PRMT5-MTA inhibitors

Abstract

The present invention provides a compound for use as a PRMTS-MTA inhibitor, which is represented by formula (I) or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof. Also provided are pharmaceutical compositions containing the compound and uses thereof in the treatment of cancer. [Formula 1] TIFF2026502215000078.tif19157

Description

[Technical Field]

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

[0002] Protein arginine methyltransferase ( Protein arginine methyltransferase PRMTs (proteomics transcription factors, PRMTs) can methylate both histone and non-histone proteins, thereby regulating 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). Currently, 11 PRMT family members have been identified, and they can be classified into type I, type II, and type III based on differences in the catalytic arginine methylation mechanism. PRMT5 belongs to type II, and its catalytic form is symmetric dimethylation.

[0003] As an epigenetic enzyme, PRMT5 is involved in various biological processes, including transcriptional regulation, RNA metabolism, ribosome biogenesis, and cell cycle regulation. PRMT5 protein is overexpressed in various types of cancer, including B-cell and T-cell lymphoma, metastatic melanoma, neuroblastoma, glioblastoma, ovarian cancer, and breast cancer, and increasing evidence suggests that it plays an important role in tumor initiation and progression. Cell Stress . 2020 Aug;4(8):199-215) (Cancer Gene Ther. 2022 Mar;29(3-4):264-276). For these reasons, PRMT5 inhibitors have become a hot spot in R&D for anti-cancer treatments.

[0004] Early PRMT5 inhibitors can be classified into two types: substrate-competitive inhibitors, represented by GSK3326595, and SAM-competitive inhibitors, represented by JNJ64619178. These two types of drugs exhibit strong inhibitory activity against PRMT5 and potent antitumor activity. However, due to their potent inhibitory effects on PRMT5 in both normal and tumor cells, severe hematological toxicity has been observed, limiting their clinical application and affecting their therapeutic efficacy (Bioorg Med Chem Lett. 2019 July 1;29(11):1264-1269) (Expert Opin Ther Pat. 2019 February;29(2):97-114) (Annals of Oncology(2020)31(suppl_4):S462-S504.10.1016 / annonc / annonc271) (Annals of Oncology(2019)30(suppl_5):v159-v193.10.1093 / annonc / mdz244).

[0005] In 2016, a study published in Science revealed that MTAP loss exhibits synthetic lethality with PRMT5 (Science. 2016 March 11;351(6278):1214-8). MTAP has a high loss rate in various solid tumors, including pancreatic cancer and glioma. MTAP is an intracellular MTA-degrading enzyme. Loss of MTAP leads to intracellular accumulation of MTA, which can compete with SAM, the functional methyl donor substrate of PRMT5, to bind to PRMT5, thereby inhibiting PRMT5 function. Because MTA specifically accumulates in MTAP-deficient tumor cells, enhanced MTA-PRMT5 binding inhibition can achieve selective inhibition of PRMT5 activity in tumor cells while reducing its inhibitory effect on normal cells, providing a safe therapeutic window that ensures antitumor efficacy while reducing toxicity ( Nat Rev Drug Discov 2020 Jan;19(1):23-38 ) ( Cell Rep. 2016 Apr;19;15(3):574-587 ). Preclinical validation data for MTA-cooperative PRMT5 inhibitors are currently available ( J Med Chem. 2022 Feb;10;65(3):1749-1766 ). The development of MTA-cooperative PRMT5 inhibitors holds great promise for the treatment of MTAP-deficient tumors.

[0006] Although research on PRMT5 has progressed, there are still no effective and selective PRMT5-MTA inhibitors, and no PRMT5-MTA inhibitors have yet entered phase 2 clinical trials. Therefore, the development of highly selective PRMT5-MTA inhibitors would overcome the shortcomings of the first two generations of non-selective PRMT5 inhibitors to meet clinical needs. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Nat Rev Mol Cell Biol.2019 October;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 [Non-patent document 4] Cancer Gene Ther.2022 March;29(3-4):264-276 [Non-patent document 5] Bioorg Med Chem Lett.2019 / 07 / 1;29(11):1264-1269 [Non-patent document 6] Expert Opin Ther Pat.2019 / 2;29(2):97-114 [Non-Patent Document 7] Annals of Oncology(2020)31(suppl_4):S462-S504.10.1016 / annonc / annonc271 [Non-patent document 8] Annals of Oncology(2019)30(suppl_5):v159-v193.10.1093 / annonc / mdz244 [Non-Patent Document 9] Nat Rev Drug Discov 2020 January;19(1):23-38 [Non-Patent Document 10] Science.2016 / 03 / 11;351(6278):1214-8 [Non-Patent Document 11] Cell Rep.2016 Apr 19;15(3):574-587 [Non-Patent Document 12] J Med Chem.2022 Feb 10;65(3):1749-1766 Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention provides novel and highly selective PRMT5-MTA inhibitors. The present invention is realized by the following aspects or embodiments. [Means for solving the problem]

[0009] In one aspect, the present invention provides a compound of formula (I): [ka]

[0010] [During the ceremony: R1 is C 1-6 Alkyl, C 3-6 Cycloalkyl, or -CHOR a Selected from; R a is selected from H or methyl; R2 is H, C 1-6 Alkyl, C 1-6 alkoxy, or halogen; R3 is H, halogen, OR b , C.N., C. 1-6 Alkyl, or C 1-6 haloalkyl; R4 and R5 are H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Independently selected from 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 optionally substituted with 1 or 2 R6, wherein R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR b , SCF3, or 5- to 6-membered heteroaryl; Alternatively, R4, R5 and the nitrogen atom to which they are attached together form a 4- to 10-membered heterocyclyl, which can be selected from 1, 2, 3, or 4 R x may be substituted with R x is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6haloalkoxy, phenyl, or 5-10 membered heteroaryl, wherein 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 b , C 1-6 Alkoxy, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl is selected from one, two, or three 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 b is H, C 1-6 Alkyl, or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

[0011] In another aspect, the present invention provides a compound of formula (II): [ka]

[0012] [During the ceremony: R1 is C 1-6 selected from alkyl, cyclopropyl, or -CHOH; R2 is H, C 1-6 Alkyl, C 1-6 alkoxy, or halogen; R3 is selected from H, halogen, CN, or methyl; R4 and R5 are H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Independently selected from 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 optionally substituted with 1 or 2 R6, wherein R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 selected from haloalkyl, SF5, ORb, SCF3, or 5-6 membered heteroaryl; Alternatively, R4, R5 and the nitrogen atom to which they are attached together form a 4- to 10-membered heterocyclyl, which can be selected from 1, 2, 3, or 4 R x may be substituted with; R x is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 haloalkoxy, phenyl, or 5-10 membered heteroaryl, wherein 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 b , C 1-6 Alkoxy, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl is selected from one, two, or three 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 b is H, C 1-6 Alkyl, or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

[0013] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and, optionally, a pharmaceutically acceptable excipient.

[0014] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient, and further comprising another therapeutic agent.

[0015] 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 PRMT5 methyltransferase-mediated disease.

[0016] In another aspect, the present invention provides a method for treating and / or preventing a PRMT5 methyltransferase-mediated disease in a subject, comprising administering to the subject a compound of the present invention or a composition of the present invention.

[0017] 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 PRMT5 methyltransferase-mediated disease.

[0018] In certain embodiments, the disease treated by the present invention comprises a cancer selected from the following: schwannoma, adenocarcinoma, adrenal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, hemangioma), appendix cancer, benign monoclonal gammopathy, bile duct carcinoma, bladder cancer, brain cancer (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, epithelial carcinoma (e.g., ependymoma, epithelial carcinoma, sarcoma, For example, Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine carcinoma, 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 carcinoma, pharyngeal carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma)), blood cancer (e.g., leukemia, e.g., acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), L), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, Hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell non-Hodgkin's lymphomas, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (e.g., cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer / T-cell lymphoma, enteropathy-associated T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more of the foregoing leukemias / lymphomas;Multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer (e.g., nephroblastoma, 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), primary thrombocythemia (ET), idiopathic myelofibrosis (AMM), chronic idiopathic myelofibrosis, chronic granulocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibroma (e.g., neurofibromatosis type 1 or type 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, penile carcinoma;

[0019] Other objects and advantages of this invention will become apparent to those skilled in the art from the following specific embodiments, examples, and claims.

[0020] definition chemical definition Definitions of certain functional groups and chemical terms are described in more detail below.

[0021] When a range of values ​​is listed, it is intended to include each value and subrange within the specified range. 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 , C3-6, C2-5, C3-4, C 4-6 , C 4-5 , and C 5-6 Contains alkyl.

[0022] "C 1-6 "Alkyl" refers to a straight or branched saturated hydrocarbon group containing 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 The term "alkyl" also includes heteroalkyl, 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). Alkyl groups can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0023] "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" also 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). The alkenyl group may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0024] "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). The alkynyl group may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0025] "Halogenated" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0026] Therefore, "C 1-6 "Haloalkyl" refers to any of the aforementioned "C" groups in which one or more hydrogen atoms have been replaced by a halogen group. 1-6 In some embodiments, C 1-4 Haloalkyl is particularly preferred, C 1-2Haloalkyl is even more preferred. Exemplary haloalkyl 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, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0027] "C 1-6 "Alkoxy" refers to the group -OR, where R is C as defined above. 1-6 It is an alkyl. C 1-4 Alkoxy is preferred.

[0028] "C 1-6 Haloalkoxy refers to a group in which one or more hydrogen atoms have been replaced by a halogen group. 1-6 In some embodiments, C 1-4 Haloalkoxy is particularly preferred, C 1-2 Haloalkoxy is even more preferred.

