HDAC inhibitor, composition and use thereof

Abstract

The present invention relates to the field of pharmaceutical chemistry. Particularly, disclosed is an HDAC inhibitor containing a sulfinyliminobenzamide structure. The HDAC inhibitor is a compound represented by general formula (I) and an enantiomer thereof or a pharmaceutically acceptable salt thereof. Further disclosed in the present invention is a pharmaceutical composition containing the HDAC inhibitor. The HDAC inhibitor is used for treating diseases related to cancers and neurodegeneration. The HDAC inhibitor prepared by the present invention has surprisingly better HDAC1 enzyme inhibitory activity and excellent HDAC1 / 3 selectivity, and has relatively good enzyme inhibitory activity on a CoREST complex.

Description

HDAC inhibitors, compositions and uses thereof 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. Background Art

[0002] HDACs (Histone Deacetylase), also known as histone deacetylases, are a key enzyme in the histone modification process. HDACs remove acetyl groups from histone lysine residues, altering their charge and making chromosomes more compact, thereby inhibiting gene transcription. The 18 HDAC subtypes currently identified in humans can be divided into four classes based on their homology to yeast proteins. Among all HDACs, class I HDACs (HDACs 1-3 and 8) play a crucial role in activating potential tumorigenesis, disease-causing oncogenes, and therapeutic resistance. Recent studies have demonstrated that HDACs 1-3 are crucial for the expression of oncogenes regulated by super-enhancers in breast cancer and other cancers.

[0003] Currently, there are five HDAC inhibitors approved for marketing worldwide. Vorinostat, romidepsin, belinostat, and panobinostat are approved by the US FDA for the clinical treatment of peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and multiple myeloma; Chidamide (trade name: Epsom) is approved by my country's National Medical Products Administration for the treatment of peripheral T-cell lymphoma and breast cancer. However, existing HDAC inhibitors have limited clinical application due to toxicity that limits adequate exposure in solid tumors. Existing data and information indicate that HDAC3, as an essential gene, is the primary driver of myelotoxicity caused by HDAC inhibitors, and these inhibitors target multiple isoforms.

[0004] Among them, except for chidamide, which is a selective inhibitor of HDAC class I and HDAC10 subtype, the other four are pan-HDAC inhibitors. However, the current approved HDAC therapies are still unclear and are only specific for a few HDAC subtypes. Due to their broad inhibitory properties, they have shortcomings such as poor efficacy against 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 deacetylases 1 and 2). This complex can deacetylate histones, leading to the formation of a compact chromatin structure and gene silencing. This means that CoREST is involved in chromatin remodeling and gene transcriptional repression. Cancer cells often 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. Therefore, CoREST is a potential target for selective cancer treatment.

[0006] The uniqueness of the CoREST complex is that it has the dual role of a deacetylase subunit (HDAC1 or 2) and a demethylase subunit (LSD1 / KDAM1A). One of the three other 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 efficient histone deacetylation and demethylation in chromatin, thereby inhibiting cancer cell proliferation, impairing tumor growth, and further improving drug selectivity.

[0007] The sulfur functional group in sulfenyl imine compounds possesses remarkable pharmacological properties, including excellent metabolic stability and the ability to act as both a hydrogen bond donor and acceptor. The substituents on the two carbon atoms in these compounds are not necessarily identical, and the introduction of a nitrogen atom within the tetrahedron creates a chiral asymmetric structure, which broadens the structural diversity of sulfenyl imine compounds. Generally, sulfenyl imine compounds are relatively stable in structure and configuration, requiring no special treatment. Sulfenyl imine compounds with unsubstituted nitrogen atoms can undergo in situ phosphorylation. The nitrogen atom's inherent basicity can also coordinate with metal ions and form salts with inorganic acids. The hydrogen bond acceptor of sulfenyl imines is the heteroatom bound to the sulfur atom. The free sulfenyl imine can act as both a hydrogen acceptor and a hydrogen bond donor. NMR analysis shows that sulfone compounds are less electron-withdrawing than sulfenyl imines, and lower molecular weight sulfenyl imides are readily soluble in water and alcoholic solvents. The unique chemical properties of sulfenyl imine have aroused great research 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

[0009] SUMMARY OF THE INVENTION

[0010] In response to the shortcomings of the prior art, the present invention aims to provide a sulfinylimidobenzamide nucleus-based HDAC inhibitor, composition, and use thereof with high activity, excellent oral pharmacokinetic exposure in mice, and good selectivity. The compounds provided by the present invention have 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 and its enantiomers or pharmaceutically acceptable salts thereof:

[0013] wherein R1 and R7 are each independently selected from C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halogen, and 6-10 membered aryl;

[0014] A is selected from an optionally substituted 6-10 membered aryl group, a 5-10 membered heteroaryl group, wherein the substituent is selected from halogen, C1-C6 haloalkyl, C1-C6 alkyl, and amino;

[0015] 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;

[0016] R8 is selected from the group consisting of: deuterium, halogen, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 alkoxy, amino, cyano, -C(O)CH3, -C(O)CHCH2, -C(O)NH2, C1-C6 hydroxyalkyl, -OR c ;

[0017] R a 、R c Each is selected from 6-10 membered aryl, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl;

[0018] R b selected from 6-10 membered aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic group, C3-C10 heterocycloalkyl;

[0019] R3, R4, and R5 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, and halogen;

[0020] R6 is selected from hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halogen.

