PRMT5-MTA inhibitors

Abstract

The present invention provides a compound as a PRMTS-MTA inhibitor, which is represented by formula (I) or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof. Also provided in the present invention are pharmaceutical compositions containing the compound and their use in the treatment of cancer. [Formula 1] TIFF2026504087000129.tif23163

Description

[Technical Field]

[0001] The present invention belongs to the field of medicine, and in particular relates to PRMT5-MTA inhibitors. [Background technology]

[0002] Protein arginine methyltransferases (PRMTs) 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 tumorigenesis (Nat Rev Mol Cell Biol. 2019 Oct;20(10):642-657) (Nat Rev Drug Discov. 2021 Jul;20(7):509-530). Eleven members of the PRMT family have been discovered so far and can be classified into types I, II, and III based on differences in how they catalyze arginine methylation, with PRMT5 being a type II member that catalyzes symmetric dimethylation.

[0003] The epigenetic enzyme PRMT5 is involved in various biological processes, including transcriptional regulation, RNA metabolism, ribosome biogenesis, and cell cycle regulation. The PRMT5 protein is overexpressed in various cancer types, including B- and T-cell lymphoma, metastatic melanoma, neuroblastoma, glioblastoma, ovarian cancer, and breast cancer, and increasing evidence suggests that it plays a critical role in tumor initiation and development (Cell Stress 2020 August;4(8):199-215) (Cancer Gene Ther. 2022 March;29(3-4):264-276). Based on this, PRMT5 inhibitors have become an important focus of research and development for oncology therapeutics.

[0004] Early PRMT5 inhibitors can be divided into two classes: substrate-competitive inhibitors, represented by GSK3326595, and SAM-competitive inhibitors, represented by JNJ64619178. Both types of drugs are potent inhibitors of PRMT5 and exhibit potent antitumor activity. However, strong hematotoxicity has been observed due to the potent inhibitory activity against PRMT5 in both normal and tumor cells, limiting their clinical application and thus affecting the outcome of clinical therapy (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] A paper published in Science in 2016 revealed that MTAP deficiency is synthetically lethal with PRMT5 (Science 2016 March 11;351(6278):1214-8). MTAP deficiency is common in various solid tumors, including pancreatic cancer and glioma. Because MTAP is an enzyme that degrades intracellular MTA, MTAP deficiency can lead to the intracellular accumulation of MTA, which competes with its functional substrate, the methyl donor SAM, for binding to PRMT5, thereby inhibiting PRMT5 function. Because MTA specifically accumulates in MTAP-deficient tumor cells, enhancing the binding inhibition of MTA and PRMT5 allows for the specific inhibition of PRMT5 activity in tumor cells while minimizing the inhibitory effect on PRMT5 activity in normal cells, thereby providing a therapeutic safety margin that reduces toxicity without compromising antitumor efficacy (Nat Rev Drug Discov. 2020 January;19(1):23-38) (Cell Rep. 2016 April 19;15(3):574-587). Preclinical validation data are currently available for MTA-synergic PRMT5 inhibitors (J Med Chem. 2022 February 10;65(3):1749-1766), and their development holds great promise for the treatment of MTAP-deficient tumors.

[0006] Despite progress in PRMT5 research, to date, effective and selective PRMT5-MTA inhibitors are lacking. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Nat Rev Mol Cell Biol.2019 Oct;20(10):642-657 [Non-patent document 2] Nat Rev Drug Discov.2021 / 07;20(7):509-530 [Non-patent document 3] Cell Stress August 2020;4(8):199-215

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Summary of the Invention

Means for Solving the Problems

[0008] Formula (I):

Chemical Formula

[0009] 〔In the formula, X1, X2, and X3 are each independently selected from -CH=, -O-, -S-, -N=, or -NH-, wherein at least one of X1, X2, and X3 is -N= or -NH-, and the circle indicates aromaticity; R1 is C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 haloalkyl; R2 is H, C 1-6 selected from alkyl or halogen; R3 and R4 are independently H, C 1-6 Alkyl, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, wherein C in R3 or R4 1-6 Alkyl, C 3-6 Each cycloalkyl or 4- to 10-membered heterocyclyl is optionally substituted with 1 or 2 R5, where R5 is hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, CN, SF5, C 3-6 cycloalkyl, —S(O)2CF3, —OCF3, —SCF3, —SCH3, or 5-10 membered heteroaryl; the 5-10 membered heteroaryl may be further substituted with R6, where R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR a or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is selected from 1, 2, or 3 R z may be substituted with; Alternatively, R3, R4 and the nitrogen atom to which they are attached together form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen or sulfur, and which contains 1, 2, 3 or 4 R x may be substituted with; R x is C 1-6 Alkyl, C1-6 haloalkyl, phenyl, or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is selected from 1, 2, or 3 R y may be substituted with; R y is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, CN, OR a , C 1-6 Alkoxy, -NR z1 R z2 , N.R. z1 R z2 -C 1-6 Alkyl-, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl is selected from 1, 2, or 3 R z may be substituted with; R z is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 selected from alkoxy; R a is H, C 1-6 Alkyl or C 1-6 haloalkyl; R z1 and R z2 are each independently H or C 1-6 Selected from, and n is 0, 1 or 2. or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0010] In another aspect, the present invention provides a compound of formula (IIa) or (IIb): [ka]

[0011] [During the ceremony, R1 is H, C 1-6Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 haloalkyl; R2 is H, C 1-6 selected from alkyl or halogen; R3 and R4 are independently H, C 1-6 Alkyl, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, wherein C in R3 or R4 1-6 Alkyl, C 3-6 Each cycloalkyl or 4- to 10-membered heterocyclyl is optionally substituted with 1 or 2 R5, where R5 is hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, CN, SF5, C 3-6 cycloalkyl, —S(O)2CF3, —OCF3, —SCF3, —SCH3, or 5-10 membered heteroaryl; the 5-10 membered heteroaryl may be further substituted with R6, where R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR a or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is selected from 1, 2, or 3 R z may be substituted with; Alternatively, R3, R4 and the nitrogen atom to which they are attached together form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen or sulfur, and 1, 2, 3 or 4 R x may be substituted with; R x is C 1-6 Alkyl, C 1-6 haloalkyl, phenyl, or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is selected from 1, 2, or 3 R y may be substituted with; R y is a halogen, C1-6 Alkyl, C 1-6 Haloalkyl, SF5, CN, OR a , C 1-6 Alkoxy, -NR z1 R z2 , N.R. z1 R z2 -C 1-6 Alkyl, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl is selected from 1, 2, or 3 R z may be substituted with; R z is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 selected from alkoxy; R a is H, C 1-6 Alkyl or C 1-6 haloalkyl; and R z1 and R z2 are each independently H or C 1-6 selected from or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0012] In another aspect, the present invention provides certain compounds exemplified in this application.

[0013] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient, which may also include other therapeutic agents.

[0014] In another aspect, the present invention provides the use of a compound of the present invention in the preparation of a medicament for treating and / or preventing a disease mediated by PRMT5 methyltransferase.

[0015] In another aspect, the present invention provides a method for treating and / or preventing a PRMT5 methyltransferase-mediated disease in a subject, the method comprising administering to the subject a compound or composition of the present invention.

[0016] In another aspect, the present invention provides a compound of the present invention or a composition of the present invention for use in the treatment and / or prevention of a disease mediated by PRMT5 methyltransferase.

[0017] In certain embodiments, diseases treated by the present invention include acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, hemangioma), appendix cancer, benign monoclonal gammopathy, bile duct carcinoma, bladder cancer, brain tumors (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelial carcinoma (e.g., Kaposi's sarcoma, polyposi ... idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), hematopoietic cancer (e.g., leukemia, e.g., acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia, 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, lymph node marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, and 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, e.g., 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-associated T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma; anaplastic large cell lymphoma); a mixture of one or more of the above leukemias / lymphomas;Multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, μ 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., bronchial 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., polycythemia vera (PV), cancers selected from the group consisting of ectopathic thrombocythemia (ET), idiopathic extramedullary metaplasia (AMM), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibroma (e.g., neurofibromatosis type 1 or 2, schwannoma), neuroendocrine carcinoma (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, or penile cancer;

[0018] Other objects and advantages of the present invention will become apparent to those skilled in the art from the following detailed description, examples, and claims.

[0019] definition chemical definition Definitions of certain functional groups and chemical terms are described in more detail below.

[0020] When a range of values ​​is listed, it is intended that each value and subrange within the stated range be included. For example, "C 1-6 "Alkyl" refers to 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 Contains alkyl.

[0021] "C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C 1-2 Alkyl is preferred. 1-6 Examples of alkyl 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). 1-6 "Alkyl" further includes heteroalkyl, where one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0022] "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 include: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. 2-6"Alkenyl" further includes heteroalkenyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkenyl groups may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0023] "C 2-6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl is preferred. 2-6 Examples of alkynyl 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. 2-6 "Alkynyl" also includes heteroalkynyl in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0024] "C 1-6 "Alkylene" is C 1-6 It refers to a divalent group formed by removing another hydrogen from an alkyl, which may be substituted or unsubstituted. 1-4 Alkylene, C 2-4 Alkylene and C 1-3Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Exemplary substituted alkylene groups, e.g., alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene groups (-CH(CH)-, -C(CH)-), substituted ethylene groups (-CH(CH)CH-, -CHCH(CH)-, -C(CH)CH-, -CHC(CH)-), substituted propylene groups (-CH(CH)CHCH-, -CHCH(CH)CH-, -CHCHCH(CH)-, -C(CH)CHCHCH-, -CHC(CH)CH-, -CHCHC(CH)-), and the like.

[0025] "C 2-6 Alkenylene" is C 2-6 refers to a divalent group formed by removing another hydrogen from an alkenyl group, which may be substituted or unsubstituted. 2-4 Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene groups (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene groups (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-).

[0026] "C 2-6 "Alkynylene" is C2-6 It refers to a divalent group formed by removing another hydrogen atom from an alkynyl group, and may be substituted or unsubstituted. In some embodiments, C2-4 alkynylene is particularly preferred. Exemplary alkynylene groups include, but are not limited to, ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH2-), and the like.

[0027] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0028] Therefore, "C 1-6 "Haloalkyl" refers to any of the aforementioned "C" groups substituted with one or more halogen groups. 1-6 In some embodiments, C 1-4 Haloalkyl 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. Haloalkyl groups can be substituted at any available point of attachment with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0029] "C 1-6 "Alkoxy" refers to the group -OR, where R is C as defined above. 1-6 It is an alkyl group. 1-4 Alkoxy is preferred.

[0030] "C 1-6 Haloalkoxy refers to a C alkoxy group substituted with one or more halogen groups. 1-6 In some embodiments, C haloalkoxyalkyl is particularly preferred, with C 1-2 Haloalkoxyalkyl is more preferred.

[0031] "C3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and 0 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, C 5-6 Cycloalkyl is more preferred. Cycloalkyl also includes ring systems in which the cycloalkyl ring is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring; in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), cycloheptyl (C), cycloheptenyl (C), cycloheptadienyl (C), cycloheptatrienyl (C), and the like. The cycloalkyl group may be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0032] "3- to 12-membered heterocyclyl" refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. In some embodiments, the 3- to 10-membered heterocyclyl is preferably a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, the 4- to 10-membered heterocyclyl is preferably a 4- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, the 5- to 10-membered heterocyclyl is preferably a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, the 5- to 8-membered heterocyclyl is preferably a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, the 3- to 7-membered heterocyclyl is preferably a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms. a 3- to 6-membered heterocyclyl which is a 3- to 7-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; a 3- to 6-membered heterocyclyl which is a 3- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; a 4- to 7-membered heterocyclyl which is a 4- to 7-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; a 4- to 6-membered heterocyclyl which is a 4- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; a 5- to 6-membered heterocyclyl which is a 5- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; a 3- to 5-membered heterocyclyl which is a 3- to 5-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the heterocyclyl ring is fused to one or more cycloalkyl groups (wherein the point of attachment is on the cycloalkyl ring), or to one or more aryl or heteroaryl groups (wherein the point of attachment is on the heterocyclyl ring); in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system.Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, pyrrolinyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered 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, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl groups) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclyl groups) fused to a C6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyranopyridinyl, and the like.The heterocyclyl group may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0033] "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 to 10 ring carbon atoms and 0 heteroatoms. In some embodiments, an aryl has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl has 10 ring carbon atoms ("C 10 Aryl"; for example, naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the aryl ring is fused to one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0034] "5-14-membered heteroaryl" refers to a group of 5-14-membered monocyclic or bicyclic 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 π-electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, where 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 valence permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclic 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 heteroaryls that are 5-10-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms are preferred. In some embodiments, 5- to 10-membered heteroaryls are preferred, which are 6- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5- to 9-membered heteroaryls are preferred, which are 5- to 9-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5- to 6-membered heteroaryls are particularly preferred, which are 5- to 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 (eg, 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, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0035] A "cycloalkylene," "heterocyclylene," "arylene," or "heteroarylene" is a divalent group formed by removing another hydrogen from a "cycloalkyl," "heterocyclyl," "aryl," or "heteroaryl" as defined above, and may be substituted or unsubstituted. For example, "C 5-7 "Cycloalkylene" is C 5-7"5- to 8-membered heterocyclylene" refers to a divalent group formed by removing another hydrogen from a 5- to 8-membered heterocyclyl, and "C 6-10 "Arylene" is C 6-10 "5- to 6-membered heteroarylene" refers to a divalent group formed by removing another hydrogen from an aryl, and "5- to 6-membered heteroarylene" refers to a divalent group formed by removing another hydrogen from a 5- to 6-membered heteroaryl.