[0029] "C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group containing 3 to 10 ring carbon atoms and no 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 5-6Cycloalkyl is even more preferred. Cycloalkyl also includes fused 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 carbon number refers to the number of carbons in the cycloalkyl system. Exemplary cycloalkyls 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. Cycloalkyl groups can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0030] "3- to 12-membered heterocyclyl" refers to a 3- to 12-membered non-aromatic ring group containing 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, 3- to 10-membered heterocyclyl is preferred, which is a 3- to 10-membered non-aromatic ring system containing ring carbon atoms and 1-3 ring heteroatoms; in some embodiments, 4- to 10-membered heterocyclyl is preferred, which is a 4- to 10-membered non-aromatic ring system containing ring carbon atoms and 1-4 ring heteroatoms; in some embodiments, 5- to 10-membered heterocyclyl is preferred, which is a 5- to 10-membered non-aromatic ring system containing ring carbon atoms and 1-5 ring heteroatoms; in some embodiments, 5- to 8-membered heterocyclyl is preferred, which is a 5- to 8-membered non-aromatic ring system containing ring carbon atoms and 1-5 ring heteroatoms; in some embodiments, 3- to 7-membered heterocyclyl is preferred, which is a 5- to 8-membered non-aromatic ring system containing ring carbon atoms and 1-5 ring heteroatoms. A 3- to 7-membered non-aromatic ring system containing 1 to 3 ring carbon atoms and 1 to 4 ring heteroatoms; a 3- to 6-membered heterocyclyl is preferred, which is a 3- to 6-membered non-aromatic ring system containing 1 to 3 ring carbon atoms and 1 to 3 ring heteroatoms; a 4- to 7-membered heterocyclyl is preferred, which is a 4- to 7-membered non-aromatic ring system containing 1 to 3 ring carbon atoms and 1 to 3 ring heteroatoms; a 4- to 6-membered heterocyclyl is preferred, which is a 4- to 6-membered non-aromatic ring system containing 1 to 3 ring carbon atoms and 1 to 3 ring heteroatoms; a 5- to 6-membered heterocyclyl is more preferred, which is a 5- to 6-membered non-aromatic ring system containing 1 to 3 ring carbon atoms and 1 to 3 ring heteroatoms; a 3- to 5-membered heterocyclyl is more preferred, which is a 3- to 5-membered non-aromatic ring system containing 1 to 3 ring carbon atoms and 1 to 3 ring heteroatoms.Heterocyclyl also includes fused ring systems in which a heterocyclyl ring is fused to one or more cycloalkyl rings, where the point of attachment is on the cycloalkyl ring, or in which a heterocyclyl ring is fused to one or more aryl or heteroaryl rings, where the point of attachment is on the heterocycle; and in such cases, the number of ring members continues to represent the number of members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. 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, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyls containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyls containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyls containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyls containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiacyclohexanyl, and dioxanyl. Exemplary 6-membered heterocyclyls containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyls containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.Exemplary 5-membered heterocyclyls (also referred to herein as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclyls (also referred to herein as 6,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyranopyridinyl, etc. The heterocyclyl group may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0031] "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 the ring 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 fused ring systems in which an aryl ring is fused to one or more cycloalkyls or heterocyclyls, and the point of attachment is on the aryl ring; in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0032] "5-14-membered heteroaryl" refers to a monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi-electrons shared in the ring arrangement) having 5-14 ring carbon atoms and 1-4 heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, where valence permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. Heteroaryl also includes fused ring systems in which a heteroaryl ring is fused to one or more cycloalkyls or heterocyclyls, and the point of attachment is on the heteroaryl ring; in such cases, 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 are preferred, which are 5-10-membered monocyclic or bicyclic 4n+2 aromatic ring systems containing ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5- to 10-membered heteroaryls are preferred, which are 6- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring systems containing 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 containing 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 containing ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl), and thiadiazolyl.Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridyl. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyrazinyl, pyrimidinyl, and pyridazinyl. Exemplary 6-membered heteroaryls containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl. Exemplary 7-membered heteroaryls containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzoxadiazolyl, benzothiazolyl, isobenzothiazolyl, benzothiadiazolyl, cinnolinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to, quinolinyl, isoquinolinyl, 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.

[0033] "Alkylene," "heterocyclene," "arylene," or "heteroarylene" refers to a divalent group formed by removing another hydrogen from a "cycloalkyl," "heterocyclyl," "aryl," or "heteroaryl" as defined above, which may be substituted or unsubstituted. For example, "C 5-7 "Alkylene" means C 5-7"C" refers to a divalent group formed by removing another hydrogen from a cycloalkyl, "5- to 8-membered heterocyclene" refers to a divalent group formed by removing another hydrogen from a 5- to 8-membered heterocyclyl, and "C 6-10 "Arylene" means 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- or 6-membered heteroaryl.

[0034] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, as defined herein, are optionally substituted groups.

[0035] Exemplary substituents on carbon atoms include, but are not limited to, 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 )Raa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(Raa )2, -B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl (wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group); Alternatively, the two geminal hydrogens on the carbon atom can be bonded to the groups =O, =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 be replaced by; Each 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 heterocyclic 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; Each R bb are independently hydrogen, -OH, or -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, independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R bb The groups are joined to form a heterocyclic 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; Each R cc are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc 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; Each R dd are independently 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 , -OCO2Ree , -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, heterocycloalkyl, 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 are joined to form =O or =S; Each R ee are 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; Each 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; Each R gg are independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 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)(C1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclyl, C5-C 10 heteroaryl; or two geminal R gg The substituents may combine to form =O or =S, where X - is the counter ion.

[0036] 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 attached to a nitrogen atom ccThe 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, and wherein R aa , R bb , R cc , and R dd is as defined above.

[0037] The term "deuterium (D or 2H)" refers to a stable isotope of hydrogen, which occurs naturally at an abundance of 0.015 mole %. The term "deuteration" refers to the replacement of one or more hydrogen atoms (H) in a group or compound with deuterium (D).

[0038] A "deuterated compound" refers to a compound in which one or more hydrogen atoms bonded to a carbon atom are replaced with 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 with one or more deuterium atoms, such as "deuterated alkyl," "deuterated cycloalkyl," "deuterated heterocycloalkyl," and "deuterated aryl." 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 with deuterium. In a deuterated alkyl, at least one carbon atom is bonded to at least one deuterium atom, and a carbon atom may be bonded to multiple deuterium atoms, and multiple carbon atoms in an alkyl may be bonded to deuterium. For example, deuterated methyl includes methyl-d3, in which three hydrogen atoms are replaced with deuterium, and also includes mono-deuterated methyl and di-deuterated methyl. In some embodiments, the compounds of the present invention include deuterated compounds.

[0039] Other definitions As used herein, the term "pharmaceutically acceptable salts" refers to carboxylate and amino acid addition salts of the compounds of the present invention which, within the scope of sound medical judgment, are suitable for contact with patient tissues without undue toxicity, irritation, allergic response, or other adverse effect, commensurate with a reasonable benefit / risk ratio, and are effective for their intended application, including zwitterionic forms of the compounds of the present invention (when applicable).

[0040] A "subject" for drug administration includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) and / or a non-human animal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and / or a dog. 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.

[0041] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0042] Generally, the "effective amount" of a compound refers to the amount that is sufficient to induce desired biological response.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 target, pharmacokinetics of the compound, the disease to be treated, administration method, and the age, health condition and symptoms of the subject.Effective amount includes both therapeutically effective amount and prophylactically effective amount.

[0043] The term "in combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or may be administered together in a single unit dosage form. DETAILED DESCRIPTION OF THE INVENTION

[0044] Specific Embodiments As used herein, "compounds of the invention" refers to compounds of formula (I) (including subformulas such as formula (II), (III-1), (III-1a), (III-1b), (III-2), (III-2a), (III-2b), (III-3), (III-3a), (III-3b), (IV-1), (IV-1a), (IV-1b), (IV-2), (IV-2a), (IV-2b), (IV-3), (IV-3a), or (IV-3b)), pharmaceutically acceptable salts, enantiomers, diastereomers, or isotopic isomers thereof, and mixtures thereof.

[0045] In one embodiment, the present invention provides a compound of formula (I): [ka]

[0046] [During the ceremony: R1 is C 1-6 Alkyl, C 3-6 Cycloalkyl, or -CHOR a Selected from; R a is selected from H or methyl; R2 is H, C 1-6 Alkyl, C 1-6 alkoxy, or halogen; R3 is H, halogen, OR b , C.N., C. 1-6 Alkyl, or C 1-6 haloalkyl; R4 and R5 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl; the 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl may be substituted with one or two R6, where R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR b, SCF3, or 5-6 membered heteroaryl; Alternatively, R4, R5 and the nitrogen atom to which they are attached together form a 4- to 10-membered heterocyclyl, which can be selected from 1, 2, 3, or 4 R x may be substituted with; R x is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 haloalkoxy, phenyl, or 5-10 membered heteroaryl, wherein 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 b , C 1-6 Alkoxy, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl is selected from one, two, or three 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 b is H, C 1-6 Alkyl, or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

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

[0048] [During the ceremony, R1 is C 1-6 selected from alkyl, cyclopropyl, or -CHOH; R2 is H, C 1-6 Alkyl, C 1-6 alkoxy, or halogen; R3 is selected from H, halogen, CN, or methyl; R4 and R5 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl; the 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl may be substituted with one or two R6, where R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR b , SCF3, or 5-6 membered heteroaryl; Alternatively, R4, R5 and the nitrogen atom to which they are attached together form a 4- to 10-membered heterocyclyl, which can be selected from 1, 2, 3, or 4 R x may be substituted with; R x is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 haloalkoxy, phenyl, or 5-10 membered heteroaryl, wherein 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 b , C 1-6 Alkoxy, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl is selected from one, two, or three R z may be substituted with; R zis C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl, or C 1-6 selected from alkoxy; R b is H, C 1-6 Alkyl, or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

[0049] In some embodiments of the compounds of Formula (I) or (II), R 1 is cyclopropyl.

[0050] In some embodiments of the compounds of Formula (I) or (II), R 1 is hydroxymethyl.

[0051] In some embodiments of the compounds of Formula (I) or (II), R is hydroxymethyl; R is H or C 1-6 R5 is 4- to 12-membered heterocyclyl; the 4- to 12-membered heterocyclyl may be substituted with one or two R6.

[0052] In some embodiments of the compounds of Formula (I) or (II), R is hydroxymethyl; R is H or C 1-6 R5 is 4- to 12-membered heterocyclyl; the 4- to 12-membered heterocyclyl may be substituted with one or two R6.

[0053] In some embodiments of compounds of Formula (I) or (II), R is hydroxymethyl; R, R, and the nitrogen atom to which they are attached together form a 4- to 10-membered heterocyclyl, which may be substituted with 1, 2, 3, or 4 R x It may be substituted with a substituent.

[0054] In another embodiment, the present invention provides a compound of formula (III-1), (III-1a), or (III-1b): [ka]

[0055] [During the ceremony, R2 is selected from H, methyl, ethyl, methoxy, or F; R3 is selected from H, F, Cl, CN, or methyl; R x1 is selected from phenyl or 5-10 membered heteroaryl, and 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 b , C 1-6 Alkoxy, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl is selected from one, two, or three 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 b is H, C 1-6 Alkyl, or C 1-6 haloalkyl; R x2 is C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 haloalkoxy; X is -CH2-, O, S, or -NR c -Selected from; R c is H or C 1-6 alkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

[0056] In another more specific embodiment, the present invention provides the above compound of formula (III-1), (III-1a), or (III-1b), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein: R2 is selected from H, methyl, ethyl, methoxy, or F; R3 is selected from H, F, Cl, CN, or methyl; R x is selected from phenyl or 6-membered heteroaryl, and the phenyl or 6-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 b , C 1-6 Alkoxy, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl is selected from one, two, or three 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 b is H, C 1-6 Alkyl, or C 1-6 haloalkyl; R x2 is selected from methyl, ethyl, trifluoromethyl, or trifluoromethoxy; X is selected from —CH 2 —, O, or S.

[0057] In some embodiments, R2 is selected from H, methyl, or ethyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl.

[0058] In some embodiments, R3 is selected from H, F, or Cl. In some embodiments, R3 is F or Cl. In some embodiments, R3 is F.

