HDAC1-CoREST highly selective inhibitors

Abstract

The invention provides a compound as shown in formula (I) as a high-selectivity HDAC1 (CoREST) inhibitor, a compound or a pharmaceutically acceptable salt, an isotope variant, a tautomer or a stereoisomer thereof. The invention also provides a pharmaceutical composition comprising the compound, and its use in the treatment of cancer.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to an HDAC1 selective (CoREST) ​​inhibitor. Background Art

[0002] Immunotherapy PD-1 / PD-L1 inhibitors: such as pembrolizumab or nivolumab, have produced very good therapeutic effects in multiple advanced solid tumors. In patients with advanced NSCLC (non-small cell lung cancer) without EGFR mutations and ALK fusions, multiple PD-1 inhibitors have seen good clinical benefits in the treatment of 1-line advanced NSCLC. The combination with chemotherapy has greatly improved the median progression-free survival (PFS) and has been approved by the FDA for marketing (N. Engl. J. Med. 2018, 378, 2078-2092), but there are still many NSCLC patients with limited benefits. On the other hand, NSCLC patients with KRAS mutations benefit better from PD-1 / PD-L1 treatment than KRASwt (wild-type) patients; but when KRAS mutations are combined with STK11 gene mutations, tumor patients have limited response to PD-1, and most patients will become resistant in the short term. Not only that, other patients with advanced solid tumors with STK11 gene mutations will quickly become resistant to PD-1 immunotherapy (J.Clin.Onco.2019,37,102).

[0003] Epigenetic inhibitors have shown good inhibitory activity in multiple hematological tumors in recent years, such as HDAC inhibitors, vorinostat, belinostat or tucidinostat. However, in the treatment of patients with solid tumors, HDAC inhibitors are rarely used in the treatment of solid tumors due to their strong hematological side effects. HDAC (histone deacetylase) is an epigenetic drug target, and its mechanism of action is to catalyze the removal of the acetyl group of the ε-amino nitrogen of histone lysine and some non-histone proteins in the cytoplasm. At present, 18 HDAC subtypes have been identified in mammals, (HDAC 1-11) or NAD +(SIRT 1-7). HDAC class I includes four types: HDAC1, HDAC2, HDAC3 and HDAC8, and HDAC class IIa includes two types: HDAC6 and HDAC10. Non-selective pan-HDAC inhibitors do not distinguish selectivity and inhibit multiple subtypes within the family. While producing anti-tumor inhibitory effects, they also bring obvious toxic side effects (J.Med.Chem.2020,63,12460-12484). Type I HDAC inhibitors, especially HDAC1, have recently been found to have a more important mechanism of action for regulating the effect of immunotherapy: 1) Upregulating the major histocompatibility complex MHC I / II to increase antigen presentation; 2) Upregulating CD4 + and CD8 + T lymphocyte expression; 3) reduce the immunosuppressant Treg cell population, etc. (Oncogene, 2021, 40, 1836-1850). Therefore, if a highly selective HDAC1 inhibitor is developed, it may work synergistically with PD-1 to treat cancer patients. At the 2023 US AACR meeting, Tango reported that its HDAC1-CoREST complex TNG260, combined with PD-1, can treat mouse MC-38 colon cancer with a lasting therapeutic effect. In addition, the CoREST complex in HDAC1 is the key to synergy with PD-1. By inhibiting the HDAC1-CoREST complex without inhibiting other complexes such as Sin3, hematological side effects will be greatly reduced, and it is expected to be used clinically to treat patients with solid tumors.

[0004] Although some progress has been made in the research of highly selective HDAC1, no other inhibitors of the HDAC1 complex CoREST have been disclosed. The highly selective HDAC1-CoREST complex of the present invention is expected to solve the problem of PD-1-resistant STK11 mutated tumor patients and address unmet clinical needs. Summary of the invention

[0005] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0006]

[0007] in,

[0008] X m , X p and X n are each independently selected from CH or N;

[0009] Ring A is selected from 4-12 membered heterocyclic groups; R5 is selected from H,

[0010] Provided that: when R5 is selected from H, Ring A is selected from

[0011] When ring A is empty, R5 is selected from

[0012] Y is selected from NH or O;

[0013] R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 5-12 membered heteroaryl, -(CH2) p -OR a 、-(CH2) p -N(R a )2 or -(CH2) p -(5-12 membered heterocyclic group); said R1 is optionally replaced by 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH2;

[0014] R6 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl or 5-12 membered heteroaryl;

[0015] R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0016] R3 is selected from C 3-6 Cycloalkyl or 5-12 membered heteroaryl; said R3 is optionally replaced by 1 or 2 R y Replacement, R y Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NH2, -OR a 、-SR a , -SF5, -C(O)OH, -C(O)NH2 or -CH2C(O)OH;

[0017] R4 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0018] R a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0019] n is selected from 0, 1 or 2;

[0020] p is selected from 0, 1 or 2.

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

[0022]

[0023] in,

[0024] X m is selected from CH or N;

[0025] Ring A is selected from 4-12 membered heterocyclic groups; R5 is selected from H,

[0026] Provided that: when R5 is selected from H, Ring A is selected from

[0027] When ring A is empty, R5 is selected from

[0028] Y is selected from NH or O;

[0029] R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 5-12 membered heteroaryl, -(CH2) p -OR a 、-(CH2) p -N(R a )2 or -(CH2) p -(5-12 membered heterocyclic group); said R1 is optionally replaced by 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH2;

[0030] R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0031] R6 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl or 5-12 membered heteroaryl;

[0032] R y Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NH2, -OR a 、-SR a , -SF5, -C(O)OH, -C(O)NH2 or -CH2C(O)OH;

[0033] R4 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0034] R a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0035] n is selected from 0, 1 or 2;

[0036] p is selected from 0, 1 or 2.

[0037] In one aspect, the present invention provides the following compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof:

[0038]

[0039]

[0040] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.

[0041] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, which may also contain another therapeutic agent.