[0036] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, etc., as defined herein are optionally substituted groups.

[0037] Exemplary substituents on carbon atoms include halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —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(=NRbb )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(R cc )3、-B(R aa )2、-B(ORcc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; Or two geminal hydrogen atoms on a carbon atom can be bonded to the 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 Replaced by; R aa are independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa The groups are joined to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb each independently represents 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 groups joined to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R cc are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups joined to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd each independently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3+X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff)2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents may combine to form =O or =S; R eeis independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ff groups joined to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R gg each independently being: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 Alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 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)(OC1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2- C6 alkenyl, C 2- C6 alkynyl, C 3- C7 cycloalkyl, C 6- C 10 Aryl, C 3- C7 heterocyclyl, C 5- C 10 Heteroaryl; or two geminal R gg The substituents may combine to form =0 or =S; where X is a counterion.

[0038] Exemplary substituents on a nitrogen atom include 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 bonded to a nitrogen atom ccThe groups combine to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd group, where R aa , R bb , R cc and R dd is as above.

[0039] The term "deuterium (D or 2H)" is a stable isotope of hydrogen that exists 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 have been replaced with D.

[0040] A "deuterated compound" refers to a compound in which one or more hydrogen atoms bonded to a carbon atom are replaced by one or more deuterium atoms. Similarly, "deuterated" refers to a chemical structure or organic group in which one or more hydrogen atoms bonded to a carbon atom are replaced by one or more deuterium atoms, such as a "deuterated alkyl," a "deuterated cycloalkyl," a "deuterated heterocycloalkyl," a "deuterated aryl," and the like. For example, a "deuterated alkyl" refers to an alkyl group, as defined herein, in which at least one hydrogen atom bonded to a carbon atom is replaced by a deuterium atom. In a deuterated alkyl group, at least one carbon atom is bonded to a deuterium atom; a carbon atom can be bonded to multiple deuterium atoms; multiple carbon atoms in an alkyl group can also be bonded to deuterium atoms. For example, deuterated methyl includes methyl-d3, in which three hydrogen atoms are replaced by deuterium atoms; it also includes monodeuterated methyl and dideuterated methyl. In some embodiments, the compounds of the present invention include deuterated compounds.

[0041] Other definitions As used herein, the term "pharmaceutically acceptable salts" refers to carboxylic acid and 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 excessive toxicity, irritation, allergic response, or the like, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including zwitterionic forms (where possible) of the compounds of the present invention.

[0042] "Subjects" for administration 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 elderly adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0043] "Disease," "disorder," and "condition" are used interchangeably herein.

[0044] Generally, the "effective amount" of a compound refers to the amount that is sufficient to cause the biological response of interest.As understood by those skilled in the art, the effective amount of the compound of the present invention can vary depending on factors such as biological purpose, pharmacokinetics of the compound, the disease to be treated, administration method, and the age, health condition and symptoms of the subject.The effective amount includes a therapeutically effective amount and a prophylactically effective amount.

[0045] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compound of the invention can be administered simultaneously or sequentially with the other therapeutic agent in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agent in a single unit dosage form.

[0046] Detailed Description of the Preferred Embodiments As used herein, "compounds of the invention" refers to compounds of the following formula (I) (including subformulas such as formulas (IIa), (IIb), (III), (IV), (III-1), (III-2), (III-3), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1) or (VII-2)), pharmaceutically acceptable salts, enantiomers, diastereomers or isotopic variants thereof, and mixtures thereof.

[0047] In one embodiment, the present invention provides a compound of formula (I): [ka]

[0048] [During the ceremony, X1, X2 and X3 are each independently selected from CH, O, S or N, wherein X1, X2 and X3 contain at least one N atom, and the circle indicates aromaticity; R1 is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 haloalkyl; R2 is H, C 1-6 selected from alkyl or halogen; R3 and R4 are independently H, C 1-6 Alkyl, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, wherein C in R3 or R4 1-6 Alkyl, C 3-6 Each cycloalkyl or 4- to 10-membered heterocyclyl is optionally substituted with 1 or 2 R5, where R5 is hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, CN, SF5, C 3-6cycloalkyl, —S(O)2CF3, —OCF3, —SCF3, —SCH3, or 5-10 membered heteroaryl; the 5-10 membered heteroaryl may be further substituted with R6, where R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR a or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is selected from 1, 2, or 3 R z may be substituted with; Alternatively, R3, R4 and the nitrogen atom to which they are attached together form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen or sulfur, and 1, 2, 3 or 4 R x may be substituted with; R x is C 1-6 Alkyl, C 1-6 haloalkyl, phenyl, or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is selected from 1, 2, or 3 R y may be substituted with; R y is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, CN, OR a , C 1-6 Alkoxy, -NR z1 R z2 , N.R. z1 R z2 -C 1-6 Alkyl-, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl is selected from 1, 2, or 3 R z may be substituted with; R z is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 selected from alkoxy; R ais H, C 1-6 Alkyl or C 1-6 haloalkyl; R z1 and R z2 are each independently H or C 1-6 Selected from: n is 0, 1 or 2. or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

[0049] In some embodiments, X1, X2, and X3 are each independently selected from -CH=, -O-, -S-, -N=, or -NH-, and at least one of X1, X2, and X3 is -N= or -NH-.

[0050] In some embodiments, -NR3R4 is [ka]

[0051] is.

[0052] In some embodiments, -NR3R4 is [ka]

[0053] is.

[0054] In some embodiments, -NR3R4 is [ka]

[0055] is.

[0056] In some embodiments, -NR3R4 is [ka]

[0057] is.

[0058] In another embodiment, the present invention provides a compound of formula (IIa) or (IIb): [ka]

[0059] [During the ceremony, R1 is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 haloalkyl; R2 is H, C 1-6 selected from alkyl or halogen; R3 and R4 are independently H, C 1-6 Alkyl, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, wherein C in R3 or R4 1-6 Alkyl, C 3-6 Each cycloalkyl or 4- to 10-membered heterocyclyl is optionally substituted with 1 or 2 R5, where R5 is hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, CN, SF5, C 3-6 cycloalkyl, —S(O)2CF3, —OCF3, —SCF3, —SCH3, or 5-10 membered heteroaryl; the 5-10 membered heteroaryl may be further substituted with R6, where R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR a or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is selected from 1, 2, or 3 R z may be substituted with; Alternatively, R3, R4 and the nitrogen atom to which they are attached together form a 4-10 membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen or sulfur, and 1, 2, 3 or 4 R x may be substituted with; R x is C 1-6 Alkyl, C 1-6 haloalkyl, phenyl, or 5-10 membered heteroaryl, where phenyl or 5-10 membered heteroaryl is selected from 1, 2, or 3 R y may be substituted with; R y is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, CN, OR a , C 1-6 Alkoxy, -NR z1 R z2 , N.R. z1 R z2 -C 1-6 Alkyl-, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl is selected from 1, 2, or 3 R z may be substituted with; R z is C 1-6 Alkyl, halogen, CN, C 1-6 selected from haloalkyl or C1-6 alkoxy; R a is H, C 1-6 Alkyl or C 1-6 haloalkyl; and R z1 and R z2 are each independently H or C 1-6 selected from or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0060] In another embodiment, the present invention provides a compound of formula (III) or formula (IV): [ka]

[0061] [During the ceremony, R1 is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 haloalkyl; R2 is selected from H, methyl, Cl or F; R 5a or R 5b are each independently selected from 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl may be substituted with R6, where R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR a or 5-6 membered heteroaryl; the 5-6 membered heteroaryl is selected from 1, 2 or 3 R z may be substituted with; R x1 is selected from phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is selected from 1, 2 or 3 R y may be substituted with; R y is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, CN, OR a , C 1-6 Alkoxy, -NR z1 R z2 , N.R. z1 R z2 -C 1-6 Alkyl-, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl is selected from 1, 2, or 3 R z may be substituted with; Rz is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 selected from alkoxy; R a is H, C 1-6 Alkyl or C 1-6 haloalkyl; R x2 is C 1-6 Alkyl or C 1-6 haloalkyl; R z1 and R z2 are each independently H or C 1-6 Selected from: Y is selected from O, S or CH2. or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0062] In another embodiment, the present invention provides a compound represented by formula (VI) or formula (VII): [ka]

[0063] [During the ceremony, R1 is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 haloalkyl; R2 is selected from H, methyl, Cl or F; R3 is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl or 4- to 10-membered heterocyclyl; C 1-6 The alkyl or 4-10 membered heterocyclyl may be substituted with 1 or 2 R5; R5 is hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Haloalkyl, C 1-6 Haloalkoxy, CN, SF5, C 3-6 cycloalkyl, —S(O)2CF3, —OCF3, —SCF3, —SCH3, or 5-10 membered heteroaryl; the 5-10 membered heteroaryl may be further substituted with R6, where R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR a or 5-6 membered heteroaryl; the 5-6 membered heteroaryl is selected from 1, 2 or 3 R z may be substituted with; R z is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 selected from alkoxy; R a is H, C 1-6 Alkyl or C 1-6 haloalkyl; Y is selected from NH, O, S or CH2; Z is selected from N or CH. or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0064] In some embodiments, R1 is CH3 or CD3.

[0065] In some embodiments, the compound is [ka]

[0066] is.

[0067] In some embodiments, the compound is [ka]

[0068] is.

[0069] In some embodiments, [ka]

[0070] teeth, [ka]

[0071] is.