[0059] In some embodiments, R x1 is selected from phenyl or 6-membered heteroaryl, and the phenyl or 6-membered heteroaryl is selected from one R y may be substituted with R y is a halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy, 5- to 10-membered heteroaryl, or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl is selected from one R z may be substituted with R z is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl, or C 1-6 In some embodiments, R z is selected from methyl, ethyl, F, Cl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, or isopropoxy.

[0060] In some embodiments, R x2 is C 1-6 In some embodiments, R x2 is methyl or ethyl. In some embodiments, R x2 is methyl.

[0061] In some embodiments, X is O. In some embodiments, X is -CH2-. In some embodiments, X is S. In some embodiments, X is -NH-.

[0062] In some embodiments, R3 is F and R x2 is C 1-6 In some embodiments, R is F and R is alkyl. x2 is methyl or ethyl.

[0063] In another embodiment, the present invention provides a compound of formula (III-2), (III-2a), or (III-2b): [ka]

[0064] [During the ceremony, R2 is selected from H, methyl, ethyl, methoxy, or F; R3 is selected from H, F, Cl, CN, or methyl; R4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, or 4- to 12-membered heterocyclyl; R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR b or 5-6 membered heteroaryl; R b is H, C 1-6 Alkyl, C 1-6 haloalkyl; X is -CH2-, O, S, or -NR c -Selected from; Y is selected from CH or N; R c is H or C 1-6 alkyl; m is 0, 1, or 2; n is 0, 1, 2, or 3. or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

[0065] In another more specific embodiment, the present invention provides a compound of formula (III-3), (III-3a), or (III-3b): [ka]

[0066] [During the ceremony, R2 is selected from H, methyl, ethyl, methoxy, or F; R3 is selected from H, F, Cl, CN, or methyl; R4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, or 4- to 12-membered heterocyclyl; R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR b , SCF3, or 5-6 membered heteroaryl; R b is H, C 1-6 Alkyl, or C 1-6 haloalkyl; X is -CH2-, O, S, or -NR c -Selected from; Y is selected from CH or N; R c is H or C 1-6 alkyl; m is 0, 1, or 2. or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

[0067] In another embodiment, the present invention provides a compound of formula (IV-1), (IV-1a), or (IV-1b): [ka]

[0068] [During the ceremony, R2 is selected from H, methyl, ethyl, methoxy, or F; R3 is selected from H, F, Cl, CN, or methyl; R x1 is selected from phenyl or 5-10 membered heteroaryl, and 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 b , C 1-6 Alkoxy, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl is selected from one, two, or three 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 b is H, C 1-6 Alkyl, or C 1-6 haloalkyl; R x2 is C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 haloalkoxy; X is -CH2-, O, S, or -NR c -Selected from; R c is H or C 1-6 alkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

[0069] In another more specific embodiment, the present invention provides a compound of formula (IV-1), (IV-1a), or (IV-1b) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein: R2 is selected from H, methyl, ethyl, methoxy, or F; R3 is selected from H, F, Cl, CN, or methyl; R x1 is selected from phenyl or 6-membered heteroaryl, and the phenyl or 6-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 b , C 1-6 Alkoxy, C 3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl is selected from one, two, or three 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 b is H, C 1-6 Alkyl, or C 1-6 haloalkyl; R x2 is selected from methyl, ethyl, trifluoromethyl, or trifluoromethoxy; X is selected from —CH 2 —, O, or S.

[0070] In some embodiments, R2 is selected from H, methyl, or ethyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl.

[0071] In some embodiments, R3 is selected from H, F, or Cl. In some embodiments, R3 is F or Cl. In some embodiments, R3 is F. In some embodiments, R3 is Cl.

[0072] In some embodiments, R x1 is selected from phenyl or 6-membered heteroaryl, and the phenyl or 6-membered heteroaryl is selected from one R y In some embodiments, the 6-membered heteroaryl is pyridyl or pyrimidyl. In some embodiments, the 6-membered heteroaryl is pyridyl.

[0073] In some embodiments, R y is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 haloalkoxy, 5-10 membered heteroaryl, or phenyl, wherein the 5-10 membered heteroaryl or phenyl 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 In some embodiments, R y is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 haloalkoxy, pyridyl, or phenyl, wherein pyridyl or phenyl is selected from one, two, or three R z may be substituted with R z is C 1-6 Alkyl, halogen, CN, C 1-6 Haloalkyl, or C 1-6 In some embodiments, R z is selected from methyl, ethyl, F, Cl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropoxy.

[0074] In some embodiments, R x2 is C 1-6 In some embodiments, R x2 is methyl or ethyl. In some embodiments, R x2 is methyl.

[0075] In some embodiments, X is O. In some embodiments, X is -CH2-. In some embodiments, X is S. In some embodiments, X is -NH-.

[0076] In another embodiment, the present invention provides a compound of formula (IV-2), (IV-2a), or (IV-2b): [ka]

[0077] [During the ceremony, R2 is selected from H, methyl, ethyl, methoxy, or F; R3 is selected from H, F, Cl, CN, or methyl; R4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, or 4- to 12-membered heterocyclyl; R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR b , SCF3, or 5-6 membered heteroaryl; R b is H, C 1-6 Alkyl, or C 1-6 haloalkyl; X is -CH2-, O, S, or -NR c -Selected from; Y is selected from CH or N; R c is H or C 1-6alkyl; m is 0, 1, or 2; n is 0, 1, 2, or 3. or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

[0078] In another more specific embodiment, the present invention provides the compound described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein: R2 is selected from H, methyl, ethyl, methoxy, or F; R3 is selected from H, F, Cl, CN, or methyl; R4 is selected from H, methyl, ethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, or tetrahydrofuran; R6 is H, CN, F, Cl, methyl, ethyl, trifluoromethyl, trifluoroethyl, SF5, methoxy, trifluoromethoxy, difluoromethoxy, pyridyl, [ka]

[0079] Selected from; X is selected from -CH2-, O, S, or -NH-; Y is selected from CH or N; m is 1; n is 0, 1, 2, or 3.

[0080] In some embodiments, R2 is selected from H, methyl, or ethyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl.

[0081] In some embodiments, R3 is selected from H, F, or Cl. In some embodiments, R3 is F or Cl. In some embodiments, R3 is F. In some embodiments, R3 is Cl.

[0082] In some embodiments, R4 is H or C 1-6 alkyl. R4 is selected from C 1-6 In some embodiments, R4 is selected from methyl or ethyl.

[0083] In some embodiments, R6 is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 In some embodiments, R6 is selected from halogen, C 1-6 Haloalkyl, C 1-6 In some embodiments, R6 is selected from H, F, Cl, trifluoromethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, pyridyl, [ka]

[0084] is selected from.

[0085] In some embodiments, X is selected from O or S; and Y is selected from CH or N. In some embodiments, X is O; and Y is CH or N. In some embodiments, X is O; and Y is N.

[0086] In some embodiments, m is 1.

[0087] In some embodiments, n is 0. In some embodiments, n is 1.

[0088] In another embodiment, the present invention provides a compound of formula (IV-3), (IV-3a), or (IV-3b): [ka]

[0089] [During the ceremony, R2 is selected from H, methyl, ethyl, methoxy, or F; R3 is selected from H, F, Cl, CN, or methyl; R4 is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, or 4- to 12-membered heterocyclyl; R6 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, SF5, OR b , SCF3, or 5-6 membered heteroaryl; R b is H, C 1-6 Alkyl, or C 1-6 haloalkyl; X is -CH2-, O, S, or -NR c -Selected from; Y is selected from CH or N; R c is H or C 1-6 alkyl; m is 0, 1, or 2. or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

[0090] In another more specific embodiment, the present invention provides the compound described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein: R2 is selected from H, methyl, ethyl, methoxy, or F; R3 is selected from H, F, Cl, CN, or methyl; R4 is selected from H, methyl, methyl-d3, ethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, azetidine, oxetane, or tetrahydrofuran; R6 is H, CN, F, Cl, methyl, ethyl, trifluoromethyl, trifluoroethyl, SF5, methoxy, trifluoromethoxy, difluoromethoxy, pyridyl, [ka]

[0091] Selected from; X is selected from -CH2-, O, S, or -NH-; Y is selected from CH or N; m is 1.

[0092] In some embodiments, R2 is selected from H, methyl, or ethyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl.

[0093] In some embodiments, R3 is selected from H, F, or Cl. In some embodiments, R3 is F or Cl. In some embodiments, R3 is F. In some embodiments, R3 is Cl.

[0094] In some embodiments, R4 is H or C 1-6 In some embodiments, R4 is selected from C 1-6 In some embodiments, R4 is selected from methyl, methyl-d3, or ethyl.

[0095] In some embodiments, R6 is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6In some embodiments, R6 is selected from halogen, C 1-6 Haloalkyl, or C 1-6 In some embodiments, R6 is selected from H, F, Cl, trifluoromethyl, trifluoroethyl, difluoromethoxy, or trifluoromethoxy.

[0096] In some embodiments, X is selected from O or S; and Y is selected from CH or N. In some embodiments, X is O; and Y is CH or N. In some embodiments, X is O; and Y is CH.

[0097] In some embodiments, m is 1.

[0098] In another more specific embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein said compound is selected from: [ka]

[0099] TIFF2026502215000016.tif232151

[0100] TIFF2026502215000017.tif220149

[0101] TIFF2026502215000018.tif247150

[0102] TIFF2026502215000019.tif161156

[0103] The compounds of the present invention may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of the present invention may exist as a single enantiomer, diastereomer, or geometric isomer (e.g., cis isomer and trans isomer), 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 using methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, preferred isomers can be prepared by asymmetric synthesis.

[0104] The compounds of the invention may also exist as tautomers. For compounds that exist in different tautomeric forms, a given compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

[0105] The present invention also includes isotope-labeled compounds (isotopologues) that are equivalent to those described in Formula (A) except that one or more atoms are replaced by atoms having an atomic mass or mass number different from that typically found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, 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 Compounds of the present invention that contain the aforementioned isotopes and / or other atomic isotopes, their prodrugs, and pharmaceutically acceptable salts of such compounds or prodrugs are all within the scope of the present invention. 3 H and14 Certain isotopically labeled compounds of the present invention, such as those incorporating tritium (C), may be used for drug and / or substrate tissue distribution studies. 3 H) and carbon-14 ( 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, can provide therapeutic benefits due to increased metabolic stability, e.g., prolonged in vivo half-life or reduced dosage requirements, and therefore may be preferred in some cases. Isotopically labeled compounds of formula (A) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents in the procedures that follow and / or in the processes disclosed in the Examples and Preparation Methods.

[0106] 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.

[0107] The pharmaceutically acceptable excipient used in the present invention refers to the non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound that is formulated with it.The pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the compositions of the present invention include (but are not limited to) ion exchange resin, aluminum oxide, aluminum stearate, lecithin, serum protein (such as human serum albumin), buffer (such as phosphate), glycine, sorbic acid, potassium sorbate, the mixture of partial glycerides of saturated vegetable fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium phosphate, dipotassium 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.

[0108] The present invention also 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 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 and second containers can be combined to form a single unit dosage form.

[0109] Drug administration The pharmaceutical compositions provided by the present invention can be administered through a variety of routes, including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration, administration via an implant, or other administration methods. For example, as used herein, parenteral administration includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion techniques.

