HDAC inhibitor and use thereof in medicine

Abstract

The present invention relates to a compound as shown in general formula (I), or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, and a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as a drug for treating and / or preventing HDAC-mediated diseases.

Description

HDAC inhibitors and their medical applications Technical Field

[0001] The present invention belongs to the field of medical technology, and particularly relates to an HDAC inhibitor and its application in medicine. Background Art

[0002] HDACs (Histonedeacetylases), also known as histone deacetylases in Chinese, are important enzymes in the histone modification process, catalyzing and regulating histone deacetylation. Currently, 18 HDACs have been discovered in the human body, belonging to four categories (Class I, II, III, and IV).

[0003] The principle of HDAC inhibitors as anticancer drugs is to inhibit the activity of histone deacetylase, increase the acetylation level of histones and trigger chromatin remodeling, thereby producing changes in the expression of genes in multiple signaling pathways involved in tumorigenesis, and promoting tumor cell growth arrest, differentiation and apoptosis.

[0004] Several HDAC inhibitors have been approved by the U.S. Food and Drug Administration (FDA), but currently approved HDAC therapies are unclear and target only a few HDAC isoforms, increasing the likelihood of adverse reactions due to their broad inhibitory properties. Therefore, there is a need for selective HDAC inhibitors for treating diseases or conditions such as cancer. Summary of the Invention

[0005] In one aspect, the present invention relates to a compound represented by formula (I), or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof:

[0006] in,

[0007] The ring A is selected from C 6-14 Aryl or 5-14 membered heteroaryl, the C 6-14 The aryl or 5-14 membered heteroaryl may be optionally further substituted with one or more R a or two R on the same atom a Formation C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0008] The L is absent, -CH2-, -(CH2)2- or C 3-8 Cycloalkyl; wherein said -CH2-, -(CH2)2-, C 3- 8 Cycloalkyl may be further optionally substituted with one or more R a replaced by;

[0009] The R1 is selected from H, hydroxyl, amino, cyano, halogen, -C(=O)R c 、-C(=O)OR c 、C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl SO2-, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl), the R c H or C 1- 6 alkyl; the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl) is optionally further substituted with one or more R a replaced by;

[0010] Said R8 is selected from hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6- 14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C0-3 Alkylene-(5-14 membered heteroaryl) may be optionally further substituted with one or more R a replaced by;

[0011] Alternatively, the R1 and R8 together with the nitrogen and sulfur to which they are attached form a 4-7 membered heterocyclic group, which may be further optionally replaced by one or more R a replaced by;

[0012] Said R2 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0013] Said R3 is selected from amino or hydroxyl;

[0014] The R4, R5, and R7 are each independently selected from H, hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0015] The R6 is selected from C 6-14 Aryl or 5-14 membered heteroaryl, the C 6-14 The aryl or 5-14 membered heteroaryl may be optionally further substituted with one or more R a replaced by;

[0016] The m is selected from 1 or 2;

[0017] Said n is selected from 1 or 2;

[0018] The R a are independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-S(=O)R b 、-C 0-3 Alkylene-S(=O)2R b 、-C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-S(R b )5. -C 0-3Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)OR b 、-C 0-3 Alkylene-C(=O)N(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace;

[0019] Each R b are independently H, hydroxy, amino, halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 1- 6 alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Substituted with a haloalkyl group.

[0020] In some embodiments of the present invention, the ring A is selected from C 6-14 Aryl or 5-14 membered heteroaryl, the C 6- 14 The aryl or 5-14 membered heteroaryl may be optionally further substituted with one or more R aor two R on the same atom a Formation C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 Cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0021] Said L is absent, -CH2- or -(CH2)2-;

[0022] The R1 is selected from H, hydroxyl, amino, cyano, halogen, -C(=O)R c 、-C(=O)OR c 、C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl), the R c H or C 1-6 Alkyl; the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl) is optionally further substituted with one or more R a replaced by;

[0023] Said R8 is selected from hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6- 14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 Alkyl hydroxyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl) may be optionally further substituted with one or more R a replaced by;

[0024] Alternatively, said R1 and R8 together with the nitrogen and sulfur to which they are attached form a 4-7 membered heterocyclic group having 0-2 heteroatoms selected from O, S and N, said 4-7 membered heterocyclic group being optionally further substituted by one or more R a replaced by;

[0025] R2 is selected from H or C 1-6 alkyl;

[0026] Said R3 is selected from amino or hydroxyl;

[0027] The R4, R5, and R7 are each independently selected from H, hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0028] The R6 is selected from C 6-14 Aryl or 5-14 membered heteroaryl, the C 6-14 The aryl or 5-14 membered heteroaryl may be optionally further substituted with one or more R a replaced by;

[0029] The m is selected from 1 or 2;

[0030] Said n is selected from 1 or 2;

[0031] The R a are independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-S(=O)R b 、-C 0-3Alkylene-S(=O)2R b 、-C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-S(R b )5. -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)OR b 、-C 0-3 Alkylene-C(=O)N(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace;

[0032] Each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C 1-6 Alkyl or C 1-6 Substituted with a haloalkyl group.

[0033] In some embodiments of the present invention, the ring A is selected from phenyl or 5-6 membered heteroaryl, and the phenyl or 5-6 membered heteroaryl may be optionally further substituted with one or more R a or two R on the same atom a Formation C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace.

[0034] In some embodiments of the present invention, the ring A is a phenyl group, which may be further optionally substituted with one or more R a substituted, the R a Preferably H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy.

[0035] In some embodiments of the present invention, the ring A is selected from described Optionally further represented by one or more R a substituted, the R a Preferably H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy.

[0036] In some embodiments of the present invention, the compound represented by general formula (I), or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, is a compound represented by general formula (IA).

[0037] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R a , m, n, L are as defined in the general formula (I), and t is selected from 0, 1 or 2.

[0038] In some embodiments of the present invention, the compound represented by general formula (I), or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, is a compound represented by general formula (IB),

[0039] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R a, m, n, L are as defined in the general formula (I), and t is selected from 0, 1 or 2.

[0040] In some embodiments of the present invention, the compound represented by general formula (I), or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, is a compound represented by general formula (IC).

[0041] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R a , m, n, L are as defined in the general formula (I), and t is selected from 0, 1 or 2.

[0042] In some embodiments of the present invention, the compound represented by the general formula (I), or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, is a compound represented by the general formula (ID),

[0043] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R a , m, n, L are as defined in the general formula (I), and t is selected from 0, 1 or 2.

[0044] In some embodiments of the present invention, the compound represented by general formula (I), or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, is a compound represented by general formula (IE),

[0045] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R a The definitions of m, n, and L are as defined in the general formula (I), and t is selected from 0, 1 or 2.

[0046] In some embodiments of the present invention, the R1 is selected from H, cyano, -C(=O)R c 、-C(=O)OR c 、C 1- 6 alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl), the R c H or C 1-6 Alkyl; the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl) is optionally further substituted with one or more R a replaced.

[0047] In some embodiments of the present invention, the R8 is selected from hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclyl) is optionally further substituted with one or more R a replaced.

[0048] In some embodiments of the present invention, the R1 and R8 together with the nitrogen and sulfur to which they are attached form a 4-7 membered heterocyclic group having 0-2 heteroatoms selected from O, S and N, and the 4-7 membered heterocyclic group may be optionally further replaced by one or more R a replaced.

[0049] In some embodiments of the present invention, R2 is selected from H.

[0050] In some embodiments of the present invention, the R3 is selected from amino.

[0051] In some embodiments of the present invention, the R3 is selected from hydroxyl.

[0052] In some embodiments of the present invention, R4, R5, and R7 are each independently selected from H, halogen, or C 1-6 alkyl.

[0053] In some embodiments of the present invention, the R6 is selected from phenyl or 5-6 membered heteroaryl, and the phenyl or 5-6 membered heteroaryl may be optionally further replaced by one or more R a replaced.

[0054] Furthermore, the 5-6 membered heteroaryl group is described Optionally further represented by one or more R a replaced.

[0055] In some embodiments of the present invention, the R6 is selected from

[0056] In some embodiments of the present invention, the compound of formula (I) is selected from the following compounds:

[0057] The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of at least one compound represented by formula (I), or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof.

[0058] The present invention provides use of a compound represented by general formula (I) or a pharmaceutical composition thereof in preparing medicines.

[0059] The present invention further provides a preferred technical solution for the application:

[0060] Preferably, the application is for preparing a drug for treating and / or preventing diseases mediated by histone deacetylase (HDAC).

[0061] Preferably, the disease is selected from the group consisting of glioma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., urothelial bladder carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric gland cancer, carcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, stomach cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, multiple myeloma, cervical cancer, rhabdomyosarcoma, small cell lung cancer, multiforme lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatobiliary carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, lichenoid keratosis, synovial sarcoma, skin cancer, testicular cancer, pleural cancer, and colorectal cancer or sarcoma.

[0062] The present invention also provides a method for treating and / or preventing a disease, comprising administering to a subject a therapeutically effective amount of at least one compound represented by structural formula (I), its stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts, or a pharmaceutical composition containing the same.

[0063] Preferably, in the above method, the disease is a disease mediated by histone deacetylase (HDAC), and the disease is selected from glioma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DFL), leukemia (e.g., melanoma), leukemia (e.g., leukemia), scleroderma (SLS), myeloma (e.g., leukemia), scleroderma (SLS ... LBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, as well as brain cancer, stomach cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, multiple myeloma, cervical cancer, rhabdomyosarcoma, small cell lung cancer, multiform lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, lichenoid keratosis, synovial sarcoma, skin cancer, testicular cancer, pleural cancer, and colorectal cancer or sarcoma.

[0064] Unless otherwise indicated, general chemical terms used in the structural formulae have their usual meanings.

[0065] For example, the term "halogen," as used herein, refers to fluorine, chlorine, bromine, or iodine, unless otherwise indicated.

[0066] In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 The "1-6" in "alkyl" refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms in a straight chain or branched form.

[0067] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl groups, ie, -O-alkyl.

[0068] The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane with two C—H bonds replaced as the point of attachment of the alkylene to the rest of the compound. Similarly, C 1-3 The "C" in the alkylene 1-3 ” refers to an alkylene group containing 1, 2 or 3 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.

[0069] The term "haloalkyl" refers to an alkyl group in which one or more H groups have been replaced by a halogen atom.