[0021] 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.

[0022] As a preferred technical solution, R1 and R7 are each independently selected from methyl, cyclopropyl, phenyl, cyclobutyl, cyclohexyl, cyclopentyl, isopropyl, ethyl, -CD3, -CHF2, -CH2F, and -CF3.

[0023] As a preferred technical solution, the R3 is selected from hydrogen, fluorine, chlorine, methyl, difluoromethyl, and trideuteromethyl; the R4 is selected from hydrogen, fluorine, chlorine, methyl, difluoromethyl, and trideuteromethyl; and the R5 is selected from hydrogen, fluorine, chlorine, methyl, difluoromethyl, and trideuteromethyl.

[0024] As a preferred technical solution, R6 is selected from hydrogen, fluorine, chlorine, methyl, trifluoromethyl, and trideuterated methyl.

[0025] As a more preferred technical solution, R6 is selected from hydrogen.

[0026] As a preferred technical solution, the 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 selected from N, O, S, -OR a 、-C(O)R b .

[0027] As a preferred technical solution, the R a Selected from 6-10 membered aryl groups, preferably aryl groups.

[0028] As a preferred technical solution, the R b Selected from C3-C containing 1-3 selected from N, O, S 10 Heterocycloalkyl is preferably selected from morpholine.

[0029] As a preferred technical solution, the R cSelected from 6-10 membered aryl, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, preferably methyl, trifluoromethyl, phenyl, cyclohexyl.

[0030] As a preferred technical solution, 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.

[0031] As a preferred technical solution, the R2 is selected from

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

[0033] The R1 is selected from methyl, ethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, isopropyl, cyclopropyl, CD3. In one aspect, the present invention also provides the following compounds and enantiomers thereof or pharmaceutically acceptable salts thereof:

[0034] On the other hand, the present invention also provides a pharmaceutical composition comprising any one of the above-mentioned compounds and enantiomers thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients.

[0035] On the other hand, the present invention also provides the use of any one of the above-mentioned compounds and enantiomers thereof 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).

[0036] 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, bile duct sarcoma, 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.

[0037] The present invention also provides a method for preparing the following compound (018) and its enantiomers or pharmaceutically acceptable salts thereof, comprising the steps of:

[0038] Compound (018-3) and its enantiomers or pharmaceutically acceptable salts thereof undergo a coupling reaction with compound (018-2) to obtain (018-1) and its enantiomers or pharmaceutically acceptable salts thereof. The obtained (018-1) and its enantiomers or pharmaceutically acceptable salts thereof are then deprotected by removing the Boc protecting group to obtain the product compound (018) and its enantiomers or pharmaceutically acceptable salts thereof, wherein Boc is tert-butyloxycarbonyl.

[0039] The present invention also provides a method for preparing a compound represented by the following formula (I) and its enantiomers or pharmaceutically acceptable salts thereof, comprising the steps of:

[0040] Compound (Ia) and its enantiomers or pharmaceutically acceptable salts thereof are subjected to a coupling reaction with compound (Ia-1) to prepare (Ib) and its enantiomers or pharmaceutically acceptable salts thereof. The prepared (Ib) and its enantiomers or pharmaceutically acceptable salts thereof are subjected to deprotection of the Boc protecting group to obtain the product compound (I) and its enantiomers or pharmaceutically acceptable salts thereof, wherein Boc is tert-butyloxycarbonyl.

[0041] The present invention also provides a compound shown in the following formula and its enantiomer or a pharmaceutically acceptable salt thereof:

[0042] The present invention also provides a compound shown in the following formula and its enantiomer or a pharmaceutically acceptable salt thereof:

[0043] Detailed Description of the Invention

[0044] Various aspects and features of the present invention are further described below.

[0045] The compounds according to the present invention may exist in tautomeric forms and the present invention then includes all tautomeric forms.

[0046] 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 is stable after the substitution.

[0047] 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.

[0048] "Haloalkyl" refers to an alkyl group as described herein (e.g., C1-C6 alkyl) in which one or more hydrogen atoms are replaced by a 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.

[0049] "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.

[0050] "Haloalkoxy" refers to an alkoxy group as described herein (e.g., C1-C6 alkoxy) in which one or more hydrogen atoms are replaced by a 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.

[0051] "Alkyl" refers to an alkyl group having a specified number of carbon atoms, which is a straight chain or branched alkyl group, and it may include its sub-groups. For example, when referring to "C1-C6 alkyl", it may also include sub-range groups represented by C1-C4 alkyl, C1-C3 alkyl, C2-C6 alkyl, C2-C4 alkyl, etc., as well as specific groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.

[0052] The terms "heterocycle", "heterocyclyl" and "heterocyclic radical" 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 having at least one heteroatom (O, S or N) in at least one ring, the heteroatom-containing ring preferably having 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 bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or fully unsaturated. A heterocyclic group may be attached to any available nitrogen or carbon atom.

[0053] "Heterocycloalkyl" refers to a saturated or partially unsaturated ring radical containing two to twenty carbon atoms and at least one heteroatom. In certain embodiments, the heteroatoms are independently selected from N, O, Si, P, B, and S atoms. The heterocycloalkyl group can be selected from a monocyclic or bicyclic ring (when fused to an aryl or heteroaryl ring, the heterocycloalkyl group is bonded through 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 group is connected to the rest of the molecule through any atom of the heterocycloalkyl group (valence permitting), such as any carbon atom or nitrogen atom of the heterocycloalkyl group. In certain embodiments, the heterocycloalkyl group contains 5 to 20 carbon atoms. In certain embodiments, the heterocycloalkyl group contains 5 to 10 carbon atoms. In other embodiments, the heterocycloalkyl group contains 5 to 7 carbon atoms. In some embodiments, the heterocycloalkyl group 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 a "heterocycloalkenyl." Examples of heterocycloalkenyl groups include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 2-oxo-1,3-dioxolyl, and the like. 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.

