PRMT5-MTA inhibitors

Abstract

The invention provides a compound as a PRMT5-MTA inhibitor. The compound is a compound shown in a formula (I) or pharmaceutically acceptable salt, isotope variant, tautomer or stereoisomer thereof. The invention also provides a pharmaceutical composition comprising the compound, and its use in the treatment of cancer. # imgabs0 #

Description

PRMT5-MTA inhibitors Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a PRMT5-MTA inhibitor. Background Art

[0002] Protein arginine methyltransferase (PRMT) can methylate histones and non-histones, thereby participating in the regulation of biological processes such as gene transcription, signal transduction, protein stability, cell proliferation, differentiation, apoptosis, and tumor formation (Nat Rev Mol Cell Biol. 2019 Oct; 20(10): 642-657)(Nat Rev Drug Discov. 2021 Jul; 20(7): 509-530). Currently, 11 PRMT family members have been discovered, which can be divided into types I, II, and III according to the different ways they catalyze arginine methylation. Among them, PRMT5 belongs to type II, and its catalytic form is symmetrical dimethylation.

[0003] As an epigenetic enzyme, PRMT5 is involved in a variety of biological processes, including transcriptional regulation, RNA metabolism, ribosome biogenesis, and cell cycle regulation. PRMT5 protein is overexpressed in a variety of cancer types, including B and T cell lymphoma, metastatic melanoma, neuroblastoma, glioblastoma, ovarian cancer, breast cancer, etc., and increasing evidence indicates that it plays an important role in tumor occurrence and development (Cell Stress. 2020 Aug; 4(8): 199-215) (Cancer Gene Ther. 2022 Mar; 29(3-4): 264-276.). On this basis, PRMT5 inhibitors have become a hot topic in the research and development of tumor treatment drugs.

[0004] Early PRMT5 inhibitors can be divided into two categories: one is substrate-competitive inhibitors, represented by GSK3326595; the other is SAM-competitive inhibitors, represented by JNJ64619178. Both types of drugs have strong inhibitory activity against PRMT5 and show strong anti-tumor activity. However, due to their strong inhibitory activity against PRMT5 in both normal cells and tumor cells, strong blood toxicity has been observed, which limits their clinical application and thus affects their clinical therapeutic effects (Bioorg Med Chem Lett. 2019 Jun 1; 29(11): 1264-1269)(Expert Opin Ther Pat. 2019 Feb; 29(2): 97-114.)(Annals of Oncology (2020) 31(suppl_4): S462-S504.10.1016 / annonc / annonc271)(Annals of Oncology (2019) 30(suppl_5): v159-v193.10.1093 / annonc / mdz244).

[0005] In 2016, a paper published in Science revealed that MTAP deficiency and PRMT5 are synthetically lethal (Science. 2016 Mar 11;351(6278):1214-8). MTAP is highly deficient in various solid tumors, including pancreatic cancer and glioma. MTAP is an intracellular MTA-degrading enzyme. MTAP deficiency leads to the intracellular accumulation of MTA, which competes with the methylation donor SAM, a functional substrate of PRMT5, for binding to PRMT5, thereby inhibiting PRMT5 function. Since MTA accumulates specifically in MTAP-deficient tumor cells, by strengthening the binding inhibition of MTA and PRMT5, PRMT5 activity can be specifically inhibited in tumor cells, while the inhibitory effect on PRMT5 activity in normal cells is weak, thereby providing a therapeutic safety window, while ensuring anti-tumor efficacy while reducing toxicity (Nat Rev Drug Discov. 2020 Jan; 19(1): 23-38)(Cell Rep. 2016 Apr 19; 15(3): 574-587). Currently, MTA-synergistic PRMT5 inhibitors have obtained preclinical validation data (J Med Chem. 2022 Feb 10; 65(3): 1749-1766). The development of MTA-synergistic PRMT5 inhibitors has great potential in the treatment of MTAP-deficient tumors.

[0006] Although progress has been made in PRMT5 research, there is still a lack of effective and selective PRMT5-MTA inhibitors, and no PRMT5-MTA inhibitor has entered Phase 2 clinical trials. Therefore, the development of highly selective PRMT5-MTA inhibitors will overcome the shortcomings of the first two generations of non-selective PRMT5 inhibitors in order to meet clinical needs.

[0007] Summary of the Invention

[0008] The present invention provides novel, highly selective PRMT5-MTA inhibitors. The present invention is achieved by the following aspects or embodiments.

[0009] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0010] in:

[0011] R1 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or -CH2OR a ;

[0012] R a Selected from H or methyl;

[0013] R2 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy or halogen;

[0014] R3 is selected from H, halogen, OR b 、CN、C 1-6 Alkyl or C 1-6 alkyl halide;

[0015] R4 and R5 are independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl; said 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by 1 or 2 R6, R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b , SCF3 or 5-6 membered heteroaryl;

[0016] Alternatively, R4, R5 and the nitrogen atom to which they are attached together form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally substituted by 1, 2, 3 or 4 R x replace;

[0017] R x Selected from halogen, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace;

[0018] R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace;

[0019] R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0020] R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0021] In another aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0022] in:

[0023] R1 is selected from C 1-6 Alkyl, cyclopropyl or -CH2OH;

[0024] R2 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy or halogen;

[0025] R3 is selected from H, halogen, CN or methyl;

[0026] R4 and R5 are independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl; said 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by 1 or 2 R6, R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b, SCF3 or 5-6 membered heteroaryl;

[0027] Alternatively, R4, R5 and the nitrogen atom to which they are attached together form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally substituted by 1, 2, 3 or 4 R x replace;

[0028] R x Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace;

[0029] R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace;

[0030] R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0031] R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0032] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.

[0033] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, and further comprising another therapeutic agent.

[0034] 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 disease mediated by PRMT5 methyltransferase.

[0035] In another aspect, the present invention provides a method for treating and / or preventing a PRMT5 methyltransferase-mediated disease in a subject, comprising administering to the subject a compound or composition of the present invention.

[0036] In another aspect, the present invention provides a compound of the present invention or a composition of the present invention for use in treating and / or preventing a disease mediated by PRMT5 methyltransferase.

[0037] In a specific embodiment, the diseases treated by the present invention include cancers selected from the group consisting of acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, hemangioma), appendix cancer, benign monoclonal gamma disease, bile duct cancer, bladder cancer, brain cancer (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchogenic carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, large intestinal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma), cerebrospinal fluid (e.g., glioma ...cerebrospinal fluid (e.g., glioma, astrocytoma, oligodendroglioma, medulloblastoma), cerebrospinal fluid (e.g., glioma, astrocytoma, oligodendroglioma, sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's gland carcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), hypereosinophilia, gallbladder cancer, stomach cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancer (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), Acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoma Plasma cell lymphoma, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell non-Hodgkin lymphomas, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (e.g., cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more of the above leukemias / lymphomas;Multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer (e.g., Wilms tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma, malignant hepatocellular carcinoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., true Polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myeloid metaplasia (AMM), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibromas (such as neurofibromatosis type 1 or type 2, schwannomatosis), neuroendocrine cancers (such as gastroenteropancreatic neuroendocrine tumors (GEP-NET), carcinoid tumors), osteosarcoma, ovarian cancer (such as cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, and penile cancer.

[0038] Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims.

[0039] definition

[0040] Chemical definition

[0041] Definitions of specific functional groups and chemical terms are described in more detail below.

[0042] 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.

[0043] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C1-2 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). Alkyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: M e (-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0044] “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.

[0045] “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, C2-4 alkynyl is preferred. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. The term "C 2-6"Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0046] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0047] Therefore, “C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl is particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0048] “C 1-6 "Alkoxy" refers to an -OR group, wherein R is a C 1-6 Alkyl. C 1-4 Alkoxy groups are preferred.

[0049] “C 1-6 "Haloalkoxy" refers to "C 1-6 Alkoxy", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkoxyalkyl is particularly preferred, more preferably C 1-2 Halogenated alkoxyalkyl.

[0050] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-10 Cycloalkyl, C 5-10 Cycloalkyl, C 4-7 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl and C 3-4 Cycloalkyl is particularly preferred, more preferably C 5-6Cycloalkyl. Cycloalkyl also includes a ring system in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such a case, the number of carbons continues to represent the number of carbons in the cycloalkyl system. 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), and the like. The cycloalkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0051] "3-12 membered heterocyclyl" refers to a group of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, 3-10 membered heterocyclyl is preferably a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 4-10 membered heterocyclyl is preferably a 4-10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, 5-10 membered heterocyclyl is preferably a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5-8 membered heterocyclyl is preferably a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3-7 membered heterocyclyl is preferably a A 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; preferably a 3- to 6-membered heterocyclyl, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 4- to 7-membered heterocyclyl, which is a 4- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 4- to 6-membered heterocyclyl, which is a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5- to 6-membered heterocyclyl, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 3- to 5-membered heterocyclyl, which is a 3- to 5-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl 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. 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, oxetane, and thietidinyl. Exemplary 5-membered heterocyclyls 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, dioxolane, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thianyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyranopyridinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0052] “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.

[0053] "5-14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-10 membered heteroaryls are preferred, which are 6-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-9 membered heteroaryls are preferred, which are 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryls are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered 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, pyridinyl. 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, quinolyl, isoquinolyl, 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.

[0054] "Cycloalkylene", "heterocyclylene", "arylene" or "heteroarylene" is a divalent group formed by removing another hydrogen from the above-defined "cycloalkyl", "heterocyclyl", "aryl" or "heteroaryl", and may be substituted or unsubstituted. For example, "C 5-7 "Cycloalkylene" refers to the removal of C 5-7 The "5-8 membered heterocyclylene" refers to a divalent group formed by removing another hydrogen atom of a 5-8 membered heterocyclyl. The "C 6-10 "Arylene" refers to the removal of C 6-10 The "5- to 6-membered heteroarylene group" refers to a divalent group formed by removing another hydrogen atom of a 5- to 6-membered heteroaryl group.