[0070] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to C, and forms a sulfoxide group or a sulfone group or an N-oxide group when attached to a heteroatom.

[0071] In the present invention, unless otherwise specified, the term "aromatic ring", "aromatic ring" or "aromatic heterocycle" refers to a polyunsaturated carbon ring or heterocycle with aromatic characteristics (having (4n+2) delocalized π electrons, where n is an integer).

[0072] The term "aryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or condensed ring aromatic group containing carbon ring atoms. 6-18 Aryl, more preferably C 6-10 A monocyclic or bicyclic aromatic ring group. Phenyl or naphthyl is preferred; naphthyl is most preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring connecting to the parent structure is an aryl ring. Non-limiting examples include, but are not limited to, benzocyclopentyl.

[0073] The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heteroatom, wherein the heteroatom is selected from N, O and / or S. The heterocyclyl group may include a monocyclic or polycyclic ring (e.g., having 2, 3 or 4 fused rings, spirocyclic rings, bridged rings, etc.). The heterocyclyl group may be connected to the other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom. Preferably, the heterocyclyl group is a 3-14 membered group, wherein the "3-14 members" in the 3-14 membered heterocyclyl group refers to a heterocyclyl group consisting of 3-14 C, N, O or S ring atoms; wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. Examples of such heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclic group.

[0074] The term "heteroaryl" as used herein, unless otherwise specified, refers to a monocyclic or polycyclic (e.g., 2, 3, or 4 fused, spiro, or bridged) aromatic heterocycle having at least one heteroatom, wherein the heteroatom is selected from N, O, and / or S, and wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. A 5- to 18-membered heteroaryl is preferred, wherein the "5- to 18-membered" in the 5- to 18-membered heteroaryl refers to a heteroaryl group consisting of 5 to 18 ring atoms of C, N, O, or S. A 5- to 10-membered heteroaryl is more preferred; a 5- to 6-membered heteroaryl is even more preferred. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolyl, or isoquinolyl. The heteroaryl group may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring.

[0075] The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. 3-14 Cycloalkyl, where "C 3-14 " means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms. The cycloalkyl group may include a monocyclic ring and a polycyclic ring (for example, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, the cycloalkyl group includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group may also be fused to an aryl, heterocyclyl or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl group.

[0076] The term "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include but are not limited to halogen (F, Cl, Br or I), C 1-6 Alkyl, C 3-12 Cycloalkyl, -OR 1 、-SR 1 , =O, =S, -C(O)R 1 、-C(S)R 1 、=NR 1 、-C(O)OR 1 、-C(S)OR 1 、-NR 1 R 2 、-C(O)NR 1 R 2 , cyano, nitro, -S(O)2R 1 、-OS(O2)OR1 、-OS(O)2R 1 、-OP(O)(OR 1 )(OR 2 ); where R 1 and R 2 Independently selected from -H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH3, -SC2H5, formaldehyde, -COCH3, cyano, nitro, -CF3, amino, dimethylamino, sulfonyl, and acetyl.

[0077] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0078] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.

[0079] When the compound provided by the present invention is an acid, its corresponding salt can be easily prepared from pharmaceutically acceptable nontoxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc and the like. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Nontoxic organic bases that can be derived into pharmaceutically acceptable salts include primary amines, secondary amines and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0080] When compound provided by the invention is a base, it is possible to conveniently prepare its corresponding salt from pharmaceutically acceptable nontoxic acid, including inorganic and organic acids. Such acid includes, as, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, tamoxifen, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0081] Prodrugs of the compounds of the present invention are included within the scope of protection of the present invention. Generally, such prodrugs are functional derivatives that are readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, ester salt, or other derivative of the compounds of the present invention, which, upon administration to a recipient, can directly or indirectly provide the compounds of the present invention or their pharmaceutically active metabolites or residues.

[0082] The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.

[0083] When the compound represented by formula (I) exists in tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0084] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0085] In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient composition can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0086] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0087] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0088] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0089] The term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be therapeutic in terms of partial or complete stabilization or cure of a disease and / or side effects caused by the disease. As used herein, "treat" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., arresting its progression; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or its symptoms.

[0090] The term "effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0091] The room temperature mentioned in the present invention refers to the temperature of the indoor environment, which is generally 18-25°C. DETAILED DESCRIPTION

[0092] To make the above content clearer and more specific, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific embodiments of the present invention, technical means or methods not specifically described are conventional technical means or methods in the art.

[0093] Unless otherwise stated, all temperatures herein are in degrees Celsius.

[0094] The following abbreviations are used in the examples:

[0095] RT: room temperature

[0096] (Boc)2O: Di-tert-butyl dicarbonate

[0097] DMAP: 4-dimethylaminopyridine

[0098] TEA: triethylamine

[0099] Pd(dppf)Cl2:[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

[0100] K2CO3: Potassium carbonate

[0101] Dioxane: Dioxane

[0102] Pd / C: Palladium on carbon

[0103] MeOH: methanol

[0104] THF: Tetrahydrofuran

[0105] mCPBA: meta-chloroperbenzoic acid

[0106] PhI(OAc)2:iodophenyldiacetic acid

[0107] NH2Boc: tert-butyl carbamate

[0108] MgO: magnesium oxide

[0109] Rh2(OAc)4: Rhodium acetate dimer

[0110] LiOH: lithium hydroxide

[0111] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0112] Py:pyridine

[0113] DCM: dichloromethane

[0114] BH3: Borane

[0115] TFAA: trifluoroacetic anhydride

[0116] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0117] DIEA: N,N-diisopropylethylamine

[0118] DMF: N,N-dimethylformamide

[0119] TFA: trifluoroacetic acid

[0120] dppf: 1,1'-bis(diphenylphosphino)ferrocene

[0121] Cs2CO3: cesium carbonate

[0122] Na2S2O3: Sodium thiosulfate

[0123] TBAB: Tetrabutylammonium bromide

[0124] MeCN: acetonitrile

[0125] NH2CO2NH4: Ammonium carbamate

[0126] CbzCl: benzyl chloroformate

[0127] Pd(PPh3)4:Tetrakistriphenylphosphine palladium

[0128] BTC: Triphosgene

[0129] DMSO: dimethyl sulfoxide

[0130] NaSMe: sodium methyl mercaptan

[0131] HCOONH4: ammonium formate

[0132] EtBr: ethyl bromide

[0133] Pd(dppf)Cl2CH2Cl2:[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex

[0134] EtOH: ethanol

[0135] CuBr2: copper bromide

[0136] t-Butyl nitrite: tert-butyl nitrite

[0137] DIBAL-H: Diisobutylaluminum hydride

[0138] MsCl: Methanesulfonyl chloride

[0139] AcOK: Potassium acetate

[0140] AIBN: Azobisisobutyronitrile

[0141] Ni(dppe)Cl2:1,2-bis(diphenylphosphine)ethane nickel chloride

[0142] PMBBr: p-methoxybenzyl bromide

[0143] MeSSMe: dimethyl disulfide.

[0144] Synthesis of Intermediate M1 4'-Fluoro-4-nitro-[1,1'-biphenyl]-3-amine

[0145] Step 1: Synthesis of intermediate M1

[0146] The compound 5-chloro-2-nitroaniline (2.4 g), 4-fluorophenylboronic acid (2.16 g, 1.1 eq), tetrakistriphenylphosphine palladium (0.8 g, 0.05 eq), and cesium carbonate (9.08 g, 2 e.q.) were dissolved in 1,4-dioxane (20 mL) and water (2 mL). The atmosphere was purged with nitrogen and the reaction was carried out at 100°C for 2 h. After completion of the reaction, the mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound M1 (2.76 g, 85.46% yield). ESI-MS m / z: 233.2 [M+H] + .

[0147] Example 1: Synthesis of N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-5-(S-methylsulfonylimino)isoindoline-2-carboxamide

[0148] Step 1: Synthesis of compound 1-1

[0149] Intermediate M1 (161 mg) and triethylamine (0.48 mL) were dissolved in dichloromethane (10.00 mL). Triphosgene (207 mg) was added under ice-cooling and the mixture was allowed to react at 25°C for 3 h. 5-(Methylthio)isoindoline (115 mg) and triethylamine (0.19 mL) were then added and the mixture was allowed to react at 25°C for 3 h. After the reaction was complete, ammonia was added to quench the reaction, the mixture was extracted with dichloromethane, concentrated, slurried with methanol, and filtered to obtain compound 1-1 (269 mg). ESI-MS m / z: 424.27 [M+H] + .

[0150] Step 2: Synthesis of compound 1-2

[0151] Compound 1-1 (269 mg), ammonium formate (80 mg), and iodophenyldiacetic acid (511 mg) were dissolved in methanol (5 mL) and dichloromethane (5 mL) and reacted at 25°C for 16 h. After completion of the reaction, the mixture was concentrated and purified by column chromatography (dichloromethane / methanol) to obtain compound 1-2 (182 mg). ESI-MS m / z: 455.28 [M+H] + .

[0152] Step 3: Synthesis of compound 1

[0153] Compound 1-2 (182 mg) was dissolved in methanol (8.00 mL) and tetrahydrofuran (8.00 mL), and 10% palladium on carbon (85 mg) was added. The atmosphere was replaced with hydrogen and the mixture was allowed to react at 25°C for 1 h. After completion of the reaction, the mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol) to obtain compound 1 (128 mg). ESI-MS m / z: 425.18 [M+H] + .1 H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.88(dd,J=8.0,1.7Hz,1H),7.80(s,1H),7.62–7.52(m,3H),7.41(d,J =2.2Hz,1H),7.25–7.17(m,3H),6.80(d,J=8.3Hz,1H),5.08(s,2H),4.86(s,4H),4.24(s,1H),3.08(s,3H).

[0154] After chiral separation (YMC-IA chromatographic column, A: 0.1% diethylamine n-hexane solution, B: 0.1% diethylamine ethanol solution, concentration gradient: 90% B, flow rate: 20 mL / min, 254 nm; retention time A: 25.60 min, retention time B: 32.47 min); the compound corresponding to retention time A and retention time B respectively is one of compound 2 or compound 3.