[0072] In another embodiment, the present invention provides a compound of formula (III-1): [ka]

[0073] [During the ceremony, R1 is selected from methyl, CD3, ethyl, or cyclopropyl; R 5a or R 5b are each independently selected from 6-membered heteroaryl; the 6-membered heteroaryl may be further substituted with R6, where R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR a or 5-6 membered heteroaryl; the 5-6 membered heteroaryl is selected from 1, 2 or 3 R z may be substituted with; R z is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 selected from alkoxy; R a is H, C 1-6 Alkyl or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0074] In another more specific embodiment, the present invention provides a compound of formula (III-2): [ka]

[0075] [During the ceremony, R1 is selected from methyl, CD3, ethyl, or cyclopropyl; R 5b teeth, [ka]

[0076] which may be further substituted by R6, where R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR a or 5-6 membered heteroaryl; the 5-6 membered heteroaryl is selected from 1, 2 or 3 R z may be substituted with; R z is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 selected from alkoxy; R a is H, C 1-6 Alkyl or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0077] In another more specific embodiment, the present invention provides a compound of formula (III-3): [ka]

[0078] [During the ceremony, R1 is selected from methyl, CD3, ethyl or cyclopropyl; R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR a or 5-6 membered heteroaryl; the 5-6 membered heteroaryl is selected from 1, 2 or 3 R z may be substituted with; R z is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 selected from alkoxy; R a is H, C 1-6 Alkyl or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0079] In another embodiment, the present invention provides a compound of formula (IV-1): [ka]

[0080] [During the ceremony, R1 is C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 haloalkyl; R x1 is selected from phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is selected from 1, 2 or 3 R y may be substituted with; R y is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, CN, OR a , C 1-6 Alkoxy, C 3-6 cycloalkyl, [ka]

[0081] 4-12 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 4-12 membered heterocyclyl or 5-10 membered heteroaryl is selected from 1, 2 or 3 R z may be substituted with; R z is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 selected from alkoxy; R a is H, C 1-6 Alkyl or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0082] In another more specific embodiment, the present invention provides a compound of formula (IV-2): [ka]

[0083] [During the ceremony, R1 is selected from methyl, CD3, ethyl or cyclopropyl; R y is C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a , C 1-6 Alkoxy, C 3-6 cycloalkyl, [ka]

[0084] 4-12 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 4-12 membered heterocyclyl or 5-10 membered heteroaryl is selected from 1, 2 or 3 R z may be substituted with; R z is C1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 alkoxy] or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0085] In another embodiment, the present invention provides a compound of formula (V-1): [ka]

[0086] [During the ceremony, R1 is C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 haloalkyl; R x1 is a 5-10 membered heteroaryl group, which is selected from 1, 2 or 3 R y optionally substituted with a group; R y is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, CN, OR a , C 1-6 Alkoxy, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from 1, 2, or 3 R z may be substituted with; R z is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 selected from alkoxy; R a is H, C 1-6 Alkyl or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0087] In another more specific embodiment, the present invention provides a compound of formula (V-2): [ka]

[0088] [During the ceremony, R1 is selected from methyl, CD3, ethyl or cyclopropyl; R y is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, CN, OR a , C 1-6 Alkoxy, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from 1, 2, or 3 R z may be substituted with; R z is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6 selected from alkoxy; R a is H, C 1-6 Alkyl or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0089] In another more specific embodiment, the present invention provides a compound of formula (V-3): [ka]

[0090] [During the ceremony, R1 is selected from methyl, CD3, ethyl or cyclopropyl; R z is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl or C 1-6selected from alkoxy; R a is H, C 1-6 Alkyl or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0091] In another embodiment, the present invention provides a compound represented by formula (VI-1) or (VII-1): [ka]

[0092] [During the ceremony, R1 is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 haloalkyl; R3 is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl or 4- to 10-membered heterocyclyl; C 1-6 The alkyl or 4-10 membered heterocyclyl may be substituted with 1 or 2 R5; R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, CN, SF5, C 3-6 cycloalkyl, —S(O)2CF3, —OCF3, —SCF3, —SCH3, or 5-10 membered heteroaryl; the 5-10 membered heteroaryl may be further substituted with R6, where R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR a or 5-6 membered heteroaryl; R a is H, C 1-6 Alkyl or C 1-6haloalkyl; Z is selected from N or CH. or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0093] In some embodiments, R3 is C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, or 4- to 10-membered heterocyclyl; C 1-6 The alkyl or 4- to 10-membered heterocyclyl may be substituted with 1 or 2 R5.

[0094] In another more specific embodiment, the present invention provides a compound of formula (VI-2) or (VII-2): [ka]

[0095] [During the ceremony, R1 is selected from H, methyl, CD3, ethyl or cyclopropyl; R3 is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 selected from cycloalkyl or 4-10 membered heterocyclyl; R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, CN, SF5, C 3-6 selected from cycloalkyl, -S(O)2CF3, -OCF3, -SCF3, -SCH3, or 5-10 membered heteroaryl; In some embodiments, R3 is C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, or 4- to 10-membered heterocyclyl. or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0096] In another more specific embodiment, R1 is selected from H, methyl, CD3, ethyl or cyclopropyl; R3 is selected from H, methyl, CD3, ethyl or cyclopropyl; R5 is selected from hydrogen, F, Cl, Br, methyl, CD3, ethyl, methoxy, trifluoromethyl, difluoromethyl, CN, SF5, cyclopropyl, -S(O)2CF3, -OCF3, -OCF2Cl, -SCF3, -SCH3 or pyridyl; A compound of formula (VI-2) or (VII-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0097] In some embodiments, R3 is selected from methyl, CD3, ethyl, or cyclopropyl.

[0098] In some embodiments, the compound is [ka]

[0099] is.

[0100] In some embodiments, the compound is [ka]

[0101] is.

[0102] In some embodiments, the compound is [ka]

[0103] is.

[0104] In some embodiments, the compound is [ka]

[0105] is.

[0106] In some embodiments, the compound is [ka]

[0107] is.

[0108] In some embodiments, the compound is [ka]

[0109] is.

[0110] In some embodiments, R1 is selected from methyl or CD3.

[0111] In some embodiments, R3 is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 3-6 In some embodiments, R is selected from C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 3-6 In some embodiments, R3 is selected from H, methyl, CD3, ethyl, or propyl. In some embodiments, R3 is selected from methyl, CD3, ethyl, or propyl.

[0112] In some embodiments, R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Haloalkyl, C 1-6 Haloalkoxy, CN, SF5, C 3-6 cycloalkyl, —S(O)CF, —OCF, —SCF, —SCH, or pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl); pyridyl may be further substituted with R, where R is H, CN, halogen, C 1-6 Alkyl, C 1-6 In some embodiments, R is selected from hydrogen, F, Cl, Br, methyl, CD, ethyl, methoxy, trifluoromethyl, difluoromethyl, CN, SF, cyclopropyl-S(O)CF, -OCF, -SCF, -SCH, or pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), wherein the pyridyl is optionally substituted with a halogen.

[0113] In some embodiments, Z is selected from CH2 or NH.

[0114] In a more specific embodiment, the present invention provides: [ka]

[0115] TIFF2026504087000036.tif238160

[0116] TIFF2026504087000037.tif229162

[0117] TIFF2026504087000038.tif175163

[0118] or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof.

[0119] The compounds of the present invention may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomeric 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 a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from mixtures 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 can be prepared by asymmetric synthesis.

[0120] The compounds of the invention may also exist as tautomers. For compounds that exist in different tautomeric forms, the compounds are not limited to any particular tautomer, but are intended to encompass all tautomeric forms.

[0121] The compounds of the present invention may be amorphous or crystalline (polymorphic). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention encompasses all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates) with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, photoelectric properties, stability, and solubility. The recrystallization solvent, crystallization rate, storage temperature, and other factors may affect the predominant crystalline form. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0122] The present invention also includes isotopically labeled compounds (isotopic variants) equivalent to those described in formula (A), but in which one or more atoms are replaced by atoms whose atomic mass or mass number is different from that common in nature. 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 The compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of the compounds or prodrugs that contain the above isotopes and / or other isotopes of other atoms are all within the scope of the present invention. 3 H and 14 Certain isotopically labeled compounds, such as those incorporating tritium (C), can be used to measure the tissue distribution of drugs and / or substrates. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 Substitution with heavier isotopes, such as H, may be preferred in some cases due to greater metabolic stability, which may provide therapeutic benefits such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of formula (A) of the present invention and prodrugs thereof can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent when carrying out the processes disclosed in the following schemes and / or examples and preparations.

[0123] Pharmaceutical Compositions and Kits 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.

[0124] The pharmaceutically acceptable excipient used in the present invention refers to the non-toxic carrier, adjuvant or vehicle that does not impair the pharmacological activity of the compound that is formulated together.The pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the compositions of the present invention includes but is not limited to ion exchanger, aluminum oxide, aluminum stearate, lecithin, serum protein (such as human serum albumin), buffer substance (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acid, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and lanolin.

[0125] The present invention further includes kits (e.g., pharmaceutical packages). The provided kits may include a compound of the invention, another therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packages or other suitable containers) containing the compound of the invention and the other therapeutic agent. In some embodiments, the provided kits may also include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or the other therapeutic agent. In some embodiments, the compound of the invention and the other therapeutic agent provided in the first container and the second container are combined to form a unit dosage form.

[0126] Administration The pharmaceutical compositions provided by the present invention can be administered in a number of ways, including but not limited to oral, parenteral, inhalation, topical, rectal, nasal, oral, vaginal, implant, or other modes of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0127] Generally, an effective amount of the compound provided herein is administered. The amount of the compound actually administered can be determined by a physician according to relevant circumstances, including the condition to be treated, the selected administration route, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0128] When used to prevent the conditions described herein, the compounds provided herein are typically administered to the subject at risk of developing the condition at dosage levels as described above, under the advice and supervision of a physician.The subject at risk of developing a particular condition typically includes the subject with a family history of the condition, or the subject identified by genetic testing or screening as being susceptible to developing the condition.

[0129] The pharmaceutical compositions provided herein can also be administered long-term ("chronically administered"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof for 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, e.g., within the therapeutic window, for an extended period of time.

[0130] Various administration methods can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for example, to increase the concentration of the compound in the blood to an effective level. The bolus administration depends on the desired systemic level of the active ingredient through the body; for example, intramuscular or subcutaneous bolus administration will slowly release the active ingredient, while a bolus injection delivered directly into a vein (e.g., by intravenous infusion) can be delivered more quickly, so that the concentration of the active ingredient in the blood is quickly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in the form of continuous infusion, for example, by intravenous infusion, to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the pharmaceutical composition can be administered first as a bolus administration, and then as a continuous infusion.

[0131] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dose for human patients and other mammals, each unit containing a predetermined amount of active agent and suitable pharmaceutical excipients appropriate for producing the desired therapeutic effect. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In these compositions, the compound is typically a relatively 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.

[0132] For oral administration, a typical regimen is 1 to 5 oral doses, particularly 2 to 4 oral doses, and typically 3 oral doses per day. Using these dosage forms, each dose provides about 0.01 to about 20 mg / kg of a compound of the invention, with preferred doses providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg, respectively.

[0133] To provide blood levels equivalent to or lower than those using injectable doses, transdermal administration is generally 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.

[0134] Injection dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may be administered to achieve adequate steady-state levels. For a 40-80 kg human patient, the maximum total dose should not exceed about 2 g / day.

[0135] Liquid forms suitable for oral administration can include suitable aqueous or nonaqueous carriers and buffers, suspending and dispersing agents, colorants, flavors, etc. Solid forms can include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0136] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable vehicles known in the art. As noted above, in such compositions, the active compound is typically a minor component, often about 0.05-10% by weight, with the remainder being injectable vehicles and the like.

[0137] Typically, transdermal compositions are formulated as topical ointments or creams containing active ingredients.When formulated as ointments, active ingredients are typically combined with paraffin or water-miscible ointment bases.Alternatively, active ingredients can be formulated as ointments with, for example, oil-in-water cream bases.Such transdermal formulations are well known in the art, and typically contain other ingredients to enhance the stable skin penetration of active ingredients or formulations.All such known transdermal formulations and ingredients are included in the scope provided by the present invention.

[0138] The compounds of the present invention may also be administered by transdermal means. Thus, transdermal administration can be accomplished using a patch of the reservoir or porous membrane type, or a solid matrix of some variety.

[0139] The above ingredients for oral, injectable, or topical administration of the compositions are merely representative. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Part 8, which is incorporated herein by reference.

[0140] The compounds of this invention can also be administered in sustained release forms or from sustained release delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0141] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation contains water. In another embodiment, the formulation contains a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of 6, 7, and 8 α-1,4-linked glucose units, respectively, and may contain one or more substituents on the linked sugar moiety, including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, also known as Captisol. See, e.g., U.S. Pat. No. 5,376,645. In some embodiments, the formulation contains hexapropyl-β-cyclodextrin (e.g., 10-50% in water). [Example]

[0142] The reagents used in the present invention are commercially available reagents that are either purchased directly or synthesized by common methods well known in the art.

[0143] Notes on commonly used abbreviations: Abbreviations: 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; TE A = triethylamine; DIEA = diisopropylethylamine; CuI = cuprous iodide; CuCN = cuprous cyanide; triphosgene = triphosgene; p-TsOH = para-toluenesulfonic acid; T3P = 1-propylphosphonic acid cyclic anhydride; TsN3 = para-toluenesulfonyl azide; PPA = polyphosphoric acid; BINAP = 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); m-CPBA = meta-chloroperbenzoic acid; Hex = n-hexane.

[0144] MTAPwt = methylthioadenosine phosphorylase wild type; MTAPdel = methylthioadenosine phosphorylase deficiency; MTA = methylthioadenosine; SAM = adenosylmethionine.

