HDAC inhibitors, compositions and uses thereof

Abstract

The invention belongs to the field of medical chemistry, and particularly discloses an HDAC (histone deacetylase) inhibitor containing a sulfinyl iminobenzamide structure, and the HDAC inhibitor is a compound as shown in a general formula (I) or a pharmaceutically acceptable salt thereof. The invention also discloses a pharmaceutical composition containing the HDAC inhibitor, and the HDAC inhibitor is used for treating cancers and diseases related to neurodegeneration. The HDAC inhibitor prepared by the preparation method disclosed by the invention has surprisingly better HDAC1 enzyme inhibition activity and excellent HDAC1 / 3 selectivity, and has better enzyme inhibition activity on a CoREST compound. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to an HDAC inhibitor or a pharmaceutically acceptable salt thereof, a composition and use thereof. Background Art

[0002] HDAC (Histone Deacetylase), full name histone deacetylase, is an important enzyme in the process of histone modification. HDAC can remove the acetyl group on the lysine residue of histone, change the charge to make the chromosome structure more compact, thereby inhibiting the transcriptional expression of genes. Based on the homology of yeast proteins, HDACs can divide the 18 HDACs subtypes currently found in the human body into four categories. Among all HDACs, class I HDACs (HDAC1-3 and 8) play an important role in activating potential tumorigenesis, disease-causing oncogenes, and treatment resistance. Recent studies have shown that HDACs 1-3 are essential for the expression of oncogenes regulated by super enhancers in breast cancer and other cancers.

[0003] At present, there are 5 HDAC inhibitors approved for marketing worldwide. Vorinostat, romidepsin, belinostat, and panobinostat are approved for marketing by the US FDA for the clinical treatment of peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and multiple myeloma; cedabendine (trade name: Epsom) is approved for marketing by my country's NMPA for peripheral T-cell lymphoma and breast cancer. However, the existing HDAC inhibitors have limited clinical application due to their toxicity, which limits adequate exposure in solid tumors. Existing data and information show that HDAC3, as an essential gene, is the main driver of bone marrow toxicity caused by HDAC inhibitors, and these inhibitors target multiple isomers.

[0004] Among them, except for Chidamide, which is a selective inhibitor of HDAC class I and HDAC10 subtype, the other four are HDAC pan-inhibitors. However, the currently approved HDAC therapies are still unclear and are only specific to a few HDAC subtypes. Due to their broad inhibitory properties, they have disadvantages such as poor effects on solid tumors, limited efficacy, drug resistance and toxicity, which increase the possibility of adverse reactions. Therefore, the market urgently needs HDAC inhibitors with higher selectivity to treat diseases or conditions.

[0005] CoREST (also known as RCOR1) belongs to the corepressor family of proteins. It plays an important role in gene regulation. CoREST can interact with transcription factors and histone modification enzyme complexes to regulate gene transcription. CoREST was originally discovered to form a complex with HDAC1 and HDAC2 (histone deacetylase 1 and 2), which can deacetylate histones, leading to the formation of a tight chromatin structure and gene silencing. This means that CoREST is involved in chromatin remodeling and gene transcriptional repression. Cancer cells usually express high levels of REST, resulting in the repression of genes related to cell growth and proliferation. CoREST inhibitors can block the interaction between REST and CoREST, thereby activating these genes and causing cancer cell death. It can be seen that CoREST is a potential target for selective cancer treatment.

[0006] The uniqueness of the CoREST complex lies in its dual role as a deacetylase subunit (HDAC1 or 2) and a demethylase subunit (LSD1 / KDAM1A). One of the other three RCOR proteins (RCOR 1, 2 and 3, also known as CoREST1, 2 and 3) serves as a scaffold that directly binds to HDAC1 / 2 and LSD1. These three types of proteins are the core subunits of the CoREST complex. They can work synergistically through deacetylase and demethylase activities to achieve effective histone deacetylation and demethylation in chromatin, thereby inhibiting cancer cell proliferation, impairing tumor growth, and further improving the selectivity of the drug.

[0007] The sulfur functional group in sulfenyl imine compounds has excellent pharmacological properties, such as excellent metabolic stability, and can interact with hydrogen bonds as donors and acceptors. The substituents of the two carbon atoms in the structure of this type of compound are not necessarily the same, and the introduction of nitrogen atoms forms a chiral asymmetric structure in the tetrahedron, making the structure of sulfenyl imine compounds diverse. In general, the structure and configuration of sulfenyl imine compounds are relatively stable and do not require special treatment. Compounds in which the nitrogen atom is not replaced in sulfenyl imine can be phosphorylated in situ. The alkalinity of the nitrogen atom itself can also bind and coordinate with metal ions, and can also form salts with inorganic acids. The hydrogen bond acceptor of sulfenyl imines is a heteroatom bound to the sulfur atom. Free sulfenyl imine can act as both a hydrogen acceptor and a hydrogen bond donor. NMR results show that the electron-withdrawing ability of sulfone compounds is not as good as that of sulfenyl imine compounds, and sulfenyl imines with lower molecular weight are easily soluble in water and alcohol solvents. The special chemical properties of sulfenyl imine have aroused great interest among researchers.

[0008] However, to date, there are few reports on HDAC inhibitors discovered based on the sulfonyliminobenzamide core, which have strong application prospects. Summary of the invention SUMMARY OF THE INVENTION

[0010] In view of the shortcomings of the prior art, the present invention aims to provide a HDAC inhibitor based on a sulfinyl iminobenzamide core with high activity, low side effects and good selectivity, a composition and its use. The compound provided by the present invention has a good inhibitory effect on HDAC.

[0011] The present invention solves the above technical problems through the following technical solutions.

[0012] In one aspect, the present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof:

[0013]

[0014] Among them, R 1 , R 7 Each independently selected from C 1 -C 6 Alkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, halogen, 6-10 membered aryl;

[0015] A is selected from the group consisting of an optionally substituted 6-10 membered aryl group, a 5-10 membered heteroaryl group, wherein the substituent is selected from the group consisting of halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkyl, amino;

[0016] R 2 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, C 3 -C 6 Cycloalkyl, -OR a 、-C(O)R b , containing 1-3 C selected from N, O, S 3 -C 10 Heterocycloalkyl, wherein 6-10 membered aryl, 5-10 membered heteroaryl, C 3 -C 6 Cycloalkyl, -C(O)R b , containing 1-3 C selected from N, O, S 3 -C 10 The heterocycloalkyl group is optionally substituted with one or more R 8 Substituent substitution;

[0017] R 8Selected from: deuterium, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, amino, cyano, -C(O)CH 3 、-C(O)CHCH 2 、-C(O)NH 2 , C 1 -C 6 Hydroxyalkyl, -OR c ;

[0018] R a , R c Each is selected from 6-10 membered aryl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl;

[0019] R b is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic group, containing 1-3 C selected from N, O, S 3 -C 10 Heterocycloalkyl;

[0020] R 3 , R 4 , R 5 are each independently selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Haloalkyl, halogen;

[0021] R 6 Selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, halogen.

[0022] As a preferred technical solution, A is a 6-membered aryl group or a 6-membered heteroaryl group, preferably a benzene ring, pyridine, pyrimidine, or pyridazine, and more preferably above Connect the N on the left, below Connect the carbonyl group on the right.

[0023] As a preferred technical solution, the R 1 , R 7 Each is independently selected from methyl, cyclopropyl, phenyl, cyclobutyl, cyclohexyl, cyclopentyl, isopropyl, ethyl, -CD 3 , -CHF 2 、-CH 2 F, -CF 3 .

[0024] As a preferred technical solution, the R 3 is selected from hydrogen, fluorine, chlorine, methyl, difluoromethyl, trideuterated methyl; said R 4 is selected from hydrogen, fluorine, chlorine, methyl, difluoromethyl, trideuterated methyl; said R 5 is selected from hydrogen, fluorine, chlorine, methyl, difluoromethyl, trideuterated methyl; said R 6 Selected from hydrogen, fluorine, chlorine, methyl, trifluoromethyl, trideuterated methyl.