[0155] Example 4: Synthesis of N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-5-(N-ethyl-S-methylsulfonylimino)isoindoline-2-carboxamide

[0156] Step 1: Synthesis of compound 4-1

[0157] 5-Bromo-isoindolin-1-one (3.0 g) was dissolved in dimethyl sulfoxide (30.0 mL), and sodium thiomethoxide (1.29 g) was added. The mixture was reacted at 110°C for 1 h. After completion of the reaction, the mixture was poured into 200 mL of water. The product precipitated and was filtered, washed with water, dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4-1 (1.15 g). ESI-MS m / z: 180.05 [M+H] + .

[0158] Step 2: Synthesis of compound 4-2

[0159] Compound 4-1 (400 mg) was dissolved in tetrahydrofuran (5.00 mL), and borane-tetrahydrofuran solution (6.70 mL, 1.00 mol / L) was added under ice-cooling. The mixture was reacted at 65°C for 8 h. After completion of the reaction, methanol was added to quench the reaction, the mixture was concentrated, and concentrated hydrochloric acid (10 mL) was added. The mixture was refluxed at 90°C for 3 h. After completion of the reaction, the pH was adjusted to 9 with sodium hydroxide solution, and the mixture was extracted with dichloromethane / methanol (5:1). The organic phase was separated and purified by column chromatography (dichloromethane / methanol) to obtain compound 4-2 (216 mg). ESI-MS m / z: 166.06 [M+H] + .

[0160] Step 3: Synthesis of compound 4-3

[0161] Compound 4-2 (110 mg) was dissolved in dichloromethane (5.00 mL), and triethylamine (0.18 mL) and di-tert-butyl dicarbonate (218 mg) were added. The mixture was reacted at 25°C for 2 h. After completion of the reaction, the mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 4-3 (139 mg). ESI-MS m / z: 210.09 [M+H-56] + .

[0162] Step 4: Synthesis of compound 4-4

[0163] Compound 4-3 (139 mg), ammonium formate (66 mg), and iodophenyl diacetic acid (422 mg) were dissolved in methanol (5.00 mL) and reacted at 25°C for 16 h. After completion of the reaction, the mixture was concentrated and purified by column chromatography (dichloromethane / methanol) to obtain compound 4-4 (85 mg). ESI-MS m / z: 297.18 [M+H] + .

[0164] Step 5: Synthesis of compound 4-5

[0165] Compound 4-4 (85 mg), bromoethane (156 mg), and potassium hydroxide (32 mg) were dissolved in dimethyl sulfoxide (5.00 mL) and reacted at 80°C for 1 h. After completion of the reaction, ethyl acetate, tetrahydrofuran, and water were added for extraction. The organic phase was washed with saturated brine, concentrated, and purified by column chromatography (dichloromethane / methanol) to obtain compound 4-5 (65 mg). ESI-MS m / z: 325.11 [M+H] + .

[0166] Step 6: Synthesis of Compound 4-6

[0167] Compound 4-5 (65 mg) was dissolved in dichloromethane (3.00 mL), trifluoroacetic acid (1.00 mL) was added, and the mixture was allowed to react at 25°C for 1 h. After completion of the reaction, the mixture was concentrated, dissolved in dichloromethane / methanol, and neutralized with sodium bicarbonate solution. The organic phase was extracted, concentrated, and purified by column chromatography (dichloromethane / methanol) to obtain compound 4-6 (32 mg). ESI-MS m / z: 225.12 [M+H] + .

[0168] Step 7: Synthesis of Compound 4-7

[0169] Intermediate M1 (31 mg) and triethylamine (0.09 mL) were dissolved in dichloromethane (5.00 mL). Triphosgene (40 mg) was added under ice-cooling and the mixture was allowed to react at 25°C for 3 h. Compound 4-6 (32 mg) and triethylamine (0.04 mL) were then added and the mixture was allowed to react at 25°C for 3 h. After the reaction was complete, ammonia was added to quench the reaction, the mixture was extracted with dichloromethane, concentrated, and purified by column chromatography (dichloromethane / methanol) to obtain compound 4-7 (47 mg). ESI-MS m / z: 483.32 [M+H] + .

[0170] Step 8: Synthesis of compound 4

[0171] Compound 4-7 (47 mg) was dissolved in methanol (5.00 mL) and tetrahydrofuran (2.00 mL), and 10% palladium on carbon (10 mg) was added. The atmosphere was replaced with hydrogen and the mixture was allowed to react at 25°C for 1 h. After completion of the reaction, the mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol) to obtain compound 4 (12.1 mg). ESI-MS m / z: 453.23 [M+H] + . 1 H NMR(500MHz, DMSO-d6)δ7.85(s,1H),7.79(d,J=9.0Hz,2H),7.61(d,J=7.9Hz,1H),7.59–7.52(m,2H),7.41(d,J=2.2Hz,1H) ,7.25–7.17(m,3H),6.80(d,J=8.4Hz,1H),5.08(s,2H),4.86(s,4H),3.13(s,3H),1.05(t,J=7.2Hz,3H),0.89–0.82(m,2H).

[0172] Example 5: Synthesis of N-(2-amino-5-(thiophen-2-yl)phenyl)-5-(S-methylsulfonylimino)isoindoline-2-carboxamide

[0173] Step 1: Synthesis of compound 5-1

[0174] 5-Bromo-2-nitroaniline (1 g), 2-thiopheneboronic acid (884 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (380 mg), and potassium carbonate (1.91 g) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 2 h. After completion of the reaction, the mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 5-1 (462 mg).

[0175] Step 2: Synthesis of compound 5-2

[0176] Compound 5-1 (100 mg) and triethylamine (0.32 mL) were dissolved in dichloromethane (5 mL). Triphosgene (135 mg) was added under ice-cooling and the mixture was allowed to react at 25°C for 3 h. 5-(Methylthio)isoindoline (75 mg) and triethylamine (0.13 mL) were then added and the mixture was allowed to react at 25°C for 3 h. After the reaction was complete, ammonia was added to quench the reaction, the mixture was extracted with dichloromethane, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 5-2 (158 mg). ESI-MS m / z: 412.26 [M+H] + .

[0177] Step 3: Synthesis of compound 5-3

[0178] Compound 5-2 (158 mg), ammonium formate (48 mg), and iodophenyl diacetic acid (309 mg) were dissolved in methanol (5 mL) and dichloromethane (5 mL) and reacted at 25°C for 16 h. After completion of the reaction, the mixture was concentrated and purified by column chromatography (dichloromethane / methanol) to obtain compound 5-3 (63 mg). ESI-MS m / z: 443.23 [M+H] + .

[0179] Step 4: Synthesis of compound 5

[0180] Compound 5-3 (63 mg) was dissolved in methanol (5.00 mL) and tetrahydrofuran (5.00 mL), and 10% palladium on carbon (15 mg) was added. The atmosphere was replaced with hydrogen and the mixture was allowed to react at 25°C for 1 h. After completion of the reaction, the mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol) to obtain compound 5 (16.3 mg). ESI-MS m / z: 413.32 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ7.93(s,1H),7.88(dd,J=8.0,1.8Hz,1H),7.81(s,1H),7.59(d,J=8.0Hz,1H),7.39(d,J=2.2Hz,1H),7.34(dd,J=5 .1,1.2Hz,1H),7.26–7.19(m,2H),7.04(dd,J=5.1,3.5Hz,1H),6.75(d,J=8.2Hz,1H),5.13(s,2H),4.85(s,4H),4.25(s,1H),3.09(s,3H).

[0181] Example 6: Synthesis of N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-2-(S-methylsulfonylimino)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxamide

[0182] Step 1: Synthesis of compound 6-1

[0183] Compound 2-chloro-3-oxosuccinate (10.0 g) was dissolved in anhydrous ethanol (60 mL) and stirred under reflux for 2.0 h. After the reaction was complete, the solvent was concentrated and water was added. A large amount of white solid precipitated and filtered. The filter cake was rinsed with water and dried. Compound 6-1 (12.5 g) was obtained and directly carried to the next step. ESI-MS m / z: 245.1 [M+H] + .

[0184] Step 2: Synthesis of compound 6-2

[0185] Dissolve tert-butyl nitrite (4.6 g) and copper bromide (10.3 g) in acetonitrile (100 mL). Cool to below 0°C in an ice bath, slowly add a solution of compound 6-1 (12.5 g) in acetonitrile (30 mL) dropwise, and stir at room temperature for 1.0 h. After the reaction is complete, concentrate the solvent, add 0.1 M hydrochloric acid, extract with ethyl acetate, wash with saturated sodium bicarbonate solution, wash with saturated brine, dry over anhydrous sodium sulfate, filter, spin dry, and column chromatography (DCM:MeOH=50:1) to obtain compound 6-2 (11.0 g). ESI-MS m / z: 308.1 [M+H] + .

[0186] Step 3: Synthesis of compound 6-3

[0187] Compound 6-2 (11.0 g) was dissolved in dry toluene (80 mL), cooled to -78°C, and DIBAL-H (25.0 g) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 8.0 h. After the reaction was complete, saturated sodium potassium tartrate solution was added to quench the reaction. Silica gel was added directly to the sample and the mixture was purified by column chromatography (DCM:MeOH = 12:1). Compound 6-3 (3.0 g) was obtained and directly carried to the next step. ESI-MS m / z: 225.3 [M+H] + .

[0188] Step 4: Synthesis of compound 6-4

[0189] Compound 6-3 (3.0 g) was dissolved in anhydrous acetonitrile (20 mL) and TEA (2.6 g) was added. The mixture was cooled to below 0°C in an ice bath and MsCl (1.5 mL) was slowly added dropwise. After completion, the mixture was stirred and reacted for 20 min. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to give compound 6-4 (2.5 g), which was directly carried out to the next step. ESI-MS m / z: 380.1 [M+H] + .

[0190] Step 5: Synthesis of compound 6-5

[0191] Compound 6-4 (2.5 g) and 2,4-dimethoxyphenylamine (2.2 g) were dissolved in DMSO (20 mL), and TEA (2.8 g) was added. The mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. Column chromatography (PE:EA = 3:1) afforded compound 6-5 (1.1 g). ESI-MS m / z: 355.2 [M+H] + .

[0192] Step 6: Synthesis of compound 6-6

[0193] Compound 6-5 (1.1 g) and sodium thiomethoxide (0.4 g) were dissolved in DMF (20 mL) and stirred at room temperature overnight. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. Column chromatography (PE:EA=3:1) afforded compound 6-6 (0.7 g). ESI-MS m / z: 323.2 [M+H] + .