[0054] "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 group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C10 aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms ("C14 aryl"; e.g., anthracenyl). Aryl groups may be described, for example, as C6-C10 aryl. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of aryl may independently be optionally substituted, e.g., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). 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:

[0055] 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 having at least one heteroatom (O, S, or N) in at least one ring, the heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the heteroaryl group containing heteroatoms may 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 may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. A heteroaryl group as a bicyclic or tricyclic group must include at least one fully aromatic ring, but the other one or more fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached to any available nitrogen or carbon atom of any ring. Where valence permits, if the other ring is a cycloalkyl or heterocycle, it is further optionally substituted with =0 (oxo). Representative heteroaryl examples include, but are not limited to:

[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 when performing chiral resolution. 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 used herein, the term "disease" refers to a physical condition of the subject that is associated with the disease described herein. For example, inflammatory diseases and neurodegenerative diseases described herein. Cancer described herein includes standard treatments such as surgery, radiation therapy, 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 through 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 and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, larynx cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach 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 plasmacytoma, lymphoma, pancreatic ductal adenocarcinoma, etc.

[0059] The compound of the present invention or the pharmaceutical composition containing the same can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, 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, w / o, and multiple emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols (powders), and sprays; semisolid dosage forms can be ointments, gels, pastes, and the like.

[0061] 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 method of administration.

[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. Through computer simulation, molecular docking analysis, and drug structure-activity relationship studies, a variety of novel compounds were screened. This series of compounds can specifically bind to the CoREST complex and inhibit its function, with extremely strong CoREST complex and HDAC inhibitory activity, and IC50s are equivalent to or less than those of the positive control drug TNG260. The present invention provides a class of CoREST complex inhibitor compounds with novel structures, strong activity, and excellent oral pharmacokinetic exposure in mice. These compounds have promising application prospects in the prevention and / or treatment of 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 of 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 degrees 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 were confirmed by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are expressed in parts per million (ppm). NMR measurements were performed using a Bruker Avance-400 NMR spectrometer. The solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

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

[0069] The starting materials used in the examples of the present invention are known and can be purchased commercially, or can be used or synthesized 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] Step 1: Synthesis of compound 1-bromo-4-methylsulfonylbenzene

[0073] (4-Bromophenyl)(methyl)sulfane (400 mg, 2.0 mmol, 1.0 eq) was added to dichloromethane (10 mL) under an ice-water bath, followed by m-chloroperbenzoic acid (531 mg, 3.0 mmol, 1.0 eq). After complete addition, the mixture was allowed to react at room temperature for 18 hours. After completion, the pH was adjusted to a weakly alkaline state by adding saturated sodium bicarbonate solution. Dichloromethane and water were then added, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined and concentrated to yield crude 1-bromo-4-methylsulfonylbenzene (403 mg, 92.8% yield). 1 H NMR (400MHz, DMSO-d6) δ7.82-7.75(m,2H),7.67-7.61(m,2H),2.77-2.72(m,3H).

[0074] Step 2: Synthesis of (methylsulfinyl)cyclopropane

[0075] 1-Bromo-4-methylsulfonylbenzene (4.0 g, 18.4 mmol, 1.0 eq) was added to tetrahydrofuran (40 mL). The nitrogen atmosphere was replaced twice. Cyclopropylmagnesium bromide (36.6 mL, 36.6 mmol, 2.0 eq) was then slowly added dropwise at 0°C over approximately 1 hour. The reaction was allowed to proceed at 0°C for 3 hours. After the reaction was complete, saturated ammonium chloride solution (10 mL) was added and stirred for 10 minutes. The mixture was filtered through celite, rinsed with methanol, and the filtrate was concentrated. A small amount of dichloromethane was added for dissolution. The sample was wet loaded and separated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain (methylsulfinyl)cyclopropane (1.34 g, 70.1% yield) as a pale yellow liquid. 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).

[0076] Step 3: Cyclopropyliminomethyl-λ 6 Synthesis of -sulfonone

[0077] Dissolve (methylsulfinyl)cyclopropane (700 mg, 6.7 mmol, 1.0 eq) in methanol (10 mL), add ammonia methanol solution (4.5 mL), and add iodophenyldiacetic acid (6.5 g, 20.2 mmol, 3.0 eq) in batches at 0°C. After addition, transfer to room temperature and stir, 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 the liquid. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated. Column chromatography (dichloromethane: methanol = 20:1) is used to obtain cyclopropyliminomethyl-λ as a light yellow oily liquid. 6 -sulfonone (472 mg, yield 59.2%). LCMS (ESI) [M+H] +: 120.