[0025] As a preferred technical solution, the R 2 is selected from a benzene ring, a 5-membered, 6-membered or 9-membered heteroaryl, a C 3 -C 6 Cycloalkyl, containing 1-3 C selected from N, O, S 4 -C 8 Heterocycloalkyl, -OR a 、-C(O)R b .

[0026] As a preferred technical solution, the R a Selected from 6-10 membered aryl groups, preferably aryl groups.

[0027] As a preferred technical solution, the R b Selected from C containing 1-3 selected from N, O, S 3 -C 10 The heterocycloalkyl group is preferably selected from morpholine.

[0028] As a preferred technical solution, the R c Selected from 6-10 membered aryl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 The haloalkyl group is preferably selected from methyl, trifluoromethyl, phenyl and cyclohexyl.

[0029] As a preferred technical solution, the R 8 Selected from deuterium, fluorine, chlorine, methoxy, amino, cyano, -C(O)CHCH 2 、-C(O)CH3 、-C(O)NH 2 , hydroxyethyl, methyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, phenoxy, and cyclohexyloxy.

[0030] As a preferred technical solution, the R 2 Selected from

[0031]

[0032] As a preferred technical solution, the compound is selected from the compounds shown in the following formulas (I-1) to (I-6):

[0033]

[0034] The R 1 is selected from methyl, ethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, isopropyl, cyclopropyl, CD 3 In one aspect, the present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0035]

[0036]

[0037]

[0038]

[0039] On the other hand, the present invention also provides a pharmaceutical composition comprising any one of the above-mentioned compounds or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients.

[0040] On the other hand, the present invention also provides use of any one of the above-mentioned compounds or pharmaceutically acceptable salts thereof or the pharmaceutical composition in the preparation of a medicament for treating a disease or condition by inhibiting histone deacetylase (HDAC).

[0041] As a preferred technical solution, the disease or condition is cancer, neurodegenerative disease, and the cancer is preferably free glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (such as esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (such as bladder urothelial carcinoma), pancreatic cancer, mesothelioma, melanoma, non-small cell lung cancer (NSCLC; such as lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, myxofibrosarcoma, cholangiosarcoma, and brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, lung cancer, soft tissue cancer, colorectal cancer, cervical cancer, pleural cancer and colorectal cancer or sarcoma, more preferably melanoma, bladder cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer and gastric cancer. DETAILED DESCRIPTION OF THE INVENTION

[0043] Various aspects and features of the present invention are further described below.

[0044] The compounds according to the invention may exist in tautomeric forms and the present invention then includes all tautomeric forms.

[0045] The term "substituted" means that any one or more hydrogen atoms on a specified group are replaced with a substituent as long as the valence of the specified atom is normal and the resulting compound after the substitution is stable.

[0046] As used herein, the terms "halogen", "halo" and the like represent fluorine, chlorine, bromine or iodine, and particularly represent fluorine, chlorine and bromine, with fluorine and chlorine being particularly preferred.

[0047] "Haloalkyl" refers to an alkyl group as described herein (e.g., C1-C6 alkyl) in which one or more hydrogen atoms are replaced by halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro-fluoroalkyl, chloro-difluoroalkyl, and 2-fluoroisobutyl.

[0048] "Alkoxy" refers to an alkyl group as described herein (e.g., C1-C6 alkyl) attached to the molecule through an oxygen atom. This includes groups in which the alkyl portion can be straight or branched, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0049] "Haloalkoxy" refers to an alkoxy group as described herein (e.g., C1-C6 alkoxy) in which one or more hydrogen atoms are replaced by halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloro-fluoroalkoxy, chloro-difluoroalkoxy, and 2-fluoroisobutoxy.

[0050] "Alkyl" refers to an alkyl group having a specified number of carbon atoms, which is a straight chain or branched chain alkyl group, and which may include its subgroups, for example, referring to "C 1 -C 6 When "alkyl" is present, it may also include C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 2 -C 6 Alkyl, C 2 -C 4 Alkyl and the like represent sub-ranges of groups, as well as specific groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like.

[0051] The terms "heterocycle", "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 3 to 7-membered monocyclic groups, 7 to 11-membered bicyclic groups, and 10 to 15-membered tricyclic groups, which have at least one heteroatom (O, S or N) in at least one ring, and the heteroatom-containing ring preferably has 1, 2 or 3 heteroatoms selected from O, S and N. Each ring of this heteroatom-containing group can contain one or two oxygen or sulfur atoms or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. Nitrogen and sulfur atoms may be optionally oxidized, and nitrogen atoms may be optionally quaternized. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms, and may be saturated, partially saturated or completely unsaturated. The heterocyclic group may be attached to any available nitrogen or carbon atom.

[0052] "Heterocycloalkyl" refers to a saturated or partially unsaturated ring radical containing two to twenty carbon atoms and at least one heteroatom. In certain embodiments, heteroatoms are independently selected from N, O, Si, P, B and S atoms. Heterocycloalkyl can be selected from a monocyclic or bicyclic ring (fused when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded by a non-aromatic ring atom) or a bridged ring system. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heterocycloalkyl is connected to the rest of the molecule through any atom of the heterocycloalkyl (valence permitting), such as any carbon atom or nitrogen atom of the heterocycloalkyl. In certain embodiments, the heterocycloalkyl contains 5 to 20 carbon atoms. In certain embodiments, the heterocycloalkyl contains 5 to 10 carbon atoms. In other embodiments, the heterocycloalkyl contains 5 to 7 carbon atoms. In some embodiments, the heterocycloalkyl is fully saturated. Examples of fully saturated heterocycloalkyl radicals include, but are not limited to, 1,4-dioxanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, Pyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1,1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. In some embodiments, the heterocycloalkyl moiety is unsaturated or is also referred to as "heterocycloalkenyl". Examples of heterocycloalkenyl groups include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 2-oxo-1,3-dioxolyl, etc. In certain embodiments, heterocycloalkyl is optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and the like.

[0053] "Aryl" refers to a group having a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) with 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-C14 aryl"). In some embodiments, the aryl has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl has ten ring carbon atoms ("C10 aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl has fourteen ring carbon atoms ("C14 aryl"; e.g., anthracenyl). Aryl may be described, for example, as C6-C10 aryl. Aryl includes, but is not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of aryl may be independently optionally substituted, e.g., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In certain embodiments, the aryl group is an unsubstituted or substituted C6-C14 aryl group, representative examples of aryl groups include, but are not limited to:

[0054] The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11- to 14-membered tricyclic groups, which have at least one heteroatom (O, S or N) in at least one ring, and the heteroatom-containing ring preferably has 1, 2 or 3 heteroatoms selected from O, S and N. Each ring of the heteroaryl containing heteroatoms can contain one or two oxygen or sulfur atoms or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups can contain only carbon atoms and can be saturated, partially saturated or unsaturated. Nitrogen and sulfur atoms can be optionally oxidized, and nitrogen atoms can be optionally quaternized. As a bicyclic or tricyclic heteroaryl, it must include at least one completely aromatic ring, but the other one or more fused rings can be aromatic or non-aromatic. Heteroaryl can be attached to any available nitrogen or carbon atom of any ring. If the other ring is a cycloalkyl or heterocycle, it is optionally substituted with =O (oxo) where valence permits. Representative heteroaryl examples include, but are not limited to:

[0055]

[0056] The term "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to the subject, but also refers to a synthetic substance with pharmaceutical use value, such as a salt formed as an intermediate during chiral separation. Although the salt of this intermediate cannot be directly administered to the subject, the salt can play a role in obtaining the final product of the present invention.