[0194] Step 7: Synthesis of compound 6-7

[0195] Compound 6-6 (0.7 g) was dissolved in TFA (10 mL) and stirred under reflux for 4.0 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. Column chromatography (PE:EA = 5:1) afforded compound 6-7 (0.4 g). ESI-MS m / z: 269.4 [M+H] + .

[0196] Step 8: Synthesis of Compounds 6-8

[0197] Compound 6-7 (0.4 g) and 0.5 M sodium hydroxide solution (5 mL) were dissolved in anhydrous ethanol (10 mL) and stirred at room temperature for 2.0 h. After the reaction was complete, the solvent was dried by rotary evaporation. Column chromatography (DCM:MeOH = 10:1) afforded compound 6-8 (0.18 g). ESI-MS m / z: 173.4 [M+H] + .

[0198] Step 9: Synthesis of Compounds 6-9

[0199] Intermediate M1 (0.24 g) and TFA (0.8 mL) were dissolved in dichloromethane (10 mL). Triphosgene (0.31 g) was added under ice-cooling and stirred at room temperature for 3.0 h. 6-8 (0.18 g) and TFA (0.3 mL) were then added and stirred at room temperature for 3.0 h. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. Column chromatography (PE:EA=3:1) afforded compound 6-9 (0.12 g). ESI-MS m / z: 431.3 [M+H] + .

[0200] Step 10: Synthesis of Compounds 6-10

[0201] Compound 6-9 (0.12 g) and m-CPBA (0.05 g) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 1.0 h. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. Compound 6-10 (0.15 g) was obtained and used directly in the next step. ESI-MS m / z: 447.3 [M+H] + .

[0202] Step 11: Synthesis of Compound 6-11

[0203] Compound 6-10 (0.15 g), ammonium carbamate (0.12 g), and iodophenyldiacetic acid (0.51 g) were dissolved in dichloromethane (5 mL) and methanol (10 mL) and stirred at 40°C for 6.0 h. After the reaction was complete, the solvent was dried by rotary evaporation. Column chromatography (PE:EA = 1:1) afforded compound 6-11 (0.1 g). ESI-MS m / z: 462.1 [M+H] + .

[0204] Step 12: Synthesis of target compound

[0205] Compound 6-11 (0.1 g) and 10% palladium on carbon (0.02 g) were dissolved in methanol (10 mL), replaced with hydrogen five times, and stirred at room temperature for 3.0 h. After the reaction was complete, the mixture was filtered and the concentrate was separated and purified by Pre-HPLC to obtain the target compound 6 (12.1 mg). ESI-MS m / z: 432.1 [M+H] + 1H NMR (500MHz, DMSO) δ8.20 (s, 1H), 7.61 (s, 2H), 7.47 (s, 1H), 7.35 (d, J = 7.4Hz, 1H),7.25(t,J=8.3Hz,2H),7.02(s,1H),4.80(d,J=38.9Hz,4H),3.28(s,6H).

[0206] Example 7: Synthesis of the compound N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-5-(tetrahydro-2H-pyran-4-sulfonylimino)isoindoline-2-carboxamide

[0207] Step 1: Synthesis of compound 7-1

[0208] To a reaction flask were added tert-butyl 5-bromoisoindoline-2-carboxylate (1.6 g), methyl 3-mercaptopropionate (0.71 mL, 1.2 eq), DIEA (1.77 mL, 2 e.q.), Pd2(dba)3 (0.25 g, 0.05 eq), XantPhos / 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.31 g, 0.1 eq), and 1,4-dioxane / dioxane (20 mL). After nitrogen substitution, the reaction mixture was transferred to 100°C for 8 h. After completion of the reaction, the reaction solution was cooled to room temperature, filtered through celite, and washed with EA. The filtrate was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (PE / EA = 3:1) to obtain the target compound 7-1 (1.7 g, 93.89% yield). ESI-MS m / z:238.2[M+H-100] + .

[0209] Step 2: Synthesis of compound 7-2

[0210] To a reaction flask, 7-1 (1.7 g) and THF / tetrahydrofuran (25 mL) were added sequentially. Sodium tert-butoxide (590 mg, 1.2 eq) was added with stirring at 0°C, and the reaction mixture was then transferred to room temperature for 30 min. After completion of the reaction, dilute hydrochloric acid (1 M) was added to adjust the pH to 5. The aqueous phase was then washed twice with ethyl acetate. The combined organic phases were evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (PE / EA = 4:1) to obtain the target compound 7-2 (780 mg, 61.59% yield). ESI-MS m / z: 196.2 [M+H-56] + .

[0211] Step 3: Synthesis of compound 7-3

[0212] To the reaction flask, 7-2 (360 mg) and DMF (4 mL) were added sequentially, followed by NaH (63 mg, 60%, 1.1 eq) at room temperature. The reaction was allowed to proceed at room temperature for 30 min. 4-Bromotetrahydropyran (260 mg, 1.1 eq) was then added, and the reaction mixture was moved to 80°C for 3 h. After the reaction, ethyl acetate (20 mL) and H₂O / water (20 mL) were added. The aqueous phase was washed twice with ethyl acetate. The combined organic phases were evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (PE / EA = 3:1) to afford the target compound 7-3 (405 mg, 84.29% yield). ESI-MS m / z: 236.2 [M+H-100] + .

[0213] Step 4: Synthesis of compound 7-4

[0214] To the reaction flask, 7-3 (405 mg) and DCM (10 mL) were added sequentially, followed by trifluoroacetic acid (5 mL), and the mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure, dissolved in dichloromethane / methanol, and neutralized with sodium bicarbonate solution. The organic phase was extracted and concentrated to give the crude product 7-4 (250 mg, 87.99% yield). ESI-MS m / z: 236.1 [M+H] + .

[0215] Step 5: Synthesis of compound 7-5

[0216] To the reaction flask were added intermediate M1 (200 mg), triethylamine (0.60 mL, 5 e.q.), and DCM (20 mL) in sequence. Triphosgene (256 mg, 1 e.q.) was added at 0°C, followed by reaction at room temperature for 3 h. Triethylamine (0.24 mL, 2 e.q.) and compound 7-4 (203 mg) were then added, and the reaction continued at room temperature for 3 h. After completion of the reaction, ammonia was added to quench the reaction, and the mixture was extracted with dichloromethane. The resulting organic phase was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM / MeOH = 20:1) to obtain product 7-5 (320 mg, 75.16% yield). ESI-MS m / z: 494.3 [M+H] + .

[0217] Step 6: Synthesis of compound 7-6

[0218] 7-5 (250 mg) and DCM (8 mL) were added to the reaction flask in sequence. mCPBA / m-chloroperbenzoic acid (96 mg, 1.1 eq) was added at 0°C, and the mixture was then transferred to room temperature for 30 min. After the reaction, saturated sodium sulfite solution (20 mL) was added for washing. The aqueous phase was washed twice with DCM, and the combined organic phases were evaporated to dryness under reduced pressure to obtain the crude product 7-6 (250 mg, 96.87% yield). ESI-MS m / z: 510.3 [M+H] + .

[0219] Step 7: Synthesis of compound 7-7

[0220] To a reaction flask were added 7-6 (250 mg), NH2Boc (115 mg, 2.0 eq), PhI(OAc)2 (237 mg, 1.5 eq), MgO (99 mg, 5.0 eq), dimerized rhodium acetate (7 mg, 0.05 eq), and DCM (10 mL) in sequence, followed by reaction at 40°C for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite, and washed with DCM. The filtrate was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM / EA = 14:1) to obtain the target compound 7-7 (200 mg, 65.26% yield). ESI-MS m / z: 569.3 [M+H-56] + .

[0221] Step 7: Synthesis of Compound 7-8

[0222] To the reaction flask were added 7-7 (250 mg), Pd / C / palladium on carbon (85 mg), MeOH (5 mL), and THF (5 mL) in sequence. After H2 substitution, the reaction was stirred at room temperature for 12 h. After completion of the reaction, the reaction solution was filtered through celite and washed with EA. The filtrate was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM / MeOH = 12:1) to obtain the target compound 7-8 (220 mg, 92.44% yield). ESI-MS m / z: 495.2 [M+H-100] + .

[0223] Step 8: Synthesis of compound 7

[0224] To the reaction flask were added 7-8 (220 mg) and DCM / dichloromethane (8 mL), followed by TFA / trifluoroacetic acid (4 mL). The reaction was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure, and the concentrate was purified by preparative chromatography to afford the TFA salt of target compound 7 (28.4 mg, 15.31% yield). 1H NMR(500MHz,DMSO)δ8.02(s,1H),7.86(s,1H),7.84–7.77(m,1H),7.68–7.54(m,3 H),7.45(d,J=2.1Hz,1H),7.30(dd,J=8.3,2.1Hz,1H),7.24(t,J=8.9Hz,2H),6.92 (d,J=8.3Hz,1H),4.88(s,4H),3.91–3.87(m,2H),3.69(br,3H),3.37–3.30(m,1H) ,3.26(t,J=11.1Hz,2H),1.76(dd,J=34.1,11.8Hz,2H),1.60–1.42(m,2H).ESI-MS m / z:495.1[M+H] + .

[0225] Example 10: Synthesis of N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-2-(S-methylsulfonylimino)-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-carboxamide

[0226] Step 1: Synthesis of compound 10-1

[0227] Compound 3-methylthiophene-2-carboxylic acid methyl ester (20.0 g) was dissolved in carbon tetrachloride (60 mL), and NBS (44.5 g) and AIBN (41.1 g) were added sequentially. The mixture was stirred at 80°C for 16.0 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was then purified by column chromatography (PE:EA = 20:1) to obtain compound 10-1 (32.0 g). ESI-MS m / z: 235.1 [M+H] + .

[0228] Step 2: Synthesis of compound 10-2

[0229] Compound 10-1 (32.0 g) was dissolved in methanol (80 mL) and ammonia methanol (80 mL, 7 M) was slowly added dropwise under an ice bath. After completion, the mixture was stirred at room temperature for 2.0 h. After the reaction was complete, the mixture was concentrated and slurried with petroleum ether to obtain crude compound 10-2 (20.0 g), which was directly processed into the next step. ESI-MS m / z: 172.3 [M+H] + .

