HDAC1-CoREST highly selective inhibitors

Abstract

The invention provides a compound as shown in formula (A) 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

Highly selective HDAC1-CoREST inhibitor 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 and nivolumab, have demonstrated excellent efficacy in a variety of advanced solid tumors. Several PD-1 inhibitors have demonstrated promising clinical benefits in first-line treatment of advanced NSCLC (non-small cell lung cancer) patients without EGFR mutations or ALK fusions. Combining these inhibitors with chemotherapy significantly improves median progression-free survival (PFS) and has been approved by the FDA (N. Engl. J. Med. 2018, 378, 2078-2092). However, many NSCLC patients still experience limited benefit. On the other hand, NSCLC patients with KRAS mutations benefit more from PD-1 / PD-L1 therapy than those with KRAS wild-type tumors. However, when KRAS mutations coexist with STK11 mutations, tumor responses to PD-1 are limited, and most patients develop resistance within a short period of time. Not only that, other patients with advanced solid tumors who carry STK11 gene mutations will quickly develop resistance 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 acetyl groups from 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 between 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 immunotherapy effects: 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 be possible to synergize 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, the 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 mutant tumor patients and address unmet clinical needs.

[0005] Summary of the Invention

[0006] In one aspect, the present invention provides a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0007] in,

[0008] Indicates a single bond or a double bond;

[0009] X m 、X p and X n are each independently selected from CH or N;

[0010] Y is selected from NH or O;

[0011] Z is selected from CH2, O, N or NH;

[0012] R1 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, 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;

[0013] Or two optionally substituted R1 and the carbon atom to which they are connected may form a 3-6 membered cycloalkyl or a 3-12 membered heterocyclic group; the cycloalkyl or heterocyclic group may be optionally substituted by one or two R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH2;

[0014] R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0015] 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;

[0016] Or R3 and R4 are connected to the carbon atoms where they are located to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group;

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

[0019] m is selected from 0 or 1;

[0020] n is selected from 0, 1 or 2;

[0021] p is selected from 0, 1 or 2;

[0022] Provided that, when m and n are both 0, R3 and R4 are linked to the carbon atom where they are located to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group.

[0023] 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:

[0024] in,

[0025] Indicates a single bond or a double bond;

[0026] X m and X n are each independently selected from CH or N;

[0027] Y is selected from NH or O;

[0028] R1 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, 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;

[0029] R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0030] 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; or R3 and R4 are connected to the carbon atom where they are located to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group;

[0031] R4 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0032] R a Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0033] p is selected from 0, 1 or 2.

[0034] In another aspect, the present invention provides a compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0035] in,

[0036] X m and X n are each independently selected from CH or N;

[0037] Y is selected from NH or O;

[0038] Z is selected from CH2, NH or O;

[0039] R1 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6Cycloalkyl, 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;

[0040] R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0041] 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; or R3 and R4 are connected to the carbon atom where they are located to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group;

[0042] R4 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0043] R a Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0044] p is selected from 0, 1 or 2.

[0045] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.

[0046] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, and further comprising another therapeutic agent.

[0047] In another aspect, the present invention provides use of the compound of the present invention in the preparation of a medicament for treating and / or preventing HDAC1 (COREST)-mediated diseases.

[0048] 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 to the subject a compound or composition of the present invention.

[0049] 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.

[0050] In a specific embodiment, the diseases treated by the present invention include cancers selected from the group consisting of acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, hemangioma), appendix cancer, benign monoclonal gamma disease, bile duct cancer, bladder cancer, brain cancer (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchogenic carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, large intestinal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma), cerebrospinal fluid (e.g., glioma ...cerebrospinal fluid (e.g., glioma, astrocytoma, oligodendroglioma, medulloblastoma), cerebrospinal fluid (e.g., glioma, astrocytoma, oligodendroglioma, sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's gland carcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), hypereosinophilia, gallbladder cancer, stomach cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancer (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), Acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoma Plasma cell lymphoma, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell non-Hodgkin lymphoma, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (such as cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more of the above leukemias / lymphomas;Multiple myeloma (MM), heavy chain diseases (such as α chain disease, γ chain disease, μ chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer (such as Wilms tumor, renal cell carcinoma), liver cancer (such as hepatocellular carcinoma, malignant hepatocellular carcinoma), lung cancer (such as 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 (MPDs) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myeloid metaplasia (AMM), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibromas (e.g., neurofibromatosis type 1 or type 2, schwannomatosis), neuroendocrine cancers (e.g., gastroenteropancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, embryonal carcinoma, adenocarcinoma), papillary adenocarcinoma, and penile cancer.

[0051] 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.

[0052] definition

[0053] Chemical definition

[0054] Definitions of specific functional groups and chemical terms are described in more detail below.

[0055] 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.

[0056] “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 with one or more substituents, for example, 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).

[0057] “C 2-6 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl is preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6 "Alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0058] “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 can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0059] “C 1-6 "Alkylene" refers to the removal of C 1-6 In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0060] “C 2-6 "Alkenylene" refers to the removal of C 2-6 In some embodiments, C 2-4Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0061] “C 2-6 "Alkynylidene" refers to the removal of C 2-6 In some embodiments, C 2-4 Alkyne is particularly preferred. Exemplary alkynyl includes, but is not limited to, ethynyl (-C≡C-), substituted or unsubstituted propynyl (-C≡CCH2-), and the like.

[0062] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0063] Therefore, “C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl is particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0064] “C 1-6 "Alkoxy" refers to an -OR group, wherein R is a C 1-6 Alkyl. C 1-4 Alkoxy groups are preferred.