[0057] As described herein, the term "disease" refers to a physical state of the subject, which is related to the disease described in the present invention. For example, the inflammatory diseases and neurodegenerative diseases described in the present invention. The cancer of the present invention includes standard treatments such as surgery, radiotherapy, chemotherapy and hormone therapy.

[0058] "Cancer" or "malignancy" refers to any of a variety of diseases characterized by uncontrolled abnormal proliferation of cells, the ability of affected cells to spread locally or via the bloodstream and lymphatic system to other sites in the body (i.e., metastasis), and any of a number of characteristic structural and / or molecular features. "Cancer cell" refers to a cell that is undergoing an early, intermediate, or advanced stage of multistep neoplastic progression. Cancers include mesothelioma, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis cancer and hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumors, head and neck cancer, acute lymphoblastic leukemia ( ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gallbladder cancer, bronchial tumor, advanced solid tumors, small cell lung cancer, metastatic non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasma cell tumor, lymphoma, pancreatic ductal adenocarcinoma, etc.

[0059] The compounds of the present invention or pharmaceutical compositions containing the same can be administered in unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, intravenous drip, subcutaneous injection, nasal cavity, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

[0060] The dosage form can be a liquid dosage form, a solid dosage form or a semisolid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w types, w / o types and multiple emulsions), suspensions, injections (including water injections, powder injections and infusions), eye drops, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols (powders), sprays, etc.; semisolid dosage forms can be ointments, gels, pastes, etc.

[0061] In order to achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

[0062] The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0063] Beneficial technical effects

[0064] The present invention modifies (TNG260 analogs) through computer-aided design, and screens a variety of novel structural compounds through computer simulation, molecular docking analysis, and drug structure-activity relationship research. This series of compounds can specifically bind to the CoREST complex and inhibit the function of the CoREST complex, and has extremely strong CoREST complex inhibitory activity and HDAC inhibitory activity, and the IC50 is equivalent to or less than the positive control drug TNG260. The present invention provides a class of novel structural and highly active CoREST complex inhibitor compounds, which have good application prospects in preventing and / or treating indications related to histone deacetylase inhibition. DETAILED DESCRIPTION

[0065] The following embodiments are intended to help those skilled in the art better understand the technical solutions of the present invention, but are not intended to limit the present invention in any way.

[0066] For all the following examples, standard procedures and methods known to those skilled in the art can be used. Unless otherwise indicated, all temperatures are expressed in ° C (Celsius). The structures of the compounds are determined by nuclear magnetic resonance spectroscopy (NMR) and / or mass spectroscopy (MS).

[0067] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is in parts per million (ppm). The NMR was measured using a Bruker avance-400 NMR spectrometer, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).

[0068] Liquid phase mass spectrometry LC-MS measurement The liquid phase part uses ACQUITY UPLC ultra-high pressure liquid chromatography, and the mass spectrometry part uses Xevo G2-S Qtof mass spectrometer.

[0069] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0070] Example 018: N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-4-(cyclopropylmethyloxy)-λ 6 Synthesis of -sulfonylideneamino)benzamide

[0071] Intermediate: Cyclopropyliminomethyl-λ 6 Synthesis of -sulfonone

[0072]

[0073] Step 1: Synthesis of compound 1-bromo-4-methylsulfonylbenzene

[0074] Under an ice-water bath, (4-bromophenyl)(methyl)sulfane (400 mg, 2.0 mmol, 1.0 eq) was added to dichloromethane (10 mL), followed by m-chloroperbenzoic acid (531 mg, 3.0 mmol, 1.0 eq), and the mixture was transferred to room temperature for reaction for 18 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to adjust the pH to a weak alkaline state, dichloromethane and water were added, the aqueous phase was extracted three times with dichloromethane, and the organic phases were combined and concentrated to obtain a crude product of 1-bromo-4-methylsulfonylbenzene (403 mg, yield 92.8%). 1 HNMR (400MHz, DMSO-d6) δ7.82-7.75(m,2H),7.67-7.61(m,2H),2.77-2.72(m,3H).

[0075] Step 2: Synthesis of (methylsulfinyl)cyclopropane

[0076] 1-Bromo-4-methylsulfonylbenzene (4.0 g, 18.4 mmol, 1.0 eq) was added to tetrahydrofuran (40 mL), nitrogen was replaced twice, and then cyclopropylmagnesium bromide (36.6 mL, 36.6 mmol, 2.0 eq) was slowly added dropwise at 0°C for about 1 hour, and the reaction was carried out at 0°C for 3 hours. After the reaction was complete, saturated ammonium chloride solution (10 mL) was added, stirred for 10 minutes, filtered through diatomaceous earth, washed with methanol, concentrated the filtrate, dissolved in a small amount of dichloromethane, wet loaded, separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain a light yellow liquid (methylsulfinyl) cyclopropane (1.34 g, yield 70.1%). 1H NMR (400MHz, Chloroform-d) δ2.65 (s, 3H), 2.17 (m, J = 8.0, 4.8Hz, 1H), 1.21-1.13 (m, 1H), 1.03-0.92 (m, 2H), 0.82 (m), J = 10.9, 6.1, 3.6Hz, 1H).

[0077] Step 3: Cyclopropylimidomethyl-λ 6 Synthesis of -sulfonone

[0078] Dissolve (methylsulfinyl)cyclopropane (700 mg, 6.7 mmol, 1.0 eq) in methanol (10 mL), add ammonia methanol solution (4.5 mL), add iodophenyl diacetic acid (6.5 g, 20.2 mmol, 3.0 eq) in batches at 0 ° C, transfer to room temperature and stir after adding, and react for 16 hours. After the reaction is complete, add saturated sodium carbonate solution to adjust the pH to weak alkalinity, add water and ethyl acetate to extract and separate the liquids, extract the aqueous phase with ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate, column chromatography (dichloromethane: methanol = 20: 1) to obtain a light yellow oily liquid cyclopropyl iminomethyl-λ 6 -sulfonone (472 mg, yield 59.2%). LCMS (ESI) [M+H] +: 120.

[0079] N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-4-(cyclopropylmethyloxy)-λ 6 Synthesis of -sulfonylideneamino)benzamide

[0080]

[0081] Step 1: Synthesis of tert-butyl (4-bromo-2-nitrophenyl)carbamate

[0082] Under ice-water bath conditions, 4-bromo-2-nitroaniline (2g, 9.2mmol, 1.0eq) and sodium hydride (404mg, 10.12mmol, 1.1eq) were added, nitrogen was replaced, and N,N-dimethylformamide (60mL) was added. Stir for 15 minutes, then di-tert-butyl dicarbonate (2.6g, 11.96mmol, 1.3eq) was dissolved in N,N-dimethylformamide (20mL), and slowly added dropwise to the reaction bottle. The reaction was allowed to react at room temperature for 5 hours. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction, water and ethyl acetate were added, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and concentrated, and separated by normal phase column chromatography to obtain yellow solid (4-bromo-2-nitrophenyl) tert-butyl carbamate (1.968g, yield 67.5%).

[0083] Step 2: Synthesis of tert-butyl (4'-fluoro-3-nitro-[1,1'-biphenyl]-4-yl)carbamate

[0084] Dissolve tert-butyl (4-bromo-2-nitrophenyl)carbamate (1.9 g, 6 mmol, 1.0 eq), (4-fluorophenyl)boric acid (1.25 g, 9 mmol, 1.5 eq), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (0.44 g, 0.6 mmol, 0.1 eq) and potassium carbonate (2.5 g, 18 mmol, 3.0 eq) in a mixed solution of 1,4-dioxane (75 mL) and water (15 mL), replace nitrogen, and stir at 100°C for 12 hours. After the reaction is complete, add diatomaceous earth to filter, add water and ethyl acetate to the filtrate, extract the aqueous phase with ethyl acetate three times, combine and concentrate the organic phases, and separate with a normal phase column to obtain tert-butyl (4'-fluoro-3-nitro-[1,1'-biphenyl]-4-yl)carbamate (1.67 g, yield 83.8%).