[0042] In another aspect, the present invention provides the use of the compound of the present invention in the preparation of a medicament for treating and / or preventing a disease mediated by HDAC1 (COREST).

[0043] In another aspect, the present invention provides a method for treating and / or preventing a disease mediated by HDAC1 (COREST) ​​in a subject, comprising administering a compound or composition of the present invention to the subject.

[0044] 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 HDAC1 (COREST)-mediated diseases.

[0045] In a specific embodiment, the diseases treated by the present invention include cancers selected from the group consisting of acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, hemangioma), appendix cancer, benign monoclonal gamma disease, bile duct cancer, bladder cancer, brain cancer (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchial cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), hypereosinophilia, gallbladder cancer, 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 carcinoma, oropharyngeal cancer)), hematopoietic system cancer (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), Acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoma Plasma cell lymphoma, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell non-Hodgkin lymphoma, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (such as cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more of the above leukemias / lymphomas;Multiple myeloma (MM), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer (e.g., Wilms tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma, malignant hepatocellular carcinoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., true Polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myeloid metaplasia (AMM), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibroma (such as type 1 or type 2 neurofibromatosis, neurothecoma), neuroendocrine cancer (such as gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (such as cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, penile cancer. ;

[0046] Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims.

[0047] definition

[0048] Chemical Definition

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

[0050] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.

[0051] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C1-2 Alkyl groups are preferred. 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term “C 1-6 "Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0052] “C 2-6 "Alkenyl" refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl is preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term “C 2-6 "Alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0053] “C 2-6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl is preferred. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. The term “C 2-6"Alkynyl" also includes heteroalkynyl groups, in which one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0054] “C 1-6 "Alkylene" refers to the removal of C 1-6 The other hydrogen of C alkyl forms a divalent group, and may be substituted or unsubstituted. 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0055] “C 2-6 "Alkenylene" means removing the C 2-6 The divalent group is formed by the other hydrogen of the alkenyl group and may be substituted or unsubstituted. 2-4Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene includes, but is not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene, for example, alkenylene substituted with one or more alkyl (methyl) groups, includes, but is not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0056] “C 2-6 "Alkynylidene" refers to the removal of C 2-6 The other hydrogen of the alkynyl group forms a divalent group, and may be substituted or unsubstituted. 2-4 Alkyne is particularly preferred. Exemplary alkynyl includes, but is not limited to, ethynyl (-C≡C-), substituted or unsubstituted propynyl (-C≡CCH2-), and the like.

[0057] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0058] Therefore, “C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 "alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Haloalkyl is particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyls include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0059] “C 1-6 "Alkoxy" refers to an -OR group, wherein R is a C 1-6 Alkyl. C 1-4 Alkoxy groups are preferred.

[0060] “C 1-6 "Haloalkoxy" refers to "C 1-6Alkoxy", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkoxyalkyl is particularly preferred, more preferably C 1-2 Halogenated alkoxyalkyl.

[0061] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-10 Cycloalkyl, C 5-10 Cycloalkyl, C 4-7 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl and C 3-4 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl. Cycloalkyl also includes a ring system in which the above-mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the cycloalkyl ring, and in such a case, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), etc. The cycloalkyl group may be optionally substituted by one or more substituents, for example, substituted by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0062] "3-12 membered heterocyclyl" refers to a group of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valence permits. In some embodiments, a 3-10 membered heterocyclyl is preferably a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, a 4-10 membered heterocyclyl is preferably a 4-10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, a 5-10 membered heterocyclyl is preferably a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 5-8 membered heterocyclyl is preferably a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3-7 membered heterocyclyl is preferably a A 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; preferably a 3- to 6-membered heterocyclyl, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 4- to 7-membered heterocyclyl, which is a 4- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 4- to 6-membered heterocyclyl, which is a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5- to 6-membered heterocyclyl, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 3- to 5-membered heterocyclyl, which is a 3- to 5-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidine, oxirane, and thiorenyl. Exemplary 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazine (triazinanyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepane, and thianyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyranopyridinyl, etc. The heterocyclyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0063] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, aryl has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, aryl has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0064] "5-14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5-10 membered heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-10 membered heteroaryls are preferred, which are 6-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems with ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-9 membered heteroaryls are preferred, which are 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring systems with ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryls are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems with ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl) and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxacycloheptatrienyl and thiacycloheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.A heteroaryl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0065] "Cycloalkylene", "heterocyclylene", "arylene" or "heteroarylene" is a divalent group formed by removing another hydrogen from the above-defined "cycloalkyl", "heterocyclyl", "aryl" or "heteroaryl", and may be substituted or unsubstituted. For example, "C 5-7 "Cycloalkylene" refers to the removal of C 5-7 The "5- to 8-membered heterocyclylene" refers to a divalent group formed by removing another hydrogen atom of a 5- to 8-membered heterocyclyl. 6-10 "Arylene" refers to the removal of C 6-10 The "5-6 membered heteroarylene group" refers to a divalent group formed by removing another hydrogen atom of a 5-6 membered heteroaryl group.

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

[0067] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb , -SH, -SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc 2. -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2, -OC(=O)N(R bb )2.-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2, -C(=NR bb )R aa 、-C(=NR bb )OR aa、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(Rcc )3. -B(R aa )2、-B(OR cc )2. -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0068] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN (R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or = NOR cc replace;

[0069] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0070] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc 2. -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc 2. -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa,-P(=O)(R aa )2、-P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0071] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0072] R dd Each of is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2,-N(R ff )3 + X - 、-N(OR ee )R ff , -SH, -SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2, -OC(=O)N(R ff )2.-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee、-C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2.-NR ff C(=NR ff )N(R ff )2.-NR ff S02R ee 、-SO2N(R ff 2. -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3.-OSi(R ee )3. -C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee ,-P(=O)(R ee )2.-OP(=O)(R ee )2.-OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0073] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0074] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0075] R ggEach of is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl)3, -OSi(C 1-6 Alkyl)3, -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 Alkyl)2, -OP(=O)(C 1-6 Alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0076] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc 2. -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc 2. -SO2R cc 、-SO2OR cc 、-SORaa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa ,-P(=O)(R aa )2、-P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd substituted with a group, and wherein R aa , R bb , R cc and R dd As mentioned above.