[0110] Generally, the effective amount of compound provided herein is administered.The actual amount of compound administered can be determined by a physician as appropriate under relevant conditions, including the disease to be treated, the selected administration route, the actual compound to be administered, the age, weight and response of individual patient and the severity of the patient's symptoms.

[0111] When used to prevent the diseases described in the present invention, the compounds provided herein are administered to subjects at risk of developing the disease at the dosage levels described above, typically based on the recommendation of a doctor and under the supervision of a doctor.Subjects at risk of developing a particular disease typically include subjects with a family history of the disease, or subjects identified as susceptible to developing the disease through genetic testing or screening.

[0112] The pharmaceutical compositions provided herein can also be administered over a long period of time ("long-term administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or indefinitely, such as for the life of the subject. In some embodiments, long-term administration is intended to provide a stable level of the compound in the bloodstream, for example, within the therapeutic range, over an extended period of time.

[0113] Various administration methods can be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered via bolus injection, for example, to increase the concentration of the compound in the blood to an effective level. The bolus injection dosage depends on the target systemic level of the active ingredient in the body. For example, intramuscular or subcutaneous bolus injection allows the active ingredient to be released slowly, while direct intravenous bolus injection (e.g., via IV drip) allows for more rapid delivery, quickly increasing the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of continuous infusion, such as via IV drip, thereby maintaining a steady-state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered initially, followed by continuous infusion.

[0114] Compositions for oral administration may be in the form of bulk liquid solutions, 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 physically discrete units suitable as single doses for human patients and other mammals, each unit containing a predetermined amount of active agent and suitable pharmaceutical excipients appropriate to achieve the desired therapeutic effect. Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or tablets, pills, capsules, and the like for solid compositions. In such compositions, the compound typically constitutes a minor component (about 0.1 to about 50% by weight, preferably about 1 to about 40% by weight), with the remainder comprising various carriers or excipients and processing aids useful for forming the desired dosage form.

[0115] For oral administration, a typical regimen is 1 to 5 oral doses per day, particularly 2 to 4 doses, typically 3. 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.

[0116] To achieve blood levels similar to or lower than those obtained with injectable dosages, transdermal doses are typically selected in the range of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and most preferably about 0.5 to about 15% by weight.

[0117] Injection dosage 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. Preloading bolus doses of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed about 2 g / day.

[0118] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous carrier, as well as buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following ingredients or compounds with similar properties: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as mint, methyl salicylate, or orange flavoring.

[0119] 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 typically constitutes a minor component, often about 0.05 to 10% by weight, with the remainder consisting of the injectable vehicle and the like.

[0120] 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 can be combined with a water-miscible ointment matrix.Alternatively, active ingredients can be formulated as creams, for example, using a water-encapsulated oil cream matrix.Such transdermal formulations are well known in the art, and generally contain other ingredients to enhance the stability and skin penetration of active ingredients or formulations.All such known transdermal formulations and ingredients are included in the scope of the present invention.

[0121] The compounds of the present invention can also be administered via a transdermal device. Thus, transdermal administration can be accomplished using a reservoir or porous membrane type patch or a patch having a variety of solid matrices.

[0122] The above-mentioned ingredients for compositions for oral, injectable, or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0123] The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0124] 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-cyclodextrin, which consist of 6, 7, and 8 α-1,4-linked glucose units, respectively, and optionally 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. Patent No. 5,376,645. In some embodiments, the formulation contains hexapropyl-β-cyclodextrin (e.g., 10-50% in water). [Example]

[0125] The reagents used in the present invention are either directly purchased commercially available reagents or are synthesized by methods generally known in the art.

[0126] Interpretation of common 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; TEA = triethylamine; DIEA = diisopropylethylamine; CuI = copper(I) iodide; CuCN = copper(I) cyanide; triphosgene = triphosgene; p-TsOH = p-toluenesulfonic acid; TBAS = tetrabutylammonium hydrogen sulfate.

[0127] As detailed below, the following specific reaction pathways or steps are used in the present invention: Example 1 Main intermediate a1 - a6 Preparation of Intermediates a1, a2 Synthesis of [ka]

[0128] Step 1: Under nitrogen protection, 2-iodo-4-bromo-5-fluoroaniline a1-1 (10.0 g, 31.6 mmol), tributyl(1-ethoxyvinyl)tin a1-2 (13.0 mL) and CuI (600 mg, 3.2 mmol) were dissolved in 200 mL of acetonitrile, and the catalyst Pd(PPh3)3Cl2 (2.2 g, 3.17 mmol) was added. The reaction was continued at 80 °C for 2 h, and then the reaction was stopped. The reaction mixture was filtered, and the solvent was removed under reduced pressure. The crude product was directly purified by flash column chromatography (PE / EA, 10 / 1) to give compound (III). a1-3 (5.0 g) was obtained in a yield of 68%. LCMS ESI-MS m / z: 232 [M+H] + Step 2: Intermediate from the previous step a1-3 (5.0 g, 21.5 mmol) and cyclopropylacetonitrile a1-4 (3.5 g, 43.1 mmol) was dissolved in 50 mL of DMSO. Potassium tert-butoxide (4.8 g, 43.1 mmol) was added, and the mixture was reacted at 50 °C for 2 hours, after which the reaction was stopped. 200 mL of water was added to the reaction system, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was directly purified by flash column chromatography (PE / EA, 1 / 1) to give compound (III). a1-5 (1.2 g) was obtained, the yield was 19%. LCMS ESI-MS m / z: 295 [M+H] + Step 3: Under nitrogen protection, the compound from the previous step a1-5(1.2 g, 4.1 mmol), Zn(CN)2 (600 mg, 4.88 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (dppf) (200 mg, 0.41 mmol) were dissolved in 24 mL of DMF. Catalyst Pd2(dba)3 (0.04 mL, 0.13 mmol) was added, and the mixture was heated to 100 °C for 2 h, after which the reaction was stopped. 100 mL of water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was directly purified by flash column chromatography (acetonitrile / water, 4 / 5) to give compound (III). a1 (150 mg) was obtained in a yield of 15%. LCMS ESI-MS m / z: 242 [M+H] + The following intermediates were synthesized with reference to the synthetic route of intermediate a1. [Table 1]

[0129] Intermediates a3 - a5 Synthesis of: [ka]

[0130] Step 1: Compound a3-1 (7.0 g, 28.2 mmol) was dissolved in a mixture of 70 mL of ethanol and 70 mL of water. Reduced iron powder (7.9 g, 141 mmol) and ammonium chloride (15.1 g, 282 mmol) were added. The reaction mixture was heated under reflux for 3 hours, after which the reaction was stopped and then filtered. 400 mL of ice water was added to the reaction system, followed by extraction with ethyl acetate. The organic phase was concentrated, and the crude product was purified by column chromatography to give a yellow solid. a3-2 (5.3 g, 24.3 mmol) was obtained in 86% yield. LCMS ESI-MS m / z: 218 [M+H] + Step 2: Intermediate from the previous step a3-2 (5.3 g, 24.3 mmol) and cyclopropylacetonitrile a1-4(3.9 g, 48.6 mmol) was dissolved in 55 mL of DMSO. After stirring for 5 minutes, potassium tert-butoxide (5.5 g, 48.6 mmol) was added to the reaction system, and the mixture was heated to 50 °C and reacted for 2 hours. 150 mL of ice water was added to the reaction system, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give a yellow solid a3-3 (3.3 g, 11.7 mmol) was obtained in a yield of 48%. LCMS ESI-MS m / z: 281 [M+H] + Step 3: Under nitrogen protection, the intermediate from the previous step a3-3 (3.3 g, 11.7 mmol), catalyst Pd2(dba)3 (0.5 g, 0.59 mmol), and dppf (0.7 g, 1.2 mmol) were dissolved in 66 mL of DMF. Zn(CN)2 (1.7 g, 14.1 mmol) was added, and the mixture was heated to 100 °C and reacted for 2 h. After that, it was cooled to room temperature and filtered. 200 mL of ice water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash column chromatography to give a yellow solid a3 (1.1 g, 4.84 mmol) was obtained. Yield: 41%. LCMS ESI-MS m / z: 228 [M+H] + Intermediates a3 The following intermediates were synthesized by referring to the synthetic route of [Table 2]

[0131] Intermediates a6 Synthesis of: [ka]

[0132] Step 1: Under nitrogen protection, the starting material 3-bromo-6-difluoromethoxypyrazine a6-1 (1.0 g, 4.5 mmol), vinylboronic acid pinacol ester a6-2(2.0 g, 13.5 mmol) and sodium carbonate (1.4 g, 13.6 mmol) were dissolved in 20 mL of a mixture of 1,4-dioxane and water (v / v, 8 / 1). Catalyst Pd(dppf)Cl2 (0.3 g, 0.45 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h, then cooled to room temperature and filtered. 100 mL of ice water was added to the reaction system, followed by extraction with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash column chromatography (PE / EA, 5 / 1) to give a white solid a6-3 (730 mg) was obtained, and the yield was 94%. LCMS ESI-MS m / z: 262 [M+H] + Step 2: Intermediate from the previous step a6-3 (720 mg, 4.2 mmol) was dissolved in 12 mL of a mixed solution of acetone and water (v / v, 5 / 1). N-methylmorpholine N-oxide (NMO) (1.7 g, 14.6 mmol) and K2OsO4·2H2O (154 mg, 0.41 mmol) were added and reacted at room temperature for 1 hour. The reaction was then stopped and filtered. 100 mL of ice water was added to the reaction system, followed by extraction with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash column chromatography (PE / EA, 2 / 1) to give a white solid. a6-4 (360 mg) was obtained, and the yield was 42%. LCMS ESI-MS m / z: 207 [M+H] + Step 3: Intermediate from the previous step a6-4 (360 mg, 1.74 mmol) was dissolved in 17 mL of a mixture of tetrahydrofuran and water (v / v, 11 / 1). Sodium periodate (NaIO4) (11.2 g, 5.24 mmol) was added and the reaction was allowed to proceed at room temperature for 1 hour, after which the reaction was stopped and filtered. 50 mL of ice water was added to the reaction system, followed by extraction with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a white solid. a6 (290 mg) was obtained, and the yield was 95%. LCMS ESI-MS m / z: 175 [M+H] + Main intermediate b1 - b7 Preparation of Intermediates b1 - b5 Synthesis of [ka]

[0133] Step 1: Intermediate a1 The resulting mixture (150 mg, 0.62 mmol) was dissolved in 3 mL of concentrated hydrochloric acid (35%) and heated to 100° C. for 2 hours. The solvent was removed under reduced pressure, and the crude product was purified by flash reverse-phase column chromatography (acetonitrile / water) to give a yellow solid b1-1 (100 mg) was obtained in a yield of 62%. LCMS ESI-MS m / z: 261 [M+H] + Step 2: Intermediate from the previous step b1-1 The reaction mixture was heated to 70°C and reacted for 2 hours, after which the reaction was stopped. The solvent was removed under reduced pressure to give a yellow solid. b1 (80 mg) was obtained, which was used directly in the next reaction step in 75% yield.