[0085] Step 3: Synthesis of tert-butyl (3-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)carbamate

[0086] Add tert-butyl (4'-fluoro-3-nitro-[1,1'-biphenyl]-4-yl)carbamate (8g, 24.1mmol, 1.0eq) and iron powder (6.743g, 120.4mmol, 5.0eq) to the reaction bottle, add a condenser, replace the nitrogen, then add methanol (160mL) and water (40mL), and react at 80°C for 3 hours. After the reaction is completed, filter while hot, concentrate the filtrate, column chromatography, add ethyl acetate to slurry, and obtain white solid (3-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)carbamate (7.1g, yield 97.6%). 1 H NMR (400MHz, DMSO) δ8.37(s,1H),7.62–7.54(m,2H),7.28(m,J=17.7,8.5Hz,3H ),6.97(d,J=2.1Hz,1H),6.81(dd,J=8.2,2.1Hz,1H),4.98(s,2H),1.49(s,9H).

[0087] Step 4: Synthesis of tert-butyl [3-(4-bromobenzamido)-4'-fluoro-[1,1'-biphenyl]-4-yl]carbamate

[0088] Add p-bromobenzoic acid (382.3 mg, 1.9 mmol, 1.15 eq), tert-butyl (3-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)carbamate (500 mg, 1.65 mmol, 1.0 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (940.5 mg, 2.45 mmol, 1.5 eq) and N,N-diisopropylethylamine (0.86 mL, 4.95 mmol, 3.0 eq) to N,N-dimethylformamide (15 mL) and react for 15 h. After the reaction is complete, water and ethyl acetate are added, the aqueous phase is extracted with ethyl acetate, the organic phase is concentrated, and column chromatography is performed to obtain tert-butyl [3-(4-bromobenzamido)-4'-fluoro-[1,1'-biphenyl]-4-yl)carbamate (200 mg, yield 21.7%). LCMS (ESI) [M+H] + :509.

[0089] Step 5: (3-(4-((cyclopropyl(methyloxy)-λ 6 Synthesis of tert-butyl (4'-fluoro-[1,1'-biphenyl]-4-yl)carbamate

[0090] Cyclopropyliminomethyl-λ 6 -sulfonone (50 mg, 0.42 mmol, 1.0 eq) was dissolved in 1,4-dioxane (4 mL), and then tert-butyl [3-(4-bromobenzamido)-4'-fluoro-[1,1'-biphenyl]-4-yl]carbamate (203 mg, 0.42 mmol, 1.0 eq), tris(dibenzylideneacetone)dipalladium(0) (76.9 mg, 0.084 mmol, 0.2 eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (53.4 mg, 0.092 mmol, 0.22 eq) and cesium carbonate (410.6 mg, 1.26 mmol, 3.0 eq) were added, and the system was replaced with nitrogen, and the reaction was carried out at 80°C for 12 hours. After the reaction was completed, diatomaceous earth was added for filtration, concentration was carried out, and normal phase column separation was performed to obtain (3-(4-((cyclopropyl(methyloxy)-λ 6 -sulfonylideneamino)benzamido)-4'-fluoro-[1,1'-biphenyl]-4-ylcarbamic acid tert-butyl ester (51 mg, yield 23.3%). 1 H NMR (400 MHz, CDCl 3)δ7.92(d,J=1.9Hz,1H),7.88–7.80(m,2H),7.54–7.49(m,2H),7.35–7.30(m,2H),7.18–7.00(m,5H),6 .94(s,1H),3.16(s,3H),2.61(m,J=8.0,4.7Hz,1H),1.51(s,9H),1.49-1.40(m,2H),1.22–1.04(m,2H).

[0091] Step 6: N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-4-(cyclopropylmethyloxy)-λ 6 Synthesis of -sulfonylideneamino)benzamide

[0092] N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-4-(cyclopropylmethyloxy)-λ 6 -sulfonylamino)benzamide (35 mg, 0.067 mmol, 1.0 eq) and trifluoroacetic acid (76 mg, 0.67 mmol, 10.0 eq) were added to dichloromethane (2.5 mL) and stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated and high performance liquid preparative chromatography was used to obtain N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-4-(cyclopropylmethyloxy)-λ 6 -sulfonylideneamino)benzamide (5 mg, yield 17.6%). LCMS (ESI) [M+H] +: 424.1864. 1 HNMR(400MHz,DMSO)δ9.49(s,1H),7.82(s,2H),7.56-7.50(m,2H),7.44(d,J=2.2Hz,1H),7.24(m,J=8.3,2.2Hz,1H),7.17(t,J=8.7Hz,2H),7.00– 6.95(m,2H),6.81(d,J=8.3Hz,1H),5.01(s,2H),3.21(s,3H),2.83(m,J= 7.7, 4.8Hz, 1H), 1.20 (d, J = 4.1Hz, 2H), 1.01 (m, J = 12.2, 9.1, 3.8Hz, 2H).

[0093] Example 042: N-(4-amino-[1,1'-biphenyl]-3-yl)-4-[(cyclopropyl(methyl)(oxo)-λ 6 Synthesis of [-sulfinyl)amino]benzamide

[0094]

[0095] Step 1: 4-{[cyclopropyl(methyloxy)-λ 6 Synthesis of methyl benzoate

[0096] Cyclopropyliminomethyl-λ 6 -sulfonone (100 mg, 0.84 mmol, 1.0 eq) was added to 1,4-dioxane (15 mL), followed by methyl 4-bromobenzoate (216.8 mg, 1.01 mmol, 1.2 eq), tris(dibenzylideneacetone)dipalladium (153.8 mg, 0.17 mmol, 0.2 eq), (R)-3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphorene (61.1 mg, 0.18 mmol, 0.22 eq) and cesium carbonate (821.1 mg, 2.52 mmol, 3.0 eq), and the mixture was reacted at 80°C for 12 hours. After the reaction was completed, the mixture was filtered with diatomaceous earth, extracted three times with ethyl acetate and water, the organic phase was concentrated, separated by a normal phase column, and the resulting solution was concentrated to obtain a light yellow solid 4{-[cyclopropyl(methyloxy)-λ 6 -sulfonylidene]amino}benzoic acid methyl ester (126 mg, yield 59.4%). LCMS (ESI) [M+H] + :254.

[0097] Step 2: 4-{[cyclopropyl(methyloxy)-λ 6 Synthesis of sulfonylidene]amino}benzoic acid

[0098] 4-{[cyclopropyl(methyloxy)-λ 6 -sulfonylidene]amino}benzoic acid methyl ester (100 mg, 0.39 mmol, 1.0 eq) was added to a mixture of methanol (3 mL) and water (1 mL), and then lithium hydroxide (94.86 mg, 3.9 mmol, 10.0 eq) was added and reacted at 40°C for 4 hours. After the reaction was complete, water was added and the pH value was adjusted to 5 with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was concentrated to obtain the crude product 4-{[cyclopropyl(methyloxy)-λ 6 -sulfonylidene]amino}benzoic acid (112 mg). LCMS (ESI) [M+H] + :240.08.

[0099] Step 3: Synthesis of tert-butyl (3-amino-[1,1'-biphenyl]-4-yl)carbamate

[0100] Tert-butyl (2-amino-4-bromophenyl)carbamate (400 mg, 1.4 mmol, 1.0 eq) was added to a mixture of 1,4-dioxane (4 mL) and water (1 mL), followed by phenylboric acid (204.7 mg, 1.67 mmol, 1.2 eq) / [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (101 mg, 0.14 mmol, 0.1 eq) and potassium carbonate (387 mg, 2.8 mmol, 2.0 eq), nitrogen was replaced, and the mixture was reacted at 100°C for 12 hours. After the reaction was completed, the mixture was filtered with diatomaceous earth, concentrated, and separated by a normal phase column, and the resulting solution was concentrated to obtain tert-butyl (3-amino-[1,1'-biphenyl]-4-yl)carbamate (182 mg, yield 45.8%). LCMS (de-Boc) [M+H]+: 185.1059.