[0065] “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.

[0066] “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 to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such a case, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. The cycloalkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0067] "3-12 membered heterocyclyl" refers to a group of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, 3-10 membered heterocyclyl is preferably a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 4-10 membered heterocyclyl is preferably a 4-10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, 5-10 membered heterocyclyl is preferably a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5-8 membered heterocyclyl is preferably a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3-7 membered heterocyclyl is preferably a A 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; preferably a 3- to 6-membered heterocyclyl, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 4- to 7-membered heterocyclyl, which is a 4- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 4- to 6-membered heterocyclyl, which is a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5- to 6-membered heterocyclyl, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 3- to 5-membered heterocyclyl, which is a 3- to 5-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thiidine. Exemplary 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolane, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.Exemplary 6-membered 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, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyls containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclyls containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thienyl. Exemplary 5-membered heterocyclyls fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyls) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyranopyridinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0068] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0069] "5-14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-10 membered heteroaryls are preferred, which are 6-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-9 membered heteroaryls are preferred, which are 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryls are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxacycloheptatrienyl, and thiacycloheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.A heteroaryl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0070] "Cycloalkylene", "heterocyclylene", "arylene" or "heteroarylene" is a divalent group formed by removing another hydrogen from the above-defined "cycloalkyl", "heterocyclyl", "aryl" or "heteroaryl", and may be substituted or unsubstituted. For example, "C 5-7 "Cycloalkylene" refers to the removal of C 5-7 The "5-8 membered heterocyclylene" refers to a divalent group formed by removing another hydrogen atom of a 5-8 membered heterocyclyl. The "C 6-10 "Arylene" refers to the removal of C 6-10 The "5- to 6-membered heteroarylene group" refers to a divalent group formed by removing another hydrogen atom of a 5- to 6-membered heteroaryl group.

[0071] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc., as defined herein, are optionally substituted groups.

[0072] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(Rcc )3、-B(R aa )2、-B(OR cc )2. -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0073] 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;

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

[0075] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0076] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0077] R dd Each of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2,、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2, -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0078] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0079] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0080] R ggEach of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6Alkyl)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.

[0081] 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 replaced by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0082] Other definitions

[0083] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0084] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0085] "Disease," "disorder," and "condition" are used interchangeably herein.

[0086] Generally, an "effective amount" of a compound is an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0087] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. Specific implementation plan

[0088] As used herein, "compounds of the present invention" refer to compounds of the following formula (A) or formula (I) (including sub-formulas, such as formula (II), (II-1), (II-2), (III), (III-1) or (IV)), pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates or isotopic variants thereof, and mixtures thereof.

[0089] In one embodiment, the present invention provides a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0090] in,

[0091] Indicates a single bond or a double bond;

[0092] X m 、X p and X n are each independently selected from CH or N;

[0093] Y is selected from NH or O;

[0094] Z is selected from CH2, O, N or NH;

[0095] R1 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, 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;

[0096] Or two optionally substituted R1 and the carbon atom to which they are connected may form a 3-6 membered cycloalkyl or a 3-12 membered heterocyclic group; the cycloalkyl or heterocyclic group may be optionally substituted by one or two R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH2;

[0097] R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0098] 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;

[0099] Or R3 and R4 are connected to the carbon atoms where they are located to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group;

[0100] R4 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0101] R a Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0102] m is selected from 0 or 1;

[0103] n is selected from 0, 1 or 2;

[0104] p is selected from 0, 1 or 2;

[0105] Provided that, when m and n are both 0, R3 and R4 are linked to the carbon atom where they are located to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group.

[0106] In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0107] Indicates a single bond or a double bond;

[0108] X m and X n are each independently selected from CH or N;

[0109] Y is selected from NH or O;

[0110] R1 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, 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;

[0111] R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0112] 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;

[0113] Or R3 and R4 are connected to the carbon atoms where they are located to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group;

[0114] R4 is selected from H, halogen, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0115] R a Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0116] m is selected from 0 or 1;

[0117] n is selected from 0, 1 or 2;

[0118] p is selected from 0, 1 or 2;

[0119] Provided that, when m and n are both 0, R3 and R4 are linked to the carbon atom where they are located to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group.

[0120] 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:

[0121] Indicates a single bond or a double bond;

[0122] X m and X n are each independently selected from CH or N;

[0123] Y is selected from NH or O;

[0124] R1 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, 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;

[0125] R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0126] 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; or R3 and R4 are connected to the carbon atom where they are located to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group;

[0127] R4 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0128] R a Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0129] p is selected from 0, 1 or 2.

[0130] In another embodiment, the present invention provides a compound of the following formula (II-1), formula (II-2), or formula (III-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0131] Indicates a single bond or a double bond;

[0132] represents aromaticity, X1, X2, X3, X4 and X5 are each independently selected from CH, N, NH, O or S, and X1, X2, X3, X4 and X5 contain at least one N atom;

[0133] X m and X n are each independently selected from CH or N;

[0134] Y is selected from NH or O;

[0135] Z is selected from O, S or NH;

[0136] R1 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heteroaryl 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;

[0137] R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0138] 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;

[0139] R4 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0140] R a Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0141] p is selected from 0, 1 or 2.