[0077] Other definitions

[0078] The term "pharmaceutically acceptable salt" as used herein refers to those carboxylates, amino acid addition salts of the compounds of the present invention which are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0079] "Subjects" for administration include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0080] "Disease," "disorder," and "condition" are used interchangeably herein.

[0081] Generally, the "effective amount" of a compound refers to an amount sufficient to cause a target biological response. As will be appreciated by those of ordinary skill in the art, the effective amount of the compounds of the invention may vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes a therapeutically effective amount and a prophylactically effective amount.

[0082] "Combination" and related terms refer to the simultaneous or sequential administration of the compounds of the invention and other therapeutic agents. For example, the compounds of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. Specific implementation plan

[0083] As used herein, "compounds of the present invention" refers to compounds of the following formula (I) (including sub-formulae, such as formula (II), (II-1), (II-2), (II-3) or (III)), pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates or isotopic variants thereof, and mixtures thereof.

[0084] In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0085]

[0086] in,

[0087] X m , X p and X n are each independently selected from CH or N;

[0088] Ring A is selected from 4-12 membered heterocyclic groups; R5 is selected from H,

[0089] Provided that: when R5 is selected from H, Ring A is selected from

[0090] When ring A is empty, R5 is selected from

[0091] Y is selected from NH or O;

[0092] R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 5-12 membered heteroaryl, -(CH2) p -OR a 、-(CH2) p -N(R a )2 or -(CH2) p -(5-12 membered heterocyclic group); said R1 is optionally replaced by 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a, CN or NH2;

[0093] R6 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl or 5-12 membered heteroaryl;

[0094] R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0095] R3 is selected from C 3-6 Cycloalkyl or 5-12 membered heteroaryl; said R3 is optionally replaced by 1 or 2 R y Replacement, R y Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NH2, -OR a 、-SR a , -SF5, -C(O)OH, -C(O)NH2 or -CH2C(O)OH;

[0096] R4 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0097] R a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0098] n is selected from 0, 1 or 2;

[0099] p is selected from 0, 1 or 2.

[0100] In another embodiment, the present invention provides a compound of the following formula (II) or formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0101]

[0102] in,

[0103] X m is selected from CH or N;

[0104] Ring A is selected from 4-12 membered heterocyclic groups; R5 is selected from H,

[0105] Provided that: when R5 is selected from H, Ring A is selected from

[0106] When ring A is empty, R5 is selected from

[0107] Y is selected from NH or O;

[0108] R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 5-12 membered heteroaryl, -(CH2) p -OR a 、-(CH2) p -N(R a )2 or -(CH2) p -(5-12 membered heterocyclic group); said R1 is optionally replaced by 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH2;

[0109] R6 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl or 5-12 membered heteroaryl;

[0110] R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0111] R y Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NH2, -OR a 、-SR a , -SF5, -C(O)OH, -C(O)NH2 or -CH2C(O)OH;

[0112] R4 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0113] R a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0114] n is selected from 0, 1 or 2;

[0115] p is selected from 0, 1 or 2.

[0116] In another embodiment, the present invention provides a compound of the following formula (II-1), formula (II-2), or formula (II-3), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0117]

[0118] in,

[0119] X m is selected from CH or N;

[0120] Ring A is selected from 4-7 membered nitrogen-containing heterocyclic groups;

[0121] R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 5-12 membered heteroaryl, -(CH2) p -OR a 、-(CH2) p -N(R a )2 or -(CH2) p -(5-12 membered heterocyclic group); said R1 is optionally replaced by 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH2;

[0122] R2 is selected from H, F, Cl, Me, -CF3, -OMe or cyclopropyl;

[0123] R y Selected from F, Cl, Me, CF3, CN, NH2, -OH, -SMe, -SF5, -C(O)OH, -C(O)NH2 or -CH2C(O)OH;

[0124] R4 is selected from H, F, Cl, Me, -CF3, -OMe or cyclopropyl;

[0125] R a Selected from H, C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0126] p is selected from 0, 1 or 2.

[0127] In another more specific embodiment, the compound is selected from:

[0128]

[0129]

[0130] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereoisomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0131] The compounds of the present invention may also exist as tautomers. For compounds that exist in different tautomeric forms, a compound is not limited to any specific tautomer, but is intended to encompass all tautomeric forms.

[0132] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described by formula (A) but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36Cl. Compounds of the present invention containing the above isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which a radioactive isotope (e.g. 3 H and 14 C) can be used for drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged half-life in vivo or reduced dosage requirements, and thus may be preferred in some cases. Isotope-labeled compounds of formula (A) of the present invention and their prodrugs can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents when carrying out the processes disclosed in the following schemes and / or Examples and Preparation Examples.

[0133] Pharmaceutical compositions and kits

[0134] On the other hand, the present invention provides a pharmaceutical composition 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 preventive effective amount of a compound of the present invention.

[0135] The pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the composition of the present invention include (but are not limited to) ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0136] The present invention also includes a kit (e.g., a pharmaceutical package). The kit provided may include a compound of the invention, other therapeutic agents, and a first and second container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispersible package or other suitable container) containing the compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first container and the second container are combined to form a unit dosage form.

[0137] Drug administration

[0138] Pharmaceutical composition provided by the invention can be administered by many ways, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial cavity administration, intrasternal administration, intrathecal administration, intralesional administration and intracranial injection or infusion technology.

[0139] Generally, an effective amount of the compounds provided herein is administered. The amount of the compound actually administered can be determined by a physician according to the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0140] When used to prevent the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice of a physician and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a specific condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0141] The pharmaceutical compositions provided herein can also be administered over a long period of time ("chronic administration"). Chronic administration refers to administration of a compound or a pharmaceutical composition thereof over a long period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration may continue indefinitely, e.g., for the rest of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a long period of time, e.g., within a therapeutic window.

