 1s 、R 2s 、R a 、R b and R c The individual radicals in the definitions are optionally deuterated, up to full deuteration.

33. The compound of formula (IV) of claim 32, 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; R 2s Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; X3 for CR 2d ; R 2a OR a or NR b R c ; R 2d H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3a 、R 3b 、R 3c and R 3d Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; Ar1 is Z4 for CR 1b or N; Z5 is CR 1b or N; R 1a Selected from H, D, halogen, CN, SF5, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 1b Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; m = 0, 1, or 2; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

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 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; R 2s Selected from H, D or Me; X3 for CR 2d ; R 2a is NH2; R 2d H or D; R 3a 、R 3b and R 3c Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; or CR 3a R 3b Together they form C 3-6 cycloalkylene; R 3d Selected from H or D; Ar1 is Z4 for CR 1b or N; Z5 is CR 1b or N; R 1a Selected from H, D, SF5, OR a 、C 1-6 Alkyl or C 1-6 alkyl halide; R 1b is selected from H, D or halogen; m=0, 1 or 2, preferably m=0; R a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

35. The compound of formula (IV) of claim 34, 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 is CH; R 2a is NH2; R 3a is H or Me; R 3b is H or Me; or CR 3a R 3b Together they form a cyclopropylene group; R 3c is H or Me; R 3d is H; Ar1 is Preferably selected from More preferably selected from Z4 for CR 1b or N; Z5 is CR 1b or N; R 1a Selected from CF3, CF2CF3, SF5, OCH3, OCF3, OCHF2, OCH2CH3 or OCH2CH2CF3, preferably CF3; R 1b H or F; m=0, 1 or 2, preferably m=0.

36. The compound of formula (II) of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, L1-L2 is X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 for CR 2d or N; R 2a Selected from H, D, CN, OR a or NR b R c ; R 2b Selected from H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; 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 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2s Independently selected from H, D, halogen, ═O, C 1-6 Alkyl or C 1-6 alkyl halide; Y1 is selected from (CR3R3) q ; Y2 is selected from O, S, NR', S(O) or S(O)2; q = 1 or 2; R' is selected from H, D, C(O)R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; R3 is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, and at least one of the two R3 in the geminal position is H or D; or CR3R3 together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; Ar1 is phenyl or a 5-6 membered heteroaryl, preferably a phenyl or a 6 membered nitrogen heteroaryl, preferably a phenyl, pyridyl, pyrimidinyl or pyridazinyl group, which is substituted by n R1, or Ar1 is H or D; R1 is independently selected from H, D, halogen, CN, OR a SR a NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(OR a )2、P(OR a )2、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace; Or the two adjacent ring atoms on Ar1 and their substituents together form a C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; R 1s Independently selected from H, D, halogen, CN, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1- 6 haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3- 7-membered cycloalkyl or 3-7-membered heterocyclic group; p = 0, 1, 2, 3, or 4; 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 3-7 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

37. The compound of formula (II) according to claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1-L2 is X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 for CR 2d or N; R 2a OR a or NR b R c ; R 2b Selected from H, D, halogen, C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 2c and R 2d Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; Y1 is selected from (CR3R3) q ; Y2 is selected from O, S, NR' or S(O)2; q = 1 or 2; R' is selected from H, D, C 1-6 Alkyl and C 1-6 alkyl halide; R3 is independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, and at least one of the two R3 in the geminal position is H or D; or CR3R3 together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; Ar1 is or Ar1 is H or D; Z4, Z5, Z7 and Z8 are independently CR 1b or N; Z6 is CR 1a or N; Or Z6, Z5 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 1s replace; R 1a Selected from H, D, halogen, CN, SF5, OR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace; R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl and C 1-6 alkyl halide; R 1b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; p = 0, 1, or 2; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; Preferably, among Z4, Z5, Z6, Z7 and Z8, at most 3 are N, preferably at most 2 are N, and preferably at most 1 is N.