[0145] The specific reaction pathways or steps exemplified below are used in the present invention and are as follows: Example 1 Preparation of key intermediates a1–a43 Intermediates a1, a7~a8, a27 Synthesis of [ka]

[0146] Step 1: Starting Material 4-Bromo-1-pyrazolo[3,4-c]pyridine a1-1(1.1 g, 5.2 mmol) was dissolved in 20 mL of dichloromethane. The oxidizing agent m-chloroperbenzoic acid (m-CPBA) (1.3 g, 7.8 mmol) was slowly added and reacted at room temperature for 3 hours. The reaction was then stopped and filtered. The filter cake was washed with dichloromethane and dried to give a white solid. a1-2 (1.0 g) was obtained in 84% yield.

[0147] Step 2: In an ice bath, a1-2 (1.0 g, 4.4 mmol) was dissolved in 10 mL of acetonitrile, and POCl3 (1.0 mL) was slowly added dropwise. The mixture was reacted in an ice bath for 1 hour, and then the reaction was stopped. The solvent was evaporated under reduced pressure, and 50 mL of ice water was added to the system. The pH was adjusted to approximately 8 with a saturated aqueous solution of sodium bicarbonate. After extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration, the crude product was separated by reverse-phase flash column chromatography (C18, CH3CN / H2O, 4 / 5) to give a white solid. a1-3 (900 mg) was obtained in a yield of 83%. LCMS ESI-MS m / z: 246 [M+H] + .

[0148] Step 3: Under nitrogen protection, the intermediate from the previous step a1-3 (900 mg, 3.65 mmol), benzophenone imine (2.6 g, 14.6 mmol), and cesium carbonate (4.8 g, 14.6 mmol) were dissolved in 27 mL of anhydrous toluene, and the catalyst Pd(OAc)2 (164 mg, 0.73 mmol) and the ligand BINAP (900 mg, 1.46 mmol) were added. The mixture was heated to 140 °C and reacted for 7 h. After that, the reaction was stopped, filtered, and the solvent was removed under reduced pressure. The crude product was directly isolated by reverse-phase flash column chromatography (C18, CH3CN / H2O, 4 / 5) to give a white solid. a1-4 (400 mg) was obtained in a yield of 22%. LCMS ESI-MS m / z: 492 [M+H] + .

[0149] Step 4: Intermediate a1-4(400 mg, 0.81 mmol) was dissolved in 2 mL of tetrahydrofuran. 8 mL of dilute hydrochloric acid (concentration: 2 M) was added, and the reaction was allowed to proceed at room temperature for 3 hours, after which the reaction was stopped. The reaction mixture was adjusted to pH 8 by adding saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by reversed-phase flash column chromatography (C18, CH3CN / H2O, 1 / 3) to obtain the desired intermediate in 75% yield. a1 (100 mg) was obtained. LCMS ESI-MS m / z: 164 [M+H] + .

[0150] Using similar starting materials / intermediates, compounds a1 The following target intermediates were synthesized in the same manner as in the synthetic route of [Table 1]

[0151] Intermediates a2~a5, a9~a26, a28~a32, a35~a37, a40~a42 Synthesis of: [ka]

[0152] Step 1: Intermediate e1 (200 mg, 0.71 mmol) and triethylamine (143 mg, 1.42 mmol) were dissolved in 4 mL of dichloromethane. Methyl oxalyl chloride (134 mg, 1.1 mmol) was added and the mixture was allowed to react at room temperature for 1 hour. The solvent was then evaporated under reduced pressure to give the crude compound. a2-1 was obtained, which was used directly in the next step.

[0153] Step 2: Crude compound a2-1(30 mg, 0.05 mmol) was dissolved in 6 mL of a mixed solution of tetrahydrofuran and water (v / v, 1 / 1). LiOH (65 mg, 1.62 mmol) was added and the reaction was allowed to proceed at room temperature for 4 hours. Dilute hydrochloric acid (concentration: 4 M) was slowly added to the system to adjust the pH to approximately 6, and the solvent was then distilled off under reduced pressure. The crude product was separated by flash column chromatography (C18, CH3CN / H2O, 1 / 1) to obtain the compound. a2 (110 mg) was obtained in 43% overall yield over two steps. LCMS ESI-MS m / z: 355 [M+H] + .

[0154] Using similar starting materials / intermediates, compounds a2 or intermediates a2-1 The following target intermediates were synthesized in the same manner as in the synthetic route of [Table 2]

[0155] TIFF2026504087000043.tif252167

[0156] TIFF2026504087000044.tif242166

[0157] TIFF2026504087000045.tif45166

[0158] Intermediates a6 Synthesis of: [ka]

[0159] Step 1: In an ice bath under nitrogen protection, a6-1(800 mg, 3.75 mmol) and methanol (183 mg, 5.63 mmol) were dissolved in 16 mL of anhydrous tetrahydrofuran. Diisopropyl azodicarboxylate (DIAD) (134 mg, 1.1 mmol) and PPh3 (1.18 g, 4.50 mmol) were added and the reaction was carried out at room temperature for 1 hour. The solid was precipitated and filtered. The filtrate was concentrated under reduced pressure to give a white solid a6-2 (290 mg) was obtained in a yield of 34%. LCMS ESI-MS m / z: 227 [M+H] + .

[0160] Step 2: Under nitrogen protection, the intermediate from the previous step a6-2 (290 mg, 1.27 mmol), benzophenone imine (347 mg, 1.91 mmol), and cesium carbonate (1.7 g, 5.2 mmol) were dissolved in 9 mL of anhydrous toluene, followed by the addition of the catalyst Pd(OAc)2 (29 mg, 0.12 mmol) and the ligand BINAP (159 mg, 0.25 mmol). The mixture was heated to 140 °C and reacted for 48 h. After that, the reaction was stopped, filtered, and the solvent was removed under reduced pressure to give the crude product. a6-3 LCMS ESI-MS m / z: 328 [M+H] + .

[0161] Step 3: Crude product a6-3 (230 mg, 0.70 mmol) was dissolved in 5 mL of tetrahydrofuran. 3 mL of dilute hydrochloric acid (concentration: 2 M) was added, and the reaction was allowed to proceed at room temperature for 2 hours, after which the reaction was stopped. The reaction mixture was adjusted to pH 8 by adding saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by reversed-phase flash column chromatography (C18, CH3CN / H2O, 3 / 5) to obtain the desired intermediate in 61% yield. a6 (70 mg) was obtained. LCMS ESI-MS m / z: 164 [M+H] + ..

[0162] Intermediates a33, a34, a38, a43 Synthesis of: [ka]

[0163] Step 1: Under nitrogen protection, the intermediate a31 (120 mg, 0.36 mmol), the ligand BrettPhos (39.2 mg, 0.07 mmol), and the catalyst Pd(COD)(CH2TMS)2 (28.4 mg, 0.07 mmol) were dissolved in 3 mL of anhydrous toluene. The mixture was heated to 80 °C and stirred for 10 min. AgSCF3 (99 mg, 0.47 mmol) and triethylphenylammonium iodide PhEt3NI (145 mg, 0.47 mmol) were added to the reaction mixture, and the reaction was continued at 80 °C for 2 h. After that, the reaction was stopped, filtered, and the solvent was removed under reduced pressure. The crude product was separated by reverse-phase flash column chromatography (C18, CH3CN / H2O, 9 / 10) to give a brown oil. a33 (100 mg) was obtained in a yield of 78%. LCMS ESI-MS m / z: 350 [M+H] + .

[0164] Step 2: Intermediate a33 (100 mg, 0.28 mmol) was dissolved in 2 mL of a mixed solution of tetrahydrofuran and water (v / v, 1 / 1). Aqueous LiOH (0.5 mL, 1N) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 hour, after which the reaction was stopped. Dilute hydrochloric acid was added to the reaction solution to adjust the pH to approximately 5, and the solvent was evaporated under reduced pressure. The crude product was separated by reverse-phase flash column chromatography (C18, CH3CN / H2O, 1 / 1) to obtain the target intermediate. a34 (50 mg) was obtained in a yield of 54%. LCMS ESI-MS m / z: 322 [M+H] + .

[0165] Using similar starting materials / intermediates, compounds a34 The following target intermediates were synthesized in the same manner as in the synthetic route of [Table 3]

[0166] Synthesis of intermediate a39: [ka]

[0167] Step 1: In an ice bath, a33 (360 mg, 1.03 mmol) was dissolved in 8 mL of chloroform. After stirring for 5 minutes, m-CPBA (531 mg, 3.09 mmol) was added to the reaction solution. The mixture was heated to 60°C and reacted for 12 hours, after which the reaction was stopped and filtered. 10 mL of saturated aqueous sodium thiosulfate solution was added to the reaction solution, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a brown oil. a39-1 (480 mg) was obtained in a yield of 90%. LCMS ESI-MS m / z: 382 [M+H] + .

[0168] Step 2: In an ice bath, a39-1 (480 mg, 0.92 mmol) was dissolved in 7 mL of tetrahydrofuran. After stirring for 5 minutes, aqueous LiOH solution (1.0 mL, 2N) was added to the reaction solution. The mixture was reacted at room temperature for 1 hour, after which the reaction was stopped and the solvent was distilled off under reduced pressure. Next, dilute hydrochloric acid was added to the reaction solution to adjust the pH to about 5, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by reverse-phase flash column chromatography (C18, CH3CN / H2O, 1 / 1) to give a white solid. a39 (190 mg) was obtained in a yield of 58%. LCMS ESI-MS m / z: 354 [M+H] + .

[0169] Preparation of key intermediates b1–b5 Intermediates b1, b2, b4~b9 Synthesis of [ka]

[0170] First step: At −78° C. under nitrogen protection, the starting material b1-1(8.8 g, 41.3 mmol) was dissolved in 88 mL of anhydrous tetrahydrofuran, and a solution of LiHMDS in tetrahydrofuran (10.4 g, 61.9 mmol, 61.9 mL) was slowly added dropwise. After the addition was complete, the reaction solution was stirred at -78 °C for 1.5 hours. N-phenylbis(trifluoromethanesulfonyl)imide (20.1 g, 51.6 mmol) was added to the reaction solution, which was then heated to room temperature and reacted for 2 hours before being quenched. 50 mL of ice water was added to the reaction solution, which was then extracted with methyl tert-butyl ether, dried over anhydrous sodium sulfate, concentrated, and the crude product was isolated by reverse-phase flash column chromatography (C18, CH3CN) to obtain a red oil. b1-2 (10.1 g) was obtained in 71% yield. LCMS ESI-MS m / z: 346 [M+H] + .

[0171] Step 2: Under nitrogen protection, the oil from the previous step b1-2 (2.1 g, 6.08 mmol) was added to 5-boronic acid pinacol ester-1,3-benzothiazole b1-3 The resulting mixture was dissolved in 40 mL of a mixture of 1,4-dioxane and water (v / v, 3 / 1) together with 1.1 g (7.62 mmol) and sodium carbonate (1.9 g, 18.2 mmol), and the 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 and filtered. 100 mL of water was added to the reaction solution, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a white solid. b1-3 (2.7 g) was obtained in 96% yield. LCMS ESI-MS m / z: 331 [M+H] + .

[0172] Step 3: White solid b1-3 The reaction mixture (2.7 g, 8.17 mmol) was dissolved in 15 mL of trifluoroacetic acid and reacted at room temperature for 1 hour, after which the reaction was stopped. The solvent was removed by distillation under reduced pressure, and the reaction solution was adjusted to pH 8 by adding a saturated aqueous solution of sodium bicarbonate. The mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a yellow oil. b1-4(1.8 g) was obtained in 96% yield. LCMS ESI-MS m / z: 231 [M+H] + .

[0173] Step 4: In an ice bath, remove the oily substance. b1-4 (1.0 g, 4.34 mmol) was dissolved in 20 mL of methanol. The reducing agent NaBH4 (250 mg, 6.51 mmol) was added, and the reaction was continued in an ice bath for 1 hour, after which the reaction was stopped. 100 mL of ice water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by reversed-phase flash column chromatography (C18, CH3CN / H2O, 3 / 5) to give a yellow oil. b1 (370 mg) was obtained in a yield of 37%. LCMS ESI-MS m / z: 233 [M+H] + .

