Benzimidazole derivative serving as novel HDAC inhibitor, pharmaceutical composition containing benzimidazole derivative, pharmaceutical preparation and application of benzimidazole derivative

Abstract

The invention belongs to the technical field of biological medicine, and relates to a benzimidazole derivative serving as a novel HDAC inhibitor, a pharmaceutical composition containing the benzimidazole derivative, a pharmaceutical preparation containing the benzimidazole derivative and medical application of the benzimidazole derivative. The benzimidazole derivative is a compound with a structure as shown in a formula (I), has excellent HDAC inhibitory activity, can inhibit HDAC6 and / or HDAC1 with high strength, and shows excellent HDAC6 selectivity. Meanwhile, the compound disclosed by the invention shows remarkable anti-tumor cell proliferation activity. The compound provided by the invention can be used as a therapeutic drug for tumors, autoimmune diseases, inflammation or Alzheimer's disease.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and relates to a benzimidazole derivative as a novel HDAC inhibitor, a pharmaceutical composition containing the same, a pharmaceutical preparation, and a medical use thereof. BACKGROUND

[0002] Malignant tumor is the second leading cause of death worldwide, and its incidence and mortality continue to rise, becoming a major public health challenge. In recent years, research has found that the occurrence and development of cancer are closely related to abnormal epigenetic regulation. Epigenetics regulates gene expression through reversible mechanisms such as DNA methylation and histone modification, without changing the DNA sequence. Among them, histone deacetylases (HDACs) affect various life processes, including gene transcription, DNA damage repair, apoptosis, cycle regulation, metabolism and angiogenesis, through deacetylation of histones and non-histones. The mutation and abnormal expression of HDACs can lead to the occurrence of various diseases, especially tumors, and can also cause other nervous system diseases, autoimmune diseases, inflammatory diseases and heart diseases, making HDACs an important target for cancer and neurodegenerative disease treatment. So far, 18 HDAC subtypes have been identified in the epigenetic modification family of HDACs, and they are divided into four classes according to their homology with yeast proteins: Class I (HDAC1, 2, 3 and 8), Class II (IIa: HDAC4, 5, 7, 9; IIb: 6 and 10), Class III (SIRT 1-7), and Class IV (HDAC11). Among them, Class I, II and IV are zinc ion (Zn 2+ ) dependent enzymes, and Class III is an NAD + dependent enzyme.

[0003] The development of anti-tumor drugs targeting HDACs has become a hot spot in the field of epigenetic therapy. The pharmacophore model of the structure of HDAC inhibitors (HDACIs) is mainly divided into three parts: the recognition group (Cap) interacting with the surface of the receptor, the chelating group (ZBG) acting with Zn 2+ in the bottom of the active pocket, and the hydrophobic long chain (Linker) connecting the two parts. According to the structural characteristics, HDACIs can be divided into hydroxamic acids, benzamides, cyclic peptides and short-chain fatty acids, etc. So far, five HDAC inhibitors (SAHA, FK-228, PXD-101, LBH-589 and Chidamide) have been approved for marketing worldwide, mainly for the treatment of hematological malignancies. However, HDAC inhibitors face challenges in the treatment of solid tumors, and the research of anti-tumor drugs targeting HDACs has both profound scientific significance and urgent clinical needs. SUMMARY

[0004] Problem to be solved by the invention

[0005] The present application aims to design, synthesize and verify a series of benzimidazole derivatives as targeted HDAC small molecule inhibitors, which can treat acute myeloid leukemia, colorectal cancer, non-small cell lung cancer and breast cancer and other diseases related to HDAC by inhibiting the enzymatic function of HDAC.

[0006] Solution for solving the problem

[0007] In a first aspect, the present application provides a compound as shown in formula (I) or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof:

[0008]

[0009] wherein,

[0010] A1and A3are each independently selected from CR' and N;

[0011] A2is selected from CR3and N;

[0012] A4is selected from CR2and N;

[0013] R2and R3are each independently selected from H, hydroxyl, halogen (selected from F, Cl, Br and I), C1-C6alkoxy, C1-C6alkylamino, C1-C6alkoxycarbonyl, substituted or unsubstituted C1-C6acylamino, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered alicyclic, substituted or unsubstituted 3-12 membered heterocyclic and substituted or unsubstituted benzyl, if present; 10 alkyl, substituted or unsubstituted C6-C 12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered alicyclic, substituted or unsubstituted 3-12 membered heterocyclic and substituted or unsubstituted benzyl;

[0014] R1is selected from H, C1-C6alkoxy, C1-C6alkylamino, C1-C6alkoxycarbonyl, substituted or unsubstituted C1-C6acylamino, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered alicyclic, substituted or unsubstituted 3-12 membered heterocyclic and substituted or unsubstituted benzyl; 10 alkyl, substituted or unsubstituted C6-C 12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered alicyclic, substituted or unsubstituted 3-12 membered heterocyclic and substituted or unsubstituted benzyl;

[0015] X is selected from CR' and N;