[0101] Step 4: (3-(4-((cyclopropyl(methyl)(oxo)-λ 6 Synthesis of tert-butyl (1,1'-sulfinylidene)amino)benzamido)-[1,1'-biphenyl]-4-yl)carbamate

[0102] Tert-butyl (3-amino-[1,1'-biphenyl]-4-yl)carbamate (28 mg, 0.1 mmol, 1.0 eq) was added to acetonitrile (0.5 mL), and then 4-{[cyclopropyl(methyl)(oxo)-λ 6 -sulfinyl]amino}benzoic acid (20 mg, 0.084 mmol, 1.0 eq), N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (35 mg, 0.126 mmol, 1.5 eq) and N-methylimidazole (24 mg, 0.294 mmol, 3.5 eq) were reacted at room temperature for 2 hours. Water and ethyl acetate were added for extraction three times, and the organic layer was concentrated and separated by preparative plate to obtain (3-(4-((cyclopropyl(methyl)(oxo)-λ 6 -sulfinyl)amino)benzamido)-[1,1'-biphenyl]-4-yl)carbamic acid tert-butyl ester (25 mg, yield 50.1%). LCMS (de-Boc) [M+H] + :506.2111.

[0103] Step 5: N-(4-amino-[1,1'-biphenyl]-3-yl)-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of 1-sulfinyl]amino}benzamide

[0104] (3-(4-((cyclopropyl(methyl)(oxo)-λ 6-sulfinyl)amino)benzamide)-[1,1'-biphenyl]-4-yl)carbamic acid tert-butyl ester (25 mg, 0.05 mmol, 1.0 eq) was added to dichloromethane (1.2 mL), followed by trifluoroacetic acid (0.4 mL) and reacted at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate was added to adjust the pH to weak alkalinity, and ethyl acetate was added for extraction three times. The organic phase was concentrated and high performance liquid preparative chromatography was used to obtain N-(4-amino-[1,1'-biphenyl]-3-yl)-4-{[cyclopropyl(methyl)(oxo)-λ 6 -sulfinylidene]amino}benzamide (8 mg, yield 40%). LCMS [M+H] + :406.2149. 1 H NMR(400MHz,DMSO)δ9.58(s,1H),7.98–7.85(m,2H),7.64–7.50(m,3H),7.47–7.21(m,4H),7.09–7.01( m,2H),6.89(d,J=8.3Hz,1H),5.08(s,2H),3.28(s,3H),2.89(m,J=7.8,4.8Hz,1H),1.29–1.05(m,4H).

[0105] Example 050: N-[2-amino-5-(pyridazin-3-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of 1-sulfinyl]amino}benzamide

[0106]

[0107] Step 1: Synthesis of tert-butyl [2-amino-4-(pyridazin-3-yl)phenyl]carbamate

[0108] Tert-butyl (2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (200.0 mg, 0.60 mmol, 1.0 equiv.), 3-bromopyridazine (142.2 mg, 0.90 mmol, 1.5 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (43.6 mg, 0.06 mmol, 0.1 equiv.) and potassium carbonate ( 165.6mg, 1.20mmol, 2.0equiv.) was dissolved in 1,4-dioxane (12mL) and water (3mL), and nitrogen was introduced to replace the system three times, and the temperature was raised to 95°C and stirred for 18h. After the reaction was complete, it was filtered using diatomaceous earth, and the filtrate was extracted three times with water and ethyl acetate. The organic phase was dried, concentrated, and column chromatography was performed to obtain tert-butyl [2-amino-4-(pyridazin-3-yl)phenyl]carbamate (125mg, yield 72.8%). LCMS: [M-Boc+H]+=187.1040.

[0109] Step 2: Compound (2-(4-((cyclopropyl(methyl)(oxo)-λ 6 Synthesis of tert-butyl (4-(pyridazin-3-yl)phenyl)carbamate

[0110] Tert-butyl [2-amino-4-(pyridazin-3-yl)phenyl]carbamate (12 mg, 0.042 mmol, 1.0 equiv.), 4-((cyclopropyl(methyl)(oxo)-λ 6 -sulfylidene)amino)benzoic acid (12 mg, 0.042 mmol, 1.0 equiv.), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (17.6 mg, 0.063 mmol, 1.5 equiv.) and N-methylimidazole (8.6 mg, 0.105 mmol, 2.5 equiv.) were added to acetonitrile (1 mL) in sequence and stirred at room temperature for 18 hours. After the reaction was complete, the reaction solution was concentrated and column chromatography was performed to obtain the compound ((2-(4-((cyclopropyl(methyl)(oxo)-λ 6 -sulfylidene)amino)benzamido)-4-(pyridazin-3-yl)phenyl)carbamic acid tert-butyl ester (21 mg, 89.1%).

[0111] Step 3: Synthesis of N-[2-amino-5-(pyridazin-3-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ6-sulfinyl]amino}benzamide

[0112] First, the compound ((2-(4-((cyclopropyl(methyl)(oxo)-λ 6-sulfuryl)amino)benzamide)-4-(pyridazin-3-yl)phenyl)carbamic acid tert-butyl ester (19 mg, 0.037 mmol, 1.0 equiv.) was dissolved in dichloromethane (1.5 mL), and then trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was directly concentrated to remove dichloromethane and trifluoroacetic acid, and then dissolved in methanol (1.0 mL) to prepare and purify a yellow solid compound N-[2-amino-5-(pyridazin-3-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 -sulfinyl]amino}benzamide (8 mg, yield 53.1%). LCMS: [M+H]+=408.1117. 1H NMR (400 MHz, CDCl3) δ9.10 (s, 1H), 8.13 (s, 1H), 7.93-7.78 (m, 5H), 7.50 (s, 1H), 7.20 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.4 Hz, 1H), 3.19 (s, 3H), 2.68–2.59 (m, 1H), 1.49 (d, J=17.3 Hz, 1H), 1.21-1.07 (m, 3H).

[0113] Example 075: N-[2-amino-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of 1-sulfinyl]amino}benzamide

[0114]

[0115] Step 1: Synthesis of tert-butyl [2-amino-4-(1-methyl-1H-pyrazol-4-yl)phenyl]carbamate

[0116] Tert-butyl (2-amino-4-bromophenyl)carbamate (429 mg, 1.5 mmol, 1.0 equiv.) was added to a mixture of 1,4-dioxane (12 mL) and water (3 mL), followed by 1-methylpyrazole-4-boronic acid pinacol ester (374 mg, 1.7 mmol, 1.1 equiv.), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (33 mg, 0.045 mmol, 0.03 equiv.) and potassium carbonate (414 mg, 3.0 mmol, 2.0 equiv.), the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 95 ° C for 3 hours. After the reaction was completed, water was added to dilute the mixture, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and separated by a forward column to obtain tert-butyl [2-amino-4-(1-methyl-1H-pyrazol-4-yl)phenyl]carbamate (380 mg, yield 88%). LCMS: m / z = [M+H]-Boc 189.

[0117] Step 2: (2-(4-((cyclopropyl(methyl)(oxo)-λ 6 Synthesis of tert-butyl (4-(1-methyl-1H-pyrazol-4-yl)phenyl)carbamate

[0118] Tert-butyl [2-amino-4-(1-methyl-1H-pyrazol-4-yl)phenyl]carbamate (58 mg, 0.2 mmol, 1.0 eq) was added to acetonitrile (4 mL), and then 4-[(cyclopropyl(methyl)(oxo)-λ 6 -sulfinyl)amino]benzoic acid (48 mg, 0.2 mmol, 1.0 eq), N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (84 mg, 0.3 mmol, 1.5 eq) and N-methylimidazole (41 mg, 0.5 mmol, 2.5 eq) were reacted at room temperature for 12 hours. After the reaction was complete, water and ethyl acetate were added for extraction three times, the organic layer was concentrated, and column chromatography was used to separate (2-(4-((cyclopropyl(methyl)(oxo)-λ 6 -sulfinyl)amino)benzamido)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)carbamic acid tert-butyl ester (60 mg, yield 56%). LCMS (de-Boc) [M+H] + :510.