[0174] Using similar starting materials / intermediates, compounds b1 The following target intermediates were synthesized in the same manner as in the synthetic route of [Table 4]

[0175] Intermediates b3 and b10 to b13 Synthesis of [ka]

[0176] Step 1: Under nitrogen protection, the starting material 2-methyl-5-bromo-1,3-benzothiazole b3-1 (1.2 g, 5.26 mmol) was dissolved in 6 mL of ethylene glycol, and aqueous NaOH (40%, 6 mL) was added dropwise slowly. After the addition was complete, the temperature was raised to 140°C and the reaction was allowed to proceed for 4 hours, after which it was cooled to room temperature. 50 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 6 with dilute hydrochloric acid. The reaction solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid. b3-2 (900 mg) was obtained in a yield of 42%. LCMS ESI-MS m / z: 405 [M+H] + .

[0177] Step 2: 1-Methyl-4-piperidine acid b3-3 (630 mg, 4.44 mmol) was dissolved in 14 mL of PPA, heated to 160° C., and stirred for 30 minutes. b3-2 (900 mg, 2.22 mmol) was added, and the mixture was heated to 180 °C for 3 hours, after which the reaction was stopped. 100 mL of ice water was poured into the reaction solution. After adjusting the pH to about 8 with a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (C18, CH3CN / H2O, 3 / 5) to give a yellow solid. b3-4 (250 mg) was obtained in a yield of 36%. LCMS ESI-MS m / z: 311 [M+H] + .

[0178] Step 3: Under nitrogen protection, a yellow solid b3-4 (3.0 g, 9.64 mmol) was dissolved in 30 mL of 1,4-dioxane together with pinacol diboronate (2.9 g, 11.6 mmol) and KOAc (2.8 g, 28.9 mmol), and the catalyst Pd(dppf)Cl2 (390 mg, 0.48 mmol) was added. The mixture was heated to 90 °C and reacted for 2 hours, after which the reaction was stopped and filtered. 100 mL of water was added to the reaction solution, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a brown solid. b3 (2.7 g) was obtained in 78% yield. LCMS ESI-MS m / z: 359 [M+H] + .

[0179] Using similar starting materials / intermediates, compounds b3 The following target intermediates were synthesized in the same manner as in the synthetic route of [Table 5]

[0180] Preparation of key intermediates c1–c4 Intermediates c1~c4 Synthesis of [ka]

[0181] Step 1: Under nitrogen protection, the starting material 5-trifluoromethyl-pyridine-2-carboxaldehyde c1-1 (558 mg, 3.53 mmol) and starting material c1-2 (508 mg, 1.34 mmol) was dissolved in 5.0 mL of dichloromethane. 4A molecular sieves (1.0 g) were added, and the solution was reacted at room temperature for 12 hours, after which the reaction was stopped and filtered. The filtrate was concentrated under reduced pressure to give a yellow oil. c1-3 (600 mg) was obtained in 84% yield. LCMS ESI-MS m / z: 537 [M+H] + .

[0182] Step 2: Under nitrogen protection, 2,6-dimethylpyridine (48 mg, 0.45 mmol) and Cu(OTf) (162 mg, 0.45 mmol) were dissolved in 3 mL of hexafluoroisopropanol and reacted at room temperature for 7 hours. c1-3 (600 mg, 1.12 mmol) was added dropwise to the reaction solution. After the addition was completed, the reaction was continued for 10 hours and then stopped. 6 mL of aqueous ammonia was added to the reaction solution, and the mixture was stirred for 1 hour. The mixture was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 1 / 1) to give the cis-configured intermediate. c1 (140 mg) was obtained in a yield of 51%. LCMS ESI-MS m / z: 247 [M+H] + .

[0183] The following target molecules were c1 It was synthesized from a similar skeleton structure using the same synthetic route as that of [Table 6]

[0184] Preparation of key intermediates d1–d17 Intermediates d1~d3, d5~d8, d11, d15~d17 Synthesis of [ka]

[0185] Step 1: Under nitrogen protection, the starting material 2-hydroxy-4-trifluoromethylbenzaldehyde d1-1 (1.0 g, 5.26 mmol) and methylamine tetrahydrofuran solution (5.3 mL, 2 M) were dissolved in 20 mL of anhydrous dichloromethane. Magnesium sulfate (2.5 g, 21.0 mmol) was added, and the reaction was carried out at room temperature for 12 hours. The reaction was then stopped and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid. d1-2 (470 mg) was obtained in a yield of 44%. LCMS ESI-MS m / z: 204 [M+H] + .

[0186] 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. d1-2 (470 mg, 2.31 mmol) was added to the reaction solution, and the temperature was raised to 50°C for 4 hours, after which the reaction was 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, after which the reaction was stopped and filtered. The solvent was removed under reduced pressure, and the crude product was separated by reverse-phase flash column chromatography (C18, CHCN / H2O, 1 / 1) to give a white product. d1 (40 mg) was obtained in 8% yield. LCMS ESI-MS m / z: 218 [M+H] + .

[0187] Intermediates d1 The following intermediates were synthesized in the same manner as in the synthetic route of [Table 7]

[0188] Intermediates d4, d9, d10 Synthesis of: [ka]

[0189] Step 1: Under nitrogen protection, the starting material d4-1 (12.2 g, 81.0 mmol) and starting materials d4-2 (13.6 g, 81.0 mmol) was dissolved in 20 mL of acetic acid. Ammonium acetate (12.5 g, 162 mmol) was added, and the mixture was heated to 120°C and reacted for 1 hour, then cooled to room temperature. 100 ml of ice water was added to the reaction solution, which was then 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 give a white solid. d4-3 (10.5 g) was obtained in a yield of 51%. LCMS ESI-MS m / z: 254 [M+H] + .

[0190] Step 2: Under nitrogen protection, the intermediate d4-3 (10.5 g, 41.4 mmol) and methyl 2-hydroxyacetate (7.5 g, 82.8 mmol) were dissolved in 105 mL of DMF, and then NaH (3.3 g, 82.8 mmol, 60%) was added and the reaction was allowed to proceed at room temperature for 2 hours. 300 mL of ice water was added to the reaction solution, which was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a yellow oil. d4-4 (5.0 g) was obtained in a yield of 44%. LCMS ESI-MS m / z: 276 [M+H] + .

[0191] Step 3: Intermediate d4-4 (5.0 g, 18.2 mmol) was dissolved in 50 mL of ethanol. Concentrated hydrochloric acid (100 mL, 12 M) was added, and the solution was heated to 100°C and reacted for 1 hour, then cooled to room temperature. 300 mL of aqueous ammonia was added dropwise to the reaction solution, which was then 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 give a yellow solid. d4-5 (366 mg) was obtained in a yield of 9%. LCMS ESI-MS m / z: 218 [M+H] + .

[0192] Step 4: Under nitrogen protection, the intermediate d4-5 (110 mg, 0.51 mmol) and methylamine tetrahydrofuran solution (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. The reaction was then stopped and filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated by reverse-phase flash column chromatography (C18, CH3CN / H2O, 7 / 10) to obtain a white solid. d4 (60 mg) was obtained in a yield of 51%. LCMS ESI-MS m / z: 233 [M+H] + .

[0193] The following intermediates are prepared by d4 It was synthesized in the same manner as in the synthesis route of [Table 8]

[0194] Intermediates d12~d14 Synthesis of: [ka]

[0195] Step 1: Under nitrogen protection, the intermediate d11 (1.0 g, 4.4 mmol), potassium carbonate (1.2 g, 8.77 mmol) and the starting material 5-chloro-pyridine-3-boronic acid e6-2 (1.0 g, 4.4 mmol) was dissolved in 20 mL of a mixture of 1,4-dioxane and water (v / v, 4 / 1), and the catalyst Pd(dppf)Cl2 (321 mg, 0.44 mmol) was added. The solution was heated at 100 °C for 1 h, filtered, and the solvent was removed under reduced pressure. After adding 100 mL of water to the mixture, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was isolated by reverse-phase flash column chromatography (C18, CH3CN / H2O, 6 / 10) to give a yellow oil in 84% yield. d12 (960 mg) was obtained. LC-MS: [M+H] +=261.

[0196] The following intermediates are prepared by d12 It was synthesized in the same manner as in the synthesis route of [Table 9]

[0197] Preparation of key intermediates e1–e9 Intermediates e1~e4 Synthesis of [ka]

[0198] Step: Under nitrogen protection, the starting material e1-1 (558 mg, 3.53 mmol) and starting material e1-2 (618 mg, 3.53 mmol) was dissolved in 13 mL of dichloromethane. NaBH(OAc)3 (2.25 g, 10.6 mmol) was added and the reaction was continued at room temperature for 1 hour, after which the reaction was stopped. The solvent was removed by evaporation under reduced pressure, and the mixture was dissolved in 2 mL of methanol. Aqueous ammonia was added to the system to adjust the pH to approximately 8, and the solvent was removed by evaporation under reduced pressure. Separation was performed by reverse-phase flash column chromatography (C18, CH3CN / H2O, 4 / 5) to obtain a green oily product. e1 (320 mg) was obtained in 29% yield. LC-MS: [M+H] + =283.

[0199] The following target molecules were e1 It was synthesized from a similar skeleton structure using the same synthetic route as that of [Table 10]

[0200] Intermediates e5 Synthesis of [ka]

[0201] Step 1: Under nitrogen protection, the starting material 1-methyl-1,2,4-triazole-3-carboxaldehyde e5-1 (3.1 g, 27.9 mmol) and the starting material (R)-configured tert-butylsulfenamide (3.4 g, 27.9 mmol) were dissolved in 62 mL of anhydrous toluene. KHSO4 (3.8 g, 27.9 mmol) was added, and the mixture was heated to 50 °C and reacted for 12 hours. After cooling to room temperature, the mixture was filtered. The filtrate was evaporated under reduced pressure to remove the solvent, and an oily product was obtained. e5-2 (4.9 g) was obtained in 91% yield. LCMS ESI-MS m / z: 215 [M+H] + .

[0202] Step 2: Oil at -78℃ under nitrogen protection e5-2 (4.9 g, 22.87 mmol) was dissolved in 98 mL of anhydrous tetrahydrofuran, and a hexane solution of the Grignard reagent methylmagnesium bromide (45.8 mL, 45.73 mmol) was added dropwise. After the addition was complete, the reaction was continued at this temperature for 45 minutes. The temperature was slowly raised to room temperature, and 100 mL of saturated aqueous sodium bicarbonate solution was added to the system to quench the reaction. After removing the organic solvent under reduced pressure, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by reverse-phase flash column chromatography (C18, CH3CN / H2O, 7 / 10) to obtain an oily product. e5-3 (1.1 g) was obtained in a yield of 21%. LCMS ESI-MS m / z: 231 [M+H] + .

[0203] Step 3: Under nitrogen protection, the intermediate e5-3 (2.1 g, 9.12 mmol) was dissolved in 42 mL of methanol, and a solution of hydrogen chloride in dioxane (3.7 mL, 14.6 mmol) was added. The reaction was allowed to proceed at room temperature for 1 hour, after which the reaction was stopped. After adding 30 mL of water to the system, the system was extracted with methyl tert-butyl ether, dried over anhydrous sodium sulfate, and concentrated to obtain compound (III) in 95% yield. e5 (1.8 g) was obtained. LCMS ESI-MS m / z: 127 [M+H] + .

[0204] Intermediates e6~e9 Synthesis of [ka]

[0205] Step 1: Under nitrogen protection, the starting material 5-bromo-2-pyridine c6-1 (2.9 g, 15.7 mmol), potassium carbonate (4.4 g, 31.5 mmol) and the starting material 5-chloro-pyridine-3-boronic acid e6-2 (22.5 g, 15.7 mmol) was dissolved in 58 mL of a mixture of 1,4-dioxane and water (v / v, 2 / 1), and the catalyst Pd(dppf)Cl2 (929 mg, 1.57 mmol) was added. The system was heated to 100 °C for 1 h, filtered, and the solvent was removed by distillation under reduced pressure. 100 mL of water was added to the mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 5 / 1) to give a yellow solid. e6-3 (2.5 g) was obtained in 73% yield. LC-MS: [M+H] + =219.