[0142] In another more specific embodiment:

[0143] Indicates a single bond or a double bond;

[0144] represents aromaticity, X1, X2, X3, X4 and X5 are each independently selected from CH, N, NH, O or S, and X1, X2, X3, X4 and X5 contain at least one N atom;

[0145] X m and X n are each independently selected from CH or N;

[0146] Y is selected from NH or O;

[0147] Z is selected from O, S or NH;

[0148] R1 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heteroaryl 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;

[0149] R2 is selected from H, F, Cl, methyl, trifluoromethyl, methoxy or cyclopropyl;

[0150] R y is selected from H, F, Cl, methyl, trifluoromethyl, methoxy, cyclopropyl, CN, NH2, -OH, -SMe, -SF5, -C(O)OH, -C(O)NH2 or -CH2C(O)OH;

[0151] R4 is selected from H, F, Cl, methyl, trifluoromethyl, methoxy or cyclopropyl;

[0152] p is selected from 0, 1 or 2.

[0153] In another embodiment, the present invention provides a compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0154] in,

[0155] X m and X n are each independently selected from CH or N;

[0156] Y is selected from NH or O;

[0157] Z is selected from CH2, NH or O;

[0158] R1 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, 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;

[0159] R2 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0160] 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; or R3 and R4 are connected to the carbon atom where they are located to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group;

[0161] R4 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 3-6 Cycloalkyl;

[0162] R a Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0163] p is selected from 0, 1 or 2;

[0164] In another more specific embodiment, the compound is selected from:

[0165] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0166] 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.

[0167] The compounds of the present invention can be in amorphous or crystalline form (polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can cause one crystalline form to dominate. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0168] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (A) except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P.32 P. 35 S. 18 F and 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (A) of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0169] Pharmaceutical compositions and kits

[0170] 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.

[0171] Pharmaceutically acceptable excipients used in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0172] The present invention also includes kits (e.g., pharmaceutical packaging). The kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0173] Drug administration

[0174] Pharmaceutical compositions provided by the invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion technology.

[0175] Typically, an effective amount of the compounds provided herein is administered. The amount of compound actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0176] When used to prevent the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0177] The pharmaceutical compositions provided herein can also be administered long-term ("chronic administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within the therapeutic window.

[0178] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by injection, for example, in order to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient by the body, for example, an intramuscular or subcutaneous bolus dose slowly releases the active ingredient, and the bolus (for example, by IV intravenous drip) delivered directly to the vein can be delivered more quickly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the bolus dose can be first given, and then continuous infusion.

[0179] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the compositions are provided in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substance suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids useful for forming the desired dosage form.

[0180] For oral dosage, a representative regimen is one to five oral doses per day, particularly two to four oral doses, typically three oral doses. Using these dosage administration modes, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, with preferred doses each providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0181] To provide blood levels similar to, or lower than, those obtained with an injectable dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0182] From about 1 to about 120 hours, and particularly from 24 to 96 hours, the injected dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To achieve adequate steady-state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered. For a 40 to 80 kg human patient, the maximum total dose may not exceed about 2 g / day.

[0183] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0184] Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0185] Typically, transdermal compositions are formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components that enhance the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.

[0186] The compounds of the present invention may also be administered by transdermal devices.Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or various solid matrices.

[0187] The above components for oral administration, injection or topical administration are representative only. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0188] The compounds of the invention can also be administered in sustained release form or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0189] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar portion, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0190] Example

[0191] The reagents used in the present invention are commercial reagents purchased directly or synthesized using common methods well known in the art.

[0192] Notes on commonly used abbreviations:

[0193] 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.

[0194] Example 1: Preparation of key intermediates

[0195] Preparation of intermediate a1

[0196] Step 1: Dissolve 5-benzothiophenecarboxylic acid a1-1 (300 mg, 1.68 mmol) in 5 mL of acetic acid. Slowly add 30% H₂O₂ (1.2 mL) dropwise. Heat to 120°C and react for 16 hours. Cool to room temperature. Pour the reaction mixture into 100 mL of ice water, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a1-2 (220 mg) as a yellow solid in a 62% yield.

[0197] Step 2: Dissolve intermediate a1-2 (150 mg, 0.71 mmol) in 5 mL of dichloromethane and slowly add oxalyl chloride (272 mg, 2.14 mmol). After addition, add 2 drops of DMF. Allow to react at room temperature for 1 hour, then stop the reaction. Concentrate the reaction mixture under reduced pressure to obtain a1 as a yellow oil, which is used directly in the next step.

[0198] Preparation of intermediates a2-a5

[0199] Step 1: Dissolve raw materials 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, then stop the reaction. Pour the reaction solution into 30 mL of ice water, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 2 / 1) to obtain a2-2 (160 mg) as a yellow solid in a 59% yield. LCMS ESI-MS m / z: 226 [M+H] + .

[0200] 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). Allow to react at room temperature for 2 hours, then stop the reaction. Pour the reaction mixture into 30 mL of ice water, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 1 / 1) to obtain a2-3 (210 mg) as a yellow solid in an 81% yield. LCMS ESI-MS m / z: 360 [M+H] + .

[0201] Step 3: Dissolve the intermediate a2-3 (210 mg, 0.58 mmol) from the previous step in 2 mL of a mixture of tetrahydrofuran and water (v / v, 1 / 1). Slowly add NaOH (35 mg, 0.87 mmol) and react at room temperature for 2 hours, then stop the reaction. The reaction solution is slowly adjusted to pH 3 with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to afford a2-4 (200 mg) as a yellow solid in a 98% yield. LCMS ESI-MS m / z: 346 [M+H] + .