[0230] Step 3: Synthesis of compound 10-3

[0231] Compound 10-2 (20.0 g) was dissolved in anhydrous methanol (50 mL) and anhydrous ethanol (50 mL), potassium carbonate (8.1 g) was added, and the mixture was stirred at 80°C overnight. After the reaction was complete, the sample was added to silica gel and column chromatography (DCM:MeOH = 8:1) was performed to obtain compound 10-3 (1.5 g). ESI-MS m / z: 380.1 [M+H] + .

[0232] Step 4: Synthesis of compound 10-4

[0233] Compound 10-3 (1.5 g) was dissolved in water (20 mL) and glacial acetic acid (3 mL). The ice bath was cooled to below 0°C, and bromine was slowly added dropwise. The reaction was stirred for 1.0 h. After the reaction was complete, the mixture was quenched with saturated sodium thiosulfate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. Column chromatography (PE:EA = 1:1) afforded compound 10-4 (2.1 g). ESI-MS m / z: 218.2 [M+H] + .

[0234] Step 5: Synthesis of compound 10-5

[0235] Compound 10-4 (2.1 g), benzothiazole methyl sulfide (1.7 g), palladium acetate (0.05 g), Ni(dppe)Cl2 (0.1 g), dppf (0.1 g), dipotassium hydrogen phosphate (3.2 g), and zinc powder (1.5 g) were dissolved in DMA (100 mL) and stirred at 100°C for 6.0 h. After the reaction was complete, the mixture was cooled to room temperature, the solvent was concentrated, the sample was added to silica gel, and column chromatography (DCM:MeOH = 10:1) was performed to obtain compound 10-5 (320 mg). ESI-MS m / z: 186.2 [M+H] + .

[0236] Step 6: Synthesis of compound 10-6

[0237] Compound 10-5 (320 mg), PMBBr (0.5 g), cesium carbonate (1.4 g), and 18-crown ether (0.05 g) were dissolved in acetone (10 mL) and stirred under reflux for 2.5 h. After the reaction was complete, the solvent was concentrated, the sample was added to silica gel, and column chromatography (PE:EA = 1:1) was performed to obtain compound 10-6 (280 mg). ESI-MS m / z: 306.2 [M+H] + .

[0238] Step 7: Synthesis of compound 10-7

[0239] Compound 10-6 (280 mg) was dissolved in THF (10 mL), and borane dimethyl sulfide (10 mL) was added. The mixture was stirred under reflux for 3.0 h. After the reaction was complete, the solvent was concentrated, the sample was added to silica gel, and column chromatography (PE:EA = 1:1) was performed to obtain compound 10-7 (160 mg). ESI-MS m / z: 292.2 [M+H] + .

[0240] Step 8: Synthesis of compound 10-8

[0241] Compound 10-7 (160 mg) and chloroethyl chloroformate (220 mg) were dissolved in DCM (10 mL) and stirred at room temperature overnight. After the reaction was complete, methanol (10 mL) was added and the reaction was stirred at 80°C for 3.0 h. After the reaction was complete, the solvent was dried by rotary evaporation. Column chromatography (DCM:MeOH = 10:1) gave compound 10-8 (60 mg). ESI-MS m / z: 172.4 [M+H] + Step 9: Synthesis of compound 10-9

[0242] Compound 4'-fluoro-4-nitro-[1,1'-biphenyl]-3-amine (50 mg) and TFA (0.2 mL) were dissolved in dichloromethane (10 mL). Triphosgene (60 mg) was added under ice bath and stirred at room temperature for 3.0 h. Compound 10-8 (60 mg) and TFA (0.1 mL) were then added and stirred at room temperature for 3.0 h. After the reaction was complete, ammonia was added to quench the reaction, methanol was added to slurry, the reaction mixture was filtered, rinsed with methanol, the filter cake was collected, and dried to obtain compound 10-9 (40 mg). ESI-MS m / z: 430.3 [M+H] + .

[0243] Step 10: Synthesis of compound 10-10

[0244] Compound 10-9 (40 mg) and m-CPBA (20 mg) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 1.0 h. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. Compound 10-10 (27 mg) was obtained and used directly in the next step. ESI-MS m / z: 446.3 [M+H] + .

[0245] Step 11: Synthesis of Compounds 10-11

[0246] Compound 10-10 (27 mg), NH2Boc (10 mg), rhodium acetate (6 mg), magnesium oxide (10 mg), and iodophenyl diacetic acid (30 mg) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 2.0 h. After the reaction was complete, the solvent was dried. Column chromatography (DCM:MeOH = 20:1) afforded compound 10-11 (31 mg). ESI-MS m / z: 561.1 [M+H] + Step 12: Synthesis of Compounds 10-12

[0247] Compound 10-11 (31 mg) and 10% palladium on carbon (0.02 g) were dissolved in methanol (10 mL), replaced with hydrogen five times, and stirred at room temperature for 3.0 h. After the reaction was complete, the mixture was filtered and dried to give compound 10-12 (17 mg), which was directly used for the next step. ESI-MS m / z: 531.1 [M+H] + .

[0248] Step 13: Synthesis of compound 10

[0249] Compound 10-12 (17 mg) was dissolved in DCM (10 mL), and TFA (2 mL) was slowly added dropwise. The reaction was stirred at room temperature for 1.0 h. After the reaction was complete, the solvent was concentrated, and the concentrate was separated and purified by Pre-HPLC to obtain the target product 10 (12.1 mg). ESI-MS m / z: 431.1 [M+H] +1 H NMR (500MHz, DMSO) δ7.78(s,1H),7.56(s,1H),7.55(d,J=3.4Hz,1H),7.40(d,J=2.1Hz,1H),7.23(s,2H),7.19(s,1 H),6.79(d,J=8.3Hz,1H),6.68(s,1H),5.09(s,2H),4.80(s,2H),4.70(s,1H),4.64(s,2H),3.20(d,J=1.0Hz,3H).

[0250] Example 12: Synthesis of N-(2-amino-5-(pyridin-4-yl)phenyl)-5-(S-methylsulfonylimino)isoindoline-2-carboxamide

[0251] Step 1: Synthesis of compound 12-1

[0252] Compound 5-bromo-2-nitroaniline (1.0 g) was dissolved in 1,4-dioxane (15 mL) and water (5 mL). 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.9 g), tetrakistriphenylphosphine palladium (0.3 g), and cesium carbonate (3.0 g) were added sequentially. The mixture was stirred at 100°C for 8.0 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA = 3:1) to obtain compound 12-1 (0.9 g). ESI-MS m / z: 216.1 [M+H] + .

[0253] Step 2: Synthesis of compound 12-2

[0254] Compound 4'-fluoro-4-nitro-[1,1'-biphenyl]-3-amine (130 mg) and TFA (0.5 mL) were dissolved in dichloromethane (10 mL). Triphosgene (180 mg) was added under ice bath and stirred at room temperature for 3.0 h. Compound 12-1 (100 mg) and TFA (0.2 mL) were then added and stirred at room temperature for 3.0 h. After the reaction was complete, ammonia was added to quench the mixture, methanol was added to slurry, the mixture was filtered, rinsed with methanol, the filter cake was collected, and dried to obtain compound 12-2 (150 mg). ESI-MS m / z: 430.3 [M+H] + Step 3: Synthesis of compound 12-3

[0255] Compound 12-2 (150 mg), ammonium formate (40 mg), and iodophenyl diacetic acid (230 mg) were dissolved in dichloromethane (5 mL) and methanol (10 mL) and stirred at room temperature overnight. After the reaction was complete, the solvent was dried by rotary evaporation. Column chromatography (DCM:MeOH = 10:1) afforded compound 12-3 (70 mg). ESI-MS m / z: 438.1 [M+H] + .

[0256] Step 4: Synthesis of compound 12

[0257] Compound 12-3 (70 mg) and 10% palladium on carbon (0.03 g) were dissolved in methanol (10 mL), replaced with hydrogen five times, and stirred at room temperature for 3.0 h. After the reaction was complete, the concentrate was concentrated, and the concentrate was separated and purified by Pre-HPLC to obtain the target product 12 (23.7 mg). ESI-MS m / z: 408.1 [M+H] +1H NMR (500MHz, DMSO) δ8.50(d,J=6.0Hz,2H),7.93(s,1H),7.89(dd,J=8.0,1.4Hz,1H),7.85(s,1H),7.61–7.55( m,4H),7.45(dd,J=8.4,2.2Hz,1H),6.83(d,J=8.4Hz,1H),5.37(s,2H),4.86(s,4H),4.26(s,1H),3.09(s,3H).

[0258] Example 13: Synthesis of N-(4-amino-[1,1'-biphenyl]-3-yl)-5-(S-methylsulfonylimino)isoindoline-2-carboxamide

[0259] Step 1: Synthesis of compound 13-1

[0260] 5-Bromo-2-nitroaniline (1 g), phenylboronic acid (842 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (337 mg), and potassium carbonate (1.91 g) were dissolved in 1,4-dioxane (15 mL) and water (3 mL). The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 2 h. After completion of the reaction, the mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 13-1 (936 mg).

[0261] Step 2: Synthesis of compound 13-2

[0262] Compound 13-1 (100 mg) and triethylamine (0.32 mL) were dissolved in dichloromethane (5 mL). Triphosgene (138 mg) was added under ice-cooling and the mixture was allowed to react at 25°C for 3 h. 5-(Methylthio)isoindoline (77 mg) and triethylamine (0.13 mL) were then added and the mixture was allowed to react at 25°C for 3 h. After the reaction was complete, ammonia was added to quench the reaction, and the mixture was extracted with dichloromethane, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 13-2 (73 mg). ESI-MS m / z: 406.11 [M+H] + Step 3: Synthesis of compound 13-3

[0263] Compound 13-2 (73 mg), ammonium formate (23 mg), and iodophenyldiacetic acid (145 mg) were dissolved in methanol (5 mL) and dichloromethane (5 mL) and reacted at 50°C for 8 h. After completion of the reaction, the mixture was concentrated and purified by column chromatography (dichloromethane / methanol) to obtain compound 13-3 (44 mg). ESI-MS m / z: 437.28 [M+H] + .