[0206] Step 2: In an ice bath, under nitrogen protection, e6-3 (1.0 g, 4.5 mmol), triethylamine (0.9 g, 9.15 mmol) and the starting materials e1-1 (700 mg, 5.03 mmol) was dissolved in 20 mL of dichloromethane, and reducing agent NaBH3 (1.1 g, 5.48 mmol) and acetic acid (0.3 g, 5.03 mmol) were added. The reaction was allowed to proceed in an ice bath for 2 hours, after which the reaction was quenched. The pH was adjusted to approximately 8 by adding aqueous ammonia, the solvent was removed under reduced pressure, and the crude product was separated by reverse-phase flash column chromatography (C18, CH3CN / H2O, 3 / 5) to give a yellow oil. e6 (612 mg) was obtained in 41% yield. LC-MS: [M+H] + =326.

[0207] The following target molecules were e6 It was synthesized from a similar skeleton structure using the same synthetic route as that of Table 11

[0208] Chiral separation of key intermediates f1-f24 intermediate f1, f2 synthesis

change

[0209] Separation conditions: CHIRALPAK AS3; mobile phase: Hex (0.1% TFA): EtOH=90:10; flow rate: 1.0mL / min; f1 (Holding time: 2.767 minutes; 105 mg, yield 35%); 1 H NMR (300 MHz, DMSO-d6) δ 7.50 (dd, J=26.1, 7.8 Hz, 1H), 7.39-7.23 (m, 2H), 5.92 (ddd, J=163.8, 8.8, 4.0 Hz, 1H), 4.82-4.57 (m, 2H), 2.58 (d, J=39.0 Hz, 3H). f2 (Holding time: 3.853 minutes; 110 mg, yield 37%).

[0210] intermediate f3, f4 synthesis

change

[0211] Separation conditions: Chromatagrafram: CHIRALPAK IF, 2*25cm, 5μm; Mobile phase A: Hex (0.5% 2M NH3-MeOH), Mobile phase B: MeOH: CM = 1:1; Flow rate: 20mL / min; f3 (Period of stay: 1.203 minutes; 150 mg); f4 (Period of stay: 1.593 minutes; 150 mg).

[0212] intermediate f5~f6 synthesis

change

[0213] Separation conditions: Chromatgraphie: CHIRAL ART Cellulose-SB 5*25cm, 5μm; Mobile phase A: Hex (0.5% 2M NH3-MeOH), Mobile phase B: MeOH:DCM = 1:1; Flow rate: 1mL / min; f5 (Period of stay: 12.455 minutes; 110 mg); f6 (Period of stay: 13.892 minutes; 110 mg).

[0214] intermediate f7~f8 synthesis

change

[0215] Separation conditions: Chromatagrafrym Chiralpak IF, 2*25cm, 5μm; Mobile phase A: Hex (0.1% TFA), Mobile phase B: EtOH, Flow rate: 20.0 mL / min; f7 (Period of stay: 12.417 minutes; 130 mg); f8 (Period of stay: 17.931 minutes; 115 mg).

[0216] intermediate f9~f10 synthesis

change

[0217] Separation conditions: Chromatagrafrym: CHIRALPAK AS-H, 2*25cm, 5μm; Mobile phase A: Hex (0.4% TFA), Mobile phase B: EtOH, Flow rate: 20.0 mL / min; f9 (Period of stay: 9.022 minutes; 65 mg); f10 (Period of stay: 12.626 minutes; 60 mg).

[0218] Intermediates f11~f12 Synthesis of [ka]

[0219] Separation conditions: Chromatography column: CHIRALPAK AS-H, 5*25cm, 5μm; Mobile phase A: Hex (0.4% TFA), Mobile phase B: MeOH; EtOH=1:1, Flow rate: 20.0mL / min; f11 (retention time: 12.527 minutes; 83mg); f12 (retention time: 17.993 min; 82 mg).

[0220] Intermediates f13~f14 Synthesis of [ka]

[0221] Separation conditions: Chromatography column: CHIRAL ART Cellulose-SB, 2*25cm, 5μm; Mobile phase A: Hex (0.4% DEA), Mobile phase B: Isopropanol, Flow rate: 20.0mL / min; f13 (retention time: 11.775 minutes; 140mg); f14 (Retention time: 12.988 minutes; 140 mg).

[0222] Intermediates f15~f16 Synthesis of [ka]

[0223] Separation conditions: Chromatography column: Lux 5μm cellulose-4, 2.12*25cm, 5μm; Mobile phase A: Hex (0.4% DEA), Mobile phase B: Isopropanol, Flow rate: 20.0mL / min; f13 (retention time: 8.451 minutes; 170mg); f14 (Retention time: 10.379 minutes; 170mg).

[0224] Intermediates f17~f18 Synthesis of [ka]

[0225] Separation conditions: Chromatography column: CHIRALPAK AS3; Mobile phase A: Hex (0.1% TFA) / (MeOH:EtOH = 1:1) = 85 / 15; Flow rate: 1.0 mL / min; f17 (retention time: 4.784 min; 82 mg); f18 (Retention time: 6.610 minutes; 80mg).

[0226] Intermediates f19~f20 Synthesis of [ka]

[0227] Separation conditions: Chromatography column: CHIRALPAK IF 2*25cm, 5μm; Mobile phase A: Hex (0.5% 2M NH3-MeOH), Mobile phase B: EtOH; Flow rate: 20mL / min; F19 (retention time: 5.453 minutes; 160mg); F19 (Retention time: 7.197 minutes; 170mg).

[0228] Intermediates f21~f22 Synthesis of (9.5g division) [ka]

[0229] Separation conditions: Chromatography column: CHIRALPAK IF, 2*25cm, 5μm; Mobile phase A: Hex (0.5% 2M NH3-MeOH), Mobile phase B: EtOH; Flow rate: 20mL / min; f21 (Retention time: 21.302 minutes; 4.0g); f22 (Retention time: 25.063 minutes; 4.5g).

[0230] Intermediates f23~f24 Synthesis of (10.1g division) [ka]

[0231] Separation conditions: Chromatography column: UniChiralCNZ-5H, 2*25cm, 5μm; Mobile phase A: Hex (0.5% 2M NH3-MeOH), Mobile phase B: EtOH; Flow rate: 25mL / min; f23 (Retention time: 9.872 minutes; 4.1g); f24 (Retention time: 15.440 minutes; 5.1g).

[0232] Example 2: target molecule P1~P33 and control molecules A1 Synthesis of [ka]

[0233] Step: Under nitrogen protection, the intermediate a1 (100 mg, 0.61 mmol), 4-dimethylaminopyridine DMAP (225 mg, 1.84 mmol) and DIEA (396 mg, 3.1 mmol) were dissolved in 3 mL of dichloromethane to obtain the intermediate b1 A dichloromethane solution of (217 mg, 0.61 mmol, 0.5 mL) was added dropwise, followed by the addition of the condensing agent T3P (780 mg, 2.5 mmol). The mixture was reacted at room temperature for 12 hours. The solvent was removed under reduced pressure, and the crude product was separated by reversed-phase flash column chromatography (C18, CH3CN / H2O, 4 / 5) to obtain the target compound. P1 (34 mg) was obtained in 11% yield. LCMS ESI-MS m / z: 500 [M+H] + .

[0234] 1 H NMR (300 MHz, DMSO-d6) δ 10.64 (d, J=45.5 Hz, 1H), 8.89-8.68 (m, 3H), 8.20-8.06 (m, 1H), 7.82 (d, J=32.6 Hz, 1H), 7.70-7.42 (m, 2H), 7.37 (dt, J=8.8, 4.9 Hz, 1H), 6.22 (d, J=19.1 Hz, 2H), 5.73 (dq, J=41.0, 7.0 Hz, 1H), 5.29-4.63 (m, 2H), 4.23 (d, J=15.5 Hz, 3H), 1.59 (dd, J=30.7, 7.0 Hz, 3H). Similar starting materials or intermediates ( a2 The intermediate a3~a5, a9~a21, a23~a30, a32~a35, a37~a40, f1~f2, f5~f12, f17~f18 or a43 (replace with , etc.) P1 The following target molecules were synthesized using the same synthetic route as above.

[0235] * indicates a chiral center that was not resolved. [Table 12]

[0236] TIFF2026504087000081.tif251166

[0237] TIFF2026504087000082.tif255164

[0238] TIFF2026504087000083.tif236166

[0239] TIFF2026504087000084.tif255166

[0240] TIFF2026504087000085.tif255167

[0241] TIFF2026504087000086.tif218166

[0242] Example 3 MTAP-deficient cells are sensitive to PRMT5-MTA inhibitors due to the accumulation of MTA, whereas MTAP wild-type (MTAP-normal) cells do not have the MTA accumulation effect, which is independent of PRMT5. By testing activity in both, the molecules of the present invention were shown to have an inhibitory and selective effect on PRMT5 at the cellular level.

[0243] HCT116 wild-type and MTAP-deficient cells were cultured in McCoy's 5A medium containing 10% FBS and 1% penicillin-streptomycin in a 37°C, 5% CO2 incubator. 40 μL of the cell suspension was introduced into each well of a 384-well microplate. Using an echo microscope, 40 nL of test compound at different concentrations was added to each well and cultured in a 37°C, 5% CO2 incubator for 7–10 days. 40 μL of CTG solution (Promega, catalog no. G7573) was added to each well and incubated in the dark for 30 minutes in a 37°C, 5% CO2 incubator. Luminescence readings were read using an Envision multifunction microplate reader (Perkin Elmer, catalog no. Envision 2104). In this reader, 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.

[0244] I C 50 Calculation of:

number

[0245] TIFF2026504087000089.tif71165

[0246] The above experimental results show that the superior compounds of the present invention have significant anti-proliferative effects on MTAP-deficient tumor cells by inhibiting PRMT5, but only slightly inhibit wild-type cells, which is expected to provide better safety. The activity and selectivity of some molecules are comparable to those of control molecules. AM9747 , TNG908 and GSK3326595 The activity and selectivity of

[0247] The molecules of the present invention are AM9747 has activity comparable to or better than AM9747 has a much higher selectivity than TNG908 It has much higher activity and selectivity than [Table 14]

[0248] Comparison of P2A, P22, P29a, and P32 with the control molecule A1 demonstrates that the alkyl substitutions (especially methyl or deuterated methyl substitutions) of this series of molecules are important for activity; therefore, deuteration helps improve metabolism and allows activity to be maintained for longer. Example 4 In-cell arginine symmetric dimethylation inhibition assay (in-cell Western (ICW) assay) HCT116 wild-type or MTAP-deficient cells (HCT116-MTAP del) cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin were seeded in a 384-well microplate in a volume of 30 μL and incubated overnight at 37°C and 5% CO. 60 nL of various concentrations of compounds were added to each well using an echo microscope and incubated at 37°C and 5% CO for 96 hours.

[0249] Next, 50 μL of 4% paraformaldehyde solution was added to each well and incubated at room temperature for 20 minutes to fix the cells. The solution in the wells was removed, and each well was rinsed four times with PBST containing 0.1% Tween 20. 30 μL of ice-cold methanol was then added to each well. After incubation at -20°C for 10 minutes, the methanol was removed, and the wells were washed four times with PBST. 30 μL of Odyssey blocking solution containing 0.5% Tween 20 was added to each well and shaken at room temperature for 2 hours. The blocking solution was removed, and 30 μL of primary antibody (Symmetric Di-Methyl Arginine Motif [sdma-RG] MultiMab™ Rabbit mAb mix) diluted 1:500 in Odyssey blocking solution containing 0.5% Tween 20 was added to each well. After incubating the plates overnight at 4°C, the primary antibody was removed, and each well was rinsed four times with PBST for 5 minutes per rinse. Secondary antibody (goat anti-rabbit IRDye 800CW, 1:800) and nuclear stain (DRAQ5, 1:10,000) diluted in Odyssey blocking solution containing 0.5% Tween 20 were then added to each well, followed by incubation for 2 hours in the dark at room temperature. The secondary antibody was removed, and the wells were rinsed four times with PBST.

[0250] The sdme-RG and DRAQ5 signals were scanned at 800 nm and 700 nm, respectively, on a Li-Cor Odyssey instrument, and the signal values ​​were recorded. The sdme-RG / DRAQ5 ratio was used to calculate the inhibition rate of arginine symmetric dimethylation (SDMA), and the IC 50 was calculated using GraphPad Prism software. [Table 15]

[0251] The above experimental results indicate that the superior compounds of the present invention have a significant inhibitory effect on arginine symmetric methylation in MTAP-deficient tumor cells by inhibiting PRMT5, but only weakly inhibit it in wild-type cells.