[0202] Step 4: Dissolve intermediate a2-4 (200 mg, 0.58 mmol) in 3 mL of dichloromethane and slowly add oxalyl chloride (220 mg, 1.7 mmol). After addition, add 2 drops of DMF. Allow to react at room temperature for 1 hour, then stop the reaction. Concentrate the reaction mixture under reduced pressure to obtain a2 as a yellow oil, which is used directly in the next step.

[0203] Referring to the synthetic route of intermediate a2, similar raw materials / intermediates were used to synthesize the following target molecules.

[0204] Preparation of intermediate b1

[0205] Step 1: Under nitrogen, 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 9 / 1 mixture of 1,4-dioxane and water. Catalyst Pd(dppf)Cl2 (523 mg, 0.72 mmol) was added and the mixture was heated to 100°C for 3 hours, after which the reaction was stopped. The reaction mixture was poured into 50 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 5 / 1) to obtain b1-3 (1.75 g) as a yellow solid in an 84% yield. LCMS ESI-MS m / z: 433 [M+H] + .

[0206] 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).

[0207] Step 2: Under a 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. The mixture was reacted at room temperature under 4 atm of hydrogen for 2 hours. The reaction was stopped and filtered. The solvent was evaporated under reduced pressure, and the crude product was separated by column chromatography (PE / EA, 4 / 1) to obtain b1 (1.38 g), a yellow solid, in an 85% yield. LCMS ESI-MS m / z: 403 [M+H] + .

[0208] Preparation of intermediate b2

[0209] Step 1: Under nitrogen, raw material b1-1 (1.0 g, 2.4 mmol), sodium carbonate (509 mg, 4.81 mmol), and raw material thiophene-2-boronic acid b2-1 (461 mg, 3.6 mmol) were dissolved in 10 mL of a 9 / 1 mixture of 1,4-dioxane and water. Catalyst Pd(dppf)Cl2 (262 mg, 0.36 mmol) was added and the mixture was heated to 100°C for 3 hours, after which the reaction was stopped. The reaction mixture was poured into 50 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 8 / 1) to afford b2-2 (1.0 g) as a yellow solid in a 99% yield. LCMS ESI-MS m / z: 421 [M+H] + .

[0210] 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=2.1Hz,1H),8.04(dd,J=8.4,2.2Hz,1H),7.78(dd,J=3.6,0.6 Hz,1H),7.71(d,J=4.8Hz,1H),7.61(d,J=8.4Hz,1H),7.21(dd,J=4.8,3.8Hz,1H),1.34(s,18H).

[0211] Step 2: Dissolve the intermediate b2-2 (100.0 mg, 0.24 mmol) from the previous step in 3 mL of dichloromethane and add trifluoroacetic acid (41.0 mg, 0.36 mmol) dropwise. The mixture is allowed to react at room temperature for 1 hour, after which the reaction is stopped. Add 10 mL of water to the reaction solution, extract three times with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product b2-3 is used directly in the next reaction.

[0212] Step 3: Under a hydrogen atmosphere, the intermediate b2-3 (78 mg, 0.24 mmol) and Pd / C (20 mg) from the previous step were dissolved in 2 mL of methanol. The mixture was reacted at room temperature under 4 atm of hydrogen for 1 hour. The reaction was stopped and filtered. The solvent was evaporated under reduced pressure, and the crude product was separated by column chromatography (PE / EA, 4 / 1) to obtain b2 (60 mg), a yellow solid, in an 86% yield. LCMS ESI-MS m / z: 325 [M+H] + .

[0213] Referring to the synthetic route of intermediate b2, similar raw materials / intermediates were used to synthesize the following target molecules.

[0214] Preparation of intermediate c1

[0215] Step 1: Dissolve the raw materials 2-mercaptobenzoic acid c1-1 (8.0 g, 51.9 mmol) and Na2CO3 (19.25 g, 181.6 mmol) in 80 mL of water in an ice bath. Add compound c1-2 (11.98 g, 72.6 mmol) and react at room temperature for 12 hours, then stop the reaction. Slowly add 28 mL of concentrated hydrochloric acid and continue stirring for 14 hours, resulting in the precipitation of a large amount of solid. Filter, wash the filter cake with water, and dry to obtain c1-3 (11.80 g), a white solid, in a 95% yield. LCMS ESI-MS m / z: 237 [MH] - .

[0216] Step 2: Dissolve compound c1-3 (6.08 g, 25.5 mmol) and TEA (8 mL) in 40 mL of acetic anhydride, heat to 140°C, react for 4 hours, cool to room temperature, and evaporate the solvent under reduced pressure. Add 200 mL of ice water to the reaction solution, extract three times with ethyl acetate, combine the organic phases, concentrate, and dry over anhydrous sodium sulfate. The crude product is purified by column chromatography (PE / DCM, 1 / 1) to obtain c1-4 (5.27 g) as a pale yellow solid in a 94% yield. LCMS ESI-MS m / z: 221 [M+H] + .

[0217] Step 3: Dissolve compound c1-4 (2.0 g, 9.1 mmol) and triethylsilane (5.28 g, 45.4 mmol) in 25 mL of trifluoroacetic acid and react at room temperature for 12 hours, then stop the reaction. Evaporate the solvent under reduced pressure, adjust the pH to approximately 8 with saturated sodium bicarbonate solution, and extract three times with dichloromethane. The combined organic phases are concentrated, and the crude product is purified by column chromatography (PE / DCM, 1 / 1) to afford c1-5 (1.78 g) as a white solid in a 95.0% yield. LCMS ESI-MS m / z: 207 [M+H] +.