[0142] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by push injection, for example, in order to increase the concentration of the compound in the blood to an effective level. The push dose depends on the target systemic level of the active component through the body, for example, the intramuscular or subcutaneous push dose slowly releases the active component, and the push delivered directly to the vein (for example, by IV intravenous drip) can be delivered more quickly, so that the concentration of the active component in the blood is quickly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active component in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the push dose can be first given, and then continuous infusion.

[0143] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the composition is provided in unit dosage form. The term "unit dosage form" refers to a physical discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substances suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is usually a relatively small component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder is various carriers or excipients and processing aids useful for forming the desired administration form.

[0144] For oral dosage, a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these dosage modes, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, and preferred doses each provide about 0.1 to about 10 mg / kg, especially about 1 to about 5 mg / kg.

[0145] In order to provide blood levels similar to those using an injectable dose, or lower blood levels than using an injectable dose, a transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0146] From about 1 to about 120 hours, especially 24 to 96 hours, the injected dosage level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. In order to obtain sufficient steady state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be given. For a 40 to 80 kg human patient, the maximum total dose cannot exceed about 2 g / day.

[0147] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

[0148] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, and the remainder is an injectable excipient, etc.

[0149] Typically, transdermal compositions are formulated as topical ointments or creams containing active ingredients. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated as an ointment together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components for enhancing the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the invention.

[0150] The compounds of the invention may also be administered by transdermal means. Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or a variety of solid matrices.

[0151] The above components for oral administration, injection or topical administration are representative only. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Part 8, which is incorporated herein by reference.

[0152] The compounds of the invention may also be administered in sustained release form or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0153] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0154] Example

[0155] The reagents used in the present invention are commercial reagents purchased directly or synthesized by common methods well known in the art.

[0156] Notes on commonly used abbreviations:

[0157] PE = petroleum ether; EA = ethyl acetate; MeOH = methanol; DCM = dichloromethane; DCE = dichloroethane; CH3CN = acetonitrile; 1,4-dioxane = 1,4-dioxane; DMSO = dimethyl sulfoxide; HFIP = hexafluoroisopropanol; DMF = N,N-dimethylformamide; Hex = n-hexane; IPA = isopropanol; NMP = N-methylpyrrolidone; NMO = N-methylmorpholine-N-oxide; TEA = triethylamine; DIEA = diisopropylethylamine; CuI = Cuprous iodide; CuCN = cuprous cyanide; triphosgene = triphosgene; p-TsOH = p-toluenesulfonic acid; T3P = 1-propylphosphoric acid cyclic anhydride; TsN3 = p-toluenesulfonyl azide; PPA = polyphosphoric acid; SEM-Cl = 2-(trimethylsilyl)ethoxymethyl chloride; HMPA = hexamethylphosphoramide; BINAP = 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); EDCI = 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; CbzCl = benzyl chloroformate.

[0158] Embodiment 1:

[0159] Preparation of key intermediates

[0160] Preparation of intermediate a1

[0161]

[0162] Step 1: Dissolve the raw material 5-benzothiophenecarboxylic acid a1-1 (300 mg, 1.68 mmol) in 5 mL of acetic acid, slowly add 30% H2O2 (1.2 mL), and heat to 120°C for 16 hours, then cool to room temperature. Pour the reaction solution into 100 mL of ice water, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a yellow solid a1-2 (220 mg), with a yield of 62%.

[0163] Step 2: Dissolve the intermediate a1-2 (150 mg, 0.71 mmol) in 5 mL of dichloromethane, slowly add oxalyl chloride (272 mg, 2.14 mmol), add 2 drops of DMF, react at room temperature for 1 hour, and stop the reaction. Concentrate the reaction solution under reduced pressure to obtain a yellow oil a1, which is directly used in the next step.

[0164] Preparation of intermediates a2-a4

[0165]

[0166] Step 1: Dissolve the raw material a2-1 (230 mg, 1.19 mmol) and NH2COONH4 (171 mg, 1.8 mmol) in 5 mL of methanol, slowly add iodophenyl diacetic acid (881 mg, 2.7 mmol), react at room temperature for 16 hours, and stop the reaction. Pour the reaction solution into 30 mL of ice water, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography (PE / EA, 2 / 1) to obtain a yellow solid a2-2 (160 mg), yield: 59%. LCMS ESI-MS m / z: 226 [M+H] + .

[0167] Step 2: Dissolve the intermediate a2-2 (160 mg, 0.71 mmol) and pyridine (84 mg, 1.0 mmol) in 5 mL of dichloromethane, slowly add benzyl chloroformate CbzCl (151 mg, 0.89 mmol), react at room temperature for 2 hours, and stop the reaction. Pour the reaction solution into 30 mL of ice water, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography (PE / EA, 1 / 1) to obtain a yellow solid a2-3 (210 mg), yield: 81%. LCMS ESI-MS m / z: 360 [M+H] + .

[0168] Step 3: Dissolve the intermediate a2-3 (210 mg, 0.58 mmol) in a mixed solution of 2 mL tetrahydrofuran and water (v / v, 1 / 1), slowly add NaOH (35 mg, 0.87 mmol), react at room temperature for 2 hours, and stop the reaction. Slowly adjust the pH of the reaction solution to about 3 with dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to obtain a yellow solid a2-4 (200 mg), yield: 98%. LCMS ESI-MS m / z: 346 [M+H] + .

[0169] Step 4: Dissolve the intermediate a2-4 (200 mg, 0.58 mmol) in 3 mL of dichloromethane, slowly add oxalyl chloride (220 mg, 1.7 mmol), add 2 drops of DMF, react at room temperature for 1 hour, and stop the reaction. Concentrate the reaction solution under reduced pressure to obtain a yellow oil a2, which is directly used in the next step.