[0055] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0056] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(Rcc )3、-B(R aa )2、-B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0057] 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;

[0058] 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;

[0059] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0060] 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;

[0061] 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(Rff )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;

[0062] 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:

[0063] 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;

[0064] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 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 1-6Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1- 6-alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 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, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0065] 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.

[0066] The term "deuterium (D or 2H)" is a stable isotope of hydrogen that occurs at a natural abundance of 0.015 mol%. The term "deuterated" refers to a group or compound in which one or more hydrogen atoms H are replaced by D.

[0067] "Deuterated compound" refers to a compound in which one or more carbon-bonded hydrogen atoms are replaced by one or more deuterium atoms. Similarly, "deuterated" refers to a chemical structure or organic group in which one or more carbon-bonded hydrogen atoms are replaced by one or more deuterium atoms, for example, "deuterated alkyl", "deuterated cycloalkyl", "deuterated heterocycloalkyl", "deuterated aryl", etc. For example, "deuterated alkyl" refers to an alkyl group as defined herein in which at least one carbon-bonded hydrogen atom is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to one deuterium; a carbon atom can be bonded to multiple deuterium atoms; and multiple carbon atoms in an alkyl group can also be bonded to deuterium. For example, deuterated methyl includes methyl-d3, in which three hydrogen atoms are replaced by deuterium; monodeuterated methyl and dideuterated methyl are also included. In some embodiments, the compounds of the present invention include deuterated compounds.

[0068] Other definitions

[0069] 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.

[0070] "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, crickets, 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.

[0071] "Disease," "disorder," and "condition" are used interchangeably herein.

[0072] 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.

[0073] "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

[0074] As used herein, the term "compound of the present invention" refers to a compound of the following formula (I) (including sub-formulas, such as formula (II), (III-1), (III-1a), (III-1b), (III-2), (III-2a), (III-2b), (III-3), (III-3a), (III-3b), (IV-1), (IV-1a), (IV-1b), (IV-2), (IV-2a), (IV-2b), (IV-3), (IV-3a) or (IV-3b)), etc.), pharmaceutically acceptable salts, enantiomers, diastereoisomers or isotopic variants thereof, and mixtures thereof.

[0075] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0076] in:

[0077] R1 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or -CH2OR a ;

[0078] R a Selected from H or methyl;

[0079] R2 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy or halogen;

[0080] R3 is selected from H, halogen, OR b 、CN、C 1-6 Alkyl or C 1-6 alkyl halide;

[0081] R4 and R5 are independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl; said 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by 1 or 2 R6, R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b , SCF3 or 5-6 membered heteroaryl;

[0082] Alternatively, R4, R5 and the nitrogen atom to which they are attached together form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally substituted by 1, 2, 3 or 4 R x replace;

[0083] R x Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace;

[0084] R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace;

[0085] R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0086] R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0087] In another embodiment, the present invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0088] in,

[0089] R1 is selected from C 1-6 Alkyl, cyclopropyl or -CH2OH;

[0090] R2 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy or halogen;

[0091] R3 is selected from H, halogen, CN or methyl;

[0092] R4 and R5 are independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl; said 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by 1 or 2 R6, R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b , SCF3 or 5-6 membered heteroaryl;

[0093] Alternatively, R4, R5 and the nitrogen atom to which they are attached together form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally substituted by 1, 2, 3 or 4 R x replace;

[0094] R x Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace;

[0095] R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace;

[0096] R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0097] R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0098] In some embodiments of the compound of Formula (I) or (II), R1 is cyclopropyl.

[0099] In some embodiments of the compound of Formula (I) or (II), R1 is hydroxymethyl.

[0100] In some embodiments of the compound of formula (I) or (II), R1 is hydroxymethyl; R4 is H or C 1-6 alkyl; R5 is a 4-12 membered heterocyclyl; the 4-12 membered heterocyclyl is optionally substituted by 1 or 2 R6.

[0101] In some embodiments of the compound of formula (I) or (II), R1 is hydroxymethyl; R4 is H or C 1-6 alkyl; R5 is a 4-12 membered heterocyclyl; the 4-12 membered heterocyclyl is optionally substituted by 1 or 2 R6.

[0102] In some embodiments of the compound of formula (I) or (II), R1 is hydroxymethyl; R4, R5 and the nitrogen atom to which they are attached together form a 4-10 membered heterocyclic group, which is optionally substituted by 1, 2, 3 or 4 R x replace.

[0103] In another embodiment, the present invention provides a compound of formula (III-1), (III-1a) or (III-1b), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0104] in,

[0105] R2 is selected from H, methyl, ethyl, methoxy or F;

[0106] R3 is selected from H, F, Cl, CN or methyl;

[0107] R x1is selected from phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace;

[0108] R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace;

[0109] R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0110] R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0111] R x2 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0112] X is selected from -CH2-, O, S or -NR c -;

[0113] R c Selected from H or C 1-6 alkyl.

[0114] In another more specific embodiment, the present invention provides a compound of formula (III-1), (III-1a) or (III-1b) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0115] R2 is selected from H, methyl, ethyl, methoxy or F;

[0116] R3 is selected from H, F, Cl, CN or methyl;

[0117] R x1 is selected from phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace;

[0118] R y Selected from halogen, C 1-6Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace;

[0119] R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0120] R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0121] R x2 Selected from methyl, ethyl, trifluoromethyl or trifluoromethoxy;

[0122] X is selected from -CH2-, O or S.

[0123] In some embodiments, R2 is selected from H, methyl, or ethyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl.

[0124] In some embodiments, R3 is selected from H, F, or Cl. In some embodiments, R3 is F or Cl. In some embodiments, R3 is F.

[0125] In some embodiments, R x1 is selected from phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is optionally substituted by 1 R y Replacement; R y Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy, 5-10 membered heteroaryl or phenyl, the 5-10 membered heteroaryl or phenyl being optionally substituted by 1 R z Replacement; R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 In some embodiments, R Z is selected from methyl, ethyl, F, Cl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, ethoxy or isopropoxy.

[0126] In some embodiments, Rx2 C 1-6 In some embodiments, R x2 In some embodiments, R x2 It is a methyl group.

[0127] In some embodiments, X is O. In some embodiments, X is -CH2-. In some embodiments, X is S. In some embodiments, X is -NH-.

[0128] In some embodiments, R3 is F, and R x2 C 1-6 In some embodiments, R3 is F, and R x2 It is methyl or ethyl.

[0129] In another embodiment, the present invention provides a compound of formula (III-2), (III-2a) or (III-2b), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0130] in,

[0131] R2 is selected from H, methyl, ethyl, methoxy or F;

[0132] R3 is selected from H, F, Cl, CN or methyl;

[0133] R4 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 4-12 membered heterocyclic group;

[0134] R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b or a 5-6 membered heteroaryl group;

[0135] R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0136] X is selected from -CH2-, O, S or -NR c -;

[0137] Y is selected from CH or N;

[0138] R c Selected from H or C 1-6 alkyl;

[0139] m is 0, 1, or 2;

[0140] n is 0, 1, 2 or 3.

[0141] In another more specific embodiment, the present invention provides a compound of formula (III-3), (III-3a) or (III-3b), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0142] in,

[0143] R2 is selected from H, methyl, ethyl, methoxy or F;

[0144] R3 is selected from H, F, Cl, CN or methyl;

[0145] R4 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 4-12 membered heterocyclic group;

[0146] R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b , SCF3 or 5-6 membered heteroaryl;

[0147] R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0148] X is selected from -CH2-, O, S or -NR c -;

[0149] Y is selected from CH or N;

[0150] R c Selected from H or C 1-6 alkyl.

[0151] m is 0, 1 or 2.

[0152] In another embodiment, the present invention provides a compound of formula (IV-1), (IV-1a) or (IV-1b), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0153] in,

[0154] R2 is selected from H, methyl, ethyl, methoxy or F;

[0155] R3 is selected from H, F, Cl, CN or methyl;

[0156] R x1is selected from phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace;

[0157] R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace;

[0158] R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0159] R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0160] R x2 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0161] X is selected from -CH2-, O, S or -NR c -;

[0162] R c Selected from H or C 1-6 alkyl.

[0163] In another more specific embodiment, the present invention provides a compound of formula (IV-1), (IV-1a) or (IV-1b) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0164] R2 is selected from H, methyl, ethyl, methoxy or F;

[0165] R3 is selected from H, F, Cl, CN or methyl;

[0166] R x1 is selected from phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace;

[0167] R y Selected from halogen, C 1-6Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace;

[0168] R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0169] R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0170] R x2 Selected from methyl, ethyl, trifluoromethyl or trifluoromethoxy;

[0171] X is selected from -CH2-, O or S.

[0172] In some embodiments, R2 is selected from H, methyl, or ethyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl.

[0173] In some embodiments, R3 is selected from H, F, or Cl. In some embodiments, R3 is F or Cl. In some embodiments, R3 is F. In some embodiments, R3 is Cl.

[0174] In some embodiments, R x1 is selected from phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is optionally substituted by 1 R y In some embodiments, the 6-membered heteroaryl is pyridyl or pyrimidinyl. In some embodiments, the 6-membered heteroaryl is pyridyl.

[0175] In some embodiments, R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z Replacement; R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 In some embodiments, R y Selected from halogen, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6 haloalkoxy, pyridyl or phenyl, the pyridyl or phenyl being optionally substituted by 1, 2 or 3 R z Replacement; R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 In some embodiments, R z is selected from methyl, ethyl, F, Cl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy.