38. The compound of formula (II) according to claim 37, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1-L2 is X1 is a C atom or a N atom, which is optionally replaced by R 2b replace; X2 is a C atom or a N atom, which is optionally replaced by R 2c replace; X3 for CR 2d ; R 2a is OMe or NH2, preferably OMe, preferably NH2; R 2b Selected from C(O)NR b R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C(O)NR b R c or C 1-3 Alkyl, preferably C(O)NH2 or Me, preferably C(O)NH2; R 2c Selected from H, D or halogen; preferably H or D; R 2d H or D; Or X1, X2 and their substituents together form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably forming a 5-7 membered heterocyclyl or 5-6 membered heteroaryl, more preferably forming a 5 membered heterocyclyl or 5 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2s Independently selected from H, D and C 1-3 Alkyl, preferably selected from H, D and Me; Y1 is (CR3R3) q , preferably -CH2-, -CH(CH3)-, -CH2CH2-, Preferably -CH2-, -CH(CH3)- or More preferably -CH2- or -CH(CH3)-; Y2 is selected from O, NR' or S(O)2, preferably O; q=1 or 2, preferably 1; R' is H, C 1-3 Alkyl or C 1-3 Halogenated alkyl, preferably C 1-3 Alkyl, preferably Me; R3 is independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, preferably H, D, C 1-6 Alkyl or C 1-6 A haloalkyl group, wherein at least one of the two R3 groups in the geminal position is H or D; preferably, R3 is independently selected from H, Me, Et, CF3 or cyclopropyl, preferably H, Me or Et; Or CR3R3 together to form C 3-6 Cycloalkylene, preferably forming Preferred Formation Preferably, CR3R3 does not form a ring; Ar1 is Or Ar1 is H; preferably Ar1 is Z4, Z5 and Z7 are independently CR 1b or N, preferably Z7 is CR 1b ; Z6 is CR 1a or N, preferably CR 1a ; Z8 is CR 1b ; Or Z6, Z5 and their substituents together form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group, more preferably a 5 membered heterocyclic group or a 5 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 1s replace; R 1a Selected from H, D, halogen, CN, SF5, OR a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl, preferably selected from H, D, halogen, CN, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3- 7-membered cycloalkyl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace; R 1s Independently selected from H, D, CN, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D, CN, Me and CF3, preferably selected from H, D and Me; R 1b Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably selected from H, D, C 1-6 Alkyl and C 1-6 alkyl halide; p=0, 1 or 2, preferably p=0 or 1; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

39. The compound of formula (IV) of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, 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; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; X3 for CR 2d or N; R 2a Selected from H, D, CN, 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 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; R 3a 、R 3c and R 3d Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 3b H or D; or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; Ar1 is phenyl or 5-6 membered heteroaryl, preferably phenyl or 6 membered nitrogen heteroaryl, which is substituted by n R1; R1 is independently selected from H, D, halogen, CN, OR a SR a NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(OR a )2、P(OR a )2、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace; Or the two adjacent ring atoms on Ar1 and their substituents together form a C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; R 1s Independently selected from H, D, halogen, CN, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1- 6 haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3- 7-membered cycloalkyl or 3-7-membered heterocyclic group; 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 3-7 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

40. The compound of formula (IV) of claim 39, 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; R 2s Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; X3 for CR 2d ; R 2a OR a or NR b R c , preferably OMe or NH2; R 2d H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3a and R 3c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 3b and R 3d independently H or D; or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; Ar1 is Z4, Z5, Z7 and Z8 are independently CR 1b or N; Z6 is CR 1a or N; Or Z6, Z5 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 1s replace; R 1a Selected from H, D, halogen, CN, SF5, OR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace; R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl and C 1-6 alkyl halide; R 1b Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 alkyl halide; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; Preferably, among Z4, Z5, Z6, Z7 and Z8, at most 3 are N, preferably at most 2 are N, and preferably at most 1 is N.

41. The compound of formula (IV) of claim 40, 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 or 5-6 membered heteroaryl, preferably forming a 5-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably forming a 5-6 membered heteroaryl, preferably forming a 5 membered heterocyclyl or 5 membered heteroaryl, more preferably forming a 5 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replace; R 2s Selected from H, D and C 1-3 Alkyl, preferably selected from H, D and Me; X3 for CR 2d ; R 2a is NH2; R 2d H or D; R 3a and R 3c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, preferably H, D, C 1-6 Alkyl or C 1- 6 haloalkyl; R 3b and R 3d independently H or D; or CR 3a R 3b Together they form C 3-6 Cycloalkylene; or CR 3c R 3d Together they form C 3-6 cycloalkylene; Ar1 is Z4, Z5 and Z7 are independently CR 1b or N, preferably Z7 is CR 1b ; Z6 is CR 1a or N, preferably CR 1a ; Z8 is CR 1b ; Or Z6, Z5 and their substituents together form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group, preferably a 5 membered heterocyclic group or a 5 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 1s replace; R 1a Selected from H, D, halogen, CN, SF5, OR a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl, preferably selected from H, D, halogen, CN, OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3- 7-membered cycloalkyl, 3-7-membered heterocyclyl and 5-6-membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace; R 1s Independently selected from H, D, CN, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D, CN, Me and CF3, preferably selected from H, D and Me; R 1b Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably selected from H, D, C 1-6 Alkyl and C 1-6 Haloalkyl, more preferably H or D; R a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 alkyl halide; Preferably, R 3a and R 3c At least one of them is H or D; Preferably, R 3a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, preferably C 1-6 Alkyl or C 1-6 alkyl halide; R 3c H or D; Preferably, when X1, X2 and their substituents together form a cycloalkyl group or a heterocyclic group, Z6, Z5 and their substituents together do not form a phenyl group or a heteroaryl group.