[0170] Referring to the synthetic route of intermediate a2, similar raw materials / intermediates were used to synthesize the following target molecules.

[0171]

[0172] Preparation of intermediate b1

[0173]

[0174] Step 1: Under nitrogen protection, raw material b1-1 (2.0 g, 4.81 mmol), sodium carbonate (1.0 g, 9.6 mmol) and raw material 4-fluorophenylboronic acid b1-2 (1.01 g, 7.21 mmol) were dissolved in 20 mL of a mixed solution of 1,4-dioxane and water (9 / 1), and catalyst Pd(dppf)Cl2 (523 mg, 0.72 mmol) was added, and the temperature was raised to 100°C for 3 hours to stop the reaction. The reaction solution was poured into 50 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE / EA, 5 / 1) to obtain a yellow solid b1-3 (1.75 g), with a yield of 84%. LCMS ESI-MS m / z: 433 [M+H] + .

[0175] 1 H NMR(400MHz,DMSO-d6)δ8.36(d,J=2.1Hz,1H),8.09(dd,J=8.3,2.2Hz,1H),7.89( dd,J=8.8,5.4Hz,2H),7.66(d,J=8.3Hz,1H),7.36(t,J=8.8Hz,2H),1.35(s,18H).

[0176] Step 2: Under hydrogen atmosphere, the intermediate b1-1 (1.75 g, 4.05 mmol) and Pd / C (800 mg) from the previous step were dissolved in 5 mL of methanol, reacted at room temperature for 2 hours under 4 atm of hydrogen, stopped the reaction, and filtered. The solvent was evaporated under reduced pressure, and the crude product was separated by column chromatography (PE / EA, 4 / 1) to obtain a yellow solid b1 (1.38 g), with a yield of 85%. LCMS ESI-MS m / z: 403 [M+H] + .

[0177] Preparation of intermediate b2

[0178]

[0179] Steps: Under nitrogen protection, the intermediate b1 (202 mg, 0.50 mmol) was dissolved in 2 mL of dichloromethane, and an equivalent amount of trifluoroacetic acid (50 μL, 0.6 mmol) was added. The reaction was allowed to react for 3 hours at room temperature, and the reaction was stopped. The reaction solution was poured into 10 mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE / EA, 4 / 1) to obtain a yellow solid b2 (100 mg), with a yield of 67%. LCMS ESI-MS m / z: 303 [M+H] + .

[0180] Preparation of intermediate b3

[0181]

[0182] Step 1: Under nitrogen protection, the raw material methyl 4-iodobenzoate b3-1 (500 mg, 1.91 mmol), thiomorpholine b3-2 (295 mg, 2.86 mmol) and potassium carbonate (527 mg, 3.82 mmol) were dissolved in 5 mL DMSO, and the catalyst CuI (36 mg, 0.19 mmol) and the ligand L-proline (44 mg, 0.38 mmol) were added, and the temperature was raised to 100 ° C for 10 hours to stop the reaction. The reaction solution was cooled to room temperature, 30 mL of ice water was added, and ethyl acetate was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE / EA, 10 / 1) to obtain a white solid b3-3 (281.0 mg), yield: 62%, ESI-MS (m / z): [M+H] + =238.

[0183] Step 2: Dissolve the compound b3-3 (281.0 mg, 1.18 mmol) in a mixed solution of 5 mL tetrahydrofuran and water (v / v, 3 / 2), add lithium hydroxide monohydrate (70.0 mg, 1.66 mmol), heat to 60°C and react for 6 hours, then stop the reaction. Add dilute hydrochloric acid to the reaction solution to adjust the pH to about 4, extract with dichloromethane, dry with anhydrous sodium sulfate, and concentrate to obtain a white solid b3 (214 mg), yield: 81%, ESI-MS (m / z): [M+H] +- =223.

[0184] Preparation of intermediates b4, b10-b11

[0185]

[0186] Steps: Under nitrogen protection, the raw material methyl 4-iodobenzoate b3-1 (500.0 mg, 1.91 mmol), potassium tert-butoxide (748 mg, 6.68 mmol) and intermediate c3 (490.0 mg, 2.29 mmol) were dissolved in 6 mL of tert-butanol, and the ligand Ruphos (178.0 mg, 0.38 mmol) and the catalyst Pd2(dba)3 (175.0 mg, 0.19 mmol) were added, and the temperature was raised to 100°C for 4 hours to stop the reaction. The reaction solution was cooled to room temperature, 30 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by reverse phase flash column chromatography (CN3CN / H2O, 1 / 9) to obtain yellow solid b4 (150.0 mg), with a yield of 26%. LCMS: ESI-MS (m / z): [M+H] + =298.9.

[0187] Referring to the synthetic route of compound b4, the following intermediates were synthesized using similar raw materials / skeleton structures.

[0188]

[0189]

[0190] Preparation of intermediates b5, b7-b9, b12

[0191]

[0192] Step 1: Dissolve the raw material b5-1 (1.0 g, 4.91 mmol), ammonium carbonate (945 mg, 9.84 mmol) and iodophenyl diacetic acid (3.96 g, 12.3 mmol) in 15 mL of methanol, react at room temperature for 2 hours, and stop the reaction. Add 50 mL of ice water, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify the crude product by column chromatography (DCM / MeOH, 20 / 1) to obtain a white solid b5-2 (500 mg), yield: 43%, ESI-MS (m / z): [M+H] + =235.

[0193] Step 2: In an ice bath, dissolve the intermediate b5-2 (500 mg, 2.13 mmol) and pyridine (338 mg, 4.27 mmol) in 5 mL of dichloromethane, slowly add CbzCl (546 mg, 3.2 mmol), react at room temperature for 1 hour, and stop the reaction. Add 30 mL of ice water, extract with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify the crude product by column chromatography (DCM / MeOH, 80 / 1) to obtain a white solid b5-3 (503 mg), yield: 64%, ESI-MS (m / z): [M+H] + =369.