[0176] In some embodiments, R x2 C 1-6 In some embodiments, R x2 In some embodiments, R x2 It is a methyl group.

[0177] In some embodiments, X is O. In some embodiments, X is -CH2-. In some embodiments, X is S. In some embodiments, X is -NH-.

[0178] In another embodiment, the present invention provides a compound of formula (IV-2), (IV-2a) or (IV-2b) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0179] in,

[0180] R2 is selected from H, methyl, ethyl, methoxy or F;

[0181] R3 is selected from H, F, Cl, CN or methyl;

[0182] R4 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 4-12 membered heterocyclic group;

[0183] R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b , SCF3 or 5-6 membered heteroaryl;

[0184] R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0185] X is selected from -CH2-, O, S or -NR c -;

[0186] Y is selected from CH or N;

[0187] R c Selected from H or C 1-6 alkyl.

[0188] m is 0, 1, or 2;

[0189] n is 0, 1, 2 or 3.

[0190] In another more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein:

[0191] in:

[0192] R2 is selected from H, methyl, ethyl, methoxy or F;

[0193] R3 is selected from H, F, Cl, CN or methyl;

[0194] R4 is selected from H, methyl, ethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, azetidine, oxetane or tetrahydrofuranyl;

[0195] R6 is selected from H, CN, F, Cl, methyl, ethyl, trifluoromethyl, trifluoroethyl, SF5, methoxy, trifluoromethoxy, difluoromethoxy, pyridyl,

[0196] X is selected from -CH2-, O, S or -NH;

[0197] Y is selected from CH or N;

[0198] m is 1.

[0199] n is 0, 1, 2 or 3.

[0200] In some embodiments, R2 is selected from H, methyl, or ethyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl.

[0201] In some embodiments, R3 is selected from H, F, or Cl. In some embodiments, R3 is F or Cl. In some embodiments, R3 is F. In some embodiments, R3 is Cl.

[0202] In some embodiments, R4 is selected from H or C 1-6 In some embodiments, R4 is selected from C 1-6 In some embodiments, R4 is selected from methyl or ethyl.

[0203] In some embodiments, R6 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 In some embodiments, R6 is selected from halogen, C 1-6 Halogenated alkyl, C 1-6 In some embodiments, R6 is selected from H, F, Cl, trifluoromethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, pyridyl,

[0204] In some embodiments, X is selected from O or S; and Y is selected from CH or N. In some embodiments, X is O; and Y is CH or N. In some embodiments, X is O; and Y is N.

[0205] In some embodiments, m is 1.

[0206] In some embodiments, n is 0. In some embodiments, n is 1.

[0207] In another embodiment, the present invention provides a compound of formula (IV-3), (IV-3a) or (IV-3b) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0208] in,

[0209] R2 is selected from H, methyl, ethyl, methoxy or F;

[0210] R3 is selected from H, F, Cl, CN or methyl;

[0211] R4 is selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 4-12 membered heterocyclic group;

[0212] R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b , SCF3 or 5-6 membered heteroaryl;

[0213] R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0214] X is selected from -CH2-, O, S or -NRc -;

[0215] Y is selected from CH or N;

[0216] R c Selected from H or C 1-6 alkyl.

[0217] m is 0, 1 or 2.

[0218] In another more specific embodiment, the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein:

[0219] R2 is selected from H, methyl, ethyl, methoxy or F;

[0220] R3 is selected from H, F, Cl, CN or methyl;

[0221] R4 is selected from H, methyl, methyl-d3, ethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, azetidine, oxetane or tetrahydrofuranyl;

[0222] R6 is selected from H, CN, F, Cl, methyl, ethyl, trifluoromethyl, trifluoroethyl, SF5, methoxy, trifluoromethoxy, difluoromethoxy, pyridyl,

[0223] X is selected from -CH2-, O, S or -NH;

[0224] Y is selected from CH or N;

[0225] m is 1.

[0226] In some embodiments, R2 is selected from H, methyl, or ethyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl.

[0227] In some embodiments, R3 is selected from H, F, or Cl. In some embodiments, R3 is F or Cl. In some embodiments, R3 is F. In some embodiments, R3 is Cl.

[0228] In some embodiments, R4 is selected from H or C 1-6 In some embodiments, R4 is selected from C 1-6 In some embodiments, R4 is selected from methyl, methyl-d3 or ethyl.

[0229] In some embodiments, R6 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 In some embodiments, R6 is selected from halogen, C1-6 Haloalkyl or C 1-6 In some embodiments, R6 is selected from H, F, Cl, trifluoromethyl, trifluoroethyl, difluoromethoxy, or trifluoromethoxy.

[0230] In some embodiments, X is selected from O or S; and Y is selected from CH or N. In some embodiments, X is O; and Y is CH or N. In some embodiments, X is O; and Y is CH.

[0231] In some embodiments, m is 1.

[0232] In another more specific embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein the compound is selected from:

[0233] 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.

[0234] The compounds of the present invention may also exist as tautomers. For compounds that exist in different tautomeric forms, a compound is not limited to any specific tautomer, but is intended to encompass all tautomeric forms.

[0235] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (A) except that 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 (A) of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0236] Pharmaceutical compositions and kits

[0237] 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.

[0238] 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, aluminum oxide, 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.

[0239] 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.

[0240] Drug administration

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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 injection dose depends on the target systemic level of the active ingredient by the body, for example, the intramuscular or subcutaneous injection dose slowly releases the active ingredient, and the injection (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 the active ingredient of a steady-state concentration in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the injection dose can be first given, and then continuous infusion.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] The above components for oral administration, injection or topical administration are merely representative. Additional 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.

[0255] The compounds of the present 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.

[0256] 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 composed of 6, 7, and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar moiety, 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 comprises hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0257] Example

[0258] The reagents used in the present invention are commercial reagents purchased directly or synthesized using common methods well known in the art.

[0259] Notes on commonly used abbreviations:

[0260] pE = petroleum ether; EA = ethyl acetate; MeOH = methanol; DCM = dichloromethane; DCE = dichloroethane; CH3CN = acetonitrile; 1,4-dioxane = 1,4-dioxane; DMSO = dimethyl sulfoxide; HFIP = hexafluoroisopropanol; DMF = N,N-dimethylformamide; Hex = n-hexane; IPA = isopropanol; NMP = N-methylpyrrolidone; NMO = N-methylmorpholine-N-oxide; TEA = triethylamine; DIEA = diisopropylethylamine; CuI = cuprous iodide; CuCN = cuprous cyanide; triphosgene = triphosgene; p-TsOH = p-toluenesulfonic acid; TBAS = tetrabutylammonium hydrogen sulfate.

[0261] The specific reaction routes or steps exemplified below are used in the present invention, and are as follows:

[0262] Example 1

[0263] Preparation of key intermediates a1-a6

[0264] Synthesis of intermediates a1 and a2

[0265] Step 1: Under nitrogen, the raw materials 2-iodo-4-bromo-5-fluoroaniline a1-1 (10.0 g, 31.6 mmol), tributyl(1-ethoxyethylene)tin a1-2 (13.0 mL), and CuI (600 mg, 3.2 mmol) were dissolved in 200 mL of acetonitrile. The catalyst, Pd(PPh3)3Cl2 (2.2 g, 3.17 mmol), was added. The mixture was reacted at 80°C for 2 hours, after which the reaction was stopped. The mixture was filtered, the solvent was evaporated under reduced pressure, and the crude product was directly separated by flash column chromatography (PE / EA, 10 / 1) to afford compound a1-3 (5.0 g) in a 68% yield. LCMS ESI-MS m / z: 232 [M+H] + .

[0266] Step 2: Dissolve the intermediate a1-3 (5.0 g, 21.5 mmol) and cyclopropylacetonitrile a1-4 (3.5 g, 43.1 mmol) from the previous step in 50 mL of DMSO. Add potassium tert-butoxide (4.8 g, 43.1 mmol). The mixture is reacted at 50°C for 2 hours, and the reaction is stopped. Add 200 mL of water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is directly separated by flash column chromatography (PE / EA, 1 / 1) to obtain compound a1-5 (1.2 g) in a yield of 19%. LCMS ESI-MS m / z: 295 [M+H] + .

[0267] Step 3: Under nitrogen, compound a1-5 (1.2 g, 4.1 mmol), Zn(CN)2 (600 mg, 4.88 mmol), and bis(phenylphosphinoferrocene) (dppf) (200 mg, 0.41 mmol) were dissolved in 24 mL of DMF. Catalyst Pd2(dba)3 (0.04 mL, 0.13 mmol) was added. The mixture was heated to 100°C for 2 hours, and the reaction was stopped. 100 mL of water was added to the system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was directly separated by flash column chromatography (acetonitrile / water, 4 / 5) to obtain compound a1 (150 mg) in a yield of 15%.

[0268] LCMS ESI-MS m / z:242[M+H] + .

[0269] Referring to the synthetic route of intermediate a1, the following intermediate was synthesized.

[0270] Synthesis of intermediates a3-a5:

[0271] Step 1: Dissolve compound a3-1 (7.0 g, 28.2 mmol) in a mixture of 70 mL of ethanol and 70 mL of water. Add reduced iron powder (7.9 g, 141 mmol) and ammonium chloride (15.1 g, 282 mmol). The reaction mixture is heated to reflux for 3 hours, then stopped and filtered. Add 400 mL of ice water, extract with ethyl acetate, and concentrate. The crude product is separated by column chromatography to obtain a3-2 (5.3 g, 24.3 mmol) as a yellow solid in an 86% yield. LCMS ESI-MS m / z: 218 [M+H] + .