[0252] The molecules of the present invention are AM9747 has activity comparable to or better than AM9747 Much higher selectivity and TNG908 It has much higher activity than

[0253] Example 5: Liver microsome stability studies performed as follows: The compounds of the present invention were subjected to liver microsome stability tests. The compounds to be tested were co-incubated with different species of liver microsomes 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 compound concentrations in the incubation supernatant at different time points over 60 minutes were detected, and pharmacokinetic parameters (e.g., clearance Cl) were measured. int ) was calculated.

[0254] The results showed that the molecules of the present invention have good metabolic stability, especially in the human body. AMG9747 It has a lower clearance rate in human liver microsomal metabolism than acetaminophen and is therefore metabolized more slowly in the body. [Table 16]

[0255] The above results indicate that the molecules of the present invention have good metabolic stability in liver microsomes. P22 and P32 is a non-deuterated molecule P2a or P29a and are predicted to have similar or improved metabolism compared to and exhibit good in vivo exposure when administered in vivo.

[0256] Example 6: Membrane permeability evaluation test: Caco-2 assay The membrane permeability of the molecules of the present invention was evaluated. Samples were analyzed by LC-MS to determine the apparent permeability coefficient (P) of the compounds in Caco-2 cell monolayers. app ) was estimated (the pH of the apical compartment is 6.5 and that of the basolateral compartment is 7.4). Inhibitors of the efflux transporters P-gp, BCRP, and MRP2 (50 μM quinidine, 30 μM benzbromarone, and 20 μM sulfasalazine) were able to block active efflux transport of compounds, resulting in an apparent permeability (P app ) to generate data for the calculation:

number

[0257] In the formula, V A is the volume of the receptor pore (unit: mL), and area is the surface area of ​​the membrane (0.143 cm for Transwell-96 well permeable supports). 2 ) and time is the total transport time (seconds).

number

[0258] The Caco-2 assay results obtained for the molecules of the invention are shown below: [Table 17]

[0259] The above results indicate that the molecules of the present invention have good membrane permeability and are expected to achieve good tumor-inhibiting effects due to their better in vivo pharmacokinetics.

[0260] Membrane permeability evaluation test: MDCK-MDR1 assay The membrane permeability of the molecules of the present invention was assessed to predict their permeability to the brain.

[0261] The specific procedure is as follows: 1. MDCK-MDR1 cells were cultured in a 96-well plate at 1.56*10 6The cells were pre-cultured at a density of 1000 cells / mL for 7 days at 37°C. 2. The MDCKII-MDR1 plate was removed from the incubator, rinsed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), and then incubated at 37°C for 30 minutes. 3. The stock solution of the test compound was diluted with DMSO to obtain a 0.2 mM solution, which was then diluted with HBSS (10 mM HEPES, pH 7.4) to obtain a 1 μM working solution. A blank control was also diluted with DMSO to obtain a 0.2 mM solution, which was then diluted with HBSS (10 mM HEPES, pH 7.4) to obtain a 1 μM working solution. The final concentration of DMSO in the culture system was 0.5%. 4. The apical-to-basolateral transport rate of the drug was determined: 125 μL of 1 μM test compound solution was added to the Transwell insert (upper compartment), and 50 μL of the sample (D0 sample) was immediately transferred from the upper compartment to a new 96-well plate. The acceptor plate wells (basolateral compartment) were filled with 235 μL of HBSS (10 mM HEPES, pH 7.4) and incubated at 37°C for 2 hours. 5. Upon completion of incubation, 50 μL of sample from the donor and acceptor sides was transferred to wells of a new 96-well plate, followed by the addition of 4 volumes of cold acetonitrile containing the appropriate internal standard (IS). Prior to LC-MS / MS analysis, 100 μL of supernatant was removed and mixed with an appropriate volume of ultrapure water.

number

[0262] In the formula, V A is the volume of the receptor pore (unit: mL), and area is the surface area of ​​the membrane (0.143 cm for Transwell-96 well permeable supports). 2 ) and time is the total transport time (seconds).

number

[0263] The MDCK-MDR1 assay results for the molecules of the invention are shown below: [Table 18]

[0264] The above results indicate that most of the molecules of the present invention have good membrane permeability. P22 and P32 is a non-deuterated molecule P2a or P29a It is predicted to have a lower elimination ratio than HCl and give higher brain concentrations when administered in vivo.

[0265] Example 7: Pharmacokinetic study in mice CD1 female mice were used as test animals and the compounds were administered orally / intravenously (oral dose was 10 mg / kg, intravenous dose was 2 mg / kg).

[0266] Test Protocol: Each oral and intravenous group consisted of three mice. For the oral administration group, plasma samples were collected before administration (0 hours) and after administration (0.25, 0.5, 1, 2, 4, 8, and 24 hours). For the intravenous administration group, plasma samples were collected before administration (0 hours) and after administration (0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours). Plasma drug concentrations after oral and intravenous administration were determined by LC / MS / MS, and the collected data were analyzed using AB Sciex QTRAP 6500 software. The test results are shown below: [Table 19] [Table 20]

[0267] The above test results show that the compounds of the present invention have good oral absorption effect and high in vivo exposure. GSK3326595 Due to their superior selectivity compared to reported molecules such as , they are predicted to offer greater therapeutic efficacy.

[0268] Furthermore, the compound P2a andP22 In comparison with the compound P2a When the methyl group is replaced with deuterium, P22 The in vivo clearance rate of C max Higher in vivo exposure and deuterated compounds P22 teeth P2a It turns out to be better than

[0269] Similarly, P32 Deuteration of the molecule also results in higher in vivo exposure.

[0270] Example 8: hERG testing The CHO hERG-Duo cell line stably expressing the hERG channel was purchased from B'SYS GmbH and screened for monoclonal clones using a patch clamp system from Pharmaron Beijing Co., Ltd. Cells were cultured in a medium containing F12 (HAM) medium, 10% fetal bovine serum, 100 U / mL penicillin-streptomycin, 100 μg / mL hygromycin, and 100 μg / mL G418.

[0271] The membrane was depolarized to +30 mV for 4.8 seconds, and then the voltage was returned to -50 mV for 5.2 seconds to remove inactivation and measure the inactivation tail current. The sampling interval was 15 seconds, and the peak tail current size was used to quantify hERG current amplitude.

[0272] To establish a baseline, blank vehicle was applied to the cells. Test samples were introduced after allowing the hERG current to stabilize for at least 5 minutes. In the presence of test compounds, hERG currents at different working concentrations were recorded for at least 5 minutes until a steady state was reached, before five sweeps were acquired. If a steady state was not reached within 10 minutes, the average peak current of the last five sweeps was taken instead of the steady-state value. Cisapride was used as a positive control. The inhibitory effects of five concentrations of test compounds on hERG currents were detected in two independent experiments (n=2) and were calculated as IC50 It was decided.

[0273] Calculation formula:

number

[0274] The above results indicate that the molecules of the present invention have a weak effect on the heart, and that deuterated compounds P32 but P29a This shows that it is safer than

[0275] Example 9: In vivo efficacy testing in BALB / c nude mice was performed as follows: NCI-H838 (MTAPdel) non-small cell lung adenocarcinoma tumor cells were cultured and inoculated subcutaneously into 6- to 8-week-old female BALB / c nude mice (weight approximately 20 g). All mice were raised in an SPF-grade environment and had free access to a commercially available certified standard diet. The average tumor volume in mice was approximately 140 mm. 3 Once the tumors reached maturity, the test compounds were orally administered daily. The control group received blank vehicle (physiological saline containing 0.1% Tween 80 and 0.5% methylcellulose), while the test groups received drug doses of 75 mg / kg or 100 mg / kg twice daily. Tumor volume was measured in two dimensions using calipers three times a week, and animals were weighed daily. After 23 days of continuous administration, the inhibition rate (TGI / 100%) was calculated based on the final tumor volume. Volume calculation formula: V = 1 / 2a * b 2 , where a is the long diameter of the tumor and b is the short diameter of the tumor. [Table 22]

[0276] The results show that the molecules of the present invention exhibit good in vivo efficacy against MTAP-deficient tumor cells at different doses and low toxicity to mice.

number

[0277] Example 10: In vivo efficacy testing in BALB / c nude mice was performed as follows: HUP-T4 (MTAPdel) human pancreatic cancer tumor cells were cultured in MEM medium containing 10% fetal bovine serum and inoculated subcutaneously into 6-8 week-old female BALB / c nude mice (weighing approximately 25 g). All mice were housed in an SPF-grade environment and had free access to a commercially available certified standard diet. The average tumor volume in mice was approximately 176 mm. 3 Once the tumors reached the tumor size, the test compound was administered orally daily. The control group received blank vehicle (0.1% TW80 + 0.5% methylcellulose + 99.4% saline), while the test groups received drug doses of 75 mg / kg or 50 mg / kg twice daily. Tumor volume was measured in two dimensions using calipers three times a week, and animals were weighed daily. After 28 days of continuous administration, the inhibition rate (TGI / 100%) was calculated based on the final tumor volume. Volume calculation formula: V = 1 / 2a * b 2 , where a is the longest diameter of the tumor and b is the shortest diameter of the tumor. [Table 23]

[0278] The results show that the molecules of the present invention have good in vivo efficacy against MTAP-deficient pancreatic cancer cells and can induce tumor regression.

number

Claims

1. Formula (I): 【Chemistry 1】 [During the ceremony, X １ , X ２ and X ３ are each independently selected from —CH═, —O—, —S—, —N═, or —NH—; X １ , X ２ and X ３ at least one of is -N= or -NH-, the circle indicating aromaticity; R １ is H, C １－６ Alkyl, deuterated C １－６ Alkyl, C ３－６ Cycloalkyl or C １－６ haloalkyl; R ２ is H, C １－６ selected from alkyl or halogen; R ３ and R ４ are independently H, C １－６ Alkyl, C ３－６ cycloalkyl or 4-10 membered heterocyclyl, where R ３ or R ４ C in １－６ Alkyl, C ３－６ Each cycloalkyl or 4- to 10-membered heterocyclyl may have one or two R ５ where R ５ is hydrogen, deuterium, halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, CN, SF ５ , C ３－６ Cycloalkyl, —S(O) ２ CF ３ , -OCF ３ , -SCF ３ , -SCH ３ or a 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl is further selected from R ６ where R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ａ or a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; Or, R ３ , R ４ and the nitrogen atom to which they are attached together form a 4- to 10-membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and 1, 2, 3, or 4 R ｘ optionally substituted with; R ｘ is C １－６ Alkyl, C １－６ haloalkyl, phenyl, or 5-10 membered heteroaryl, where phenyl or 5-10 membered heteroaryl is selected from 1, 2, or 3 R ｙ optionally substituted with; R ｙ is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , C.N., O.R. ａ , C １－６ Alkoxy, —NR ｚ１ R ｚ２ , N.R. ｚ１ R ｚ２ -C １－６ Alkyl-, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; R ｚ is C １－６ Alkyl, halogen, CN, C １－６ haloalkyl or C １－６ alkoxy; R ａ is H, C １－６ Alkyl or C １－６ haloalkyl; R ｚ１ and R ｚ２ are each independently H or C １－６ is selected from; and n is 0, 1 or 2. or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

2. Formula (IIa) or Formula (IIb): 【Chemistry 2】 [During the ceremony, R １ is H, C １－６ Alkyl, deuterated C １－６ Alkyl, C ３－６ Cycloalkyl or C １－６ haloalkyl; R ２ is H, C １－６ selected from alkyl or halogen; R ３ and R ４ are independently H, C １－６ Alkyl, C ３－６ cycloalkyl or 4-10 membered heterocyclyl, where R ３ or R ４ C in １－６ Alkyl, C ３－６ Each cycloalkyl or 4- to 10-membered heterocyclyl may have one or two R ５ where R ５ is hydrogen, deuterium, halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, CN, SF ５ , C ３－６ Cycloalkyl, —S(O) ２ CF ３ , -OCF ３ , -SCF ３ , -SCH ３ or a 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl is further selected from R ６ where R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ａ or a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; Or, R ３ , R ４ and the nitrogen atom to which they are attached together form a 4- to 10-membered heterocyclic group, which contains 0 or 1 additional heteroatom selected from oxygen, nitrogen, or sulfur, and 1, 2, 3, or 4 R ｘ optionally substituted with; R ｘ is C １－６ Alkyl, C １－６ haloalkyl, phenyl, or 5-10 membered heteroaryl, where phenyl or 5-10 membered heteroaryl is selected from 1, 2, or 3 R ｙ optionally substituted with; R ｙ is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , C.N., O.R. ａ , C １－６ Alkoxy, —NR ｚ１ R ｚ２ , N.R. ｚ１ R ｚ２ -C １－６ Alkyl-, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; R ｚ is C １－６ Alkyl, halogen, CN, C １－６ haloalkyl or C １－６ alkoxy; R ａ is H, C １－６ Alkyl or C １－６ haloalkyl; and R ｚ１ and R ｚ２ are each independently H or C １－６ selected from 2. The compound of claim 1, which is a compound of the formula: or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