[0218] Step 4: Under nitrogen, compound c1-5 (1.60 g, 7.76 mmol) from the previous step was dissolved in 20 mL of chloroform. Indium tribromide (137.5 mg, 0.39 mmol) and triethylsilane (2.10 g, 18.06 mmol) were added. The mixture was heated to 60°C and reacted for 15 hours, after which the reaction was stopped. After cooling to room temperature, 100 mL of ice water was added to the reaction solution. The mixture was extracted three times with dichloromethane. The organic phases were combined and concentrated. The crude product was purified by column chromatography (PE / EA, 20 / 1) to afford c1-6 (814.0 mg) as a pale yellow oil in a 55% yield. LCMS ESI-MS m / z: 193 [M+H] + .

[0219] Step 5: Dissolve compound c1-6 (814 mg, 4.23 mmol) from the previous step in 10 mL of dichloromethane and add liquid bromine (676.5 mg, 4.23 mmol) dropwise. Allow to react at room temperature for 16 hours, then stop the reaction. Add 30 mL of saturated sodium thiosulfate solution to the reaction solution. Extract three times with dichloromethane. The organic phases are combined and concentrated. The crude product is purified by column chromatography (PE / EA, 20 / 1) to afford c1-7 (749.0 mg) as a pale yellow oil in a 65% yield. 1 H NMR (400MHz, DMSO-d6) δ7.43(d,J=2.0Hz,1H),7.31(dd,J=8.2,2.0Hz,1H),7.17(d,J=8.4Hz,1H),3.97–3.81(m,2H) ,3.81(d,J=8.8Hz,1H),3.78(d,J=8.8Hz,1H),3.36(d,J=16.2Hz,2H),3.30(d,J=16.2Hz,1H),2.25(t,J=7.2Hz,2H).

[0220] Step 6: At -70°C, under nitrogen, compound c1-7 (250 mg, 0.92 mmol) from the previous step was dissolved in 5 mL of anhydrous tetrahydrofuran. n-Butyl lithium (2.5 M, 1.10 mmol, 0.44 mL) was added dropwise. After stirring for 15 minutes, dry ice (1.0 g) was added to the reaction solution. The reaction was continued for 1 hour, and then the reaction was stopped. Saturated aqueous ammonium chloride was added to the system, and the pH was adjusted to approximately 2 with 1 M dilute hydrochloric acid. The solution was extracted three times with ethyl acetate, and the organic phases were combined and concentrated. The crude product was purified by flash reverse column chromatography (CH3CN / H2O, 5 / 4) to obtain c1 (89 mg) as a white solid in a yield of 41%. LCMS ESI-MS m / z: 235 [MH] - .

[0221] Preparation of intermediate c2

[0222] Step 1: Dissolve the raw materials 2-bromo-benzenethiol c2-1 (10.0 g, 52.9 mmol) and K2CO3 (9.49 g, 68.8 mmol) in 100 mL of acetone in an ice bath. Add compound c2-2 (11.4 g, 63.5 mmol) and react at room temperature for 12 hours, then stop the reaction. Evaporate the solvent under reduced pressure, add 100 mL of ice water, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography (PE / EA, 20 / 1) to obtain c2-3 (9.80 g) as a yellow oil in a 65% yield. LCMS ESI-MS m / z: 287 [MH] - .

[0223] Step 2: Under nitrogen, compound c2-3 (1.5 g, 5.22 mmol) and azobisisobutyronitrile (85.8 mg, 0.52 mmol) were dissolved in 20 mL of toluene. The temperature was raised to 120°C, and tributyltin hydride (3.0 g, 10.4 mmol) was added dropwise. The reaction was continued for 12 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. 100 mL of ice water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, concentrated, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography (PE / EA 20 / 1) to afford c2-4 (548 mg) as a pale yellow oil in a 50% yield.

[0224] Step 3: Dissolve compound c2-4 (455 mg, 2.2 mmol) in 5 mL of anhydrous tetrahydrofuran in an ice bath under nitrogen. Add LiAlH4 (91.2 mg, 2.40 mmol) and allow to react at room temperature for 2 hours. Stop the reaction. Add 30 mL of ice water to the mixture, extract three times with dichloromethane, combine the organic phases, concentrate, and purify the crude product by column chromatography (PE / EA, 5 / 1) to obtain c2-5 (299 mg) as a yellow oil in a 76% yield. LCMS ESI-MS m / z: 181 [M+H] + .

[0225] Step 4: Under nitrogen, compound c2-5 (299 mg, 1.66 mmol) and NaH (93 mg, 2.32 mmol) from the previous step were dissolved in 6 mL of anhydrous tetrahydrofuran. Methyl iodide (330 mg, 2.32 mmol) was added and the mixture was allowed to react at room temperature for 6 hours, after which the reaction was stopped. 30 mL of ice water was added to the reaction solution, and the mixture was extracted three times with dichloromethane. The organic phases were combined and concentrated. The crude product was purified by column chromatography (PE / EA, 20 / 1) to afford c2-6 (303 mg) as a pale yellow oil in a 94% yield. LCMS ESI-MS m / z: 195 [M+H] + .

[0226] Step 5: Dissolve compound c2-6 (244 mg, 1.26 mmol) from the previous step in 5 mL of dichloromethane and add liquid bromine (201 mg, 1.26 mmol) dropwise. Allow to react at room temperature for 16 hours, then stop the reaction. Add 30 mL of saturated sodium thiosulfate solution to the reaction solution. Extract three times with dichloromethane. The organic phases are combined and concentrated. The crude product is purified by column chromatography (PE / EA, 20 / 1) to afford c2-7 (294 mg) as a pale yellow oil in an 87% yield.