[0264] Step 4: Synthesis of compound 13

[0265] Compound 13-3 (44 mg) was dissolved in methanol (5.00 mL) and tetrahydrofuran (5.00 mL), and 10% palladium on carbon (15 mg) was added. The atmosphere was replaced with hydrogen and the reaction was allowed to proceed at 25°C for 1 h. After completion of the reaction, the mixture was filtered, concentrated, and purified by Pre-HPLC (C18 column, A: 0.05% diethylamine aqueous solution, B: acetonitrile, concentration gradient: 30% B to 80% B, 9 min, flow rate: 18 mL / min, 254 nm) to obtain compound 13 (20.0 mg). ESI-MS m / z: 407.18 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ7.93(s,1H),7.88(dd,J=8.0,1.8Hz,1H),7.82(s,1H),7.59(d,J=8.0Hz,1H),7.56–7.51(m,2H),7.44(d,J =2.2Hz,1H),7.39(t,J=7.8Hz,2H),7.28–7.19(m,2H),6.81(d,J=8.3Hz,1H),5.09(s,2H),4.86(s,4H),4.26(s,1H),3.09(s,3H).

[0266] Example 15: Synthesis of the compound N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-5-(2-hydroxyethylsulfonylimino)isoindoline-2-carboxamide

[0267] Step 1: Synthesis of compound 15-1

[0268] To the reaction flask were added tert-butyl 5-bromoisoindoline-2-carboxylate (1.6 g), methyl 3-mercaptopropionate (0.71 mL), DIEA (1.77 mL), Pd2(dba)3 (0.25 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.31 g), and dioxane (20 mL) in sequence. After N2 substitution, the reaction mixture was transferred to 100°C for 8 h. After completion of the reaction, the reaction solution was cooled to room temperature, filtered through celite, and washed with EA. The filtrate was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (PE / EA = 3:1) to obtain the target compound 15-1 (1.7 g, 93.89% yield). ESI-MS m / z: 238.2 [M+H-100] + .

[0269] Step 2: Synthesis of compound 15-2

[0270] To a reaction flask, 15-1 (550 mg), THF (20 mL), and pyridine were added sequentially. Potassium tert-butoxide (366 mg, 2 e.q.) was added at room temperature, followed by reaction at room temperature for 0.5 h. After the first reaction was complete as determined by LCMS, 2-bromoethanol (245 mg, 1.2 eq) was added at room temperature, and the reaction continued at room temperature. After the reaction was complete as determined by LCMS, ethyl acetate (30 mL) and water (30 mL) were added for extraction. The resulting organic phase was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (PE / EA = 1:1) to afford the target compound 15-2 (243 mg, 50.47% yield). ESI-MS m / z: 196.2 [M+H-100] + .

[0271] Step 3: Synthesis of compound 15-3

[0272] To the reaction flask, 15-2 (210 mg) and DCM / dichloromethane (6 mL) were added sequentially, followed by TFA / trifluoroacetic acid (3 mL). The reaction was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure and concentrated to afford crude compound 15-3 (130 mg, 93.64% yield). ESI-MS m / z: 196.1 [M+H] + .

[0273] Step 4: Synthesis of compound 15-4

[0274] M1 (166 mg), triethylamine (0.50 mL, 5 e.q.), and DCM (15 mL) were added to the reaction flask in sequence. Triphosgene (256 mg, 1 e.q.) was added at 0°C, followed by reaction at room temperature for 3 h. Triethylamine (0.20 mL, 2 e.q.) and compound 15-3 (130 mg) were then added, and the reaction continued at room temperature for 3 h. After the reaction was completed, ammonia was added to quench the reaction, and the mixture was extracted with dichloromethane. The resulting organic phase was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM / MeOH = 12:1) to obtain product 15-4 (238 mg, 78.84% yield). ESI-MS m / z: 454.3 [M+H] + .

[0275] Step 5: Synthesis of compound 15-5

[0276] To the reaction flask were added 15-4 (120 mg), ammonium formate (34 mg, 2.0 eq), PhI(OAc)2 (215 mg, 2.5 eq), DCM (80 mL), and MeOH (8 mL), followed by reaction at room temperature for 1 h. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM / MeOH = 12:1) to obtain the target compound 15-5 (100 mg, 77.95% yield). ESI-MS m / z: 485.1 [M+H] + .

[0277] Step 6: Synthesis of compound 15

[0278] To the reaction flask were added 15-5 (100 mg), Pd / C / palladium on carbon (22 mg), MeOH (5 mL), and THF (5 mL) in sequence. After H2 substitution, the reaction was stirred at room temperature for 12 h. After completion of the reaction, the reaction solution was filtered through celite and washed with EA. The filtrate was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM / MeOH = 11:1) to obtain the TFA salt of the target compound 15 (35.8 mg, 38.16% yield). ESI-MS m / z: 455.1 [M+H] + . 1 H NMR (500MHz, DMSO) δ8.27(s,1H),8.01(s,1H),7.94(d,J=7.8Hz,1H),7.68(d,J=8.1Hz,1H),7.62(dd,J=8.4,5.5Hz,2H),7.51(s,1H), 7.38(d,J=8.2Hz,1H),7.27(t,J=8.8Hz,2H),7.08(d,J=8.2Hz,1H),5.33(br,4H),4.90(s,4H),3.88–3.70(m,2H),3.69–3.54(m,2H).

[0279] Example 25: Synthesis of N-(2-amino-5-(thiazol-5-yl)phenyl)-5-(S-methylsulfonylimino)isoindoline-2-carboxamide

[0280] Step 1: Synthesis of compound 25-1

[0281] 5-Bromo-2-nitroaniline (1 g), pinacol diboron (1.76 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (380 mg), and potassium acetate (1.36 g) were dissolved in 1,4-dioxane (10 mL), replaced with nitrogen, and reacted at 100°C for 2 h. After completion of the reaction, the mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 25-1 (1.1 g). ESI-MS m / z: 265.22 [M+H] + .

[0282] Step 2: Synthesis of compound 25-2

[0283] Compound 25-1 (1.1 g), 5-bromothiazole (888 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (305 mg), and potassium carbonate (1.72 g) were dissolved in 1,4-dioxane (15 mL) and water (3 mL). The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 2 h. After completion of the reaction, the mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 25-2 (878 mg). ESI-MS m / z: 222.04 [M+H] + .

[0284] Step 3: Synthesis of compound 25-3

[0285] Compound 25-2 (100 mg) and triethylamine (0.31 mL) were dissolved in dichloromethane (5 mL). Triphosgene (134 mg) was added under ice-cooling and the mixture was allowed to react at 25°C for 3 h. 5-(Methylthio)isoindoline (75 mg) and triethylamine (0.13 mL) were then added and the mixture was allowed to react at 25°C for 3 h. After completion of the reaction, the mixture was quenched with ammonia, extracted with dichloromethane, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate) to afford compound 25-3 (77 mg). ESI-MS m / z: 413.26 [M+H] + Step 4: Synthesis of compound 25-4

[0286] Compound 25-3 (77 mg), ammonium formate (24 mg), and iodophenyl diacetic acid (150 mg) were dissolved in methanol (5 mL) and dichloromethane (5 mL) and reacted at 25°C for 16 h. After completion of the reaction, the mixture was concentrated and purified by column chromatography (dichloromethane / methanol) to obtain compound 25-4 (9 mg). ESI-MS m / z: 444.20 [M+H] + .

[0287] Step 5: Synthesis of compound 25

[0288] Compound 25-4 (9 mg) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), and 10% palladium on carbon (5 mg) was added. The atmosphere was replaced with hydrogen and the mixture was allowed to react at 25°C for 1 h. After completion of the reaction, the mixture was filtered, concentrated, and purified by thin-layer chromatography on silica gel (dichloromethane / methanol) to obtain compound 25 (3.29 mg). ESI-MS m / z: 414.22 [M+H] + .

[0289] Example 28: Synthesis of the compound N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-5-(2-methoxyethylsulfonylimino)isoindoline-2-carboxamide

[0290] Step 1: Synthesis of compound 28-1

[0291] To the reaction flask, 15 (100 mg), triethylamine (0.12 mL, 4 e.q.), and DCM (2 mL) were added. Methanesulfonyl chloride (27 mg, 1.05 eq) was added at 0°C, and the mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (PE / EA = 9:1) to obtain product 28-1 (60 mg, 58.33% yield). ESI-MS m / z: 467.1 [M+H] + .

[0292] Step 2: Synthesis of compound 28-2

[0293] Compound 28-1 (60 mg), potassium carbonate (21 mg, 1.2 eq), and methanol (1 mL) were added sequentially to the reaction flask and allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM / MeOH = 13:1) to obtain the target compound 28-2 (48 mg, 77.75% yield). ESI-MS m / z: 499.2 [M+H] + .

[0294] Step 3: Synthesis of compound 28

[0295] To a reaction flask were added 28-2 (48 mg), Pd / C / palladium on carbon (10 mg), MeOH (3 mL), and ethyl acetate (3 mL) in sequence. After H2 substitution, the reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was filtered through celite and washed with EA. The filtrate was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM / MeOH = 10:1) to afford the target compound 28 (18.9 mg, 41.88% yield). 1H NMR (500MHz, DMSO) δ7.89(s,1H),7.85(d,J=8.0Hz,1H),7.81(s,1H),7.65–7.49(m,3H),7.41(d,J=1.3Hz,1H),7.21(t,J=8.9Hz, 3H),6.80(d,J=8.3Hz,1H),5.10(s,2H),4.86(s,4H),4.35(s,1H),3.66–3.54(m,2H),3.43(t,J=6.2Hz,2H),3.10(s,3H).ESI-MS m / z:469.3[M+H] + .

[0296] Example 36: Synthesis of N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-7-(S-methylsulfonylimino)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[0297] Step 1: Synthesis of compound 36-1

[0298] Dissolve tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.0 g) in dry THF (45 mL), cool to -78°C, and add n-butyl lithium (6 mL) dropwise. After addition, warm to -10°C and stir for 1.0 h. Cool again to -78°C, slowly add a solution of MeSSMe (0.9 mL) in THF (10 mL), and stir at room temperature overnight. Cool to approximately 0°C in an ice bath, dissolve in acetone, add concentrated hydrochloric acid (8 mL), and continue stirring at room temperature overnight. Concentrate, dilute with water, extract with dichloromethane, adjust the aqueous phase to alkaline with 6N NaOH, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, filter, spin dry, and column chromatography (PE:EA=50:1) to obtain compound 36-1 (380 mg). ESI-MS m / z: 180.1 [M+H] + .