[0272] Step 2: Dissolve the intermediate a3-2 (5.3 g, 24.3 mmol) and cyclopropylacetonitrile a1-4 (3.9 g, 48.6 mmol) from the previous step in 55 mL of DMSO. After stirring for 5 minutes, potassium tert-butoxide (5.5 g, 48.6 mmol) was added to the system and the temperature was raised to 50°C for 2 hours. 150 mL of ice water was added to the system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography to obtain a3-3 (3.3 g, 11.7 mmol) as a yellow solid in a yield of 48%. LCMS ESI-MS m / z: 281 [M+H] + .

[0273] Step 3: Under nitrogen protection, the intermediate a3-3 (3.3 g, 11.7 mmol), catalyst Pd2(dba)3 (0.5 g, 0.59 mmol), and dppf (0.7 g, 1.2 mmol) from the previous step were dissolved in 66 mL of DMF, and Zn(CN)2 (1.7 g, 14.1 mmol) was added. The temperature was raised to 100°C and the reaction was allowed to proceed for 2 hours. The mixture was cooled to room temperature and filtered. 200 mL of ice water was added to the system, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The mixture was separated by flash column chromatography to obtain a3 (1.1 g, 4.84 mmol) as a yellow solid. Yield: 41%. LCMS ESI-MS m / z: 228 [M+H] + .

[0274] Referring to the synthetic route of intermediate a3, the following intermediate was synthesized.

[0275] Synthesis of intermediate a6:

[0276] Step 1: Under nitrogen, the raw materials 3-bromo-6-difluoromethoxypyridazine a6-1 (1.0 g, 4.5 mmol), vinylboronic acid pinacol ester a6-2 (2.0 g, 13.5 mmol), and sodium carbonate (1.4 g, 13.6 mmol) were dissolved in 20 mL of a mixture of 1,4-dioxane and water (v / v, 8 / 1). The catalyst, Pd(dppf)Cl2 (0.3 g, 0.45 mmol), was added. The mixture was heated to 80°C for 12 hours, cooled to room temperature, and filtered. Ice water (100 mL) was added to the mixture, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 5 / 1) to afford a6-3 (730 mg) as a white solid in a 94% yield. LCMS ESI-MS m / z: 262 [M+H] + .

[0277] Step 2: Dissolve the intermediate a6-3 (720 mg, 4.2 mmol) from the previous step in 12 mL of a mixture of acetone and water (v / v, 5 / 1). Add N-methylmorpholine-N-oxide (NMO) (1.7 g, 14.6 mmol) and K2OsO4.2H2O (154 mg, 0.41 mmol). React at room temperature for 1 hour, stop the reaction, and filter. Add 100 mL of ice water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash column chromatography (PE / EA, 2 / 1) to obtain a6-4 (360 mg) as a white solid in a yield of 42%. LCMS ESI-MS m / z: 207 [M+H] + .

[0278] Step 3: Dissolve the intermediate a6-4 (360 mg, 1.74 mmol) from the previous step in 17 mL of a mixture of tetrahydrofuran and water (v / v, 11 / 1). Add NaIO4 (11.2 g, 5.24 mmol) and react at room temperature for 1 hour. Stop the reaction and filter. Add 50 mL of ice water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain a6 (290 mg) as a white solid in a 95% yield. LCMS ESI-MS m / z: 175 [M+H] + .

[0279] Preparation of key intermediates b1-b7

[0280] Synthesis of intermediates b1-b5

[0281] Step 1: Dissolve intermediate a1 (150 mg, 0.62 mmol) in 3 mL of concentrated hydrochloric acid (35%) and heat to 100°C for 2 hours. Evaporate the solvent under reduced pressure, and separate the crude product by flash reverse-phase column chromatography (acetonitrile / water) to afford b1-1 (100 mg) as a yellow solid in a 62% yield. LCMS ESI-MS m / z: 261 [M+H] + .

[0282] Step 2: Dissolve the intermediate b1-1 (100 mg, 0.38 mmol) in 2 mL of thionyl chloride. Heat the reaction mixture to 70°C for 2 hours. Stop the reaction and concentrate the solvent under reduced pressure to obtain a yellow solid b1 (80 mg). Use it directly in the next step with a yield of 75%.

[0283] Referring to the synthetic route of intermediate b1, the following intermediate was synthesized.

[0284] Synthesis of intermediate b6

[0285] Step 1: Dissolve raw material b6-1 (1.2 g, 6.2 mmol) and cyclopropylacetonitrile a1-4 (1.0 g, 12.3 mmol) in 24 mL of DMSO. After stirring for 5 minutes, potassium tert-butoxide (1.4 g, 12.4 mmol) was added to the system and the temperature was raised to 50°C for 2 hours. Add 80 mL of ice water to the system, adjust the pH to approximately 5 with dilute hydrochloric acid, extract with ethyl acetate, and concentrate. The crude product was separated by flash reverse-phase column chromatography (acetonitrile / water) to obtain b6-2 (50 mg), a yellow solid, in a 4% yield. LCMS ESI-MS m / z: 243 [M+H] + .

[0286] Step 2: Dissolve intermediate b6-2 (50 mg, 0.21 mmol) in 0.5 mL of thionyl chloride. Heat the reaction mixture to 70°C for 2 hours. Stop the reaction and concentrate the solvent under reduced pressure to obtain a yellow solid b6 (50 mg), which is used directly in the next step. Yield: 93%.

[0287] Synthesis of intermediate b7

[0288] Step 1: Under nitrogen protection, raw material b6-1 (3.5 g, 19.5 mmol) and propionitrile (2.1 g, 39.0 mmol) were dissolved in 35 mL DMSO and added tBuOK (4.3 g, 39.0 mmol) was added to the reaction mixture, heated to 50°C for 2 hours, and then cooled to room temperature. 80 mL of ice water was added to the system, washed with ethyl acetate, and the aqueous phase was adjusted to a pH of approximately 7 with 1 M dilute hydrochloric acid. The mixture was filtered and the filter cake dried to obtain a yellow solid b7-2 (3.5 g, 17.3 mmol) in an 89% yield. LCMS ESI-MS m / z: 203 [M+H] + .

[0289] Step 2: Dissolve the intermediate b7-2 (500 mg, 2.4 mmol) in 10 mL of dichloromethane, add a solution of hydrogen chloride in 1,4-dioxane (0.7 mL, 4 M), react at room temperature for 30 minutes, and remove the solvent under reduced pressure. Add SOCl2 (4412 mg, 37.0 mmol) to the system, heat to 55°C and react for 1 hour, cool to room temperature, dilute with 10 mL of dichloromethane, filter, wash with n-hexane, and dry to obtain intermediate b7 (400 mg) in a yield of 73%.

[0290] Preparation of key intermediates C1-C9

[0291] Synthesis of intermediates C1-C9

[0292] Step 1: Under nitrogen, dissolve the starting materials 5-trifluoromethyl-pyridine-2-carbaldehyde c1-1 (558 mg, 3.53 mmol) and c1-2 (508 mg, 1.34 mmol) in 5.0 mL of dichloromethane. Add 4A molecular sieves (1.0 g) and react at room temperature for 12 hours. Stop the reaction. Filter, and concentrate the filtrate under reduced pressure to obtain c1-3 (600 mg) as a yellow oil. Yield: 84%. LCMS ESI-MS m / z: 537 [M+H]. + .

[0293] Step 2: Under nitrogen protection, 2,6-lutidine (48 mg, 0.45 mmol) and catalyst Cu(OTf)2 (162 mg, 0.45 mmol) were dissolved in 3 mL of hexafluoroisopropanol and reacted at room temperature for 7 hours. Intermediate c1-3 (600 mg, 1.12 mmol) was added dropwise to the reaction solution. After the addition was complete, the reaction was continued for 10 hours and then stopped. 6 mL of ammonia water was added to the reaction solution, stirred for 1 hour, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 1 / 1) to obtain intermediate cis-configuration c1 (140 mg) in a yield of 51%. LCMS ESI-MS m / z: 247 [M+H] + .

[0294] Referring to the synthetic route of compound c1, the following target molecule was synthesized using a similar skeleton structure. Cis = cis enantiomer

[0295] Preparation of key intermediates d1-d7

[0296] Synthesis of intermediates d1-d3

[0297] Step 1: Under nitrogen, dissolve the raw material 2-hydroxy-4-trifluoromethylbenzaldehyde d1-1 (1.0 g, 5.26 mmol) and a tetrahydrofuran solution of methylamine (5.3 mL, 2 M) in 20 mL of anhydrous dichloromethane. Add magnesium sulfate (2.5 g, 21.0 mmol) and allow to react at room temperature for 12 hours, then stop the reaction. Filter and concentrate the filtrate under reduced pressure to obtain d1-2 (470 mg), a yellow solid, in a 44% yield. LCMS ESI-MS m / z: 204 [M+H] + .

[0298] Step 2: Under nitrogen protection, trimethylsulfoxide iodide (1.27 g, 5.78 mmol) and potassium tert-butoxide (649 mg, 5.78 mmol) were dissolved in 13 mL of anhydrous tetrahydrofuran and stirred for 30 minutes. Intermediate d1-2 (470 mg, 2.31 mmol) was added to the reaction solution, the temperature was raised to 50 ° C for 4 hours, and then cooled to room temperature. Potassium tert-butoxide (260 mg, 2.31 mmol) was added to the reaction solution, and the reaction was continued at room temperature for 12 hours, the reaction was stopped, and filtered. The solvent was evaporated under reduced pressure, and the crude product was separated by flash reverse column chromatography (acetonitrile / water, 1 / 1) to obtain white d1 (40 mg), yield: 8%. LCMS ESI-MS m / z: 218 [M+H] + .