[0078] N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-4-(cyclopropylmethyloxy)-λ 6 Synthesis of -sulfonylideneamino)benzamide

[0079] Step 1: Synthesis of tert-butyl (4-bromo-2-nitrophenyl)carbamate

[0080] Under an ice-water bath, 4-bromo-2-nitroaniline (2 g, 9.2 mmol, 1.0 eq) and sodium hydride (404 mg, 10.12 mmol, 1.1 eq) were added to N,N-dimethylformamide (60 mL). The mixture was stirred for 15 minutes. Di-tert-butyl dicarbonate (2.6 g, 11.96 mmol, 1.3 eq) was then dissolved in N,N-dimethylformamide (20 mL) and slowly added dropwise to the reaction flask. The reaction was allowed to react at room temperature for 5 hours. After completion, saturated ammonium chloride solution was added to quench the reaction. Water and ethyl acetate were added, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, concentrated, and separated by normal phase column chromatography to obtain tert-butyl (4-bromo-2-nitrophenyl)carbamate (1.968 g, 67.5% yield) as a yellow solid.

[0081] Step 2: Synthesis of tert-butyl (4'-fluoro-3-nitro-[1,1'-biphenyl]-4-yl)carbamate

[0082] Tert-butyl (4-bromo-2-nitrophenyl)carbamate (1.9 g, 6 mmol, 1.0 eq), (4-fluorophenyl)boronic 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) were dissolved in a mixture of 1,4-dioxane (75 mL) and water (15 mL). The atmosphere was replaced with nitrogen and the mixture was stirred at 100°C for 12 hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was added with water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, concentrated, and separated by normal phase column chromatography to obtain tert-butyl (4'-fluoro-3-nitro-[1,1'-biphenyl]-4-yl)carbamate (1.67 g, 83.8% yield).

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

[0084] tert-Butyl (4'-fluoro-3-nitro-[1,1'-biphenyl]-4-yl)carbamate (8 g, 24.1 mmol, 1.0 eq) and iron powder (6.743 g, 120.4 mmol, 5.0 eq) were added to a reaction flask, a condenser was added, and the atmosphere was replaced with nitrogen. Methanol (160 mL) and water (40 mL) were then added and reacted at 80°C for 3 hours. After completion of the reaction, the mixture was hot filtered, the filtrate was concentrated, column chromatography was performed, and ethyl acetate was added to obtain tert-butyl (3-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)carbamate (7.1 g, 97.6% yield) as a white solid. 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).

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

[0086] 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.

[0087] Step 5: (3-(4-((cyclopropyl(methyloxy)-λ 6 Synthesis of tert-butyl (4'-sulfonylidene)amino)benzamido)-4'-fluoro-[1,1'-biphenyl]-4-yl)carbamate

[0088] 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(diphenylphosphino)-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. The system was replaced with nitrogen and the reaction was carried out at 80 ° C for 12 hours. After the reaction was completed, celite 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%). 1H NMR(400MHz, CDCl3)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).

[0089] Step 6: N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-4-(cyclopropylmethyloxy)-λ 6 Synthesis of -sulfonylideneamino)benzamide

[0090] N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-4-(cyclopropylmethyloxy)-λ 6 -sulfonylideneamino)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 subjected to high performance liquid chromatography 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).

[0091] Example 042: N-(4-amino-[1,1'-biphenyl]-3-yl)-4-[(cyclopropyl(methyl)(oxo)-λ 6 Synthesis of [-sulfinylidene)amino]benzamide

[0092] Step 1: 4-{[cyclopropyl(methyloxy)-λ 6 Synthesis of methyl benzoate

[0093] 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]oxaphosphole (61.1 mg, 0.18 mmol, 0.22 eq) and cesium carbonate (821.1 mg, 2.52 mmol, 3.0 eq), and the reaction was carried out at 80°C for 12 hours. After completion of the reaction, the mixture was filtered through celite, extracted three times with ethyl acetate and water, and the organic phase was concentrated and separated by a normal phase column. 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.

[0094] Step 2: 4-{[cyclopropyl(methyloxy)-λ 6 Synthesis of [-sulfonylidene]amino]benzoic acid

[0095] 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 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. The mixture was extracted with ethyl acetate and the organic phase was concentrated to give the crude product 4-{[cyclopropyl(methyloxy)-λ 6 -sulfonylidene]amino}benzoic acid (112 mg). LCMS (ESI) [M+H] + :240.08.

[0096] Step 3: Synthesis of tert-butyl (3-amino-[1,1'-biphenyl]-4-yl)carbamate

[0097] 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). Phenylboronic acid (204.7 mg, 1.67 mmol, 1.2 eq) / [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (101 mg, 0.14 mmol, 0.1 eq) and potassium carbonate (387 mg, 2.8 mmol, 2.0 eq) were then added. The atmosphere was replaced with nitrogen and the reaction was continued at 100°C for 12 hours. After completion of the reaction, the mixture was filtered through celite, concentrated, and separated by a normal phase column. The resulting solution was concentrated to afford tert-butyl (3-amino-[1,1'-biphenyl]-4-yl)carbamate (182 mg, 45.8% yield). LCMS (de-Boc) [M+H]+: 185.1059.

[0098] Step 4: (3-(4-((cyclopropyl(methyl)(oxo)-λ 6 Synthesis of tert-butyl (1,1'-sulfinylidene)amino)benzamido)-[1,1'-biphenyl]-4-yl)carbamate

[0099] 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 uronium chloride 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 and extracted three times. The organic layer was concentrated and separated by preparative plate to obtain (3-(4-((cyclopropyl(methyl)(oxo)-λ 6 -sulfinylidene)amino)benzamido)-[1,1'-biphenyl]-4-yl)carbamic acid tert-butyl ester (25 mg, yield 50.1%). LCMS (de-Boc) [M+H] + :506.2111.