42. The compound of formula (IV) of claim 41, 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: Preferred Formation Preferred Formation X3 is CH; R 2a is NH2; R 3a is H, Me, Et, CF3 or cyclopropyl, preferably H, Me or Et; R 3b is H; R 3c is H or Me; R 3d is H; or CR 3a R 3b Together or CR 3c R 3d Together Ar1 is Z4, Z5 and Z7 are independently CR 1b or N, preferably Z7 is CH or N, preferably Z7 is CH; Z6 is CR 1a or N, preferably CR 1a ; Z8 is CH; Or Z6, Z5 and their substituents together form: Preferred Formation R 1a Selected from H, Cl, Br, CN, <h2 style=";text-align:left;direction:ltr">CF3, CF2CF3, SF5, OCH3, OCF3, OCHF2, OCH2CH3, OCH2CH2CF3, and other compounds<h2 style=";text-align:left;direction:ltr"> Preferably selected from H, Br, Cl, CN, CF3, OCF3, cyclopropyl, Preferably CF3; R 1b are independently H, F, Cl or CF3, preferably H or CF3, preferably H; Preferably, R 3a and R 3c At least one of them is H; Preferably, R 3a is Me, Et, CF3 or cyclopropyl, preferably Me or Et; R 3c is H; Preferably, Ar1 is selected from: Preferably selected from:

43. The compound of formula (IV) of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, 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; R 2s Selected from H, D, halogen, =O, C 1-6 Alkyl or C 1-6 alkyl halide; X3 for CR 2d or N; R 2a Selected from H, D, CN, 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 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; R 3a 、R 3c and R 3d Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 3b H or D; or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; Ar1 is phenyl or 5-6 membered heteroaryl, preferably phenyl or 6 membered nitrogen heteroaryl, which is substituted by n R1; R1 is independently selected from H, D, halogen, CN, OR a SR a NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(OR a )2、P(OR a )2、P(O)(R a )2、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 and 5-10 membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace; Or the two adjacent ring atoms on Ar1 and their substituents together form a C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s replace; R 1s Independently selected from H, D, halogen, CN, OR a NR b R c 、C(O)R a 、C(O)OR a 、C(O)NR b R c 、C 1-6 Alkyl, C 1- 6 haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; n = 0, 1, 2, 3, 4 or 5; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl and C 1-6 haloalkyl; or R b 、R c and the atoms to which they are attached together form a 3-7 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

44. The compound of formula (IV) of claim 43, 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; R 2s Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; X3 for CR 2d ; R 2a OR a or NR b R c , preferably OMe or NH2; R 2d H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3a and R 3c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 3b and R 3d independently H or D; or CR 3a R 3b Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d Together they form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; Ar1 is Z4, Z5, Z7 and Z8 are independently CR 1b or N; Z6 is CR 1a or N; Or Z6, Z5 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 1s replace; R 1a Selected from H, D, halogen, CN, SF5, OR a NR b R c 、C(O)R a 、S(O)R a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 R 1s replace; R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; R 1b Independently selected from H, D, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups, preferably selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; R a 、R b and R c Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; Preferably, among Z4, Z5, Z6, Z7 and Z8, at most 3 are N, preferably at most 2 are N, and preferably at most 1 is N.