[0299] Referring to the synthetic route of intermediate d1, the following intermediate was synthesized.

[0300] Synthesis of intermediate d4:

[0301] Step 1: Under nitrogen, raw materials d4-1 (12.2 g, 81.0 mmol) and d4-2 (13.6 g, 81.0 mmol) were dissolved in 20 mL of acetic acid. Ammonium acetate (12.5 g, 162 mmol) was added, and the temperature was raised to 120°C for 1 hour. The mixture was then cooled to room temperature. 100 mL of ice water was added to the reaction solution, and the mixture was extracted three times with methyl tert-butyl ether. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 20 / 1) to obtain d4-3 (10.5 g) as a white solid in a 51% yield. LCMS ESI-MS m / z: 254 [M+H] + .

[0302] Step 2: Under nitrogen, the intermediate d4-3 (10.5 g, 41.4 mmol) and methyl 2-hydroxyacetate (7.5 g, 82.8 mmol) from the previous step were dissolved in 105 mL of DMF. NaH (3.3 g, 82.8 mmol, 60%) was added and the mixture was allowed to react at room temperature for 2 hours. 300 mL of ice water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford d4-4 (5.0 g) as a yellow oil in a 44% yield. LCMS ESI-MS m / z: 276 [M+H] + .

[0303] Step 3: Dissolve the intermediate d4-4 (5.0 g, 18.2 mmol) from the previous step in 50 mL of ethanol, add concentrated hydrochloric acid (100 mL, 12 M), heat to 100°C, react for 1 hour, and cool to room temperature. Add 300 mL of aqueous ammonia dropwise to the reaction solution, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash column chromatography (PE / EA, 10 / 1) to obtain d4-5 (366 mg) as a yellow solid in a 9% yield. LCMS ESI-MS m / z: 218 [M+H] + .

[0304] Step 4: Under nitrogen protection, the intermediate d4-5 (110 mg, 0.51 mmol) and a tetrahydrofuran solution of methylamine (1.3 mL, 2 M) were dissolved in 1 mL of trifluoroethanol and stirred at room temperature for 16 hours. NaBH4 (96 mg, 2.5 mmol) and 0.25 mL of methanol were added to the reaction solution, and the reaction was continued at room temperature for 1 hour to stop the reaction. The filtrate was filtered and concentrated under reduced pressure. The crude product was separated by flash reverse column chromatography (acetonitrile / water, 7 / 10) to obtain a white solid d4 (60 mg) with a yield of 51%. LCMS ESI-MS m / z: 233 [M+H] + .

[0305] Synthesis of intermediate d5:

[0306] Step 1: Under nitrogen, the raw material 3-bromo-6-chloropyridine-2-methanol d5-1 (6.0 g, 27.0 mmol) and the raw material allyl bromide d5-2 (4.9 g, 40.5 mmol) were dissolved in 120 mL of tetrahydrofuran. KOH (3.0 g, 53.9 mmol) and TBAS (1.4 g, 4.1 mmol) were added and reacted at room temperature for 12 hours, after which the reaction was stopped. 100 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 80 / 1) to obtain a colorless oil d5-3 (5.0 g) in a yield of 71%. LCMS ESI-MS m / z: 262 [M+H] + .

[0307] Step 2: Under nitrogen, the intermediate d5-3 (5.0 g, 19.1 mmol) and cesium carbonate (7.5 g, 22.9 mmol) from the previous step were dissolved in 105 mL of 1,4-dioxane. The catalyst, Pd(PPh3)4 (4.4 g, 3.8 mmol), was added. The reaction mixture was heated to 100°C for 12 hours, cooled to room temperature, and filtered. 100 mL of ice water was added to the filtrate, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 10 / 1) to obtain d5-4 (1.3 g), a pale yellow solid, in a yield of 38%. LCMS ESI-MS m / z: 182 [M+H] + .

[0308] Step 3: Dissolve the intermediate d5-4 (1.3 g, 7.2 mmol) in 30 mL of a mixture of acetone and water (v / v, 5 / 1). Add K2OsO4.2H2O (264 mg, 0.72 mmol) and NMO (2.9 g, 25.1 mmol) and allow to react at room temperature for 2 hours. Saturated aqueous sodium sulfite solution was added to the reaction mixture to quench the reaction. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford d5-5 (1.3 g) as an oil in an 84% yield. LCMS ESI-MS m / z: 216 [M+H] + .

[0309] Step 4: Under nitrogen, the intermediate d5-5 (1.3 g, 6.0 mmol) from the previous step was dissolved in 25 mL of a mixture of tetrahydrofuran and water (v / v, 5 / 1). NaIO4 (3.2 g, 15.1 mmol) was added and stirred at room temperature for 1 hour to stop the reaction. 50 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse column chromatography (acetonitrile / water, 3 / 8) to obtain d5-6 (900 mg) as a white solid in a yield of 51%. LCMS ESI-MS m / z: 184 [M+H] + .

[0310] Step 5: Under nitrogen protection, the intermediate d5-6 (900 mg, 4.9 mmol) and methylamine aqueous solution (24.5 mmol, 2.5 mL) from the previous step were dissolved in 6 mL of trifluoroethanol and stirred at room temperature for 4 hours. Methanol (3.6 mL) and reducing agent NaBH4 (927 mg, 24.5 mmol) were added to the reaction solution, and the reaction solution was reacted under an ice bath for 1 hour. Saturated sodium bicarbonate aqueous solution was added to the reaction solution to quench the reaction. Extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (acetonitrile / water, 7 / 10) to obtain a white solid d5 (500 mg) with a yield of 51%. LCMS ESI-MS m / z: 199 [M+H] + .

[0311] Synthesis of intermediates d6-d8:

[0312] Under nitrogen, intermediate d5 (80 mg, 0.4 mmol), starting material d6-1 (218 mg, 0.8 mmol), and potassium carbonate (112 mg, 0.8 mmol) were dissolved in 2 mL of a mixture of 1,4-dioxane and water (v / v, 4 / 1). Catalyst Pd(dppf)Cl2 (30 mg, 0.04 mmol) was added, and the mixture was heated to 80°C for 1 hour. The mixture was cooled to room temperature and filtered. The filtrate was added with 20 mL of ice water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (acetonitrile / water, 3 / 5) to afford d6 (80 mg) as a pale yellow solid in a 51% yield. LCMS ESI-MS m / z: 310 [M+H] + .

[0313] Referring to the synthetic route of intermediate d6, the following intermediate was synthesized.

[0314] Preparation of key intermediates e1-e6

[0315] Synthesis of intermediates e1-e3

[0316] Step 1: In an ice bath, under nitrogen protection, the raw material methyl propiolate e1-1 (2.1 g, 24.9 mmol) and the raw material 2,6-dimethylpyridine e1-2 (2.7 g, 24.9 mmol) were dissolved in 42 mL of chloromethane. TsN3 (4.1 g, 20.8 mmol) and catalyst CuI (400 mg, 2.08 mmol) were slowly added. The reaction was allowed to proceed for 4 hours in an ice bath, and the reaction was stopped. The solvent was evaporated under reduced pressure, dissolved in ethyl acetate, and the precipitated solid was filtered and dried to obtain a white solid e1-3 (2.5 g). Yield: 33%. LC-MS: [M+H] + =361.

[0317] Step 2: Under nitrogen, the intermediate e1-3 (2.5 g, 6.94 mmol) and 2-amino-4-bromoacetophenone e1-4 (1.5 g, 6.94 mmol) from the previous step were dissolved in 50 mL of dichloroethane. The mixture was heated to 90°C and reacted for 4 hours, after which the reaction was stopped. The solvent was evaporated under reduced pressure to obtain the crude product e1-5 (3.0 g). LC-MS: [M+H] + =450.

[0318] Step 3: Dissolve the crude product e1-5 (3.0 g, 6.68 mmol) from the previous step in 63 mL of dichloromethane in an ice bath. Add concentrated sulfuric acid (1.3 g, 13.4 mmol) dropwise. After completion of the addition, react at room temperature for 1 hour and stop the reaction. The reaction solution is slowly poured into ice water and the pH is adjusted to approximately 9 with saturated sodium bicarbonate aqueous solution. Extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse column chromatography (acetonitrile / water, 4 / 5) to obtain e1-6 (1.5 g) as a yellow solid in a yield of 76%. LC-MS: [M+H] + =297.

[0319] Step 4: Dissolve the intermediate e1-6 (3.0 mL, 2.5 M) in 30 mL of anhydrous tetrahydrofuran under an ice bath and nitrogen. Slowly add a solution of LiAlH4 in tetrahydrofuran (1.3 g, 13.4 mmol) dropwise. Allow to react at room temperature for 1 hour, then stop the reaction. Pour the reaction solution slowly into ice water, filter, and concentrate the filtrate under reduced pressure to obtain a yellow oil e1-7 (1.0 g) in a 74% yield. LC-MS: [M+H] + =268.

[0320] Step 5: Under nitrogen, the intermediate e1-7 (1.0 g, 3.74 mmol) and zinc cyanide (500 mg, 4.49 mmol) from the previous step were dissolved in 20 mL of anhydrous DMF. The ligand dppf (200 mg, 0.37 mmol) and the catalyst Pd2(dba)3 (200 mg, 0.19 mmol) were added. The temperature was raised to 100°C and the reaction was allowed to react for 2 hours, after which the reaction was stopped. 100 mL of ice water was added to the reaction solution, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate solution, 4 / 5) to obtain e1-8 (400 mg) as a yellow oil in a 50% yield. LC-MS: [M+H] + =214.