[0194] Step 3: In an ice bath, dissolve the intermediate b5-3 (500 mg, 1.36 mmol) in 5 mL of dichloromethane, slowly add a solution of hydrogen chloride in 1,4-dioxane (1 M, 4.2 mL), react at room temperature for 1 hour, and stop the reaction. Evaporate the solvent under reduced pressure to obtain a white solid b5-4 (360 mg), ESI-MS (m / z): [M+H] + =269.

[0195] Step 4: Under nitrogen protection, the intermediate b5-4 (350 mg, 1.3 mmol), cesium carbonate (1.28 g, 3.91 mmol) and raw material b3-1 (341 mg, 1.3 mmol) were dissolved in 5 mL 1,4-dioxane, and the ligand Ruphos (121 mg, 0.26 mmol) and catalyst Pd2(dba)3 (238 mg, 0.26 mmol) were added, and the temperature was raised to 100 ° C for 14 hours to stop the reaction. The reaction solution was cooled to room temperature, 30 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by reverse phase flash column chromatography (CN3CN / H2O, 1 / 9) to obtain white solid b5-5 (400 mg), yield: 70%. LCMS: ESI-MS (m / z): [M+H] + =403.

[0196] Step 5: Dissolve the intermediate b5-5 (200 mg, 0.5 mmol) in a mixed solution of 5 mL tetrahydrofuran and water (v / v, 3 / 2), add lithium hydroxide monohydrate (70.0 mg, 1.66 mmol), heat to 80°C for 1 hour, and stop the reaction. Add dilute hydrochloric acid to the reaction solution to adjust the pH to about 4, extract with dichloromethane, dry with anhydrous sodium sulfate, and concentrate to obtain a white solid b5 (180 mg), yield: 93%, ESI-MS (m / z): [MH] - =387.

[0197] Referring to the synthetic route of compound b5, the following intermediates were synthesized using similar raw materials / skeleton structures.

[0198]

[0199]

[0200] Preparation of intermediate b6

[0201]

[0202] Step 1: Under nitrogen protection, raw material b6-1 (1.0 g, 4.42 mmol), potassium carbonate (1.83 g, 13.3 mmol) and raw material b3-1 (1.16 g, 4.42 mmol) were dissolved in 20 mL of a mixed solution of 1,4-dioxane and water (v / v, 5 / 1), and catalyst Pd(dppf)Cl2 (924 mg, 0.44 mmol) was added, and the temperature was raised to 100°C for 14 hours to stop the reaction. The reaction solution was cooled to room temperature, 30 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash column chromatography (PE / EA, 10 / 1) to obtain yellow solid b6-2 (651 mg), with a yield of 63%. LCMS: ESI-MS (m / z): [M+H] + =235.

[0203] Step 2: Dissolve the intermediate b6-2 (650 mg, 2.77 mmol), ammonium carbonate (530 mg, 5.54 mmol) and iodophenyl diacetic acid (1.78 g, 5.54 mmol) in 15 mL of methanol, react at room temperature for 2 hours, and stop the reaction. Add 50 mL of ice water, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify the crude product by column chromatography (DCM / MeOH, 20 / 1) to obtain a white solid b6-3 (120 mg), yield: 16%, ESI-MS (m / z): [M+H] + =266.

[0204] Step 3: In an ice bath, the intermediate b6-3 (120 mg, 0.45 mmol) and pyridine (110 mg, 5.54 mmol) of the previous step were dissolved in 5 mL of dichloromethane, and CbzCl (120 mg, 0.68 mmol) was slowly added. The reaction was allowed to react for 4 hours at room temperature, and the reaction was stopped. 30 mL of ice water was added, and dichloromethane was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM / MeOH, 80 / 1) to obtain a colorless oil b6-4 (135 mg). The yield was 75%, ESI-MS (m / z): [M+H] + =400.

[0205] Step 4: Dissolve the intermediate b6-4 (135 mg, 0.33 mmol) in a mixed solution of 5 mL tetrahydrofuran and water (v / v, 3 / 2), add lithium hydroxide monohydrate (70.0 mg, 1.66 mmol), heat to 80°C for 1 hour, and stop the reaction. Add dilute hydrochloric acid to the reaction solution to adjust the pH to about 4, extract with dichloromethane, dry with anhydrous sodium sulfate, and concentrate to obtain a white solid b6 (60 mg), yield: 47%, ESI-MS (m / z): [MH] - =384.

[0206] Preparation of intermediate b13

[0207]

[0208] Step 1: Under nitrogen protection, raw material b13-1 (53 mg, 0.57 mmol), cesium carbonate (248 mg, 0.76 mmol) and raw material b3-1 (100 mg, 0.38 mmol) were dissolved in 5 mL DMSO, and catalyst CuI (15 mg, 0.08 mmol) was added, and the temperature was raised to 110 ° C for 16 hours to stop the reaction. The reaction solution was cooled to room temperature, 30 mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash column chromatography (PE / EA, 4 / 1) to obtain white solid b13-2 (71 mg), yield: 81%. LCMS: ESI-MS (m / z): [M+H] + =228.

[0209] Step 2: Dissolve the intermediate b13-2 (71 mg, 0.31 mmol) in a mixed solution of 2 mL tetrahydrofuran and water (v / v, 3 / 2), add lithium hydroxide monohydrate (35.0 mg, 0.8 mmol), heat to 80°C for 1 hour, and stop the reaction. Add dilute hydrochloric acid to the reaction solution to adjust the pH to about 4, extract with dichloromethane, dry with anhydrous sodium sulfate, and concentrate to obtain a white solid b13 (50 mg), yield: 76%, ESI-MS (m / z): [MH] - =212.

[0210] Synthesis of intermediate c1

[0211]

[0212] Step 1: Under nitrogen protection, raw material c1-1 (7.0 g, 27.7 mmol) and triethylamine (4.2 g, 41.5 mmol) were dissolved in 40 mL of dichloromethane, and methylsulfonyl chloride (3.21 g, 28.0 mmol) was added, and the mixture was reacted at room temperature for 4 hours. The reaction was stopped, and the solvent was removed under reduced pressure to obtain a crude product c1-2 (10.8 g).