[0100] Step 5: N-(4-amino-[1,1'-biphenyl]-3-yl)-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of [-sulfinyl]amino]benzamide

[0101] (3-(4-((cyclopropyl(methyl)(oxo)-λ 6To the mixture of tert-butyl (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).

[0102] Example 050: N-[2-amino-5-(pyridazin-3-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of [-sulfinyl]amino]benzamide

[0103] Step 1: Synthesis of tert-butyl [2-amino-4-(pyridazin-3-yl)phenyl]carbamate

[0104] 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]dichloropalladium (43.6 mg, 0.06 mmol, 0.1 equiv.) and potassium carbonate ( The product (165.6 mg, 1.20 mmol, 2.0 equiv.) was dissolved in 1,4-dioxane (12 mL) and water (3 mL). The system was purged with nitrogen three times and the temperature was raised to 95°C with stirring for 18 h. After the reaction was complete, the mixture was filtered through celite and the filtrate was extracted three times with water and ethyl acetate. The organic phase was dried, concentrated, and purified by column chromatography to afford tert-butyl [2-amino-4-(pyridazin-3-yl)phenyl]carbamate (125 mg, 72.8% yield). LCMS: [M-Boc+H]+ = 187.1040.

[0105] Step 2: Compound (2-(4-((cyclopropyl(methyl)(oxo)-λ 6 Synthesis of tert-butyl (4-(pyridazin-3-yl)phenyl)carbamate

[0106] 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 tert-Butyl-4-(pyridazin-3-yl)phenyl)carbamate (21 mg, 89.1%).

[0107] Step 3: Synthesis of N-[2-amino-5-(pyridazin-3-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ6-sulfinyl]amino}benzamide

[0108] First, the compound ((2-(4-((cyclopropyl(methyl)(oxo)-λ 6tert-Butyl (2-amino-5-(pyridazin-3-yl)phenyl)carbamate (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 Benzamide (8 mg, 53.1% yield). LCMS: [M+H]+ = 408.1117. 1H NMR (400 MHz, CDCl3) δ 9.10 (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).

[0109] Example 075: N-[2-amino-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of [-sulfinyl]amino]benzamide

[0110] Step 1: Synthesis of tert-butyl [2-amino-4-(1-methyl-1H-pyrazol-4-yl)phenyl]carbamate

[0111] 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]dichloropalladium (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 completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The mixture was washed with saturated sodium chloride. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and separated using a forward flow column to afford tert-butyl [2-amino-4-(1-methyl-1H-pyrazol-4-yl)phenyl]carbamate (380 mg, 88% yield). LCMS: m / z = [M+H]-Boc 189.

[0112] Step 2: (2-(4-((cyclopropyl(methyl)(oxo)-λ 6 Synthesis of tert-butyl 4-(1-methyl-1H-pyrazol-4-yl)phenyl)carbamate

[0113] 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'-tetramethyluronium chloride 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 and extracted three times. The organic layer was concentrated and separated by column chromatography to obtain (2-(4-((cyclopropyl(methyl)(oxo)-λ 6 -sulfinylidene)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.

[0114] Step 3: N-[2-amino-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of [-sulfinyl]amino]benzamide

[0115] (2-(4-((cyclopropyl(methyl)(oxo)-λ 6 To the mixture of tert-butyl 2-[2-amino-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ-pyrazol-4-yl)phenyl]-4-{ ...2-cyclopropyl(methyl)(oxo)-λ-pyrazol-4-yl)phenyl]-4-{[2 6 Synthesis of 1-sulfinyl]amino}benzamide (10 mg, yield 27%). LCMS [M+H] + :410.2322. 1H 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).

[0116] Example 080: N-[2-amino-5-(benzo[b]thiophen-5-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of [-sulfinyl)]amino]benzamide

[0117] Step 1: Synthesis of tert-butyl [2-amino-4-(benzothiophen-5-yl)phenyl]carbamate

[0118] The compound tert-butyl (2-amino-4-bromophenyl)carbamate (300 mg, 1.052 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (12 mL) and water (3 mL). 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. The gas in the system was replaced by nitrogen three times, and the temperature was raised to 95°C for 12 hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The mixture was washed with saturated sodium chloride. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and separated by column chromatography to afford tert-butyl [2-amino-4-(benzothiophen-5-yl)phenyl]carbamate (180 mg, 50% yield) as a white solid. LCMS: m / z = [M+H]-Boc 241.0732. 1 H NMR (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).

[0119] Step 2: (4-(Benzothiophen-5-yl)-2-(4-((cyclopropyl(methyl)(oxo)-λ 6 Synthesis of (1,2-dimethyl-1,2-disulfinyl)amino)benzamido)phenyl)carbamate

[0120] 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'-tetramethyluronium chloride hexafluorophosphate (36.0 mg, 0.11 mmol, 1.5 equiv.) and N-methylimidazole (24.0 mg, 0.24 mmol, 3.5 equiv.) were stirred at room temperature for 2 hours. After the reaction was completed, column chromatography was used to separate the 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.

[0121] Step 3: Compound N-[2-amino-5-(benzo[b]thiophen-5-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of [-sulfinyl)]amino]benzamide

[0122] (4-(Benzothiophene-5-yl)-2-(4-((cyclopropyl(methyl)(oxo)-λ 6 -sulfinyl)amino)benzamido)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. The 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. 1H 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).