[0299] Step 2: Synthesis of compound 36-2

[0300] Compound 4'-fluoro-4-nitro-[1,1'-biphenyl]-3-amine (550 mg) and TFA (1.5 mL) were dissolved in dichloromethane (20 mL). Triphosgene (280 mg) was added under ice bath and stirred at room temperature for 3.0 h. Compound 36-1 (380 mg) and TFA (0.3 mL) were then added and stirred at room temperature for 3.0 h. After the reaction was complete, ammonia was added to quench the reaction, methanol was added to slurry, the reaction mixture was filtered, rinsed with methanol, the filter cake was collected and dried to obtain compound 36-2 (180 mg). ESI-MS m / z: 408.3 [M+H] +Step 3: Synthesis of compound 36-3

[0301] Compound 36-2 (180 mg), ammonium formate (45 mg), and iodophenyldiacetic acid (200 mg) were dissolved in dichloromethane (5 mL) and methanol (10 mL) and stirred at room temperature overnight. After the reaction was complete, the solvent was dried. Column chromatography (DCM:MeOH = 10:1) afforded compound 36-3 (60 mg). ESI-MS m / z: 469.1 [M+H] + .

[0302] Step 4: Synthesis of compound 36

[0303] Compound 36-3 (60 mg) and 10% palladium on carbon (0.03 g) were dissolved in methanol (10 mL), replaced with hydrogen five times, and stirred at room temperature for 3.0 h. After the reaction was complete, the concentrate was concentrated, and the concentrate was separated and purified by Pre-HPLC to obtain the target product 36 (11.2 mg). ESI-MS m / z: 439.1 [M+H] +1 H NMR (500MHz, DMSO) δ8.03(s,1H),7.74(d,J=8.5Hz,2H),7.57–7.52(m,2H),7.43(d,J=7.9Hz,1H),7.33(d,J=2.1Hz,1H),7.22–7.1 7(m,3H),6.79(d,J=8.3Hz,1H),4.98(s,2H),4.75(s,2H),4.17(s,1H),3.74(t,J=5.9Hz,2H),3.05(s,3H),2.96(t,J=5.7Hz,2H).

[0304] Example 37: Synthesis of N-(4-amino-4'-chloro-[1,1'-biphenyl]-3-yl)-5-(S-methylsulfonylimino)isoindoline-2-carboxamide

[0305] Step 1: Synthesis of compound 37-1

[0306] 5-Bromo-2-nitroaniline (1.0 g) was dissolved in 1,4-dioxane (15 mL) and water (5 mL). (4-Chlorophenyl)boronic acid (0.7 g), tetrakistriphenylphosphine palladium (0.27 g), and sodium carbonate (0.1 g) were added sequentially. The mixture was stirred at 100°C for 8.0 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was then purified by column chromatography (PE:EA = 6:1) to afford compound 37-1 (1.1 g). ESI-MS m / z: 249.1 [M+H] + Step 2: Synthesis of compound 37-2

[0307] Compound 4'-fluoro-4-nitro-[1,1'-biphenyl]-3-amine (150 mg) and TFA (0.5 mL) were dissolved in dichloromethane (10 mL). Triphosgene (180 mg) was added under ice bath and stirred at room temperature for 3.0 h. Compound 37-1 (100 mg) and TFA (0.2 mL) were then added and stirred at room temperature for 3.0 h. After the reaction was complete, ammonia was added to quench the mixture, methanol was added to slurry, the mixture was filtered, rinsed with methanol, the filter cake was collected, and dried to obtain compound 37-2 (130 mg). ESI-MS m / z: 440.3 [M+H] + Step 3: Synthesis of compound 37-3

[0308] Compound 37-2 (130 mg), ammonium formate (30 mg), and iodophenyldiacetic acid (140 mg) were dissolved in dichloromethane (5 mL) and methanol (10 mL) and stirred at room temperature overnight. After the reaction was complete, the solvent was dried by rotary evaporation. Column chromatography (DCM:MeOH = 10:1) afforded compound 37-3 (60 mg). ESI-MS m / z: 471.1 [M+H] + .

[0309] Step 4: Synthesis of compound 37

[0310] Compound 37-3 (60 mg) and 10% palladium on carbon (0.03 g) were dissolved in methanol (10 mL), replaced with hydrogen five times, and stirred at room temperature for 3.0 h. After the reaction was complete, the concentrate was concentrated, and the concentrate was separated and purified by Pre-HPLC to obtain the target product 37 (19.0 mg). ESI-MS m / z: 441.1 [M+H] +1 H NMR (500MHz, DMSO) δ7.93(s,1H),7.89(d,J=8.2Hz,1H),7.82(s,1H),7.58(dd,J=12.9,8.3Hz,3H),7.43(d,J= 8.7Hz,3H),7.27(d,J=8.2Hz,1H),6.81(d,J=8.2Hz,1H),5.16(s,2H),4.86(s,4H),4.26(s,1H),3.09(s,3H).

[0311] Example 53: Synthesis of the compound N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-5-(2-methoxy-N-(methylsulfonyl)ethylsulfonylimino)isoindoline-2-carboxamide

[0312] Step 1: Synthesis of compound 53-1

[0313] Compound 15 (100 mg), triethylamine (0.12 mL, 4 e.q.), and DCM (2 mL) were added to the reaction flask. Methanesulfonyl chloride (27 mg, 1.05 eq) was added at 0°C, and the mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (PE / EA = 9:1) to obtain product 53-1 (30 mg, 26.69% yield). ESI-MS m / z: 545.1 [M+H] + .

[0314] Step 2: Synthesis of compound 53-2

[0315] Compound 53-1 (30 mg), potassium carbonate (10 mg, 1.2 eq), and methanol (1 mL) were added sequentially to the reaction flask and allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM / MeOH = 13:1) to obtain the target compound 53-2 (25 mg, 78.70% yield). ESI-MS m / z: 577.2 [M+H] + .

[0316] Step 3: Synthesis of compound 53

[0317] To a reaction flask were added 53-2 (25 mg), Pd / C / palladium on carbon (6 mg), MeOH (2 mL), and ethyl acetate (2 mL) in sequence. After H2 substitution, the reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was filtered through celite and washed with EA. The filtrate was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM / MeOH = 10:1) to afford the title compound 53 (8.1 mg, 34.20% yield). 1 H NMR (500MHz, DMSO) δ7.99(s,1H),7.93(d,J=8.0Hz,1H),7.83(s,1H),7.69(d,J=8.2Hz,1H),7.56(dd,J=8.7,5.5Hz,2H),7.40(d,J=2.0Hz,1H),7 .27–7.16(m,3H),6.80(d,J=8.3Hz,1H),5.10(s,2H),4.89(d,J=6.6Hz, 4H), 4.06 (t, J = 5.6Hz, 2H), 3.76–3.59 (m, 2H), 3.07 (s, 3H), 3.05 (s, 3H). ESI-MS m / z:547.3[M+H] + .

[0318] Other compounds of the present invention can be prepared by referring to the methods of the above examples.

[0319] Comparative compound D1:

[0320] The specific synthesis method of the comparative compound TNG260 refers to patent WO2023102162.

[0321] Biological experiments

[0322] Biological Example 1 In vitro HDAC1 enzyme activity test

[0323] This test uses a fluorescent enzyme substrate to detect the deacetylation activity of recombinant HDAC1 protein in vitro. Purified HDAC1 is incubated with a fluorescent substrate (containing an acetylated lysine side chain) to deacetylate the substrate. A chromogenic reagent is then used to generate a fluorescent substance, and the fluorescent signal is read to evaluate the enzymatic activity of HDAC1.

[0324] [Experimental Materials]

[0325] Fluorescent HDAC1 activity detection kit (Catalog#: 50061) was purchased from BPS Bioscience.

[0326] [Experimental steps]

[0327] A protease mix was prepared by mixing 5 μL of HDAC1 recombinant protease (7 ng / reaction), 5 μL of BSA (1 mg / mL), and 30 μL of HDAC Assay Buffer. The mixture was then added to a 96-well reaction plate. A compound solution with a gradient concentration was prepared using HDAC Assay Buffer. 5 μL of compound solution was added to each well of the protease mix, resulting in final compound concentrations of 20,000, 6,666.7, 2,222.2, 740.7, 246.9, 82.3, 27.4, 9.1, 3.0, 1.0, and 0 nM (final DMSO concentration was 0.05%). A negative control group without enzyme was also established under the same conditions. After incubating the 96-well reaction plate on a shaker at 25°C for 3 hours, 5 μL of 200 μM HDAC substrate 3 was added and incubated on a shaker at 37°C for an additional 30 minutes. The reaction was terminated by adding 50 μL of HDAC developer (2×) and incubating on a shaker at 37°C for 15 minutes to generate fluorescent material. Finally, the fluorescence signal was read using Envison: ex = 360 nm, em = 450 nm; inhibition rate % = (maximum value - compound group) / (maximum value - minimum value) * 100%, "maximum value" refers to the DMSO group, and "minimum value" refers to the negative control group without enzyme. Nonlinear regression fitting of the compound's IC was performed using GraphPad. 50 value.

[0328] The data of the HDAC1 inhibitory activity of the example compounds are shown in Table 1, where "A" represents "IC 50≤10nM, "B" represents "10nM <IC 50 ≤100nM, "C" represents 100nM <IC 50 ≤500nM, “D” represents IC 50 >500nM. IC of HDAC1 inhibition by example compounds 50 See Table 1 for data.

[0329] Biological Example 2 In vitro HDAC3 enzyme activity test

[0330] This test uses a fluorescent enzyme substrate to detect the deacetylation activity of recombinant HDAC3 protein in vitro. Purified HDAC3 is incubated with a fluorescent substrate (containing an acetylated lysine side chain) to deacetylate the substrate. A chromogenic reagent is then used to generate a fluorescent substance, and the fluorescent signal is read to evaluate HDAC3 enzymatic activity.

[0331] [Experimental Materials]

[0332] HDAC3 recombinant protein (Catalog#: 50003) was purchased from BPS Bioscience;

[0333] Fluorescent HDAC3 activity detection kit (Enzo / BML-AK530-0001) was purchased from Enzo Life Sciences.