[0119] Step 3: N-[2-amino-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of 1-sulfinyl]amino}benzamide

[0120] (2-(4-((cyclopropyl(methyl)(oxo)-λ6 -sulfinyl)amino)benzamide)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)carbamic acid tert-butyl ester (60 mg, 0.09 mmol, 1.0 eq) was added to dichloromethane (6 mL), followed by trifluoroacetic acid (2 mL), and reacted at room temperature for 1 hour. After the reaction was completed, saturated sodium bicarbonate was added to adjust the pH to neutral, and ethyl acetate was added for extraction three times. The organic phase was concentrated and high performance liquid preparative chromatography was used to obtain N-[2-amino-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 -Sulfinyl]amino}benzamide synthesis (10 mg, yield 27%). LCMS [M+H] + :410.2322. 1 H NMR (400MHz, DMSO) δ9.55(s,1H),7.93(s,1H),7.86(d,J=8.3Hz,2H),7.68(s,1H),7.35(d,J=2.2Hz,1H),7.19(m,J=8.3,2.1Hz,1H) ,7.03(d,J=8.4Hz,2H),6.79(d,J=8.2Hz,1H),4.86(s,2H),3.84(s,3H),3.27(s,3H),2.88(m,J=7.8,4.1Hz,1H),1.31-1.01(m,4H).

[0121] Example 080: N-[2-amino-5-(benzo[b]thiophen-5-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of 1-(2-sulfinyl)]amino}benzamide

[0122]

[0123] Step 1: Synthesis of tert-butyl [2-amino-4-(benzothiophen-5-yl)phenyl]carbamate

[0124] The compound (2-amino-4-bromophenyl)carbamic acid tert-butyl ester (300 mg, 1.052 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (12 mL) and water (3 mL), and 2-(benzo[b]thiophen-5-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (180 mg, 1.15 mmol, 1.1 equiv.), potassium carbonate (290 mg, 2.10 mmol, 2.0 equiv.) and bistriphenylphosphine palladium dichloride (76 mg, 0.11 mmol, 0.1 equiv.) were added to the system, and nitrogen was introduced to replace the gas in the system three times, and the temperature was raised to 95° C. for reaction for 12 hours. After the reaction was completed, water was added to dilute the mixture, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and separated by column chromatography to obtain white solid [2-amino-4-(benzothiophen-5-yl)phenyl]carbamic acid tert-butyl ester (180 mg, yield 50%). LCMS: m / z = [M+H]-Boc 241.0732. 1 HNMR(400MHz, DMSO-d6)δ8.45(s,1H),7.95(dd,J=7.9,1.2Hz,1H),7.83(dd,J=7.4,1.4Hz,1H),7.66( s,1H),7.43–7.29(m,3H),7.11(d,J=2.2Hz,1H),7.01(m,J=8.2,2.1Hz,1H),5.14(s,2H),1.50(s,9H).

[0125] Step 2: (4-(Benzothiophene-5-yl)-2-(4-((cyclopropyl(methyl)(oxo)-λ 6 -Synthesis of (4-(2-sulfinyl)amino)benzamido)phenyl)carbamate

[0126] tert-Butyl ((2-amino-4-(benzothiophen-5-yl)phenyl)carbamate (33.0 mg, 0.08 mmol, 1.2 equiv.) was dissolved in N,N-dimethylformamide (2 mL) and 4-{[cyclopropyl(methyl)(oxo)-λ 6 -sulfinyl]amino}benzoic acid (20 mg, 0.07 mmol, 1.0 equiv.), N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (36.0 mg, 0.11 mmol, 1.5 equiv.) and N-methylimidazole (24.0 mg, 0.24 mmol, 3.5 equiv.), stirred at room temperature for 2 hours. After the reaction was completed, column chromatography was separated to obtain a yellow solid tert-butyl (4-(benzothiophen-5-yl)-2-(4-((cyclopropyl(methyl)(oxo)-λ 6-sulfinyl)amino)benzamido)phenyl)carbamate (19 mg, yield 41%). LCMS: m / z=[M+H]562.1802.

[0127] Step 3: Compound N-[2-amino-5-(benzo[b]thiophen-5-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of 1-(2-sulfinyl)]amino}benzamide

[0128] (4-(Benzothiophene-5-yl)-2-(4-((cyclopropyl(methyl)(oxo)-λ 6 -sulfinyl)amino)benzamide)phenyl)carbamate (19 mg, 0.034 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.3 mL) was added and stirred at room temperature for 1 hour. After the reaction was completed, the solvent was dried and dissolved in methanol, and a white solid N-[2-amino-5-(benzo[b]thiophen-5-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 -sulfinyl)]amino}benzamide (3 mg, yield 20%). LCMS: m / z=[M+H]462.1338. 1 H NMR(400MHz,Chloroform-d)δ7.83(d,J=7.2Hz,2H),7.79(d,J=8.7Hz,2H),7.71(d ,J=7.8Hz,1H),7.65(d,J=2.1Hz,1H),7.45(m,J=8.2,2.1Hz,1H),7.40(s,1H),7.3 1(m,J=14.9,7.3,1.2Hz,2H),7.17(d,J=8.4Hz,2H),6.87(d,J=8.3Hz,1H),4.09(s ,2H),3.15(s,3H),2.59(m,J=8.0,4.7Hz,1H),1.46(m,J=9.9,7.1,4.7Hz,1H),1.24 -1.03(m,3H).

[0129] Example 081: N-[2-amino-5-(furan-2-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of 1-sulfinyl]amino}benzamide

[0130]

[0131] Step 1: Synthesis of tert-butyl [2-amino-4-(furan-2-yl)phenyl]carbamate

[0132] Tert-butyl (2-amino-4-bromophenyl)carbamate (429 mg, 1.5 mmol, 1.5 equiv.) was added to a mixture of 1,4-dioxane (8 mL) and water (2 mL), followed by 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (194 mg, 1.0 mmol, 1.0 equiv.), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (72.6 mg, 0.1 mmol, 0.1 equiv.) and potassium carbonate (276 mg, 2.0 mmol, 2.0 equiv.), the atmosphere was replaced with nitrogen three times, and the mixture was reacted at 100 °C for 12 hours. After the reaction was completed, the mixture was filtered through celite, the filtrate was concentrated, and the mixture was separated by a normal phase column to obtain tert-butyl [2-amino-4-(1-methyl-1H-pyrazol-4-yl)phenyl]carbamate (247 mg, yield 90.1%). LCMS (de-Boc) [M+H]+: 175.0691.

[0133] Step 2: (2-(4-((cyclopropyl(methyl)(oxo)-λ 6 Synthesis of tert-butyl (4-(furan-2-yl)phenyl)carbamate

[0134] Tert-butyl [2-amino-4-(furan-2-yl)phenyl]carbamate (42 mg, 0.15 mmol, 1.0 eq) was added to acetonitrile (1 mL), and then 4-[(cyclopropyl(methyl)(oxo)-λ 6 -sulfinyl)amino]benzoic acid (30 mg, 0.13 mmol, 1.0 eq), N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (52 mg, 0.19 mmol, 1.5 eq) and N-methylimidazole (36 mg, 0.44 mmol, 3.5 eq) were reacted at room temperature for 2 hours. After the reaction was complete, water and ethyl acetate were added for extraction three times, the organic layer was concentrated, and 2-(4-((cyclopropyl(methyl)(oxo)-λ)- 6 -sulfinyl)amino)benzamido)-4-(furan-2-yl)phenyl)carbamic acid tert-butyl ester (35 mg, yield 71.4%). LCMS (de-Boc) [M+H] + :496.2063.