[0123] Example 081: N-[2-amino-5-(furan-2-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of [-sulfinyl]amino]benzamide

[0124] Step 1: Synthesis of tert-butyl [2-amino-4-(furan-2-yl)phenyl]carbamate

[0125] 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-dioxaborolane (194 mg, 1.0 mmol, 1.0 equiv.), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (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 100 °C for 12 hours. After the reaction was complete, the mixture was filtered through celite, the filtrate was concentrated, and the residue was separated by normal phase column chromatography to give 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.

[0126] Step 2: (2-(4-((cyclopropyl(methyl)(oxo)-λ 6 Synthesis of tert-butyl 4-(furan-2-yl)phenyl)carbamate

[0127] 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'-tetramethyluronium chloride 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 and extracted three times. The organic layer was concentrated and separated by preparative plate to obtain 2-(4-((cyclopropyl(methyl)(oxo)-λ 6 -butyl)-4-(furan-2-yl)phenyl)carbamate (35 mg, yield 71.4%). LCMS (de-Boc) [M+H] + :496.2063.

[0128] Step 3: N-[2-amino-5-(furan-2-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of [-sulfinyl]amino]benzamide

[0129] (2-(4-((cyclopropyl(methyl)(oxo)-λ 6 To tert-butyl 2-[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. 1H 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).

[0130] Example 091: N-[2-amino-5-(methylthiophen-2-yl)phenyl]-4-{[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of [-sulfinyl]amino]benzamide

[0131] Step 1: Synthesis of tert-butyl [2-amino-4-(5-methylthiophen-2-yl)phenyl]carbamate

[0132] 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 complete, the mixture was filtered through celite, the filtrate was concentrated, and the product was separated by normal phase column chromatography to give tert-butyl [2-amino-4-(5-methylthiophen-2-yl)phenyl]carbamate (162 mg, yield 53.3%). LCMS (de-Boc) [M+H]+: 205.0583.

[0133] Step 2: (2-(4-((cyclopropyl(methyl)(oxo)-λ 6 Synthesis of tert-butyl 4-(5-methylthiophen-2-yl)phenyl)carbamate

[0134] 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)-λ6 -sulfinyl)amino]benzoic acid (30 mg, 0.13 mmol, 1.0 eq), N,N,N',N'-tetramethyluronium chloride 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 and extracted three times. The organic layer was concentrated and separated by preparative plate to obtain (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.

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

[0136] (2-(4-((cyclopropyl(methyl)(oxo)-λ 6 To the mixture of tert-butyl 2-[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).

[0137] Example 150: N-[2-amino-5-(thiazol-2-yl)phenyl]-4-[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of [-sulfenylamino]benzamide

[0138] Step 1: Synthesis of tert-butyl [2-amino-4-(thiazol-2-yl)phenyl]carbamate

[0139] The compound [2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamic acid tert-butyl ester (500 mg, 1.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (12 mL) and water (4 mL), and 2-bromothiazole (369 mg, 2.25 mmol, 1.5 equiv.), potassium carbonate (621 mg, 4.5 mmol, 3.0 equiv.) and bisdiphenylphosphine palladium dichloride (109 mg, 0.15 mmol, 0.1 equiv.) were added to the system. The gas in the system was replaced by nitrogen three times, and the temperature was raised to 95°C for 18 hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The mixture was washed with saturated sodium chloride. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and separated by column chromatography to obtain tert-butyl (2-amino-4-(thiazol-2-yl)phenyl)carbamate (260 mg, 59.5% yield). LCMS: [M+H-Boc]: 192.0593.

[0140] Step 2: Synthesis of tert-butyl (2-(4-((cyclopropyl(methyl)(oxo)-λ6-sulfinyl)amino)benzamido)-4-(thiazol-2-yl)phenyl)carbamate

[0141] 4-((cyclopropyl(methyl)(oxo)-λ6-sulfinyl)amino)benzoic acid (150 mg, 0.6 mmol, 1.0 equiv.) and tert-butyl (2-amino-4-(thiazol-2-yl)phenyl)carbamate (260 mg, 0.9 mmol, 1.5 equiv.) were dissolved in acetonitrile (7 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (252 mg, 0.9 mmol, 1.5 equiv.) and N-methylimidazole (172.2 mg, 2.1 mmol, 3.5 equiv.) were added and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated and separated by column chromatography to obtain tert-butyl (2-(4-((cyclopropyl(methyl)(oxo)-λ6-sulfinyl)amino)benzamido)-4-(thiazol-2-yl)phenyl)carbamate (200 mg, 65% yield). LCMS: [M+H]: 513.1608.