[0321] Step 6: Dissolve the intermediate e1-8 (400 mg, 1.88 mmol) from the previous step in 8 mL of ethanol, slowly add an aqueous NaOH solution (8.0 mL, 50%), heat to 80°C, and react for 4 hours to stop the reaction. The reaction solution was slowly poured into ice water, and the pH was adjusted to approximately 3 with dilute hydrochloric acid. Extraction was performed with ethyl acetate, and the crude product was separated by flash reverse column chromatography (acetonitrile / water, 3 / 5) to obtain a gray solid e1 (300 mg) in a yield of 69%. LC-MS: [M+H] + =233.

[0322] Referring to the synthetic route of compound e1, similar raw materials / intermediates were used to synthesize the following target molecular intermediates.

[0323] Synthesis of intermediates e4-e6

[0324] Procedure: Under nitrogen, dissolve intermediate e1 (320 mg, 1.37 mmol) in 3.2 mL of thionyl chloride, heat to 70°C, and react for 1 hour. The reaction is then terminated. Evaporate the solvent under reduced pressure to afford a yellow solid, e4 (320 mg), in an 86% yield. This solid was used directly in the next reaction.

[0325] Referring to the synthetic route of compound d4, similar raw materials / intermediates were used to synthesize the following target molecular intermediates.

[0326] Preparation of key intermediates f1-f2

[0327] Synthesis of intermediate f1-f2

[0328] Step 1: Dissolve the raw material f1-1 (8.8 g, 41.3 mmol) in 88 mL of anhydrous tetrahydrofuran at -78°C under nitrogen. Slowly add a tetrahydrofuran solution of LiHMDS (10.4 g, 61.9 mmol, 61.9 mL) dropwise. Stir at -78°C for 1.5 hours. Add N-phenylbis(trifluoromethanesulfonyl)imide (20.1 g, 51.6 mmol) to the reaction solution, warm to room temperature, and react for 2 hours before stopping the reaction. Add 50 mL of ice water to the reaction solution, extract with methyl tert-butyl ether, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse column chromatography (acetonitrile) to obtain f1-2 (10.1 g) as a red oil in a yield of 71%. LCMS ESI-MS m / z: 346 [M+H] + .

[0329] Step 2: Under nitrogen, the oil from the previous step, f1-2 (2.1 g, 6.08 mmol), 5-boronic acid pinacol ester-1,3-benzothiazole f1-3 (1.1 g, 7.62 mmol), and sodium carbonate (1.9 g, 18.2 mmol) were dissolved in 40 mL of a mixture of 1,4-dioxane and water (v / v, 3 / 1). Catalyst Pd(dppf)Cl2 (220 mg, 0.30 mmol) was added. The mixture was heated to 80°C and reacted for 2 hours, after which the reaction was stopped. The mixture was filtered, 100 mL of water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to afford f1-4 (2.7 g), a white solid, in a 96% yield. LCMS ESI-MS m / z: 331 [M+H] + .

[0330] Step 3: Dissolve the white solid f1-4 (2.7 g, 8.17 mmol) from the previous step in 15 mL of trifluoroacetic acid and allow to react at room temperature for 1 hour. The reaction was then stopped. The solvent was evaporated under reduced pressure, and the reaction mixture was adjusted to pH 8 by adding saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to afford a yellow oil f1-5 (1.8 g) in a 96% yield. LCMS ESI-MS m / z: 231 [M+H] + .

[0331] Step 4: Dissolve the oil f1-5 (1.0 g, 4.34 mmol) in 20 mL of methanol in an ice bath. Add the reducing agent NaBH4 (250 mg, 6.51 mmol). React for 1 hour in an ice bath to stop the reaction. Add 100 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse column chromatography (acetonitrile / water, 3 / 5) to obtain a yellow oil f1 (370 mg) in a yield of 37%. LCMS ESI-MS m / z: 233 [M+H]+ .

[0332] Referring to the synthetic route of compound f1, similar starting materials / intermediates were used to synthesize the following target intermediates: Trans = trans enantiomer.

[0333] Chiral resolution of key intermediate f3-f4

[0334] Synthesis of intermediates f3-f4

[0335] Separation conditions: Chromatographic column: CHIRALPAK IF, 5*25 cm, 5 μm; Mobile phase A: Hex (0.5% 2M NH3 methanol solution); Mobile phase B (EtOH); Flow rate: 20 mL / min;);

[0336] f1 (retention time: 4.807 min);

[0337] f2 (retention time: 5.943 min).

[0338] Example 2: Synthesis of target molecules P1-P12

[0339] Step 1: At room temperature, intermediate c1 (71 mg, 0.29 mmol) and triethylamine (145 mg, 1.44 mmol) were dissolved in 2 mL of dichloromethane. A solution of intermediate b1 (81 mg, 0.29 mmol, 0.5 mL) in dichloromethane was added dropwise. The mixture was reacted at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the crude product was separated by preparative HPLC chromatography (mobile phase: acetonitrile / water, 4 / 5) to obtain compound P1 (40 mg) in a yield of 29%. LCMS ESI-MS m / z: 489 [M+H] + .

[0340] Step 2: Compound P1 is separated by SFC chiral column chromatography to obtain compounds P1a and P1b.

[0341] Separation conditions: (chromatographic column: CHIRAL ART Cellulose-SC 2*25 cm, 5 μm; mobile phase A: Hex:DCM=3:1 (0.5% 2M NH 3 -MeOH); mobile phase B: IPA; flow rate: 20 mL / min).

[0342] Retention time: 17.604 min (P1a); 20.403 min (P1b).

[0343] P1a: 1H NMR (400MHz, DMSO-d6) δ9.11-8.96 (m, 1H), 8.25 (s, 1H), 7.97 (d, J=7.5Hz, 1H), 7.79 (s, 1H), 7.24 (s, 1H), 6.72 (s, 2H), 5.73 (s, 1H), 5.12 (s, 1H), 3.88-3.49 (m, 4H), 2.78-2.54 (m, 3H), 1.63 (s, 1H), 1.20 (d, J=31.9Hz, 3H), 0.78 (s, 2H), 0.48 (s, 2H).

[0344] P1b: 1 H NMR (400MHz, DMSO-d6) δ9.11-8.96 (m, 1H), 8.25 (s, 1H), 7.97 (d, J=7.5Hz, 1H), 7.79 (s, 1H), 7.24 (s, 1H), 6.72 (s, 2H), 5.73 (s, 1H), 5.12 (s, 1H), 3.88-3.49 (m, 4H), 2.78-2.54 (m, 3H), 1.63 (s, 1H), 1.20 (d, J=31.9Hz, 3H), 0.78 (s, 2H), 0.48 (s, 2H).

[0345] Referring to the synthetic route of compound P1, similar raw materials or intermediates were used to synthesize the following target molecules.

[0346] Cis represents that the compound is in cis configuration and is not split;

[0347] *Indicates chiral center, which was not resolved.

[0348] Example 3: Synthesis of target molecules H1-H3, H6-H7

[0349] Step 1: Under nitrogen, intermediate d1 (41 mg, 0.18 mmol) and triethylamine (93 mg, 0.92 mmol) were dissolved in 2 mL of dichloromethane. A solution of intermediate b5 (41 mg, 0.18 mmol, 0.5 mL) in dichloromethane was added dropwise. The mixture was reacted at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the crude product was separated by preparative HPLC (mobile phase: acetonitrile / water, 4 / 5) to obtain the target molecule H1 (12 mg) in a 15% yield. LCMS ESI-MS m / z: 428 [M+H] + .

[0350] 1 H NMR (400MHz, DMSO-d6) δ7.79 (s, 1H), 7.70 (s, 1H), 7.62 (d, J=7.8Hz, 1H), 7.57-7.46 (m, 2H), 7.33 (d, J=7.8Hz, 1H), 7.26 (s, 1H), 6.65 (s, 2H) ), 6.35 (s, 1H), 4.80 (s, 1H), 4.71 (dd, J=10.4, 4.5Hz, 1H), 2.65 (s, 3H), 1.89-1.76 (m, 1H), 1.02-0.90 (m, 2H), 0.67 (dt, J=5.6, 2.8Hz, 2H).

[0351] Referring to the synthetic route of compound H1, similar raw materials or intermediates were used to synthesize the following target molecules.

[0352] *Indicates chiral center, which was not resolved.

[0353] Example 4: Synthesis of target molecules H4-H5

[0354] Step 1: Under nitrogen, intermediate d3 (500 mg, 2.19 mmol) and triethylamine (1.11 g, 11.0 mmol) were dissolved in 12 mL of dichloromethane. A solution of intermediate b5 (541 mg, 2.19 mmol, 2 mL) in dichloromethane was added dropwise. The mixture was reacted at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the crude product was separated by preparative HPLC (mobile phase: acetonitrile / water, 9 / 10) to afford H4-1 (512 mg) as a white solid in a 52% yield. LCMS ESI-MS m / z: 438 [M+H] + .

[0355] Step 2: Under nitrogen, compound H4-1 (70 mg, 0.16 mmol), 1-N-methyl-4-pyrazoleboronic acid pinacol ester H4-2 (67 mg, 0.32 mmol), and potassium carbonate (66 mg, 0.48 mmol) were dissolved in 2 mL of a mixture of 1,4-dioxane and water (v / v, 3 / 1). Catalyst Pd(dppf)Cl2 (23 mg, 0.03 mmol) was added. After stirring for 5 minutes, the mixture was heated to 90°C and reacted for 2 hours before cooling to room temperature. The solvent was evaporated under reduced pressure, and the crude product was separated by reverse-phase flash column chromatography (acetonitrile / water, 9 / 10) to obtain the target molecule H4 (60 mg) in an 83% yield. LCMS ESI-MS m / z: 440 [M+H] + .