[0213] Step 2: Dissolve the crude product c1-2 (10.8 g) and the raw material c1-3 (4.21 g, 27.7 mmol) in 30 mL DMF, add NaH (1.11 g, 27.7 mmol), slowly heat to 80 ° C and react for 12 hours. LC-MS monitors the completion of the reaction. Add 100 mL of saturated saline solution to the system to quench the reaction, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product c1-4 (15 g). LC-MS: ESI-MS (m / z): 388.3 [M+H] + .

[0214] Step 3: Dissolve the crude product c1-4 (15 g) and LiCl (2.52 g, 60.0 mmol) in 40 mL N, N-dimethylacetamide DMA, heat to 150 ° C for 2 hours, and stop the reaction. Add 100 mL of ice water to the reaction solution, extract with dichloromethane, dry with anhydrous sodium sulfate, filter, concentrate, and separate by flash column chromatography to obtain a yellow solid c1-5 (6.42 g). The total yield of the three steps is 71%. LC-MS: ESI-MS (m / z): 330.1 [M+H] + .

[0215] Step 4: Under hydrogen atmosphere (2 atm), the intermediate c1-5 (6.42 g, 19.5 mmol) and Pd / C (1.28 g, 20%) were mixed in 40 mL of methanol, and 2 mL of trifluoroacetic acid was added. The reaction was allowed to proceed at room temperature for 16 hours, and the reaction was stopped. The mixture was filtered and concentrated to obtain a yellow oil c1 (4.5 g), which was directly used in the next step. LC-MS: ESI-MS (m / z): 164.2 [M+H] + .

[0216] Referring to the synthetic route of compound c1, the following intermediates were synthesized using similar raw materials / skeleton structures.

[0217]

[0218] Synthesis of intermediate c3

[0219]

[0220] Step 1: Add intermediate c1-2 (70.0 g, 210 mmol) to a 500 mL reaction bottle, slowly add methylamine isopropanol solution (200 mL, concentration 28%), heat to 70 ° C for 4 hours, and monitor the reaction to be complete. Evaporate the solvent under reduced pressure, separate the crude product by flash column chromatography, and obtain oily intermediate c3-1 (39.0 g), yield: 69%, LCMS: ESI-MS (m / z): 267.4 [M+H] + .

[0221] Step 2: Dissolve the intermediate c3-1 (39.0 g, 150 mmol) and triethylamine (44.5 g, 440 mmol) in 400 mL of dichloromethane, slowly add methanesulfonic anhydride (30.6 g, 180 mmol), react at room temperature for 1 hour, and stop the reaction. Place the reaction solution in an ice bath, add 1 L of ice water to the system, extract with dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain intermediate c3-2 (40 g), which is directly used in the next step. LCMS: ESI-MS (m / z): 345.5 [M+H] + .

[0222] Step 4: Under hydrogen atmosphere (1 atm), the intermediate c3-2 (40 g, 120 mmol) and trifluoroacetic acid (53.0 g, 460 mmol) from the previous step were dissolved in 200 mL of methanol, and palladium carbon (4.0 g) was slowly added. The reaction was allowed to react for 12 hours at room temperature, the reaction was stopped, filtered, and the solvent was evaporated under reduced pressure. 100 mL of water was added to the mixture, and impurities were removed by extraction with dichloromethane. The aqueous phase was freeze-dried by a freeze dryer to obtain the intermediate c3 (27.0 g), with a yield of 84%, LCMS: ESI-MS (m / z): 179.1 [M+H]+ .

[0223] Embodiment 2:

[0224] Preparation of target molecules P1-P11

[0225]

[0226] Step 1: Under nitrogen protection, intermediate b3 (214 mg, 0.96 mmol) and intermediate b4 (319 mg, 1.06 mmol) were dissolved in 3 mL of pyridine, EDCI (550 mg, 2.70 mmol) was added, and the temperature was raised to 70 ° C for 12 hours. 30 mL of water was added to the reaction solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE / EA, 5 / 1) to obtain a white solid P1-1 (362 mg), with a yield of 74%. LCMS ESI-MS m / z: 508 [M+H] + .

[0227] Step 2: Dissolve the compound P1-1 (150 mg, 0.30 mmol) in 2 mL of methanol, add ammonium carbonate (43.0 mg, 0.44 mmol) and iodobenzene acetate (190 mg, 0.59 mmol), react at room temperature for 2 hours, and stop the reaction. Evaporate the solvent under reduced pressure, separate the crude product by column chromatography (DCM / MeOH, 20 / 1), and obtain brown solid P1-2 (15 mg), yield: 9%. ESI-MS (m / z): [M+H] +- =538.9.

[0228] Step 3: Dissolve the compound P1-2 (15.0 mg, 0.028 mmol) in 1 mL of dichloromethane, add trifluoroacetic acid (0.3 mL) dropwise, react at room temperature for 1 hour, and stop the reaction. Evaporate the solvent under reduced pressure, adjust the pH of the crude product to about 8 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate, and separate the crude product by TLC chromatography (DCM / MeOH, 10 / 1) to obtain the target molecule P1 (8 mg), yield: 66%. ESI-MS (m / z): [M+H] +- =436.9.

[0229] 1H NMR (400MHz, DMSO-d6) δ9.57(s,1H),7.96(d,J=9.2Hz,2H),7.63 -7.57(m,2H),7.50(d,J=2.4Hz,1H),7.31(dd,J=8.8,2.0Hz,1H),7.28 -7.21(m,2H),7.14(d,J=8.8Hz,2H),6.89(d,J=8.4Hz,1H),5.08(s,1H),4.10–4.01(m,2H),3.87(s,1H),3.83–3.67(m,2H),3.11–2.92(m,4H).

[0230] Referring to the synthetic route of compound P1, similar raw materials / intermediates were used to synthesize the following target molecules.