[0134] Intermediates b1 The following intermediates were synthesized by referring to the synthetic route of [Table 3]

[0135] Intermediates b6 Synthesis of [ka]

[0136] Step 1: Starting Materials b6-1 (1.2 g, 6.2 mmol) and cyclopropylacetonitrile a1-4(1.0 g, 12.3 mmol) was dissolved in 24 mL of DMSO. After stirring for 5 minutes, potassium tert-butoxide (1.4 g, 12.4 mmol) was added, and the mixture was heated to 50°C and reacted for 2 hours. 80 mL of ice water was added to the reaction system, and the pH was adjusted to approximately 5 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, concentrated, and the crude product was purified by flash reverse-phase column chromatography (acetonitrile / water) to give a yellow solid b6-2 (50 mg) was obtained in a yield of 4%. LCMS ESI-MS m / z: 243 [M+H] + Step 2: Intermediate b6-2 (50 mg, 0.21 mmol) was dissolved in 0.5 mL of thionyl chloride, and the reaction mixture was heated to 70° C. for 2 hours before quenching. The solvent was removed under reduced pressure to give a yellow solid b6 (50 mg) was obtained, which was used directly in the next reaction step. Yield: 93%.

[0137] Intermediates b7 Synthesis of [ka]

[0138] Step 1: Under nitrogen protection, the starting material b6-1 (3.5 g, 19.5 mmol) and propionitrile (2.1 g, 39.0 mmol) were dissolved in 35 mL of DMSO, tBuOK (4.3 g, 39.0 mmol) was added, and the reaction mixture was heated to 50 °C and reacted for 2 hours, then cooled to room temperature. 80 mL of ice water was added to the reaction system, followed by washing with ethyl acetate. The aqueous phase was adjusted to approximately pH 7 using 1 M dilute hydrochloric acid, followed by filtration under vacuum. The filter cake was dried to give a yellow solid b7-2 (3.5 g, 17.3 mmol) was obtained in a yield of 89%. LCMS ESI-MS m / z: 203 [M+H] + Step 2: Intermediate from the previous step b7-2(500 mg, 2.4 mmol) was dissolved in 10 mL of dichloromethane, and 1,4-dioxane hydrochloride solution (0.7 mL, 4 M) was added. The reaction was carried out at room temperature for 30 minutes, and the solvent was removed under reduced pressure. SOCl2 (4412 mg, 37.0 mmol) was added to the reaction system, and the mixture was heated to 55 °C and reacted for 1 hour, then cooled to room temperature. The reaction mixture was diluted with 10 mL of dichloromethane, filtered under vacuum, washed with n-hexane, and dried to give the intermediate b7 (400 mg) was obtained, with a yield of 73%.

[0139] Main intermediate c1 - c9 Preparation of Intermediates c1 - c9 Synthesis of [ka]

[0140] Step 1: Under nitrogen protection, the starting material 5-trifluoromethyl-pyridine-2-carbaldehyde 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 reaction was carried out at room temperature for 12 hours before being stopped. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. c1-3 (600 mg) was obtained. Yield: 84%. LCMS ESI-MS m / z: 537 [M+H] + Step 2: Under nitrogen protection, 2,6-dimethylpyridine (48 mg, 0.45 mmol) and catalyst 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, and after the addition was completed, the reaction was continued for another 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 organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash column chromatography (PE / EA, 1 / 1) to obtain the intermediate cis isomer. c1(140 mg) was obtained in a yield of 51%. LCMS ESI-MS m / z: 247 [M+H] + compound c1 By referring to the synthetic route of the above, the following target molecules were synthesized using similar scaffold structures: Cis = cis-enantiomer [Table 4]

[0141] Main intermediate d1 - d7 Preparation of Intermediates d1 - d3 Synthesis of [ka]

[0142] Step 1: Under nitrogen protection, the starting material 2-hydroxy-4-trifluoromethylbenzaldehyde d1-1 (1.0 g, 5.26 mmol) and a solution of methylamine in tetrahydrofuran (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 continued at room temperature for 12 hours, after which the reaction was stopped. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid d1-2 (470 mg) was obtained, and the yield was 44%. LCMS ESI-MS m / z: 204 [M+H] + Step 2: Under nitrogen protection, trimethylsulfoxonium 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, which was heated to 50°C and reacted for 4 hours, then cooled to room temperature. Potassium tert-butoxide (260 mg, 2.31 mmol) was further added to the reaction solution, and the reaction was continued at room temperature for 12 hours, after which it was stopped and filtered. The solvent was removed under reduced pressure, and the crude product was purified by flash reverse-phase column chromatography (acetonitrile / water, 1 / 1) to give a white solid in 8% yield. d1(40 mg) was obtained. LCMS ESI-MS m / z: 218 [M+H] + The following intermediates were synthesized by referring to the synthetic route of intermediate d1. [Table 5]

[0143] Intermediates d4 Synthesis of: [ka]

[0144] 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 reaction 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 mixture, and the mixture was extracted three times with methyl tert-butyl ether (MTBE). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified 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] + Step 2: Under nitrogen protection, the intermediate from the previous step d4-3 (10.5 g, 41.4 mmol) and methyl glycolate (2-hydroxyacetic acid methyl ester) (7.5 g, 82.8 mmol) were dissolved in 105 mL of DMF. NaH (3.3 g, 82.8 mmol, 60%) was added and the mixture was allowed to react at room temperature for 2 hours. 300 mL of ice water was added to the reaction mixture, 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 oily substance. d4-4 (5.0 g) was obtained in a yield of 44%. LCMS ESI-MS m / z: 276 [M+H] + Step 3: Intermediate from the previous step d4-4(5.0 g, 18.2 mmol) was dissolved in 50 mL of ethanol, and concentrated hydrochloric acid (100 mL, 12 M) was added. The reaction mixture 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 mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash column chromatography (PE / EA, 10 / 1) to give a yellow solid d4-5 (366 mg) was obtained, and the yield was 9%. LCMS ESI-MS m / z: 218 [M+H] + Step 4: Under nitrogen protection, the intermediate from the previous step d4-5 (110 mg, 0.51 mmol) and a solution of methylamine in tetrahydrofuran (1.3 mL, 2 M) were dissolved in 1 mL of trifluoroethanol and stirred at room temperature for 16 hours. Sodium borohydride (NaBH4) (96 mg, 2.5 mmol) and 0.25 mL of methanol were added to the reaction mixture, and the reaction was continued at room temperature for 1 hour, after which the reaction was stopped. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash reverse-phase column chromatography (acetonitrile / water, 7 / 10) to give a white solid d4 (60 mg) was obtained, and the yield was 51%. LCMS ESI-MS m / z: 233 [M+H] + Intermediates d5 Synthesis of: [ka]

[0145] Step 1: Under nitrogen protection, the starting material 3-bromo-6-chloropyridine-2-methanol d5-1 (6.0 g, 27.0 mmol) and allyl bromide d5-2(4.9 g, 40.5 mmol) was dissolved in 120 mL of tetrahydrofuran. KOH (3.0 g, 53.9 mmol) and TBAS (1.4 g, 4.1 mmol) were added, and the reaction was carried out at room temperature for 12 hours before quenching. 100 mL of ice water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash column chromatography (PE / EA, 80 / 1) to give a colorless oily substance d5-3 (5.0 g) was obtained in a yield of 71%. LCMS ESI-MS m / z: 262 [M+H] + Step 2: Under nitrogen protection, the intermediate from the previous step d5-3 Pd(PPh3)4 (5.0 g, 19.1 mmol) and cesium carbonate (7.5 g, 22.9 mmol) were dissolved in 105 mL of 1,4-dioxane. Pd(PPh3)4 (4.4 g, 3.8 mmol) was added, and the reaction mixture was heated to 100 °C and reacted for 12 h, then cooled to room temperature and filtered. 100 mL of ice water was added to the filtrate, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash column chromatography (PE / EA, 10 / 1) to give a pale yellow solid d5-4 (1.3 g) was obtained, and the yield was 38%. LCMS ESI-MS m / z: 182 [M+H] + Step 3: Intermediate from the previous step d5-4 (1.3 g, 7.2 mmol) was dissolved in 30 mL of a mixed solution of acetone and water (v / v, 5 / 1). K2OsO4·2H2O (264 mg, 0.72 mmol) and NMO (2.9 g, 25.1 mmol) were added and the mixture was allowed to react at room temperature for 2 h. The reaction was quenched by adding a saturated aqueous solution of sodium bisulfite, followed by extraction three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give an oily product in 84% yield. d5-5 (1.3 g) was obtained. LCMS ESI-MS m / z: 216 [M+H] + Step 4: Under nitrogen protection, the intermediate from the previous step d5-5(1.3 g, 6.0 mmol) was dissolved in 25 mL of a mixture of tetrahydrofuran and water (v / v, 5 / 1). Sodium periodate (NaIO4) (3.2 g, 15.1 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour, after which the reaction was stopped. 50 mL of water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash reverse-phase column chromatography (acetonitrile / water, 3 / 8) to give a white solid d5-6 (900 mg) was obtained, and the yield was 51%. LCMS ESI-MS m / z: 184 [M+H] + Step 5: Under nitrogen protection, the intermediate from the previous step d5-6 (900 mg, 4.9 mmol) and an aqueous solution of methylamine (24.5 mmol, 2.5 mL) were dissolved in 6 mL of trifluoroethanol and stirred at room temperature for 4 hours. Methanol (3.6 mL) and the reducing agent NaBH4 (927 mg, 24.5 mmol) were added to the reaction solution, and the reaction was allowed to proceed in an ice bath for 1 hour. The reaction was quenched by adding 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 purified by flash reverse-phase column chromatography (acetonitrile / water, 7 / 10) to give a white solid d5 (500 mg) was obtained, and the yield was 51%. LCMS ESI-MS m / z: 199 [M+H] + Intermediates d6 - d8 Synthesis of: [ka]

[0146] Step: Under nitrogen protection, the intermediate d5 (80 mg, 0.4 mmol), starting material d6-1(218 mg, 0.8 mmol) and potassium carbonate (112 mg, 0.8 mmol) were dissolved in 2 mL of a mixture of 1,4-dioxane and water (v / v, 4 / 1). Catalyst Pd(dppf)Cl2 (30 mg, 0.04 mmol) was added, and the mixture was heated to 80 °C and reacted for 1 h, then cooled to room temperature and filtered. 20 mL of ice water was added to the filtrate, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash reverse-phase column chromatography (acetonitrile / water, 3 / 5) to give a pale yellow solid. d6 (80 mg) was obtained, and the yield was 51%. LCMS ESI-MS m / z: 310 [M+H] + Intermediates d6 The following intermediates were synthesized based on the synthetic route of [Table 6]

[0147] Main intermediate e1 - e6 Preparation of Intermediates e1 - e3 Synthesis of [ka]