[0142] Step 3: N-[2-amino-5-(thiazol-2-yl)phenyl]-4-[cyclopropyl(methyl)(oxo)-λ 6 Synthesis of [-sulfenylamino]benzamide

[0143] Tert-butyl (2-(4-((cyclopropyl(methyl)(oxo)-λ6-sulfinyl)amino)benzamido)-4-(thiazol-2-yl)phenyl)carbamate (200 mg, 0.39 mmol, 1.0 equiv.) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, dissolved with saturated sodium bicarbonate and adjusted to pH 8.0-9.0, and then concentrated again and subjected to high performance liquid chromatography to prepare the compound N-[2-amino-5-(thiazol-2-yl)phenyl]-4-[cyclopropyl(methyl)(oxo)-λ6-sulfinyl)amino]benzamido)-4-(thiazol-2-yl)phenyl]carbamate. 6 -sulfinylamino]benzamide (100 mg, yield 62.2%). LCMS: [M+H]+=413.1101. 1 H NMR (400MHz, DMSO-d6) δ9.46(s,1H),7.88–7.83(m,2H),7.82(d,J=2.2Hz,1H),7.76(d,J=3.3Hz,1H),7.58–7.53(m,2H),7. 05–7.00(m,2H),6.85(d,J=8.4Hz,1H),5.37(s,2H),3.24(s,3H),2.91–2.83(m,1H),1.26–1.20(m,1H),1.16–1.02(m,3H).

[0144] 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.

[0145] Table 1: Structure and characterization of some compounds

[0146] Experimental Example 1: Activity test of the compounds of the present invention on HDAC1 / 3 protease

[0147] Experimental purpose: The purpose of this test case is to test the effect of the compound on the HDAC1 / 3 enzyme function

[0148] Background and Principle: Histone deacetylases (HDACs) are a class of epigenetic proteins associated with a variety of diseases, including cancer. Inhibition of specific HDACs may treat or otherwise ameliorate such diseases in some patients. Currently, four families of HDACs have been found in humans, 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 the a-PD1 resistance caused by STK11 deficiency. HDAC3 is an essential gene and the main driver of bone marrow toxicity caused by HDAC inhibitors targeting multiple subtypes.

[0149] Experimental Procedure: This test example uses the Fluorogenic HDAC1 Assay Kit and Fluorogenic HDAC3 Assay Kit (BPS bioscience) to detect HDAC1 and HDCA3 enzyme activities. Step 1: The following reaction mixtures were added in duplicate to a microtiter black plate as follows: 1) Prepare a master mix: N wells × (5 μl HDAC substrate (200 μM) + 5 μl BSA (1 mg / ml) + 30 μl HDAC Assay Buffer). Add 40 μl of the master mix to all wells. 2) At a maximum concentration of 20 μM, dilute the test compound 5-fold over a 9-well gradient, adding 5 μl of the inhibitor solution to each well. For the blank and positive controls, add 5 μl of the same solution without inhibitor. Maintain the final DMSO concentration at or below 1%. 3) Add 5 μl of HDAC Assay Buffer to the blank control wells. 4) Initiate the reaction by adding 5 μl of the diluted HDAC1 enzyme to the positive control and test inhibitor wells. 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 detection wavelength of 440-460 nm. Calculate the IC50 using GraphPad software, and screen the compound by comparing it to the positive drug TNG260. IC50 (half maximal inhibitory concentration) refers to the half-inhibitory concentration of the measured antagonist. It indicates the half-dose of a drug or substance (inhibitor) in inhibiting a certain biological process (or certain substances contained in this process, such as enzymes, cell receptors, or microorganisms). The synthesis method of TNG260 is referred to WO2023102162. The structure of TNG260 is as follows:

[0150] The HDAC1 and HDAC3 IC50 results for each compound determined using the assay are shown in Table 2 below. The compound numbers correspond to the compound numbers shown in Table 1, with "A" indicating an IC50 less than 10 nM, "B" indicating an IC50 range of 10 nM to 50 nM, "C" indicating an IC50 range of 50 nM to 200 nM, "D" indicating an IC50 range of 200 nM to 2 μM, and "E" indicating an IC50 greater than 2 μM.

[0151] Table 2: IC values ​​of exemplary compounds of the present invention for HDAC1 / 3 protease activity 50 value

[0152] Conclusion: A smaller IC50 value for HDAC1 protease inhibition indicates stronger HDAC1 inhibition; a larger IC50 value for HDAC3 protease inhibition indicates weaker HDAC3 inhibition. Therefore, most of the novel sulfonyliminobenzamide compounds prepared in this invention exhibit surprisingly superior HDAC1 inhibitory activity and excellent HDAC1 / 3 selectivity compared to the positive control compound TNG260. This strong inhibitory activity and selectivity have important therapeutic implications for the treatment of conditions or diseases associated with HDAC1 inhibition.

[0153] Experimental Example 2: Testing of the Functional Effects of the Compounds of the Invention on the CoREST Complex

[0154] 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.

[0155] Background: CoREST was identified as a sensitizer to anti-PD-1 in an in vivo screen for STK11-deficient cancers. Class I HDAC enzymes function through four major complexes: HDAC1 / 2 reside in the CoREST, NuRD, and Sin3 complexes, while HDAC3 resides in the NCoR complex.

[0156] Experimental process:

[0157] Cell culture: A549 cells were grown in Ham's F-12K + 10% FBS + 1% P / S medium. Cells in logarithmic growth phase were plated in culture dishes and allowed to reach approximately 90% confluence before subsequent experiments. Immunoprecipitation: CoREST, NuRD, Sin3, and NCoR complexes were isolated using an immunoprecipitation kit (Protein A + G magnetic beads). Cell samples were lysed, the culture medium was aspirated, and the cells were washed once with PBS, followed by aspiration of any remaining liquid. 100-200 μl of lysis buffer containing inhibitors was added per 500,000-1,000,000 cells, with adequate pipetting to ensure adequate contact between the lysate and the cells. After complete lysis, centrifuge at 10,000-14,000 × g at 4°C for 3-5 minutes and remove the supernatant. Bind the antibody to Protein A+G magnetic beads and incubate with the supernatant overnight at 4°C. Using the acid elution method, add 100 μl of Acid Elution Buffer per 20 μl of the original volume of magnetic beads, mix thoroughly, and incubate on a side-by-side shaker or rotary mixer at room temperature for 5 minutes. After incubation, separate on a magnetic stand for 10 seconds. Transfer the supernatant to a new centrifuge tube and immediately add 10 μl of Neutralization Buffer and mix thoroughly. Deacetylase assay: Determine the enzyme activity of each complex based on fluorescence. Calculate the IC50 using GraphPad software and screen compounds by comparing them to the positive drug TNG260.