3. The following structure: 【Transformation 3】 [In the ceremony: R １ is H, C １－６ Alkyl, deuterated C １－６ Alkyl, C ３－６ Cycloalkyl or C １－６ haloalkyl; R ２ is selected from H, methyl, Cl or F; R ５ａ or R ５ｂ are each independently selected from 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl is selected from R ６ and R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ａ or a 5- to 6-membered heteroaryl; the 5- to 6-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; R ｘ１ is selected from phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is selected from 1, 2 or 3 R ｙ optionally substituted with; R ｙ is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , C.N., O.R. ａ , C １－６ Alkoxy, —NR ｚ１ R ｚ２ , N.R. ｚ１ R ｚ２ -C １－６ Alkyl-, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; R ｚ is C １－６ Alkyl, halogen, CN, C １－６ haloalkyl or C １－６ alkoxy; R ａ is H, C １－６ Alkyl or C １－６ haloalkyl; R ｘ２ is C １－６ Alkyl or C １－６ haloalkyl; R ｚ１ and R ｚ２ are each independently H or C １－６ is selected from; and Y is O, S or CH ２ selected from 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the formula:

4. The following structure: 【Chemistry 4】 [In the ceremony: R １ is H, C １－６ Alkyl, deuterated C １－６ Alkyl, C ３－６ Cycloalkyl or C １－６ haloalkyl; R ２ is selected from H, methyl, Cl or F; R ３ is H, C １－６ Alkyl, deuterated C １－６ Alkyl, C ３－６ cycloalkyl or 4- to 10-membered heterocyclyl; C １－６ Alkyl or 4- to 10-membered heterocyclyl is one or two R ５ optionally substituted with; R ５ is hydrogen, deuterium, halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, CN, SF ５ , C ３－６ Cycloalkyl, —S(O) ２ CF ３ , -OCF ３ , -SCF ３ , -SCH ３ or a 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl is further selected from R ６ and R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ａ or a 5- to 6-membered heteroaryl; the 5- to 6-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; R ｚ is C １－６ Alkyl, halogen, CN, C １－６ haloalkyl or C １－６ alkoxy; R ａ is H, C １－６ Alkyl or C １－６ haloalkyl; Y is NH, O, S or CH ２ is selected from; and Z is selected from N or CH.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the formula:

5. The following structure: 【Transformation 5】 [During the ceremony, R １ is C １－６ Alkyl, C ３－６ Cycloalkyl or C １－６ haloalkyl; R ５ａ or R ５ｂ are each independently selected from 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl is selected from R ６ and R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ａ or a 5- to 6-membered heteroaryl; the 5- to 6-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; R ｘ１ is selected from phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is selected from 1, 2 or 3 R ｙ optionally substituted with; R ｙ is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , C.N., O.R. ａ , C １－６ Alkoxy, —NR ｚ１ R ｚ２ , N.R. ｚ１ R ｚ２ -C １－６ Alkyl-, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; R ｚ is C １－６ Alkyl, halogen, CN, C １－６ haloalkyl or C １－６ alkoxy; R ａ is H, C １－６ Alkyl or C １－６ haloalkyl; and R ｚ１ and R ｚ２ are each independently H or C １－６ selected from 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the formula:

6. Formula (III-1): 【Transformation 6】 [During the ceremony, R １ is methyl, CD ３ , ethyl, or cyclopropyl; R ５ａ or R ５ｂ are each independently selected from 6-membered heteroaryl; the 6-membered heteroaryl may further be selected from R ６ and R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ａ or a 5- to 6-membered heteroaryl; the 5- to 6-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; R ｚ is C １－６ Alkyl, halogen, CN, C １－６ haloalkyl or C １－６ alkoxy; and R ａ is H, C １－６ Alkyl or C １－６ haloalkyl] 6. The compound of claim 5, which is a compound of the formula: or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

7. Formula (III-2): 【Transformation 7】 [During the ceremony, R １ is selected from methyl, ethyl or cyclopropyl; R ５ｂ teeth, 【Transformation 8】 which is further expressed as R ６ and R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ａ or a 5- to 6-membered heteroaryl; the 5- to 6-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; R ｚ is C １－６ Alkyl, halogen, CN, C １－６ haloalkyl or C １－６ alkoxy; and R ａ is H, C １－６ Alkyl or C １－６ haloalkyl] 7. The compound of claim 6, which is a compound of the formula: or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

8. Formula (III-3): 【Chemistry 9】 [During the ceremony, R １ is methyl, CD ３ , ethyl, or cyclopropyl; R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ａ or a 5- to 6-membered heteroaryl; the 5- to 6-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; R ｚ is C １－６ Alkyl, halogen, CN, C １－６ haloalkyl or C １－６ alkoxy; and R ａ is H, C １－６ Alkyl or C １－６ haloalkyl] 8. The compound of claim 7, which is a compound of the formula: or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

9. Formula (IV-1): 【Chemistry 10】 [During the ceremony, R １ is C １－６ Alkyl, deuterated C １－６ Alkyl, C ３－６ Cycloalkyl or C １－６ haloalkyl; R ｘ１ is selected from phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl is selected from 1, 2 or 3 R ｙ optionally substituted with; R ｙ is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , C.N., O.R. ａ , C １－６ Alkoxy, C ３－６ cycloalkyl, 【Chemistry 11】 4-12 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 4-12 membered heterocyclyl or 5-10 membered heteroaryl is selected from 1, 2 or 3 R ｚ optionally substituted with; R ｚ is C １－６ Alkyl, halogen, CN, C １－６ haloalkyl or C １－６ alkoxy; and R ａ is H, C １－６ Alkyl or C １－６ haloalkyl] 6. The compound of claim 5, which is a compound of the formula: or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

10. Formula (IV-2): 【Chemistry 12】 [During the ceremony, R １ is methyl, CD ３ , ethyl, or cyclopropyl; R ｙ is C １－６ Alkyl, C １－６ Haloalkyl, CN, OR ａ , C １－６ Alkoxy, C ３－６ cycloalkyl, 【Chemistry 13】 4-12 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 4-12 membered heterocyclyl or 5-10 membered heteroaryl is selected from 1, 2 or 3 R ｚ and R ｚ is C １－６ Alkyl, halogen, CN, C １－６ haloalkyl or C １－６ alkoxy] 10. The compound of claim 9, which is a compound of the formula: or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

11. Formula (V-1): 【Chemistry 14】 [During the ceremony, R １ is C １－６ Alkyl, deuterated C １－６ Alkyl, C ３－６ Cycloalkyl or C １－６ haloalkyl; R ｘ１ is a 5-10 membered heteroaryl group, which is selected from 1, 2 or 3 R ｙ optionally substituted with; R ｙ is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , C.N., O.R. ａ , C １－６ Alkoxy, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; R ｚ is C １－６ Alkyl, halogen, CN, C １－６ haloalkyl or C １－６ alkoxy; and R ａ is H, C １－６ Alkyl or C １－６ haloalkyl] 6. The compound of claim 5, which is a compound of the formula: or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

12. Formula (V-2): 【Chemistry 15】 [During the ceremony, R １ is methyl, CD ３ , ethyl, or cyclopropyl; R ｙ is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , C.N., O.R. ａ , C １－６ Alkoxy, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from 1, 2, or 3 R ｚ optionally substituted with; R ｚ is C １－６ Alkyl, halogen, CN, C １－６ haloalkyl or C １－６ alkoxy; and R ａ is H, C １－６ Alkyl or C １－６ haloalkyl] 12. The compound of claim 11, which is a compound of the formula: or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

13. Formula (V-3): 【Chemistry 16】 [During the ceremony, R １ is methyl, CD ３ , ethyl, or cyclopropyl; R ｚ is C １－６ Alkyl, halogen, CN, C １－６ haloalkyl or C １－６ alkoxy; and R ａ is H, C １－６ Alkyl or C １－６ haloalkyl] 13. The compound of claim 12, which is a compound of the formula: or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

14. The following structure: 【Chemistry 17】 [In the ceremony: R １ is H, C １－６ Alkyl, deuterated C １－６ Alkyl, C ３－６ Cycloalkyl or C １－６ haloalkyl; R ３ is H, C １－６ Alkyl, deuterated C １－６ Alkyl, C ３－６ cycloalkyl or 4- to 10-membered heterocyclyl; C １－６ Alkyl or 4- to 10-membered heterocyclyl is one or two R ５ optionally substituted with; R ５ is hydrogen, deuterium, halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, CN, SF ５ , C ３－６ Cycloalkyl, —S(O) ２ CF ３ , -OCF ３ , -SCF ３ , -SCH ３ or a 5- to 10-membered heteroaryl; the 5- to 10-membered heteroaryl is further selected from R ６ and R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ａ or 5-6 membered heteroaryl; R ａ is H, C １－６ Alkyl or C １－６ haloalkyl; and Z is selected from N or CH.

5. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the formula:

15. The following structure: [Chemistry 18] [In the ceremony: R １ is selected from H, methyl, deuterated methyl, ethyl or cyclopropyl; R ３ is H, C １ - ６ Alkyl, deuterated C １ - ６ Alkyl, C ３ - ６ selected from cycloalkyl or 4- to 10-membered heterocyclyl; and R ５ is hydrogen, halogen, C １ - ６ Alkyl, C １ - ６ Alkoxy, C １ - ６ Haloalkyl, C １ - ６ Haloalkoxy, CN, SF ５ , C ３ - ６ Cycloalkyl, —S(O) ２ CF ３ , -OCF ３ , -SCF ３ , -SCH ３ or 5- to 10-membered heteroaryl.

15. The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the formula:

16. R １ But H, methyl, CD ３ , ethyl, or cyclopropyl; R ３ But H, methyl, CD ３ , ethyl, or cyclopropyl; and R ５ is hydrogen, F, Cl, Br, methyl, ethyl, methoxy, trifluoromethyl, difluoromethyl, CN, SF ５ , cyclopropyl, —S(O) ２ CF ３ , -OCF ３ , -OCF ２ Cl, -SCF ３ , -SCH ３ or pyridyl, 16. The compound of claim 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof. 【Request Item 17】 【Chemistry 19】 【change】 【change】 【change】 or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

18. 18. A pharmaceutical composition comprising a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a pharmaceutically acceptable excipient, preferably further comprising another therapeutic agent.

19. 20. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, in the preparation of a medicament for treating and / or preventing a PRMT5 methyltransferase-mediated disease.

20. 19. A method for treating and / or preventing a PRMT5 methyltransferase-mediated disease in a subject, comprising administering to the subject a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition according to claim 18.

21. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition according to claim 18, for use in the treatment and / or prevention of a PRMT5 methyltransferase-mediated disease.

22. The PRMT5 methyltransferase mediated disease is cancer, and the cancer may be acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, hemangioma), appendix cancer, benign monoclonal gammopathy, bile duct carcinoma, bladder cancer, brain tumor (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelial carcinoma (e.g., Kaposi's nephroma), ... melanoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), hematopoietic cancer, for example, leukemia, for example, 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, lymph node marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, Hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell non-Hodgkin's lymphomas, e.g., 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-associated 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., α chain diseases, γ chain diseases, μ chain diseases), 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., bronchial 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., polycythemia vera (PV), essential thrombocythemia (ET), idiopathic extramedullary metaplasia) 20. The use of claim 19 or the method of claim 20 or the use of the compound or composition of claim 17, wherein the cancer is selected from the group consisting of: atherosclerosis, leukemia, myeloma (AMM), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibroma (e.g., neurofibromatosis type 1 or 2, schwannoma), neuroendocrine carcinoma (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, or penile cancer;

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