[0356] 1 H NMR (400MHz, DMSO-d6) δ8.15 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.54 (dd, J=8.5, 1.9Hz, 1H), 7.49 (d, J=8.7Hz, 1H), 7.34 (d, J=7.8Hz, 1H), 7.18 (d, J=7.7Hz, 1H), 7.10 (s, 1H), 6.63 (s, 2H), 4.69 (s, 1H), 4.59 (dd, J=10.3, 4.0Hz, 1H), 3.86 (s, 3H), 3.83 (d, J=7.3Hz, 1H), 2.64 (s, 3H), 1.911.79 (m, 1H), 1.04-0.94 (m, 2H), 0.70-0.61 (m, 2H).

[0357] Referring to the synthetic route of compound H4, similar raw materials or intermediates were used to synthesize the following target molecules.

[0358] *Indicates chiral center, which was not resolved.

[0359] Example 5: Synthesis of target molecules A1-A13

[0360] Step 1: Dissolve intermediate c1 (43 mg, 0.17 mmol) and triethylamine (88 mg, 0.87 mmol) in 2 mL of dichloromethane in an ice bath. Add a dichloromethane solution of intermediate e5 (51 mg, 0.17 mmol, 1 mL) dropwise, and incubate at room temperature for 1 hour. Evaporate the solvent under reduced pressure, and separate the crude product by flash reverse-phase column chromatography (acetonitrile / water, 4 / 5) to afford A1-1 (71 mg) as a yellow solid in an 81% yield. LCMS ESI-MS m / z: 497 [M+H] + .

[0361] Step 2: Under nitrogen, compound A1-1 (70 mg, 0.14 mmol) from the previous step was dissolved in 3 mL of a mixture of tetrahydrofuran and water (v / v, 1 / 1). KCO (78 mg, 0.56 mmol) was added and stirred for 5 minutes. The mixture was then heated to 60°C and allowed to react for 10 hours before cooling to room temperature. The solvent was evaporated under reduced pressure, and the crude product was separated by reverse-phase flash column chromatography (acetonitrile / water, 4 / 5) to obtain the target molecule A1 (55 mg) in an 82% yield. LCMS ESI-MS m / z: 479 [M+H] + .

[0362] Step 3: Compound A1 (55 mg) was separated by SFC chiral column chromatography. Separation conditions: chromatographic column: Chiral ART Cellulose-SA, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; A1a retention time: 11.935 min; A1b retention time: 15.066 min.

[0363] A1a: 1 H NMR (300MHz, DMSO-d6) δ9.00 (s, 1H), 8.23 ​​(s, 1H), 8.00 (d, J=7.6Hz, 1H), 7.79 (s, 1H), 7.21 (s, 1H), 6.49 (s , 2H), 5.71 (s, 1H), 5.11 (s, 2H), 4.57 (d, J=5.2Hz, 2H), 3.89-3.50 (m, 3H), 2.71-2.49 (m, 3H), 0.77 (s, 3H).

[0364] A1b: 1 H NMR (300MHz, DMSO-d6) δ9.00 (s, 1H), 8.23 ​​(s, 1H), 8.00 (d, J=7.7Hz, 1H), 7.79 (s, 1H), 7.21 (s, 1H), 6.49 (s, 2H) , 5.71 (s, 1H), 5.13 (d, J = 5.4Hz, 2H), 4.57 (d, J = 4.9Hz, 2H), 3.93-3.53 (m, 3H), 2.72-2.49 (m, 3H), 0.77 (s, 3H).

[0365] Referring to the synthetic route of compound A1, similar raw materials or intermediates were used to synthesize the following target molecules.

[0366] *Indicates chiral center, which was not resolved.

[0367] Example 6:

[0368] MTAP-deficient cells are sensitive to PRMT5-MTA inhibitors due to the accumulation of MTA. However, MTAP wild-type (MTAP normal) cells do not accumulate MTA and are independent of PRMT5. By testing the activity of both, the inhibitory and selectivity of the molecules of the present invention for PRMT5 at the cellular level were demonstrated.

[0369] HCT116 wild-type and MTAP-deficient cells were cultured in MCCOYS 5A medium containing 10% FBS and 1% penicillin-streptomycin, placed in a 37°C, 5% CO2 constant temperature incubator, and 40 μL of cell suspension was added to each well of a 384-well microplate. 40 nL of compounds of different concentrations were added to each well using Echo and placed in a 37°C, 5% CO2 constant temperature incubator for 7-10 days. 40 μL of CTG solution (Promega, CatNo. G7573) was added to each well and placed in a 37°C, 5% CO2 constant temperature incubator incubated in the dark for 30 minutes. The luminescence value was read using an Envision multifunctional microplate reader (Perkin Elmer, catalog number Envision 2104). The light signal is proportional to the amount of ATP in the system, and the ATP content directly characterizes the number of viable cells in the system.

[0370] IC 50 Value calculation:

[0371] Y=lower platform signal+(upper platform signal-lower platform signal) / (1+10^((LogIC 50 -X) × Hill slope)

[0372] X: log value of compound concentration

[0373] Y: Inhibition rate (%)

[0374] Table 1: 2D anti-proliferative effects of compounds on HTC116-MTAP del and wild type colorectal cancer HCT-116 cell lines.

[0375] ND = Not Tested

[0376] The above experimental results show that the excellent compounds of the present invention have a significant anti-proliferative effect on MTAP-deficient tumor cells by inhibiting PRMT5, while the inhibition on the wild type is weak. The selectivity of some molecules is very high (greater than 50 times), which is expected to bring higher safety. The selectivity of the control molecule AM9747 is only about 30 times, and the dose may be limited in clinical use due to low selectivity. TNG908, which has just entered clinical phase 1, has only 23-fold selectivity; in addition, GSK3326595 has been temporarily terminated in the clinic due to insufficient selectivity. Therefore, the high selectivity of the present invention is expected to reduce side effects and improve efficacy in clinical use.

[0377] The above experimental results show that the substitution of R2 and R3 has a greater impact on the activity compared with P2b and P1 or P4.

[0378] Example 7:

[0379] The compound's liver microsome stability test is as follows:

[0380] The compounds of the present invention were subjected to a liver microsome stability test. The test compounds were co-incubated with liver microsomes of different species with or without the addition of NADPH. The final concentration of the test compound in the test system was 1 μM, the final concentration of NADPH was 1 mM, and the final concentration of liver microsomes was 0.5 mg / mL. The concentration of the compound in the incubation supernatant at different time points within 60 minutes was measured and the pharmacokinetic parameters (such as clearance Cl) were calculated. int ).

[0381] This result indicates that the molecules of the present invention have good metabolic stability (especially in the human body). Some molecules have a lower clearance rate in human liver microsome metabolism than AM9747, resulting in slower metabolism in the human body.

[0382] ND = Not Tested

[0383] Example 8:

[0384] Membrane permeability evaluation experiment: Caco-2 assays

[0385] The membrane permeability of the molecules of the present invention will be evaluated. Samples will be analyzed by LC-MS to estimate the apparent permeability coefficient (P) of the compounds in Caco-2 monolayer cells. app ), where the pH of the apical compartment is 6.5 and the pH of the basolateral compartment is 7.4. Active efflux transport of compounds was blocked by inhibitors of the P-gp efflux transporter, BCRP, and MRP2 (50 μM quinidine, 30 μM benzbromarone, and 20 μM sulfasalazine). Data were used to calculate the apparent permeability (Papp).

[0386] P app =(V A ×[drug] acceptor ) / (Area×Time×[drug]initial,donor)

[0387] Where V A is the volume of the receptor pore (unit: mL), Area is the surface area of ​​the membrane (0.143 cm for Transwell-96 well permeable support) 2 ), time is the total transport time (in seconds).

[0388] Efflux Ratio=P app (B-A ) / P app ( A-B )

[0389] The Caco-2 membrane permeation data of the molecule of the present invention are as follows:

[0390] The above results indicate that the molecules of the present invention have good membrane permeability, especially compounds A9 and A9a, which have extremely low efflux rates (efflux < 2), and are expected to achieve good tumor inhibition effects with better in vivo pharmacokinetic properties.

[0391] Example 9:

[0392] Membrane permeability evaluation experiments: MDCK-MDR1 assays

[0393] The membrane permeability of the molecules of the present invention is evaluated to predict the permeability of the molecules to the brain.

[0394] The details are as follows: 1. Incubate MDCK-MDR1 cells in advance, density: 1.56*10 6 cells / mL, seeded in 96-well plates, and cultured at 37°C for 7 days. 2. Remove the MDCKII-MDR1 plates from the incubator, wash twice with prewarmed HBSS (10 mM HEPES, pH 7.4), and then incubate at 37°C for 30 minutes. 3. Dilute the stock solution of the test compound with DMSO to a 0.2 mM solution, which is then diluted with HBSS (10 mM HEPES, pH 7.4) to a 1 μM working solution. A blank control group was diluted with DMSO to a 0.2 mM solution, which was then diluted with HBSS (10 mM HEPES, pH 7.4) to a 1 μM working solution. The final DMSO concentration in the culture system was 0.5%. 4. Determine the rate of drug transport in the apical to basolateral direction. Add 125 μL of the 1 μM test compound solution to the Transwell insert (top chamber), and immediately transfer a 50 μL sample (D0 sample) from the top chamber to a new 96-well plate. Fill the receiver plate wells (basolateral compartment) with 235 μL of HBSS (10 mM HEPES, pH 7.4) and incubate at 37°C for 2 hours. 5. At the end of the incubation period, transfer 50 μL of each donor and acceptor sample to a new well of a 96-well plate and add 4 volumes of cold acetonitrile containing the appropriate internal standard (IS). Before LC-MS / MS analysis, mix 100 μL of the supernatant with an appropriate volume of ultrapure water.