[0148] Step 1: In an ice bath under nitrogen protection, the starting material methyl propiolate e1-1 (2.1 g, 24.9 mmol) and the starting material 2,6-dimethylpyridine e1-2 (2.7 g, 24.9 mmol) was dissolved in 42 mL of dichloromethane. TsN3 (4.1 g, 20.8 mmol) and catalyst CuI (400 mg, 2.08 mmol) were slowly added, and the reaction was stopped after 4 hours in an ice bath. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. The solid was precipitated, filtered, and dried under vacuum to give a white solid. e1-3 (2.5 g) was obtained. Yield: 33%. LC-MS: [M+H] + =361 Step 2: Under nitrogen protection, the intermediate from the previous step e1-3(2.5 g, 6.94 mmol) and 2-amino-4-bromoacetophenone e1-4 (1.5 g, 6.94 mmol) was dissolved in 50 mL of dichloroethane. The reaction mixture was heated to 90° C. for 4 hours, after which the reaction was stopped. The solvent was removed under reduced pressure to give the crude product. e1-5 (3.0 g) was obtained. LC-MS: [M+H] + =450 Step 3: In an ice bath, add the crude product from the previous step. e1-5 (3.0 g, 6.68 mmol) was dissolved in 63 mL of dichloromethane. Concentrated sulfuric acid (1.3 g, 13.4 mmol) was added dropwise, and after the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour, and then stopped. The reaction mixture was slowly poured into ice water, and the pH was adjusted to approximately 9 with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash reverse-phase column chromatography (acetonitrile / water, 4 / 5) to give a yellow solid e1-6 (1.5 g) was obtained, with a yield of 76%. LC-MS: [M+H] + =297 Step 4: In an ice bath under nitrogen protection, the intermediate from the previous step e1-6 (3.0 mL, 2.5 M) was dissolved in 30 mL of anhydrous tetrahydrofuran. A solution of LiAlH4 in tetrahydrofuran (1.3 g, 13.4 mmol) was slowly added. After the addition was completed, the reaction was allowed to proceed at room temperature for 1 hour, and then the reaction mixture was stopped. The reaction mixture was slowly poured into ice water, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily product. e1-7 (1.0 g) was obtained, with a yield of 74%. LC-MS: [M+H] + =268 Step 5: Under nitrogen protection, the intermediate from the previous step e1-7(1.0 g, 3.74 mmol) and zinc cyanide (500 mg, 4.49 mmol) were dissolved in 20 mL of anhydrous DMF. The ligand dppf (200 mg, 0.37 mmol) and the catalyst Pd2(dba)3 (200 mg, 0.19 mmol) were added, and the reaction mixture was heated to 100 °C for 2 h before being stopped. 100 mL of ice water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash reverse-phase column chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate, 4 / 5) to give a yellow oily product. e1-8 (400 mg) was obtained, the yield was 50%. LC-MS: [M+H] + =214 Step 6: Intermediate from the previous step e1-8 (400 mg, 1.88 mmol) was dissolved in 8 mL of ethanol, and aqueous NaOH solution (8.0 mL, 50%) was slowly added. The reaction mixture was heated to 80°C for 4 hours, after which the reaction was stopped. The reaction mixture was slowly poured into ice water, and the pH was adjusted to approximately 3 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the crude product was purified by flash reverse-phase column chromatography (acetonitrile / water, 3 / 5) to give a gray solid. e1 (300 mg) was obtained in a yield of 69%. LC-MS: [M+H] + =233 compound e1 By referring to the synthetic route of the compound of formula (I), the following target molecule intermediates were synthesized using similar starting materials / intermediates. [Table 7]

[0149] Intermediates e4 - e6 Synthesis of [ka]

[0150] Step: Under nitrogen protection, the intermediate e1(320 mg, 1.37 mmol) was dissolved in 3.2 mL of thionyl chloride, and the reaction mixture was heated to 70° C. for 1 hour, after which the reaction was stopped. The solvent was removed under reduced pressure to give a yellow solid e4 (320 mg) was obtained in a yield of 86%, which was used directly in the next reaction.

[0151] compound d4 By referring to the synthetic route of the compound of formula (I), the following target molecule intermediates were synthesized using similar starting materials / intermediates. [Table 8]

[0152] Main intermediate f1 - f2 Preparation of Intermediates f1 - f2 Synthesis of [ka]

[0153] Step 1: Under nitrogen protection at −78° C., the starting material f1-1 (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 mixture was stirred at -78 °C for 1.5 hours. N-phenyl-bis(trifluoromethanesulfonyl)imide (20.1 g, 51.6 mmol) was added to the reaction solution, and the reaction mixture was heated to room temperature and reacted for 2 hours, after which the reaction was stopped. 50 mL of ice water was added to the reaction solution, followed by extraction with methyl tert-butyl ether. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash reverse-phase column chromatography (acetonitrile) to give a red oily substance f1-2 (10.1 g) was obtained in 71% yield. LCMS ESI-MS m / z: 346 [M+H] + Step 2: Under nitrogen protection, the oily product from the previous step f1-2(2.1 g, 6.08 mmol), 5-boronic acid pinacol ester-1,3-benzothiazole f1-3 (1.1 g, 7.62 mmol) and sodium carbonate (1.9 g, 18.2 mmol) were dissolved in 40 mL of a mixture of 1,4-dioxane and water (v / v, 3 / 1). Catalyst Pd(dppf)Cl2 (220 mg, 0.30 mmol) was added, and the mixture was heated to 80 °C for 2 h before being stopped. The reaction mixture was filtered, and 100 mL of water was added. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a white solid in 96% yield. f1-4 (2.7 g) was obtained. LCMS ESI-MS m / z: 331 [M+H] + Step 3: White solid from the previous step f1-4 (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 under reduced pressure, and the reaction mixture was adjusted to approximately pH 8 with a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a yellow oily product. f1-5 (1.8 g) was obtained in a yield of 96%. LCMS ESI-MS m / z: 231 [M+H] + Step 4: In an ice bath, add the oily product from the previous step. f1-5 (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 stopped after 1 hour in an ice bath. 100 mL of ice water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash reverse-phase column chromatography (acetonitrile / water, 3 / 5) to give a yellow oily product. f1 (370 mg) was obtained in a yield of 37%. LCMS ESI-MS m / z: 233 [M+H] + compound f1 By referring to the synthetic route of the above, the following target intermediates were synthesized using similar starting materials / intermediates: Trans = trans-enantiomer. [Table 9]

[0154] Main intermediate f3 - f4 Optical resolution of Intermediates f3 - f4 Synthesis of [ka]

[0155] Separation conditions: Column: CHIRALPAK IF, 5 x 25 cm, 5 μm; Mobile phase A: Hex (0.5% 2M NH3 in methanol solution); Mobile phase B (EtOH); Flow rate: 20 mL / min; f1 (retention time: 4.807 minutes); f2 (Retention time: 5.943 minutes).

[0156] Example 2: Target molecules P1 - P12 Synthesis of [ka]

[0157] Step 1: At room temperature, the intermediate c1 (71 mg, 0.29 mmol) and triethylamine (145 mg, 1.44 mmol) were dissolved in 2 mL of dichloromethane. b1 A dichloromethane solution (81 mg, 0.29 mmol, 0.5 mL) of was added dropwise, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water, 4 / 5) to give compound (III). P1 (40 mg) was obtained in a yield of 29%. LCMS ESI-MS m / z: 489 [M+H] + Step 2: Compound P1 The compounds were separated by SFC chiral column chromatography. P1a and P1b obtained.

[0158] Separation conditions: (Column: CHIRAL ART Cellulose-SC 2 x 25 cm, 5 μm; Mobile phase A:Hex:DCM=3:1 (2M NH3 in 0.5% methanol); Mobile phase B: IPA; Flow rate: 20 mL / min).

[0159] Retention time: 17.604 min (P1a); 20.403 min (P1b).

[0160] [[ID= : 1 H NMR (400 MHz, DMSO-d6) δ 9.11 - 8.96 (m, 1H), 8.25 (s, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.79 (s, 1H), 7.24 (s, 1H), 6.72 (s, 2H), 5.73 (s, 1H), 5.12 (s, 1H), 3.88 - 3.49 (m, 4H), 2.78 - 2.54 (m, 3H), 1.63 (s, 1H), 1.20 (d, J = 31.9 Hz, 3H), 0.78 (s, 2H), 0.48 (s, 2H). ​ : 1 H NMR (400 MHz, DMSO-d6) δ 9.11 - 8.96 (m, 1H), 8.25 (s, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.79 (s, 1H), 7.24 (s, 1H), 6.72 (s, 2H), 5.73 (s, 1H), 5.12 (s, 1H), 3.88 - 3.49 (m, 4H), 2.78 - 2.54 (m, 3H), 1.63 (s, 1H), 1.20 (d, J = 31.9 Hz, 3H), 0.78 (s, 2H), 0.48 (s, 2H). compound P1 By referring to the synthetic route of the compound of formula (I), the following target molecules were synthesized using similar starting materials or intermediates.

[0161] Cis indicates that the compound has a cis configuration and will not resolve; * indicates a chiral center and is not resolved. [Table 10]

[0162] TIFF2026502215000046.tif202165

[0163] TIFF2026502215000047.tif215166

[0164] TIFF2026502215000048.tif127165

[0165] Example 3: Target molecules ​ Synthesis of [ka]

[0166] Step 1: Under nitrogen protection, the intermediate d1 (41 mg, 0.18 mmol) and triethylamine (93 mg, 0.92 mmol) were dissolved in 2 mL of dichloromethane. b5 A dichloromethane solution (41 mg, 0.18 mmol, 0.5 mL) of 41 mg of 4-chloromethane was added dropwise, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water, 4 / 5) to give the target molecule. H1 (12 mg) was obtained in a yield of 15%. LCMS ESI-MS m / z: 428 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.70 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.57 - 7.46 (m, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 6.65 (s, 2H), 6.35 (s, 1H), 4.80 (s, 1H), 4.71 (dd, J = 10.4, 4.5 Hz, 1H), 2.65 (s, 3H), 1.89 - 1.76 (m, 1H), 1.02 - 0.90 (m, 2H), 0.67 (dt, J = 5.6, 2.8 Hz, 2H). compound H1 By referring to the synthetic route of the compound of formula (I), the following target molecules were synthesized using similar starting materials or intermediates.