[0135] Step 3: N-[2-amino-5-(furan-2-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of 1-sulfinyl]amino}benzamide

[0136] (2-(4-((cyclopropyl(methyl)(oxo)-λ 6-sulfinyl)amino)benzamide)-4-(furan-2-yl)phenyl)carbamic acid tert-butyl ester (35 mg, 0.07 mmol, 1.0 eq) was added to dichloromethane (1.2 mL), followed by trifluoroacetic acid (0.4 mL), and reacted at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate was added to adjust the pH to neutral, and ethyl acetate was added for extraction three times, and the organic phase was concentrated and subjected to high performance liquid preparative chromatography to obtain N-[2-amino-5-(furan-2-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 -sulfinyl]amino}benzamide (15 mg, yield 53.6%). LCMS [M+H] + :396.2128. 1 H NMR (400MHz, DMSO) δ9.54(s,1H),7.90-7.83(m,2H),7.62(d,J=1.8Hz,1H),7.52(d,J=2.0Hz,1H),7.33(dd,J=8.3,2.1Hz,1H),7.06-6.99(m, 2H),6.82(d,J=8.4Hz,1H),6.62(d,J=3.3Hz,1H),6.52(m,J=3.3,1.8H z,1H),5.13(s,2H),3.27(s,3H),2.92-2.85(m,1H),1.28-1.02(m,4H).

[0137] Example 091: N-[2-amino-5-(methylthiophen-2-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of 1-sulfinyl]amino}benzamide

[0138]

[0139] Step 1: Synthesis of tert-butyl [2-amino-4-(5-methylthiophen-2-yl)phenyl]carbamate

[0140] Tert-butyl [2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (334 mg, 1.0 mmol, 1.0 eq) was added to a mixture of 1,4-dioxane (8 mL) and water (2 mL), followed by 2-bromo-5-methylthiophene (266 mg, 1.5 mmol, 1.5 equiv.), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (72.6 mg, 0.1 mmol, 0.1 equiv.) and potassium carbonate (276 mg, 2.0 mmol, 2.0 equiv.), the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 95 ° C for 12 hours. After the reaction was completed, the mixture was filtered through celite, the filtrate was concentrated, and the mixture was separated by a normal phase column to obtain tert-butyl [2-amino-4-(5-methylthiophen-2-yl)phenyl]carbamate (162 mg, yield 53.3%). LCMS (de-Boc) [M+H]+: 205.0583.

[0141] Step 2: (2-(4-((cyclopropyl(methyl)(oxo)-λ 6 Synthesis of tert-butyl (4-(5-methylthiophen-2-yl)phenyl)carbamate

[0142] Tert-butyl [2-amino-4-(5-methylthiophen-2-yl)phenyl]carbamate (46 mg, 0.15 mmol, 1.0 eq) was added to acetonitrile (0.8 mL), and then 4-[(cyclopropyl(methyl)(oxo)-λ 6 -sulfinyl)amino]benzoic acid (30 mg, 0.13 mmol, 1.0 eq), N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (52 mg, 0.19 mmol, 1.5 eq) and N-methylimidazole (36 mg, 0.44 mmol, 3.5 eq) were reacted at room temperature for 2 hours. After the reaction was complete, water and ethyl acetate were added for extraction three times, the organic layer was concentrated, and the (2-(4-((cyclopropyl(methyl)(oxo)-λ)- 6 -sulfinyl)amino)benzamido)-4-(5-methylthiophen-2-yl)phenyl)carbamic acid tert-butyl ester (52 mg, yield 78.7%). LCMS (de-Boc) [M+H] + :426.1440.

[0143] Step 3: N-[2-amino-5-(5-methylthien-2-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of 1-sulfinyl]amino}benzamide

[0144] (2-(4-((cyclopropyl(methyl)(oxo)-λ 6-sulfinyl)amino)benzamide)-4-(5-methylthiophen-2-yl)phenyl)carbamic acid tert-butyl ester (52 mg, 0.1 mmol, 1.0 eq) was added to dichloromethane (1.2 mL), followed by trifluoroacetic acid (0.4 mL), and reacted at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate was added to adjust the pH to neutral, and ethyl acetate was added for extraction three times. The organic phase was concentrated and high performance liquid preparative chromatography was used to obtain N-[2-amino-5-(5-methylthiophen-2-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 -sulfinyl]amino}benzamide (24 mg, yield 57.1%). LCMS [M+H] + :426.1370. 1 H NMR (400MHz, DMSO) δ9.56 (s, 1H), 7.90-7.83 (m, 2H), 7.40 (d, J = 2.2Hz, 1H), 7.22 (dd, J = 8.3, 2.2Hz, 1H), 7.03 (dd, J = 6.1, 2.5Hz, 3H), 6.86 -6.71(m,2H),5.08(s,2H),3.36(s,3H),2.89(m,J=7.8,4.8Hz,1H),2.47-2.42(m,3H),1.31-1.00(m,4H).

[0145] The compounds listed in Table 1 below were prepared by methods similar to those described in Example 042, with appropriate changes in reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions. Characterization data for the compounds are summarized in Table 1 below.

[0146] Table 1: Structure and characterization of some compounds

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156] Experimental Example 1: Activity test of the compounds of the present invention on HDAC1 / 3 protease

[0157] Purpose of the experiment: The purpose of this test case is to test the effect of the compound on the function of HDAC1 / 3 enzymes. Background principle: Histone deacetylases (HDACs) are a class of epigenetic proteins associated with a variety of diseases (including cancer), and inhibition of specific HDACs may treat or otherwise improve such diseases in some patients. Currently, four families of HDACs have been found in the human body, including 18 HDAC subtypes. Among them, HDAC1 was identified as a novel target gene through an in vivo CRISPR screening platform, and its inhibition reversed a-PD1 resistance caused by STK11 loss, while HDAC3 is an essential gene and the main driver of bone marrow toxicity caused by HDAC inhibitors targeting multiple subtypes.

[0158] Experimental process: In this test example, Fluorogenic HDAC1 Assay Kit and Fluorogenic HDAC3 Assay Kit (BPS bioscience) were used to detect HDAC1 and HDCA3 enzyme activities. Step 1: Add the following reaction mixture in duplicate to a microtiter black plate as follows: 1) Prepare the master mixture: N wells × (5μl HDAC substrate (200μM) + 5μl BSA (1mg / ml) + 30μl HDAC Assay Buffer). Add 40μl of the master solution to all wells. 2) Test compound with a maximum concentration of 20uM, 5-fold dilution, 9 gradients, and add 5μl of inhibitor solution to each well. For the blank control group and the positive control group, add 5μl of the same solution without inhibitor. Keep the final DMSO concentration at or below 1%. 3) Add 5μl HDAC Assay Buffer to the wells of the blank control group. 4) Add 5μl of diluted HDAC1 enzyme to the positive control group and the test inhibitor wells to start the reaction. Incubate at 37°C for 30 minutes. Step 2: Add 50 μl of undiluted HDAC developer (2x) to each well. Incubate the plate at room temperature for 15 minutes. Step 3: Read the sample in a microplate reader with an excitation wavelength of 350-380 nm and an emission light detection wavelength of 440-460 nm. Calculate IC50 using GraphPad software and screen the compound by comparing it with the positive drug TNG260. IC50 (half maximal inhibitory concentration) refers to the half inhibitory concentration of the measured antagonist. It can indicate the half amount of a drug or substance (inhibitor) in inhibiting certain biological programs (or certain substances contained in this program, such as enzymes, cell receptors or microorganisms). The synthesis method of TNG260 refers to WO2023102162. The structure of TNG260 is as follows:

[0159] The results of the HDAC1 and HDAC3 IC50 of each compound determined using the assay are shown in Table 2 below. The compound numbers correspond to the compound numbers shown in Table 1, "A" indicates an IC50 of less than 10 nM, "B" indicates an IC50 range of 10 nM to 50 nM; "C" indicates an IC50 range of 50 nM to 200 nM; "D" indicates an IC50 range of 200 nM to 2 μM; and "E" indicates an IC50 greater than 2 μM.