[0334] [Experimental steps]

[0335] 0.5 μL HDAC3 recombinant protease (2.4 ng / reaction), 0.5 μL BSA (10 mg / mL) and 19 μL HDAC Assay Buffer were mixed to prepare a protease mixture and added to a 96-well reaction plate. A gradient concentration of compound solution was prepared using HDAC Assay Buffer, and 5 μL of compound solution was added to the protease mixture in each well. The final concentrations of the compound were 100000, 33333.3, 11111.1, 3703.7, 1234.6, 411.5, 137.2, 45.7, 15.2, 5.1, 1.7, 0 nM (the final DMSO concentration was 2%). A negative control group without enzyme was also set up under the same conditions. After incubating the 96-well reaction plate in a shaker at 22°C for 3 hours, 25 μL of 16 μM Fluor dextran was added. -Green substrate, and continue incubation at 22℃ on a shaker for 1h; by adding 50μL Fluor de Developer (1×), incubate on a shaker at 25°C for 10 min to generate fluorescent material and terminate the reaction. Finally, use Envison to read the fluorescence signal: ex = 480nm, em = 530nm; inhibition rate % = (maximum value - compound group) / (maximum value - minimum value) * 100%, "maximum value" refers to the DMSO group, and "minimum value" refers to the enzyme-free negative control group. Nonlinear regression fitting of the compound IC was performed using GraphPad. 50 value.

[0336] The data on the HDAC3 inhibitory activity of the example compounds are shown in Table 1.

[0337] Table 1

[0338] This shows that the compounds of the present invention have excellent HDAC1 enzyme inhibitory activity and HDAC1 / 3 selectivity.

[0339] Although the present invention has been fully described through its embodiments, it is noteworthy that various changes and modifications are obvious to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims of the present invention.

Claims

1. A compound represented by general formula (I), or a stereoisomer, tautomer, deuterated form, or pharmaceutically acceptable salt thereof: in, The ring A is selected from C 6-14 Aryl or 5-14 membered heteroaryl, the C 6-14 The aryl or 5-14 membered heteroaryl may be optionally further substituted with one or more R a or two R on the same atom a Formation C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; The L is absent, -CH2-, -(CH2)2- or C 3-8 Cycloalkyl; wherein said -CH2-, -(CH2)2-, C 3- 8 Cycloalkyl may be further optionally substituted with one or more R a replaced by; The R1 is selected from H, hydroxyl, amino, cyano, halogen, -C(=O)R c 、-C(=O)OR c 、C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl SO2-, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl), the R c H or C 1-6 Alkyl; the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl) is optionally further substituted with one or more R a replaced by; Said R8 is selected from hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1- 6-alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C0-3 alkylene-(5-14 membered heteroaryl) may be further optionally substituted by one or more R a replaced by; Alternatively, the R1 and R8 together with the nitrogen and sulfur to which they are attached form a 4-7 membered heterocyclic group, which may be further optionally replaced by one or more R a replaced by; Said R2 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Said R3 is selected from amino or hydroxyl; The R4, R5, and R7 are each independently selected from H, hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; The R6 is selected from C 6-14 Aryl or 5-14 membered heteroaryl, the C 6-14 The aryl or 5-14 membered heteroaryl may be optionally further substituted with one or more R a replaced by; The m is selected from 1 or 2; Said n is selected from 1 or 2; The R a are independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-S(=O)R b 、-C 0-3 Alkylene-S(=O)2R b 、-C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-S(R b )5. -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)OR b 、-C 0-3 Alkylene-C(=O)N(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace; Each R b are independently H, hydroxy, amino, halogen, hydroxy, cyano, oxo, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 1- 6 alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Substituted with a haloalkyl group.

2. The compound of general formula (I) according to claim 1, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, The ring A is selected from C 6-14 Aryl or 5-14 membered heteroaryl, the C 6-14 The aryl or 5-14 membered heteroaryl may be optionally further substituted with one or more R a or two R on the same atom a Formation C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 Cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; Said L is absent, -CH2- or -(CH2)2-; The R1 is selected from H, hydroxyl, amino, cyano, halogen, -C(=O)R c 、-C(=O)OR c 、C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl), the R c H or C 1-6 Alkyl; the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl) is optionally further substituted with one or more R a replaced by; Said R8 is selected from hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6- 14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl) may be optionally further substituted with one or more R a replaced by; Alternatively, said R1 and R8 together with the nitrogen and sulfur to which they are attached form a 4-7 membered heterocyclic group having 0-2 heteroatoms selected from O, S and N, said 4-7 membered heterocyclic group being optionally further substituted by one or more R a replaced by; R2 is selected from H or C 1-6 alkyl; Said R3 is selected from amino or hydroxyl; The R4, R5, and R7 are each independently selected from H, hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 alkoxy; The R6 is selected from C 6-14 Aryl or 5-14 membered heteroaryl, the C 6-14 The aryl or 5-14 membered heteroaryl may be optionally further substituted with one or more R a replaced by; The m is selected from 1 or 2; Said n is selected from 1 or 2; The R a are independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-S(=O)R b 、-C 0-3 Alkylene-S(=O)2R b 、-C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-S(R b )5. -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)OR b 、-C 0-3 Alkylene-C(=O)N(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace; Each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3- 14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1- 6 haloalkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C 1-6 Alkyl or C 1-6 Substituted with a haloalkyl group.

3. The compound of general formula (I) according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives or a pharmaceutically acceptable salt, characterized in that The ring A is selected from phenyl or 5-6 membered heteroaryl, and the phenyl or 5-6 membered heteroaryl may be further optionally substituted with one or more R a or two R on the same atom a Formation C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace.

4. The compound of general formula (I) according to claim 2, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: The ring A is a phenyl group, which may be further optionally substituted with one or more R a substituted, the R a Preferably, H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy.

5. The compound of general formula (I) according to claim 2, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: The ring A is selected from described Optionally further represented by one or more R a substituted, the R a Preferably, H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy.

6. The compound of general formula (I) according to claim 1 or 2, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, which is a compound of general formula (IA), in, R1, R2, R3, R4, R5, R6, R7, R8, R a The definitions of m, n, and L are as defined in any one of claims 1-2, and t is selected from 0, 1 or 2.

7. The compound of general formula (I) according to claim 1 or 2, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, which is a compound of general formula (IB), in, R1, R2, R3, R4, R5, R6, R7, R8, R a The definitions of m, n, and L are as defined in any one of claims 1-2, and t is selected from 0, 1 or 2.

8. The compound of general formula (I) according to claim 1 or 2, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, which is a compound of general formula (IC), in, R1, R2, R3, R4, R5, R6, R7, R8, R a The definitions of m, n, and L are as defined in any one of claims 1-2, and t is selected from 0, 1 or 2.

9. The compound of general formula (I) according to claim 1 or 2, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, which is a compound of general formula (ID), in, R1, R2, R3, R4, R5, R6, R7, R8, R a The definitions of m, n, and L are as defined in any one of claims 1-2, and t is selected from 0, 1 or 2.

10. The compound of general formula (I) according to claim 1 or 2, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, which is a compound of general formula (IE), in, R1, R2, R3, R4, R5, R6, R7, R8, R a The definitions of m, n, and L are as defined in any one of claims 1-2, and t is selected from 0, 1 or 2.

11. The compound of general formula (I) according to any one of claims 1 to 10, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, characterized in that The R1 is selected from H, cyano, -C(=O)R c 、-C(=O)OR c 、C 1- 6 alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl), the R c H or C 1-6 Alkyl; the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-(5-14 membered heteroaryl) is optionally further substituted with one or more R a replaced.

12. The compound of general formula (I) according to any one of claims 1 to 11, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, characterized in that Said R8 is selected from hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkoxy, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclyl) is optionally further substituted with one or more R a replaced.

13. The compound of general formula (I) according to any one of claims 1 to 12, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that The R1 and R8 together with the nitrogen and sulfur to which they are attached form a 4-7 membered heterocyclic group having 0-2 heteroatoms selected from O, S and N, and the 4-7 membered heterocyclic group may be optionally further replaced by one or more R a replaced.

14. The compound of general formula (I) according to any one of claims 1 to 13, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, characterized in that The R2 is selected from H.

15. The compound of general formula (I) according to any one of claims 1 to 14, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that The R3 is selected from amino group.

16. The compound of general formula (I) according to any one of claims 1 to 15, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, characterized in that The R3 is selected from hydroxyl.

17. The compound of general formula (I) according to any one of claims 1 to 16, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, characterized in that R4, R5, R7 are each independently selected from H, halogen or C 1-6 alkyl.

18. The compound of general formula (I) according to any one of claims 1 to 17, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, characterized in that The R6 is selected from phenyl or 5-6 membered heteroaryl, and the phenyl or 5-6 membered heteroaryl may be further optionally replaced by one or more R a replaced.

19. The compound of general formula (I) according to claim 18, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that The 5-6 membered heteroaryl group is described Optionally further represented by one or more R a replaced.

20. The compound of general formula (I) according to any one of claims 1 to 19, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that The R6 is selected from 21. The compound of general formula (I) according to any one of claims 1 to 20, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that The compound represented by the general formula (I) is selected from the following compounds:

22. A pharmaceutical composition, characterized in that The pharmaceutical composition contains a therapeutically effective amount of the compound according to any one of claims 1 to 21, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof.

23. Use of the compound according to any one of claims 1 to 21, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 22 in the preparation of a medicament.

24. The use according to claim 23, characterized in that The application in preparing medicines is application in preparing medicines for treating and / or preventing diseases mediated by histone deacetylase (HDAC).

25. The use according to claim 24, characterized in that The disease is selected from the group consisting of glioma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., urothelial bladder carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, mucinous fibrosarcoma, cholangiosarcoma, brain cancer, stomach cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, multiple myeloma, cervical cancer, rhabdomyosarcoma, small cell lung cancer, multiform lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, lichenoid keratosis, synovial sarcoma, skin cancer, testicular cancer, pleural cancer, and colorectal cancer or sarcoma.

26. A method for treating and / or preventing a disease, characterized in that: The method comprises administering to a subject a therapeutically effective amount of the compound according to any one of claims 1 to 21 or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22.

27. The method according to claim 26, characterized in that The disease to be treated and / or prevented is a disease mediated by histone deacetylase (HDAC), and the disease is selected from glioma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., urothelial bladder carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBC L), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, as well as cancers of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, multiple myeloma, cervical cancer, rhabdomyosarcoma, small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, lichenoid keratosis, synovial sarcoma, skin cancer, testicular cancer, pleural cancer, and colorectal cancer or sarcoma.

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