[0167] * indicates a chiral center and is not resolved. [Table 11]

[0168] Example 4: Target molecules ​ Synthesis of [ka]

[0169] Step 1: Under nitrogen protection, the intermediate d3 (500 mg, 2.19 mmol) and triethylamine (1.11 g, 11.0 mmol) were dissolved in 12 mL of dichloromethane. b5 A dichloromethane solution (541 mg, 2.19 mmol, 2 mL) of the compound (I) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile / water, 9 / 10) to give a white solid. H4-1 (512 mg) was obtained in a yield of 52%. LCMS ESI-MS m / z: 438 [M+H] + Step 2: Under nitrogen protection, the compound from the previous stepH4-1 (70 mg, 0.16 mmol), 1-N-methyl-4-pyrazoleboronic acid pinacol ester H4-2 The catalyst Pd(dppf)Cl2 (23 mg, 0.03 mmol) was added, and the mixture was stirred for 5 min, heated to 90 °C, and reacted for 2 h, then cooled to room temperature. The solvent was removed under reduced pressure, and the crude product was purified by flash reverse-phase column chromatography (acetonitrile / water, 9 / 10) to obtain the target molecule in 83% yield. H4 (60 mg) was obtained. LCMS ESI-MS m / z: 440 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.54 (dd, J = 8.5, 1.9 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.10 (s, 1H), 6.63 (s, 2H), 4.69 (s, 1H), 4.59 (dd, J = 10.3, 4.0 Hz, 1H), 3.86 (s, 3H), 3.83 (d, J = 7.3 Hz, 1H), 2.64 (s, 3H), 1.91 - 1.79 (m, 1H), 1.04 - 0.94 (m, 2H), 0.70 - 0.61 (m, 2H). compound H4 By referring to the synthetic route of the compound of formula (I), the following target molecules were synthesized using similar starting materials or intermediates.

[0170] * indicates a chiral center and is not resolved. [Table 12]

[0171] Example 5: Target Molecules ​ Synthesis of [ka]

[0172] Step 1: Under ice bath, intermediate c1 (43 mg, 0.17 mmol) and triethylamine (88 mg, 0.87 mmol) were dissolved in 2 mL of dichloromethane, and then the intermediate e5 A solution of (51 mg, 0.17 mmol, 1 mL) in dichloromethane was added dropwise. The mixture was reacted at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the crude product was purified by flash reverse-phase column chromatography (acetonitrile / water, 4 / 5) to give a yellow solid A1-1 (71 mg) was obtained, the yield was 81%. LCMS ESI-MS m / z: 497 [M+H] + Step 2: Under nitrogen protection, the compound from the previous step A1-1 (70 mg, 0.14 mmol) was dissolved in 3 mL of a mixture of tetrahydrofuran and water (v / v, 1 / 1). K2CO3 (78 mg, 0.56 mmol) was added and stirred for 5 min. After that, the mixture was heated to 60 °C and reacted for 10 h, then cooled to room temperature. The solvent was removed under reduced pressure, and the crude product was purified by flash reverse-phase column chromatography (acetonitrile / water, 4 / 5) to obtain the target molecule. A1 (55 mg) was obtained in 82% yield. LCMS ESI-MS m / z: 479 [M+H] + Step 3: Compound A1 (55 mg) was separated by SFC chiral column chromatography under the following conditions: Chromatography column: Chiral ART Cellulose-SA, 2*25 cm, 5 μM; Mobile phase A: Hex (0.5% 2M NH3-MeOH), and Mobile phase B: EtOH; Flow rate: 20 mL / min; A1a retention time: 11.935 min; A1b retention time: 15.066 min.

[0173] ​ : 1H NMR (300 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.23 ​​(s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.21 (s, 1H), 6.49 (s, 2H), 5.71 (s, 1H), 5.11 (s, 2H), 4.57 (d, J = 5.2 Hz, 2H), 3.89 - 3.50 (m, 3H), 2.71 - 2.49 (m, 3H), 0.77 (s, 3H). ​ : 1 H NMR (300 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.23 ​​(s, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.79 (s, 1H), 7.21 (s, 1H), 6.49 (s, 2H), 5.71 (s, 1H), 5.13 (d, J = 5.4 Hz, 2H), 4.57 (d, J = 4.9 Hz, 2H), 3.93 - 3.53 (m, 3H), 2.72 - 2.49 (m, 3H), 0.77 (s, 3H). By referring to the synthetic route of compound A1, the following target molecules were synthesized using similar starting materials or intermediates.

[0174] * indicates a chiral center and is not resolved. [Table 13]

[0175] TIFF2026502215000055.tif244165

[0176] TIFF2026502215000056.tif208165

[0177] TIFF2026502215000057.tif212165

[0178] Example 6: MTAP-deficient cells are sensitive to PRMT5-MTA inhibitors for proliferation due to MTA accumulation, whereas MTAP wild-type (MTAP-normal) cells do not exhibit the MTA accumulation effect and are not dependent on PRMT5. By examining both activities, the inhibitory effect and selectivity of the molecules of the present invention for PRMT5 at the cellular level were demonstrated.

[0179] HCT116 wild-type and MTAP-deficient cells were cultured in MCCOYS 5A medium containing 10% FBS and 1% penicillin-streptomycin and incubated at 37°C in a 5% CO2 incubator. 40 μL of cell suspension was added to each well of a 384-well microplate. Using an Echo™ microscope, 40 nL of compound at different concentrations was added to each well, followed by incubation at 37°C in a 5% CO2 incubator for 7–10 days. 40 μL of CTG solution (Promega, catalog no. G7573) was added to each well and incubated at 37°C in a 5% CO2 incubator for 30 minutes in the dark. Luminescence was measured using an Envision multimode plate reader (Perkin Elmer, catalog no. Envision2104). The luminescence signal was proportional to the ATP content in the system, which directly reflected the number of viable cells in the system.

[0180] I C 50 Calculating the value: Y = Lower Plateau Signal + (Upper Plateau Signal - Lower Plateau Signal) / (1 + 10^((LogIC 50 -X)×Hillslope)) X: Logarithm of compound concentration Y: Inhibition rate (%) Table 1: 2D antiproliferative effects of compounds on HTC116-MTAP del and wild-type colorectal cancer HCT-116 cell lines. [Table 14]

[0181] The above experimental results show that by inhibiting PRMT5, the superior compounds of the present invention exhibit significant anti-proliferative effects on MTAP-deficient tumor cells, while exhibiting weaker inhibition on wild-type tumor cells. Some molecules exhibit very high selectivity (more than 50-fold), which is expected to result in higher safety. In contrast, the reference molecules ​ The selectivity of is only about 30-fold, which may lead to dose limitations in clinical use due to insufficient selectivity. ​ has only 23-fold selectivity, and ​ was temporarily discontinued in clinical trials due to insufficient selectivity. Therefore, the high selectivity of the present invention is expected to improve efficacy in clinical use while reducing side effects.

[0182] ​ and P1 or P4 Compared with the above, we showed that substitutions at R2 and R3 significantly affected activity. [Table 15]

[0183] Example 7: Microsomal stability studies of compounds, details of which are as follows: Microsomal stability studies were performed on the compounds of the present invention. Test compounds were co-incubated with liver microsomes from different species with or without the addition of NADPH. In the test system, the final concentration of the test compound 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 concentration in the incubation supernatant was measured at various time points within 60 minutes, and pharmacokinetic parameters (intrinsic clearance rate Cl ) were analyzed. int etc.) were calculated.

[0184] The results show that the molecules of the present invention have good metabolic stability (especially in humans, they show good metabolic stability).Some molecules show a lower clearance rate in human liver microsome metabolism compared to AM9747, resulting in slower metabolism in the human body. [Table 16]

[0185] Example 8: Membrane permeability evaluation experiment: Caco-2 assay Assessment of membrane permeability of the molecules of the invention. Samples were analyzed using LC-MS to determine the apparent permeability coefficient (P) of the compounds in Caco-2 cell monolayers. app ) is estimated, where the pH of the apical chamber is 6.5 and the pH of the basolateral chamber is 7.4. P-gp efflux transporter, BCRP, and MRP2 inhibitors (50 μM quinidine, 30 μM benzbromarone, and 20 μM sulfasalazine) can block active efflux transport of compounds. The data are used to calculate apparent permeability (Papp).

[0186] P app =(V A ​ 受容体 ​ 初期値,ドナー ) where VA is the volume of the receptor well (unit: mL) and Area is the membrane surface area (0.143 cm for Transwell-96 well permeable supports). 2 ) and time is the total transport time (unit: seconds).

[0187] ​ app ( B-A ) / P app ( A-B ) Caco-2 membrane permeability data for the molecules of the present invention are shown below: [Table 17]

[0188] The above results indicate that the molecules of the present invention have good membrane permeability, particularly A9 and ​ has an extremely low elimination rate (efflux < 2), making it a promising candidate for achieving better in vivo pharmacokinetics and effective tumor inhibition.

[0189] Example 9: Membrane permeability evaluation experiment: MDCK-MDR1 assay Assessment of membrane permeability of molecules of the invention to predict their permeability to the brain.

[0190] Specifically, 1. MDCK-MDR1 cells were cultured at 1.56 × 10 61. Preincubate the cells at a density of 10 ... Add 125 μL of 1 μM test compound solution to the transwell insert (apical chamber) and immediately transfer 50 μL of sample (D0 sample) from the apical chamber to a new 96-well plate. Add 235 μL of HBSS (10 mM HEPES, pH 7.4) to the receptor plate well (basolateral chamber) and incubate at 37°C for 2 hours. At the end of the incubation, transfer 50 μL of sample from both the donor and acceptor sides to 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, remove 100 μL of the supernatant and mix with an appropriate amount of ultrapure water.

[0191] P app =(V A ​ 受容体 ​ 初期値,ドナー ) where VA is the volume of the receptor well (unit: mL) and Area is the membrane surface area (0.143 cm for Transwell-96 well permeable supports). 2 ) and time is the total transport time (seconds).

[0192] ​ app ( B-A) / P app ( A-B ) The MDCK-MDR1 membrane permeability data for the molecules of the present invention are shown below: [Table 18]

[0193] The above results indicate that the molecules of the present invention have good membrane permeability, and in particular, compound A9a has an extremely low excretion rate (excretion 1.2) and is expected to achieve favorable brain concentrations when administered in vivo.

[0194] Example 10: Pharmacokinetic evaluation experiments in mice CD1 female mice were used as test animals and the compounds were administered orally or intravenously (10 mg / kg oral dose; 2 mg / kg intravenous dose).

[0195] solvent (intravenous: 5% DMSO + 95% deionized water solution containing 20% ​​HP-β-CD; oral: 0.1% Tween-80 + 0.5% methylcellulose + 99.4% deionized water).

[0196] Experimental protocol: 3 mice per group for oral administration and 3 mice per group for intravenous administration. Oral: Plasma samples were collected before administration (0 hours) and 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration; Intravenous: Plasma samples were collected before administration (0 hours) and 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Plasma drug concentrations in mice after oral and intravenous administration were determined using LC / MS / MS, and the collected data were analyzed using AB Sciex QTRAP 6500 software. The experimental results are as follows: [Table 19]

[0197] The above experimental results show that the compounds of the present invention exhibit good absorption and higher in vivo exposure when taken orally. Compared with reported molecules such as AM9747, their superior selectivity and in vivo exposure make them expected to provide higher therapeutic efficacy.