[0227] Step 6: At -70°C, under nitrogen, compound c2-7 (294 mg, 1.1 mmol) from the previous step was dissolved in 5 mL of anhydrous tetrahydrofuran. n-Butyl lithium (2.5 M, 1.31 mmol, 0.52 mL) was added dropwise. After stirring for 15 minutes, dry ice (1.0 g) was added to the reaction solution. The reaction was continued for 1 hour, and then stopped. Saturated aqueous ammonium chloride was added to the system, and the pH was adjusted to approximately 2 with 1 M dilute hydrochloric acid. The solution was extracted three times with ethyl acetate. The organic phases were combined and concentrated. The crude product was purified by flash reverse-phase column chromatography (CH3CN / H2O, 5 / 4) to obtain c2 (141 mg) as a white solid in a 55% yield. LCMS ESI-MS m / z: 237 [MH] - .

[0228] Preparation of intermediate C3

[0229] Step 1: Dissolve c3-1 (600 mg, 2.9 mmol) and (NH4)2CO3 (411 mg, 4.3 mmol) in 6 mL of methanol in an ice bath. Stir for 30 minutes, then add PHI(OAc)2 (1.84 g, 5.72 mmol). Allow to react at room temperature for 12 hours, then stop the reaction. Evaporate the solvent under reduced pressure, add 30 mL of ice water, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography (DCM / MeOH, 10 / 1) to obtain c3-2 (600 mg) as a yellow solid in an 87% yield. LCMS ESI-MS m / z: 242 [M+H] + .

[0230] Step 2: In an ice bath, under nitrogen, compound c3-2 (600 mg, 2.49 mmol) and pyridine (295 mg, 3.74 mmol) were dissolved in 6 mL of dichloromethane. CbzCl (852 mg, 4.98 mmol) was added dropwise. The reaction was allowed to react at room temperature for 3 hours. The reaction was stopped and the solvent was removed under reduced pressure. 30 mL of ice water was added to the reaction solution, and the mixture was extracted three times with dichloromethane. The organic phases were combined, concentrated, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (PE / EA, 2 / 1) to obtain c3-3 (600 mg) as a pale yellow solid in a 64% yield. LCMS ESI-MS m / z: 376 [M+H] + .

[0231] Step 3: Dissolve compound c3-3 (600 mg, 1.62 mmol) in 5 mL of anhydrous tetrahydrofuran in an ice bath under nitrogen. Add aqueous LiOH (1N, 2.0 mL) and react at room temperature for 2 hours. Stop the reaction and remove the solvent under reduced pressure. Add 30 mL of ice water to the mixture, adjust the pH to approximately 4 with dilute hydrochloric acid, and extract three times with dichloromethane. The organic phases are combined and concentrated. The crude product is purified by flash reverse-phase column chromatography (CH3CN / H2O, 1 / 2) to obtain c3 (150 mg), a yellow solid, in a yield of 26%. LCMS ESI-MS m / z: 362 [M+H] + .

[0232] Example 2: Preparation of target molecules P1-P7, P21-P22

[0233] Step 1: Under nitrogen, intermediate b1 (221 mg, 0.55 mmol) and TEA (167 mg, 1.65 mmol) were dissolved in 3 mL of dichloromethane. Intermediate a2 (200 mg, 0.55 mmol) was added dropwise and stirred at room temperature for 2 hours. 10 mL of water was added to the reaction mixture, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 3 / 1) to obtain P1-1 (130 mg) as a white solid in a 38% yield. LCMS ESI-MS m / z: 730 [M+H] + .

[0234] Step 2: Dissolve the compound P1-1 (130 mg, 0.21 mmol) from the previous step in 3 mL of dichloromethane in an ice bath. Add sulfuric acid (0.5 mL) dropwise and react for 0.5 h in an ice bath. Pour the reaction mixture into 10 mL of ice water and adjust the pH to approximately 8 with sodium hydroxide. Extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (DCM / MeOH, 20 / 1) to obtain P1 (10 mg) as a white solid in a 12% yield. LCMS ESI-MS m / z: 396 [M+H] + .

[0235] 1 H NMR (400MHz, DMSO-d6) δ9.86 (s, 1H), 8.05 (d, J = 3.5Hz, 2H), 7.76 (d, J = 8.4Hz, 1H), 7.60-7.56 (m, 2H), 7.50 (d, J = 1.7Hz, 1H), 7.31 (dd ,J=8.4,2.1Hz,1H),7.22(t,J=8.9Hz,2H),6.86(d,J=8.3Hz,1H),5.15(s,2H),4.68(s,1H),3.54(t,J=6.9Hz,2H),3.40–3.34(m,2H).

[0236] Referring to the synthetic route of compound P1, similar raw materials / intermediates were used to synthesize the following target molecules.

[0237] Example 3

[0238] Preparation of target molecules P8-P20, P23-P25

[0239] Step 1: Under nitrogen, intermediate b2 (60 mg, 0.18 mmol) and EDCI (142 mg, 0.74 mmol) were dissolved in 3 mL of pyridine. Intermediate b2 (95 mg, 0.28 mmol) was added dropwise, and the mixture was heated to 60°C and reacted for 3 hours. 10 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 1 / 1) to obtain P8-1 (80 mg) as a yellow oil in a 68% yield. LCMS ESI-MS m / z: 652 [M+H] + .