45. The compound of formula (IV) of claim 44, 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 a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group, preferably a 5-6 membered heteroaryl group, preferably a 5 membered heterocyclic group or a 5 membered heteroaryl group, more preferably a 5 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 2s Substituted; preferably, X1, X2 and their substituents together form R 2s Selected from H, D, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D and Me; X3 for CR 2d ; R 2a is NH2; R 2d H or D; R 3a and R 3c Independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, preferably H, D, C 1-6 Alkyl or C 1- 6 haloalkyl; preferably, R 3a and R 3c At least one of them is H or D, preferably R 3a Not for H and D, R 3c H or D; R 3b and R 3d independently H or D; or CR 3a R 3b Together they form C 3-6 Cycloalkylene, preferably CR 3a R 3b No ring formation; or CR 3c R 3d Together they form C 3-6 Cycloalkylene, preferably CR 3c R 3d No ring is formed; Ar1 is Z4, Z5 and Z7 are independently CR 1b or N; Z6 is CR 1a or N, preferably CR 1a ; Z8 is CR 1b ; Or Z6, Z5 and their substituents together form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group, preferably a 5-7 membered heterocyclic group, preferably a 5 membered heterocyclic group or a 5 membered heteroaryl group, preferably a 5 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1s Preferably, when Z6, Z5 and their substituents together form a heteroaryl group, Z5 is CR 1b ; Preferably, Z4 and Z5 are not N at the same time; Preferably, Z6, Z5 and their substituents do not form a ring; R 1a Selected from H, D, halogen, CN, SF5, OR a 、S(O)2R a 、P(O)(R a )2、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, preferably not P(O)(R a ) 2, preferably selected from SF5, Cl, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, -OC 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, phenyl, It is optionally replaced by 1, 2 or 3 R 1s replace; R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-7 Cycloalkyl, preferably selected from H, D, F, CN, Me, CF3 and cyclopropyl; R 1b Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D and halogen, more preferably H or D; R a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 alkyl halide; Preferably, when X1, X2 and their substituents together form a cycloalkyl group or a heterocyclic group, Z6, Z5 and their substituents together do not form a phenyl group or a heteroaryl group.

46. ​​The compound of formula (IV) according to claim 44 or 45, 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: Preferred Formation Preferred Formation X3 is CH; R 2a is NH2; R 3a is H, Me, Et, CF3 or cyclopropyl, preferably Me, Et, CF3 or cyclopropyl, preferably Me; R 3b is H; R 3c is H or Me, preferably H; R 3d is H; or CR 3a R 3b Together or CR 3c R 3d Together Ar1 is Z4, Z5 and Z7 are independently CR 1b Or N, preferably Z7 is CH or N; Z6 is CR 1a or N, preferably CR 1a ; Z8 is CH; Or Z6, Z5 and their substituents together form: Preferred Formation Preferred Formation R 1a Selected from H, Cl, Br, CN, SF5, <h2 style=";text-align:left;direction:ltr">CF3, CF2, CF3<h2 style=";text-align:left;direction:ltr"> OCH3、OCH2CH3、OCF3、OCHF2、OCH2CH2CF3、cyclopropyl group、 Preferably not Preferably selected from H, Br, Cl, CN, SF5, <h2 style=";text-align:left;direction:ltr">CF3, CF2, CF3<h2 style=";text-align:left;direction:ltr"> OCF3, OCHF2, cyclopropyl, Preferably selected from SF5, Cl, CN, <h2 style=";text-align:left;direction:ltr">CF3、<h2 style=";text-align:left;direction:ltr"> OCF3, cyclopropyl, Preferably CF3; R 1b are independently H, F, Cl or CF3, preferably H, F or Cl, preferably H; Preferably, R 3a and R 3c At least one of them is H; Preferably, R 3a is Me, Et, CF3 or cyclopropyl, preferably Me or Et; R 3c is H; Preferably, Ar1 is selected from: Preferably not Preferably selected from: Preferably selected from:

47. The compound of formula (II) of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, L1, L2, R3, Y1, Y2 and p are each as defined in any one of claims 36 to 38; X1, X2, X3, R 2a and Ar1 are each as defined in any one of claims 39 to 46.

48. The compound of formula (IV-1) of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, X1, X2, R 2a 、R 3a and Ar1 are each as defined in any one of claims 39 to 46.

49. The compound of formula (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 following:

50. A pharmaceutical composition comprising a compound according to any one of claims 1 to 49, 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.

51. The pharmaceutical composition of claim 50, 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.

52. Use of a compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutical composition according to claim 50 or 51 in the preparation of a medicament for treating or preventing a PRMT5-mediated disease.

53. 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 1-49, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutical composition of claim 50 or 51.

54. A compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutical composition according to claim 50 or 51, for use in treating or preventing a PRMT5-mediated disease.

55. The use of claim 52 or the method of claim 53 or the use of a compound or pharmaceutical composition of claim 54, wherein the disease is cancer.

56. The use of claim 52 or the method of claim 53 or the use of the compound or pharmaceutical composition of claim 54, 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.

57. The use of claim 52 or the method of claim 53 or the compound or pharmaceutical composition of claim 54, 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.

58. The use of claim 52 or the method of claim 53 or the use of the compound or pharmaceutical composition of claim 54, 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.

Images