Claims

1. Formula (I): 【Chemistry 1】 [In the ceremony: R １ is C １－６ Alkyl, C ３－６ cycloalkyl, or —CH ２ OR ａ Selected from: R ａ is selected from H or methyl; R ２ is H, C １－６ Alkyl, C １－６ alkoxy, or halogen; R ３ is H, halogen, OR ｂ , C.N., C. １－６ Alkyl, or C １－６ haloalkyl; R ４ and R ５ is H, C １－６ Alkyl, C １－６ Haloalkyl, 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 one or two R ６ and R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ｂ , SCF ３ or 5-6 membered heteroaryl; Or, R ４ , R ５ and the nitrogen atom to which they are attached together form a 4- to 10-membered heterocyclyl, which is a 4- to 10-membered heterocyclyl that is selected from 1, 2, 3, or 4 R ｘ optionally substituted with; R ｘ is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ haloalkoxy, phenyl, or 5-10 membered heteroaryl, wherein 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. ｂ , C １－６ Alkoxy, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl 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 ｂ is H, C １－６ Alkyl, or C １－６ haloalkyl] or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

2. Formula (II): 【Chemistry 2】 [In the ceremony: R １ is C １－６ Alkyl, cyclopropyl, or —CH ２ OH; R ２ is H, C １－６ Alkyl, C １－６ alkoxy, or halogen; R ３ is selected from H, halogen, CN, or methyl; R ４ and R ５ is H, C １－６ Alkyl, C １－６ Haloalkyl, 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 one or two R ６ and R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , ORb, SCF ３ or 5-6 membered heteroaryl; Or, R ４ , R ５ and the nitrogen atom to which they are attached together form a 4- to 10-membered heterocyclyl, which is a 4- to 10-membered heterocyclyl that is selected from 1, 2, 3, or 4 R ｘ optionally substituted with; R ｘ is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ haloalkoxy, phenyl, or 5-10 membered heteroaryl, wherein 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. ｂ , C １－６ Alkoxy, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl 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 ｂ is H, C １－６ Alkyl, or C １－６ haloalkyl] 2. The compound of claim 1, which is a compound of the formula:

3. The following structure: 【Transformation 3】 wherein each group is as defined in claim 1 or 2.

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

4. During the ceremony, R ２ is selected from H, methyl, ethyl, methoxy, or F; R ３ is selected from H, F, Cl, CN, or methyl; R ４ and R ５ But H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl; the 4- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl is independently selected from one or two R ６ and R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ｂ , SCF ３ or 5-6 membered heteroaryl; Or, R ４ , R ５ and the nitrogen atom to which they are attached together form a 4- to 10-membered heterocyclyl, which is a 4- to 10-membered heterocyclyl that is selected from 1, 2, 3, or 4 R ｘ optionally substituted with; R ｘ But halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ haloalkoxy, phenyl, or 5-10 membered heteroaryl, wherein phenyl or 5-10 membered heteroaryl is selected from 1, 2, or 3 R ｙ optionally substituted with; R ｙ But halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , C.N., O.R. ｂ , C １－６ Alkoxy, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl 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 ｂ is H, C １－６ Alkyl, or C １－６ selected from haloalkyl 4. The compound of claim 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

5. The following structure: 【Chemistry 4】 [During the ceremony, R ２ is selected from H, methyl, ethyl, methoxy, or F; R ３ is selected from H, F, Cl, CN, or methyl; R ４ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, or 4- to 12-membered heterocyclyl; R ｘ１ and R ｘ２ is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ haloalkoxy, phenyl, or 5-10 membered heteroaryl, wherein 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. ｂ , C １－６ Alkoxy, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl 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 ｂ is H, C １－６ Alkyl, or C １－６ haloalkyl; R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ｂ , SCF ３ or 5-6 membered heteroaryl; X is -CH ２ -, O, S, or -NR ｃ - selected from; Y is selected from CH or N; R ｃ is H or C １－６ alkyl; m is 0, 1, or 2; n is 0, 1, 2, or 3.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the formula:

6. Formula (III-1), (III-1a), or (III-1b): 【Transformation 5】 [During the ceremony, R ２ is selected from H, methyl, ethyl, methoxy, or F; R ３ is selected from H, F, Cl, CN, or methyl; R ｘ１ is selected from phenyl or 5-10 membered heteroaryl, and 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. ｂ , C １－６ Alkoxy, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl 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 ｂ is H, C １－６ Alkyl, or C １－６ haloalkyl; R ｘ２ is C １－６ Alkyl, C １－６ haloalkyl, or C １－６ haloalkoxy; X is -CH ２ -, O, S, or -NR ｃ - selected from; R ｃ is H or C １－６ alkyl] 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. During the ceremony, R ２ is selected from H, methyl, ethyl, methoxy, or F; R ３ is selected from H, F, Cl, CN, or methyl; R ｘ is selected from phenyl or 6-membered heteroaryl, and the phenyl or 6-membered heteroaryl is selected from 1, 2 or 3 R ｙ optionally substituted with; R ｙ But halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , C.N., O.R. ｂ , C １－６ Alkoxy, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl is selected from 1, 2, or 3 R ｚ optionally substituted with; R ｚ But C １－６ Alkyl, halogen, CN, C １－６ haloalkyl, or C １－６ alkoxy; R ｂ But H, C １－６ Alkyl, or C １－６ haloalkyl; R ｘ２ is selected from methyl, ethyl, trifluoromethyl, or trifluoromethoxy; X is -CH ２ -, O, or S 7. The compound of claim 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

8. Formula (III-2), (III-2a), or (III-2b): 【Transformation 6】 [During the ceremony, R ２ is selected from H, methyl, ethyl, methoxy, or F; R ３ is selected from H, F, Cl, CN, or methyl; R ４ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, or 4- to 12-membered heterocyclyl; R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ｂ or 5-6 membered heteroaryl; R ｂ is H, C １－６ Alkyl, C １－６ haloalkyl; X is -CH ２ -, O, S, or -NR ｃ - selected from; Y is selected from CH or N; R ｃ is H or C １－６ alkyl; m is 0, 1, or 2; n is 0, 1, 2, or 3.

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

9. Formula (III-3), (III-3a), or (III-3b): 【Transformation 7】 [During the ceremony, R ２ is selected from H, methyl, ethyl, methoxy, or F; R ３ is selected from H, F, Cl, CN, or methyl; R ４ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, or 4- to 12-membered heterocyclyl; R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ｂ or 5-6 membered heteroaryl; R ｂ is H, C １－６ Alkyl, or C １－６ haloalkyl; X is -CH ２ -, O, S, or -NR ｃ - selected from; Y is selected from CH or N; R ｃ is H or C １－６ alkyl; m is 0, 1, or 2.

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-1), (IV-1a), or (IV-1b): 【Transformation 8】 [During the ceremony, R ２ is selected from H, methyl, ethyl, methoxy, or F; R ３ is selected from H, F, Cl, CN, or methyl; R ｘ１ is selected from phenyl or 5-10 membered heteroaryl, and 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. ｂ , C １－６ Alkoxy, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl 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 ｂ is H, C １－６ Alkyl, or C １－６ haloalkyl; R ｘ２ is C １－６ Alkyl, C １－６ haloalkyl, or C １－６ haloalkoxy; X is -CH ２ -, O, S, or -NR ｃ - selected from; R ｃ is H or C １－６ alkyl] 6. The compound of claim 5, which is a compound of the formula: or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

11. During the ceremony, R ２ is selected from H, methyl, ethyl, methoxy, or F; R ３ is selected from H, F, Cl, CN, or methyl; R ｘ１ is selected from phenyl or 6-membered heteroaryl, and the phenyl or 6-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. ｂ , C １－６ Alkoxy, C ３－６ cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl or phenyl, wherein the 5- to 10-membered heteroaryl or phenyl 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 ｂ is H, C １－６ Alkyl, or C １－６ haloalkyl; R ｘ２ is selected from methyl, ethyl, trifluoromethyl, or trifluoromethoxy; X is -CH ２ -, O, or S 11. The compound of claim 10, which is a compound of the formula: or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

12. Formula (IV-2), (IV-2a), or (IV-2b): 【Chemistry 9】 [During the ceremony, R ２ is selected from H, methyl, ethyl, methoxy, or F; R ３ is selected from H, F, Cl, CN, or methyl; R ４ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, or 4- to 12-membered heterocyclyl; R ６ is H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ｂ or 5-6 membered heteroaryl; R ｂ is H, C １－６ Alkyl, or C １－６ haloalkyl; X is -CH ２ -, O, S, or -NR ｃ - selected from; Y is selected from CH or N; R ｃ is H or C １－６ alkyl; m is 0, 1, or 2; n is 0, 1, 2, or 3.

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

13. During the ceremony, R ２ is selected from H, methyl, ethyl, methoxy, or F; R ３ is selected from H, F, Cl, CN, or methyl; R ４ is selected from H, methyl, ethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl or oxetanyl; R ６ is H, CN, F, Cl, methyl, trifluoromethyl, SF ５ , methoxy, or pyridyl; X is -CH ２ selected from -, O, or S; Y is selected from CH or N; m is 1 or 2; n is 1 or 2 13. The compound of claim 12, wherein:

14. Formula (IV-3), (IV-3a), or (IV-3b): 【Chemistry 10】 [During the ceremony, R ２ is selected from H, methyl, ethyl, methoxy, or F; R ３ is selected from H, F, Cl, CN, or methyl; R ４ is H, C １－６ Alkyl, deuterated C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, or 4- to 12-membered heterocyclyl; R ６ H, CN, halogen, C １－６ Alkyl, C １－６ Haloalkyl, SF ５ , OR ｂ , SCF ３ or 5-6 membered heteroaryl; R ｂ is H, C １－６ Alkyl, or C １－６ haloalkyl; X is -CH ２ -, O, S, or -NR ｃ - selected from; Y is selected from CH or N; R ｃ is H or C １－６ alkyl; m is 0, 1, or 2.

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

15. During the ceremony, R ２ is selected from H, methyl, ethyl, methoxy, or F; R ３ is selected from H, F, Cl, CN, or methyl; R ４ H, methyl, methyl-d ３ , ethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, or oxetane; R ６ is H, CN, F, Cl, methyl, trifluoromethyl, SF ５ , SCF ３ , methoxy, or pyridyl; X is -CH ２ selected from -, O, or S; Y is selected from CH or N; m is 1 or 2 15. The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

16. The following groups: 【Chemistry 11】 【change】 【change】 【change】 or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, selected from:

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

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

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

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

21. The PRMT5 methyltransferase-mediated disease is cancer, and the cancer is selected from the group consisting of schwannoma, adenocarcinoma, adrenal gland cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, hemangioma), appendix cancer, benign monoclonal gammopathy, bile duct cancer, bladder cancer, brain cancer (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, epithelial carcinoma (e.g., Kaposi's sarcoma, multiple myeloma, encephaloma, thyroid cancer ... 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)), blood cancer (e.g., leukemia, e.g., acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) Myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, cytoplasmic ... cystic leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell non-Hodgkin's lymphomas, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (e.g., cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer / T-cell lymphoma, enteropathy-associated T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more of the foregoing leukemias / lymphomas;Multiple myeloma (MM), heavy chain diseases (e.g., alpha chain diseases, gamma chain diseases, mu chain diseases), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer (e.g., nephroblastoma, 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), primary thrombocythemia (ET), particularly 21. The use of claim 18, the method of claim 19, or the compound or composition of claim 20, wherein the cancer is selected from: acute myelofibrosis (AMM), chronic idiopathic myelofibrosis, chronic granulocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, penile cancer;

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