[0160] Table 2: IC values ​​of exemplary compounds of the invention for HDAC1 / 3 protease activity 50 value

[0161]

[0162]

[0163] Conclusion: The smaller the IC50 value of HDAC1 protease inhibitory activity, the stronger its HDAC1 inhibitory activity is; the larger the IC50 value of HDAC3 protease inhibitory activity is, the weaker its HDAC3 inhibitory activity is. Therefore, most of the compounds with novel sulfonyl iminobenzamide structure prepared by the present invention have surprisingly better HDAC1 enzyme inhibitory activity and excellent HDAC1 / 3 selectivity compared with the positive control compound TNG260. This strong inhibitory effect and selectivity have important therapeutic significance for the treatment of symptoms or diseases related to HDAC1 inhibition.

[0164] Experimental Example 2: Testing of the Functional Effects of the Compounds of the Invention on the CoREST Complex

[0165] Purpose of the experiment: The purpose of this test case is to test the effect of the compound on the function of the CoREST complex.

[0166] Background: CoREST was identified as a sensitizer to anti-PD1 in an in vivo screen of STK11-deficient cancers. Class I HDAC enzymes function through four major complexes, with HDAC1 / 2 located in the CoREST, NuRD, and Sin3 complexes, and HDAC3 in the NCoR complex.

[0167] Experimental process:

[0168] Cell culture: A549 cells were grown in Ham's F-12K+10% FBS+1% P / S medium. Cells in logarithmic growth phase were inoculated in culture dishes. Subsequent experiments were performed when the confluence reached about 90%; Immunoprecipitation: CoREST, NuRD, Sin3 and NCoR complexes were obtained using an immunoprecipitation kit (Protein A+G magnetic beads method). Cell samples were lysed, the culture medium was removed, and the cells were washed once with PBS, and then the remaining liquid was removed. 100-200 μl of inhibitor-containing lysis solution was added for every 500,000-1 million cells, and the lysis solution and cells were properly blown to make full contact. After full lysis, centrifuge at 10,000-14,000×g at 4°C for 3-5 minutes and take the supernatant; bind the antibody to the Protein A+G magnetic beads, and then incubate with the supernatant at 4°C overnight; use the acid elution method, add 100μl Acid Elution Buffer for every 20μl original magnetic bead volume, mix well and place on a side-swing shaker or rotary mixer, incubate at room temperature for 5 minutes, after incubation, place on a magnetic stand for 10 seconds, transfer the supernatant to a new centrifuge tube, and immediately add 10μl Neutralization Buffer (neutralization solution), mix appropriately; Deacetylase assay: The enzyme activity of each complex is measured based on fluorescence. IC50 is calculated by GraphPad software, and the compounds are screened by comparing with the positive drug TNG260.

[0169] The results of the assays for the CoREST complex function of each compound using the assay are shown in Table 3 below. The compound numbers correspond to the compound numbers shown in Table 1, "A" indicates an IC50 of less than 50 nM, "B" indicates an IC50 range of 50 nM to 200 nM; "C" indicates an IC50 range of 200 nM to 500 nM; and "D" indicates an IC50 range of 500 nM to 2 μM.

[0170] Table 3 IC values ​​of the exemplary compounds of the present invention for the functional effects on the CoREST complex 50 value

[0171]

[0172] Conclusion: The synthesized novel compounds have good enzyme inhibitory activity against CoREST complex. The inhibitory activity of most compounds is better than that of the positive drug TNG260, and they have potential potential for development of anti-tumor drugs.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, R1 and R7 are each independently selected from C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halogen, and 5-10 membered aryl; A is selected from an optionally substituted 6-10 membered aryl group, a 5-10 membered heteroaryl group, wherein the substituent is selected from a halogen, a C1-C6 haloalkyl group, a C1-C6 alkyl group, an amino group, a C1-C6 alkoxy group; R2 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, -OR a 、-C(O)R b , containing 1-3 C3-C 10 Heterocycloalkyl, including 6-10 membered aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, -C(O)R b , containing 1-3 C3-C 10 Heterocycloalkyl is optionally substituted with one or more R8 substituents; R8 is selected from: deuterium, halogen, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 alkoxy, amino, cyano, -C(O)CHCH2, -C(O)CH3, -C(O)NH2, C1-C6 hydroxyalkyl, -OR c ; R a , R c Each is selected from 6-10 membered aryl, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl; R b is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic group, C3-C 10 Heterocycloalkyl; R3, R4, R5 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, halogen; R6 is selected from hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halogen.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: A is a 6-membered aryl group or a 6-membered heteroaryl group, preferably a benzene ring, pyridine, pyrimidine, or pyridazine, and more preferably above Connect the N on the left, below Connect the carbonyl group on the right.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The R1 and R7 are each independently selected from methyl, cyclopropyl, phenyl, cyclobutyl, cyclohexyl, cyclopentyl, isopropyl, ethyl, -CD3, -CHF2, -CH2F, -CF3.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The R3 is selected from hydrogen, fluorine, chlorine, methyl, difluoromethyl, and trideuterated methyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The R4 is selected from hydrogen, fluorine, chlorine, methyl, difluoromethyl, and trideuterated methyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The R5 is selected from hydrogen, fluorine, chlorine, methyl, difluoromethyl, and trideuterated methyl.

7. The compound according to claims 1-6 or a pharmaceutically acceptable salt thereof, characterized in that: The R6 is selected from hydrogen, fluorine, chlorine, methyl, trifluoromethyl, and trideuterated methyl.

8. The compound according to claims 1-7 or a pharmaceutically acceptable salt thereof, characterized in that: R2 is selected from a benzene ring, a 5-membered, 6-membered or 9-membered heteroaryl, a C3-C6 cycloalkyl, a C4-C8 heterocycloalkyl containing 1-3 atoms selected from N, O, S, -OR a 、-C(O)R b .

9. The compound according to claims 1-8 or a pharmaceutically acceptable salt thereof, characterized in that: The R a Selected from 6-10 membered aryl groups, preferably aryl groups.

10. The compound according to claim 1-9 or a pharmaceutically acceptable salt thereof, characterized in that: The R b Selected from C3-C containing 1-3 selected from N, O, S 10 The heterocycloalkyl group is preferably selected from morpholine.

11. The compound according to claims 1-10 or a pharmaceutically acceptable salt thereof, characterized in that: The R c Selected from 6-10 membered aryl, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, preferably methyl, trifluoromethyl, phenyl, cyclohexyl.

12. The compound according to claims 1-11 or a pharmaceutically acceptable salt thereof, characterized in that: The R8 is selected from deuterium, fluorine, chlorine, methoxy, amino, cyano, -C(O)CHCH2, -C(O)CH3, -C(O)NH2, hydroxyethyl, methyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, phenoxy, and cyclohexyloxy.

13. The compound according to claims 1-12 or a pharmaceutically acceptable salt thereof, characterized in that: The R2 is selected from 14. The compound according to claims 1-13 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the compounds represented by the following formulae (I-1) to (I-7): The R1 is selected from methyl, ethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, isopropyl, cyclopropyl, and CD3.

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

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

17. Use of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating a disease or disorder by inhibiting histone deacetylase (HDAC).

18. The use according to claim 17, wherein the disease or disorder is cancer, a neurodegenerative disease, preferably glioblastoma, 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, 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, myxofibrosarcoma, cholangiosarcoma, and brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, lung cancer, soft tissue cancer, colorectal cancer, cervical cancer, pleural cancer and colorectal cancer or sarcoma, more preferably melanoma, bladder cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer and gastric cancer.

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