[0395] P app =(V A ×[drug] acceptor ) / (Area×Time×[drug]initial,donor)

[0396] Where V A is the volume of the receptor pore (unit: mL), Area is the surface area of ​​the membrane (0.143 cm for Transwell-96 well permeable support) 2 ), time is the total transport time (in seconds).

[0397] Efflux Ratio=P app ( B-A ) / P app ( A-B )

[0398] The MDCK-MDR1 membrane permeation data of the molecule of the present invention are as follows:

[0399] The above results indicate that the molecules of the present invention have good membrane permeability, especially compound A9a, which has an extremely low efflux rate (efflux 1.2), and is expected to have a good brain concentration when administered in vivo.

[0400] Example 10:

[0401] Mouse pharmacokinetic evaluation experiment

[0402] CD1 female mice were used as test animals and the drug was administered orally / intravenously (oral dosage: 10 mg / kg, intravenous dosage: 2 mg / kg).

[0403] Vehicle (intravenous: 5% DMSO + 95% deionized water containing 20% ​​HP-β-CD; oral: 0.1% Tween 80 + 0.5% methylcellulose + 99.4% deionized water).

[0404] Experimental plan: Oral administration: 3 mice per group, intravenous administration: 3 mice per group. Oral administration: Plasma samples were collected before (0 h) and after (0.25, 0.5, 1, 2, 4, 8, 24 h) administration; intravenous administration: Plasma samples were collected before (0 h) and after (0.083, 0.25, 0.5, 1, 2, 4, 8, 24 h) administration. Plasma concentrations in mice after oral and intravenous administration were determined using LC / MS / MS. The collected data were calculated using AB Sciex QTRAP 6500 software. The experimental results are as follows:

[0405] The above experimental results show that the compound of the present invention has good oral absorption effect and high in vivo exposure. Since its selectivity and in vivo exposure are better than those of reported molecules such as AM9747, it is expected to bring higher therapeutic effects.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: in, R1 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or -CH2OR a ; R a Selected from H or methyl; R2 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy or halogen; R3 is selected from H, halogen, OR b 、CN、C 1-6 Alkyl or C 1-6 alkyl halide; R4 and R5 are independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl; said 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by 1 or 2 R6, R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b , SCF3, or 5-6 membered heteroaryl; Alternatively, R4, R5 and the nitrogen atom to which they are attached together form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally substituted by 1, 2, 3 or 4 R x replace; R x Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace; R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace; R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy; R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; 2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which is a compound of formula (II): in, R1 is selected from C 1-6 Alkyl, cyclopropyl or -CH2OH; R2 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy or halogen; R3 is selected from H, halogen, CN or methyl; R4 and R5 are independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl; said 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by 1 or 2 R6, R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b , SCF3 or 5-6 membered heteroaryl; Alternatively, R4, R5 and the nitrogen atom to which they are attached together form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally substituted by 1, 2, 3 or 4 R x replace; R x Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace; R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace; R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy; R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the following structure: in, Each group is as defined in claim 1 or 2.

4. The compound of claim 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R2 is selected from H, methyl, ethyl, methoxy or F; R3 is selected from H, F, Cl, CN or methyl; R4 and R5 are independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl; said 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by 1 or 2 R6, R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b , SCF3 or 5-6 membered heteroaryl; Alternatively, R4, R5 and the nitrogen atom to which they are attached together form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally substituted by 1, 2, 3 or 4 R x replace; R x Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace; R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace; R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy; R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the following structure: in, R2 is selected from H, methyl, ethyl, methoxy or F; R3 is selected from H, F, Cl, CN or methyl; R4 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 4-12 membered heterocyclic group; R x1 and R x2 Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace; R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace; R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy; R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b , SCF3 or 5-6 membered heteroaryl; X is selected from -CH2-, O, S or -NR c -; Y is selected from CH or N; R c Selected from H or C 1-6 alkyl; m is 0, 1, or 2; n is 0, 1, 2 or 3.

6. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which is a compound of formula (III-1), (III-1a) or (III-1b): in, R2 is selected from H, methyl, ethyl, methoxy or F; R3 is selected from H, F, Cl, CN or methyl; R x1 is selected from phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace; R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace; R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy; R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R x2 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy; X is selected from -CH2-, O, S or -NR c -; R c Selected from H or C 1-6 alkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R2 is selected from H, methyl, ethyl, methoxy or F; R3 is selected from H, F, Cl, CN or methyl; R x1 is selected from phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace; R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocycle R, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace; R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy; R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R x2 Selected from methyl, ethyl, trifluoromethyl or trifluoromethoxy; X is selected from -CH2-, O or S.

8. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which is a compound of formula (III-2), (III-2a) or (III-2b): in, R2 is selected from H, methyl, ethyl, methoxy or F; R3 is selected from H, F, Cl, CN or methyl; R4 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 4-12 membered heterocyclic group; R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b or a 5-6 membered heteroaryl group; R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; X is selected from -CH2-, O, S or -NR c -; Y is selected from CH or N; R c Selected from H or C 1-6 alkyl; m is 0, 1, or 2; n is 0, 1, 2 or 3.

9. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which is a compound of formula (III-3), (III-3a) or (III-3b): in, R2 is selected from H, methyl, ethyl, methoxy or F; R3 is selected from H, F, Cl, CN or methyl; R4 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 4-12 membered heterocyclic group; R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b or a 5-6 membered heteroaryl group; R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; X is selected from -CH2-, O, S or -NR c -; Y is selected from CH or N; R c Selected from H or C 1-6 alkyl. m is 0, 1 or 2.

10. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which is a compound of formula (IV-1), (IV-1a) or (IV-1b): in, R2 is selected from H, methyl, ethyl, methoxy or F; R3 is selected from H, F, Cl, CN or methyl; R x1 is selected from phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace; R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace; R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy; R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R x2 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy; X is selected from -CH2-, O, S or -NR c -; R c Selected from H or C 1-6 alkyl.

11. The compound of claim 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R2 is selected from H, methyl, ethyl, methoxy or F; R3 is selected from H, F, Cl, CN or methyl; R x1 is selected from phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is optionally substituted by 1, 2 or 3 R y replace; R y Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, CN, OR b 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or phenyl, wherein the 5-10 membered heteroaryl or phenyl is optionally substituted by 1, 2 or 3 R z replace; R z Selected from C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy; R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R x2 Selected from methyl, ethyl, trifluoromethyl or trifluoromethoxy; X is selected from -CH2-, O or S.

12. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which is a compound of formula (IV-2), (IV-2a) or (IV-2b): in, R2 is selected from H, methyl, ethyl, methoxy or F; R3 is selected from H, F, Cl, CN or methyl; R4 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 4-12 membered heterocyclic group; R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b or a 5-6 membered heteroaryl group; R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; X is selected from -CH2-, O, S or -NR c -; Y is selected from CH or N; R c Selected from H or C 1-6 alkyl; m is 0, 1, or 2; n is 0, 1, 2 or 3.

13. The compound of claim 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: R2 is selected from H, methyl, ethyl, methoxy or F; R3 is selected from H, F, Cl, CN or methyl; R4 is selected from H, methyl, ethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl or oxetanyl; R6 is selected from H, CN, F, Cl, methyl, trifluoromethyl, SF5, methoxy or pyridyl; X is selected from -CH2-, O or S; Y is selected from CH or N; m is 1 or 2; n is 1 or 2.

14. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which is a compound of formula (IV-3), (IV-3a) or (IV-3b): in, R2 is selected from H, methyl, ethyl, methoxy or F; R3 is selected from H, F, Cl, CN or methyl; R4 is selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 4-12 membered heterocyclic group; R6 is selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, SF5, OR b , SCF3 or 5-6 membered heteroaryl; R b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; X is selected from -CH2-, O, S or -NR c -; Y is selected from CH or N; R c Selected from H or C 1-6 alkyl. m is 0, 1 or 2.

15. The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: R2 is selected from H, methyl, ethyl, methoxy or F; R3 is selected from H, F, Cl, CN or methyl; R4 is selected from H, methyl, methyl-d3, ethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl or oxetanyl; R6 is selected from H, CN, F, Cl, methyl, trifluoromethyl, SF5, SCF3, methoxy or pyridyl; X is selected from -CH2-, O or S; Y is selected from CH or N; m is 1 or 2.

16. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein the compound is selected from:

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a pharmaceutically acceptable excipient; preferably, further comprising other therapeutic agents.

18. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof in the preparation of a medicament for treating and / or preventing a disease mediated by PRMT5 methyltransferase.

19. A method for treating and / or preventing a PRMT5 methyltransferase-mediated disease in a subject, the method comprising administering to the subject a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition according to claim 17.

20. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or the pharmaceutical composition according to claim 17, for use in treating and / or preventing a disease mediated by PRMT5 methyltransferase.

21. The use of claim 18 or the method of claim 19 or the compound or composition of claim 20, wherein the PRMT5 methyltransferase-mediated disease is cancer selected from the group consisting of: acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, hemangioma), appendix cancer, benign monoclonal gamma disease, bile duct cancer, bladder cancer, brain cancer (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchogenic carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), hypereosinophilia, gallbladder cancer, stomach cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic system cancer (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) LL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell non-Hodgkin's lymphomas, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (e.g., cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more of the foregoing leukemias / lymphomas;Multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer (e.g., Wilms tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma, malignant hepatocellular carcinoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., true Polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myeloid metaplasia (AMM), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibromas (such as neurofibromatosis type 1 or type 2, schwannomatosis), neuroendocrine cancers (such as gastroenteropancreatic neuroendocrine tumors (GEP-NET), carcinoid tumors), osteosarcoma, ovarian cancer (such as cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, and penile cancer.

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