[0240] Step 2: Dissolve the compound P8-1 (80 mg, 0.12 mmol) in 3 mL of trifluoroacetic acid in an ice bath and heat to 40°C for 3 hours. Pour 10 mL of ice water into the reaction solution, adjust the pH to approximately 8 with NaOH, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (DCM / MeOH, 20 / 1) to obtain P8 (10 mg) as a yellow solid in a 20% yield. LCMS ESI-MS m / z: 418 [M+H] + .

[0241] 1 H NMR(400MHz, DMSO-d6)δ9.86(s,1H),8.04(d,J=4.8Hz,2H),7.76(d,J=8.4Hz,1H),7.42(d,J=1.8Hz,1H),7.26(dd,J=8.4,2.0Hz,1H),7 .11(d,J=3.6Hz,1H),7.05(d,J=3.6Hz,1H),6.81(d,J=8.4Hz,1H),5.29(s,2H),4.68(s,1H),3.54(t,J=6.8Hz,2H),3.40–3.35(m,2H).

[0242] Following the synthetic route of compound P8, similar raw materials / intermediates were used to synthesize the following target molecules.

[0243] Example 4 Chiral resolution of compound P1

[0244] P1 compound (150 mg) separation conditions:

[0245] Chromatographic column: UniChiral CNZ-5H, 2*25 cm, 5 μm; Mobile phase A: n-hexane / ethanol = 20 / 80 (v / v); Flow rate: 25 mL / min; Detection wavelength: 254 nm; Retention time of P1A (61 mg): 7.212 min; Retention time of P1B (62 mg): 9.828 min;

[0246] P1A: 1H NMR(400MHz, DMSO-d6)δ9.86(s,1H),8.04(s,2H),7.76(d,J=8.4Hz,1H),7.59-7.56(m,2H),7.49(s,1H),7.31(d,J=8.4H z,1H),7.21(t,J=8.8Hz,2H),6.86(d,J=8.4Hz,1H),5.13(s,2H),4.69(s,1H),3.53(t,J=6.8Hz,2H),3.40–3.26(m,2H).

[0247] P1B: 1 H NMR (400MHz, DMSO-d6) δ9.87(s,1H),8.04(s,2H),7.76(d,J=8.3Hz,1H),7.59-7.56(m,2H),7.49(s,1H),7.31(d,J=8.4H z,1H),7.21(t,J=8.3Hz,2H),6.86(d,J=8.2Hz,1H),5.13(s,2H),4.69(s,1H).3.53(t,J=6.8Hz,2H),3.40–3.26(m,2H).

[0248] Example 5:

[0249] The molecules of the invention were tested for their activity in deacetylation of histone substrates by HDAC1 (COREST) ​​or HDAC3.

[0250] The inhibitory activity of the compound on HDAC1 (or HDAC3) is calculated by measuring the fluorescence change of the acetylated histone substrate at 360nm / 460nm with a fluorescent substrate. The details are as follows:

[0251] Prepare the working solution and buffer to be tested. The test compound is dissolved in DMSO and diluted 3 times (10 μM final concentration as the starting concentration). Add the test compound solution to a 384-well plate, add 5 μL (2X) HDAC1 enzyme solution, shake and incubate in the dark for 10 minutes, then add 5 μL of fluorescent acetylated histone substrate detection solution to start the reaction, incubate at room temperature for 30 minutes, and add 10 μL of stop solution to stop the reaction. The inhibitory activity (IC) for HDAC1 (or HDAC3) enzyme is calculated based on the changes in fluorescence 360nm / 460nm of the blank group (DMSO) and the compound group. 50 ).

[0252] Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0253] X:log of cpd concentration

[0254] Y:Percent inhibition (%)

[0255] 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) ​​in synergy with PD-1 antibodies.

[0256] Example 6: Liver microsome stability test of the compound

[0257] The compounds of the present invention were subjected to a liver microsome stability test. The test compounds were co-incubated with liver microsomes of different species with or without the addition of NADPH. The final concentration of the test compound in the test system was 1 μM, the final concentration of NADPH was 1 mM, and the final concentration of liver microsomes was 0.5 mg / mL. The concentration of the compound in the incubation supernatant at different time points within 60 minutes was measured and the pharmacokinetic parameters (such as clearance Cl) were calculated. int ).

[0258] This result indicates that the molecule of the present invention has good metabolic stability (especially in the human body).

[0259] Example 7: Pharmacokinetic evaluation experiment in mice

[0260] CD1 female mice were used as test animals and the drug was administered orally / intravenously (oral dosage: 20 mg / kg, intravenous dosage: 4 mg / kg).

[0261] Experimental protocol: Oral administration (vehicle: 0.1% Tween 80 + 0.5% methylcellulose, MC) consisted of three mice per group, and intravenous administration (DMSO / solutol / H2O) consisted of three mice per group. For oral administration, plasma samples were collected before (0 h) and after (0.25, 0.5, 1, 2, 4, 8, and 24 h) administration; for intravenous administration, plasma samples were collected before (0 h) and after (0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h) administration. Plasma concentrations were determined in mice following oral and intravenous administration using LC / MS / MS. Data were calculated using AB Sciex QTRAP 6500 software. The results are as follows:

[0262] The above results indicate that the molecule of the present invention has a very high oral absorption effect and is expected to achieve a higher clinical anti-tumor effect at a lower oral dose in clinical practice.