[0231]

[0232]

[0233]

[0234] Embodiment 2:

[0235] The molecules of the invention were tested for their activity on deacetylation of histone substrates by HDAC1 (COREST) ​​or HDAC3.

[0236] The inhibitory activity of the compound on HDAC1 (or HDAC3) is calculated by testing the fluorescence change of the acetylated histone substrate with a fluorescent substrate at 360nm / 460nm. The details are as follows:

[0237] Prepare the working solution and buffer to be tested. The test compound is dissolved in DMSO and diluted 3 times (10μM final concentration as the starting concentration). Add the test compound solution to a 384-well plate, add 5μL (2X) HDAC1 enzyme solution, shake and incubate in the dark for 10 minutes, add 5μL of fluorescent acetylated histone substrate detection solution to start the reaction, incubate at room temperature for 30 minutes, and add 10μL stop solution to stop the reaction. Calculate the inhibitory activity (IC) of HDAC1 (or HDAC3) enzyme based on the changes in fluorescence 360nm / 460nm of the blank group (DMSO) and the compound group. 50 ).

[0238] Calculation formula: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0239] X: log of cpd concentration

[0240] Y:Percent inhibition (%)

[0241] Compound <![CDATA[HDAC1 / IC 50 / nM]]> <![CDATA[HDAC3 / IC 50 / nM]]> P1 58 >10000 P2 56 >10000 P3 178 >10000 P4 24 9364 P5 27 4632 P6 30 >10000 P7 117 >10000 P8 23 >10000 P9 42 >10000 P10 49 >10000

[0242] The above results show that the molecule of the present invention has a good inhibitory effect on HDAC1, but has no inhibitory effect on HDAC3. It is expected to achieve a better tumor inhibition effect by inhibiting HDAC1 (COREST) ​​and synergizing with PD-1 antibodies.

[0243] Embodiment 3:

[0244] The liver microsome stability test of the compound is as follows:

[0245] The compounds of the present invention were subjected to a liver microsome stability test. The compounds to be tested were co-incubated with liver microsomes of different species with or without the addition of NADPH. The final concentration of the compounds to be tested in the test system was 1 μM, the final concentration of NADPH was 1 mM, and the final concentration of liver microsomes was 0.5 mg / mL. The compound concentrations in the incubation supernatant at different time points within 60 minutes were detected and the pharmacokinetic parameters (e.g., clearance Cl int ).

[0246] This result shows that the molecule of the present invention has good metabolic stability (especially in the human body, has good metabolic stability).

[0247] Compound <![CDATA[Human Cl int / (mL / min / kg)]]> <![CDATA[Human Cl int μL / min / mg Protein]]> P1 1.2 1.5 P2 28 35

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: in, X m , X p and X n are each independently selected from CH or N; Ring A is selected from 4-12 membered heterocyclic groups; R5 is selected from H, Provided that: when R5 is selected from H, Ring A is selected from The condition is: when ring A is empty, R5 is selected from Y is selected from NH or O; R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 5-12 membered heteroaryl, -(CH2) p -OR a 、-(CH2) p -N(R a )2 or -(CH2) p -(5-12 membered heterocyclic group); said R1 is optionally replaced by 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH2; R6 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl or 5-12 membered heteroaryl; R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl; R3 is selected from C 3-6 Cycloalkyl or 5-12 membered heteroaryl; said R3 is optionally replaced by 1 or 2 R y Replacement, R y Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NH2, -OR a 、-SR a , -SF5, -C(O)OH, -C(O)NH2 or -CH2C(O)OH; R4 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl; R a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which is a compound of formula (II) or formula (III): in, X m is selected from CH or N; Ring A is selected from 4-12 membered heterocyclic groups; R5 is selected from H, Provided that: when R5 is selected from H, Ring A is selected from When ring A is empty, R5 is directly connected to the benzene ring, and R5 is selected from Y is selected from NH or O; R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 5-12 membered heteroaryl, -(CH2) p -OR a 、-(CH2) p -N(R a )2 or -(CH2) p -(5-12 membered heterocyclic group); said R1 is optionally replaced by 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH2; R6 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl or 5-12 membered heteroaryl; R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl; R y Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NH2, -OR a 、-SR a , -SF5, -C(O)OH, -C(O)NH2 or -CH2C(O)OH; R4 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl; R a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2.

3. The compound of claim 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the following general structure: in, X m is selected from CH or N; Ring A is selected from 4-7 membered nitrogen-containing heterocyclic groups; R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 5-12 membered heteroaryl, -(CH2) p -OR a 、-(CH2) p -N(R a )2 or -(CH2) p -(5-12 membered heterocyclic group); said R1 is optionally replaced by 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH2; R2 is selected from H, F, Cl, Me, -CF3, -OMe or cyclopropyl; R y Selected from F, Cl, Me, CF3, CN, NH2, -OH, -SMe, -SF5, -C(O)OH, -C(O)NH2 or -CH2C(O)OH; R4 is selected from H, F, Cl, Me, -CF3, -OMe or cyclopropyl; R a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; p is selected from 0, 1 or 2.

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

5. A pharmaceutical composition comprising a compound according to any one of claims 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer or isotopic variant thereof.

6. The use of a compound or composition according to claim 4, wherein the HDAC1 (COREST) ​​mediated disease is cancer, the cancer is selected from: acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, hemangioma), appendix cancer, benign monoclonal gamma disease, bile duct cancer, bladder cancer, brain cancer (e.g., meningioma, glioma, such as 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 cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), hypereosinophilia, gallbladder cancer, 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 carcinoma, oropharyngeal cancer)), hematopoietic cancer (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt'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 lymphoma, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (such as cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more of the above leukemias / lymphomas;Multiple myeloma (MM), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer (e.g., Wilms tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma, malignant hepatocellular carcinoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., true Polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myeloid metaplasia (AMM), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibroma (such as type 1 or type 2 neurofibromatosis, neurothecoma), neuroendocrine cancer (such as gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (such as cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, penile cancer. ;

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