[0158] The results of the assay for CoREST complex function for each compound using the assay are shown in Table 3 below. The compound numbers correspond to the compound numbers shown in Table 1, with "A" indicating an IC50 of less than 50 nM, "B" indicating an IC50 range of 50 nM to 200 nM, "C" indicating an IC50 range of 200 nM to 500 nM, and "D" indicating an IC50 range of 500 nM to 2 μM.

[0159] Table 3 IC values ​​of exemplary compounds of the present invention for the functional effects on the CoREST complex 50 value

[0160] Conclusion: The novel compounds synthesized have good enzyme inhibitory activity against the CoREST complex. The inhibitory activity of most compounds is better than that of the positive drug TNG260, and they have potential potential for development as anti-tumor drugs.

[0161] Experimental Example 3: Pharmacokinetics of the compounds of the present invention in mice

[0162] Experimental purpose: To administer the compound of the present invention to mice by oral gavage (PO) to investigate its pharmacokinetic characteristics

[0163] Specific experimental process:

[0164] The compound of the present invention and the control compound TNG260 were administered by oral gavage (30 mg / kg), PO solvent: 50% PEG300 + 15% Tween 80 + 35% water, prepared on the day of administration. Blood was collected from the jugular vein 0 h before administration and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h after administration (oral gavage), and about 0.02 mL of blood was collected for each sample. K2-EDTA anticoagulation was used and the samples were placed on ice after collection. Plasma sample processing: After blood collection, the blood samples were placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6800 g, 6 minutes, 2-8 ° C). Plasma samples were stored in a -80 ° C freezer before analysis. Pharmacokinetic parameters were calculated using Phoenix WinNonlin7.0 based on the blood drug concentration data at different time points. The experimental results are shown in Table 4 below:

[0165] Table 4: In vivo pharmacokinetic test results in mice

[0166] The pharmacokinetic data of the compound of the present invention in mice show that, compared with the control compound TNG260, the oral pharmacokinetic exposure of the compound in mice is better than that of the control compound TNG260.

[0167] The above examples are merely representative. It can be seen from the above examples that the compounds of the present invention are ideal and highly effective HDAC1 enzyme inhibitors and can be expected to be used for treating or preventing conditions or diseases associated with HDAC1 inhibition.

[0168] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes based on the technical solutions and inventive concepts of the present invention within the technical scope disclosed by the present invention, and these changes should be covered by the scope of protection of the present invention.

Claims

1. A compound represented by formula (I) and its enantiomer 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, and R5 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, and 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, its enantiomer 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 1-2 and its enantiomer 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 1-3 and its enantiomer 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 1-4 and its enantiomer 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 1-5 and its enantiomer 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 and its enantiomer or a pharmaceutically acceptable salt thereof, characterized in that: The R6 is selected from hydrogen, fluorine, chlorine, methyl, trifluoromethyl, trideuterated methyl, preferably hydrogen.

8. The compound according to claims 1-7 and its enantiomer 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 and its enantiomer 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 and its enantiomer 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 and its enantiomer 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 and its enantiomer 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 and its enantiomer or a pharmaceutically acceptable salt thereof, characterized in that: The R2 is selected from 14. The compound according to claims 1-13 and its enantiomer 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 and its enantiomers or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

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

17. Use of the compound according to any one of claims 1 to 15 and its enantiomer 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.

19. A method for preparing the following compound (018) and its enantiomer or a pharmaceutically acceptable salt thereof, comprising the steps of: Compound (018-3) and its enantiomer or a pharmaceutically acceptable salt thereof undergoes a coupling reaction with compound (018-2) to obtain (018-1) and its enantiomer or a pharmaceutically acceptable salt thereof; the obtained (018-1) and its enantiomer or a pharmaceutically acceptable salt thereof are subjected to deprotection to obtain the product compound (018) and its enantiomer or a pharmaceutically acceptable salt thereof, wherein Boc is tert-butyloxycarbonyl.

20. A method for preparing a compound represented by the following formula (I) and its enantiomer or a pharmaceutically acceptable salt thereof, comprising the steps of: Compound (Ia) and its enantiomer or a pharmaceutically acceptable salt thereof undergoes a coupling reaction with compound (Ia-1) to obtain (Ib) and its enantiomer or a pharmaceutically acceptable salt thereof. The obtained (Ib) and its enantiomer or a pharmaceutically acceptable salt thereof are subjected to deprotection of the Boc protecting group to obtain the product compound (I) and its enantiomer or a pharmaceutically acceptable salt thereof, wherein Boc is tert-butyloxycarbonyl.

21. A compound represented by the following formula and its enantiomer or a pharmaceutically acceptable salt thereof:

22. A compound represented by the following formula and its enantiomer or a pharmaceutically acceptable salt thereof:

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