Claims

1. A compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: in, Indicates a single bond or a double bond; X m , X p and X n are each independently selected from CH or N; Y is selected from NH or O; Z is selected from CH 2 , O, N or NH; R 1 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heteroaryl, -(CH 2 ) p -OR a 、-(CH 2 ) p -N(R a ) 2 or -(CH 2 ) p -(5-12 membered heterocyclic group); said R 1 Optional 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH 2 ; or two optionally substituted R 1 The carbon atom connected thereto may form a 3-6 membered cycloalkyl or a 3-12 membered heterocyclic group; the cycloalkyl or heterocyclic group may be optionally substituted by 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH 2 ; R 2 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 3 Selected from C 3-6 Cycloalkyl or 5-12 membered heteroaryl; said R 3 Optional 1 or 2 R y Replacement, R y Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NH 2 、-OR a 、-SR a 、-SF 5 、-C(O)OH、-C(O)NH 2 or -CH 2 C(O)OH; or R 3 With R 4 Connect the carbon atoms to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group; R 4 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; m is selected from 0 or 1; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2; The condition is that when m and n are both 0, R 3 With R 4 The carbon atoms where they are located are connected to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which is a compound of formula (I): in, Indicates a single bond or a double bond; X m and X n are each independently selected from CH or N; Y is selected from NH or O; R 1 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heteroaryl, -(CH 2 ) p -OR a 、-(CH 2 ) p -N(R a ) 2 or -(CH 2 ) p -(5-12 membered heterocyclic group); said R 1 Optional 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH 2 ; R 2 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 3 Selected from C 3-6 Cycloalkyl or 5-12 membered heteroaryl; said R 3 Optional 1 or 2 R y Replacement, R y Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NH 2 、-OR a 、-SR a 、-SF 5 、-C(O)OH、-C(O)NH 2 or -CH 2 C(O)OH; or R 3 With R 4 Connect the carbon atoms to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group; R 4 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; m is selected from 0 or 1; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2; The condition is that when m and n are both 0, R 3 With R 4 The carbon atoms where they are located are connected to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group.

3. The compound of claim 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which is a compound of formula (III): in, Indicates a single bond or a double bond; X m and X n are each independently selected from CH or N; Y is selected from NH or O; R 1 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heteroaryl-(CH 2 ) p -OR a 、-(CH 2 ) p -N(R a ) 2 or -(CH 2 ) p -(5-12 membered heterocyclic group); said R 1 Optional 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH 2 ; R 2 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 3 Selected from C 3-6 Cycloalkyl or 5-12 membered heteroaryl; said R 3 Optional 1 or 2 R y Replacement, R y Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NH 2 、-OR a 、-SR a 、-SF 5 、-C(O)OH、-C(O)NH 2 or -CH 2 C(O)OH; or R 3 With R 4 Connect the carbon atoms to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group; R 4 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; p is selected from 0, 1 or 2.

4. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which is a compound of formula (IV): in, X m and X n are each independently selected from CH or N; Y is selected from NH or O; Z is selected from CH 2 , NH or O; R 1 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heteroaryl-(CH 2 ) p -OR a 、-(CH 2 ) p -N(R a ) 2 or -(CH 2 ) p -(5-12 membered heterocyclic group); said R 1 Optional 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH 2 ; R 2 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 3 Selected from C 3-6 Cycloalkyl or 5-12 membered heteroaryl; said R 3 Optional 1 or 2 R y Replacement, R y Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, NH 2 、-OR a 、-SR a 、-SF 5 、-C(O)OH、-C(O)NH 2 or -CH 2 C(O)OH; or R 3 With R 4 Connect the carbon atoms to form a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group; R 4 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; p is selected from 0, 1 or 2.

5. The compound of claim 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the following general structure: in, Indicates a single bond or a double bond; X m and X n are each independently selected from CH or N; Y is selected from NH or O; Z is selected from O, S or NH; R 1 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heteroaryl or -(CH 2 ) p -(5-12 membered heterocyclic group); said R 1 Optional 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH 2 ; R 2 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, NH 2 、-OR a 、-SR a 、-SF 5 、-C(O)OH、-C(O)NH 2 or -CH 2 C(O)OH; R 4 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; p is selected from 0, 1 or 2.

6. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: Indicates a single bond or a double bond; X m and X n are each independently selected from CH or N; Y is selected from NH or O; Z is selected from O, S or NH; R 1 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heteroaryl or -(CH 2 ) p -(5-12 membered heterocyclic group); said R 1 Optional 1 or 2 R x Replacement, R x Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR a , CN or NH 2 ; R 2 is selected from H, F, Cl, methyl, trifluoromethyl, methoxy or cyclopropyl; R y Selected from H, F, Cl, methyl, trifluoromethyl, methoxy, cyclopropyl, CN, NH 2 、-OH、-SMe、-SF 5 、-C(O)OH、-C(O)NH 2 or -CH 2 C(O)OH; R 4 is selected from H, F, Cl, methyl, trifluoromethyl, methoxy or cyclopropyl; p is selected from 0, 1 or 2.

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

8. A pharmaceutical composition comprising a compound according to any one of claims 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer or isotopic variant thereof.

9. The use of a compound or composition according to claim 7, 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 cancer, 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'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 diseases (such as alpha chain disease, gamma chain disease, μ chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer (such as Wilms tumor, renal cell carcinoma), liver cancer (such as hepatocellular carcinoma, malignant hepatocellular carcinoma), Lung cancer (such as bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, leiomyosarcoma (LMS), mastocytosis (such as systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disease (MPD) (such as polycythemia vera (PV), essential thrombocythemia (ET), idiopathic extramedullary metaplasia of the bone marrow (AMM), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibroma (such as neurofibromatosis type 1 or type 2, schwannomatosis), 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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