[0016] Y is absent or selected from the group consisting of C1-C6alkylene, CR'2, NH, C1-C6alkyleneoxy, C1-C6alkyleneamino, C1-C6alkyleneoxycarbonyl and substituted or unsubstituted C1-C6alkylenecarbamoyl;

[0017] Z is absent or selected from the group consisting of C1-C6alkylene, substituted or unsubstituted C 6-14 arylene, substituted or unsubstituted 5-14 membered arylidene, substituted or unsubstituted C 7-12 aralkylene and substituted or unsubstituted 6-12 membered heteroaralkylene;

[0018] each R' is independently selected from the group consisting of H, C1-C6alkoxy, C1-C6alkylamino, C1-C6alkoxycarbonyl, substituted or unsubstituted C1-C6amido, substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted C6-C 12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered alicyclyl, substituted or unsubstituted 3-12 membered heterocyclyl and substituted or unsubstituted benzyl;

[0019] said substitution means that one or more hydrogen atoms of the group are each independently replaced by R:

[0020] each R is independently selected from the group consisting of halogen atom, oxo, carboxyl, hydroxyl, amino, nitro, cyano, C1-C 10 alkyl, C1-C6alkoxy, C1-C6haloalkoxy, -S-(C1-C6alkyl), C1-C6alkylamino, C1-C6alkoxycarbonyl, C1-C6amido, C6-C 10 aryl, five-membered heteroaryl and six-membered heteroaryl, and C1-C 10 alkyl, C6-C 10 aryl, five-membered heteroaryl and six-membered heteroaryl; preferably C1-C6alkyl, C1-C6alkoxy and C1-C6alkylamino.

[0021] In some embodiments, the compound is represented by formula (II):

[0022]

[0023] wherein R1, X, Y and Z are as defined in formula (I).

[0024] In some embodiments, Z is selected from the group consisting of substituted or unsubstituted C 6-14 arylene and substituted or unsubstituted 5-14 membered arylidene.

[0025] In some preferred embodiments, Z is selected from the group consisting of substituted or unsubstituted C 6-14substituted or unsubstituted C6-Ci2aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered alicyclyl, substituted or unsubstituted 3-12 membered heterocyclyl, and substituted or unsubstituted benzyl. 6-10 substituted or unsubstituted C6-Ci2aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered alicyclyl, substituted or unsubstituted 3-12 membered heterocyclyl, and substituted or unsubstituted benzyl.

[0026] In some embodiments, the compound is represented by formula (III):

[0027]

[0028] wherein, R1and Y are as defined in formula (I).

[0029] In some embodiments, R1is selected from substituted or unsubstituted C6-Ci2aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered alicyclyl, substituted or unsubstituted 3-12 membered heterocyclyl, and substituted or unsubstituted benzyl. 12 substituted or unsubstituted C6-Ci2aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered alicyclyl, substituted or unsubstituted 3-12 membered heterocyclyl, and substituted or unsubstituted benzyl.

[0030] In some preferred embodiments, R1is substituted or unsubstituted benzyl.

[0031] In some embodiments, the compound is represented by formula (IV):

[0032]

[0033] wherein, Y and R are as defined in formula (I); m is selected from an integer from 0 to 4, preferably an integer from 0 to 3, for example 0, 1, 2, 3.

[0034] In some embodiments, Y is absent, or is selected from C1-C6alkylene, NH, C1-C6alkyleneoxy, C1-C6alkylenamino, C1-C6alkyleneoxycarbonyl, and substituted or unsubstituted C1-C6alkylimino.

[0035] In some preferred embodiments, Y is absent, or is selected from C1-C6alkylene and C1-C6alkylenamino.

[0036] In some more preferred embodiments, Y is absent, or is selected from C1-C3alkylene and C1-C3alkylenamino.

[0037] In some further preferred embodiments, Y is absent, or is selected from -CH2- and methylenamino (-CH2NH-).

[0038] In the present application, when Y is “C1-C6alkylenamino”, “C1-C3alkylenamino”, or “methylenamino”, the nitrogen atom in the amino group is connected to the N-containing five-membered heteroaromatic ring in formula (I) or (II), or to the imidazole ring in formula (III) or (IV), or the nitrogen atom in the amino group is connected to Z.

[0039] In some embodiments, when Y is "C1-C6 alkylamino," "C1-C3 alkylamino," or "methylamino," wherein the nitrogen atom in the amino group is attached to the N-containing five-membered heteroaromatic ring in Formula (I) or (II) or to the imidazole ring in Formula (III) or (IV).

[0040] In other embodiments, when Y is "C1-C6 alkylamino," "C1-C3 alkylamino," or "methylamino," wherein the nitrogen atom in the amino group is attached to Z.

[0041] In some embodiments, the substitution in the present application means that one or more (e.g., 1, 2, 3, 4, 5, etc.) hydrogen atoms on a group are each independently replaced by R.

[0042] In some preferred embodiments, the substitution in the present application means that 1, 2, or 3 hydrogen atoms on a group are each independently replaced by R.

[0043] In some embodiments, each R is independently selected from the group consisting of a halogen atom, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S-(C1-C6 alkyl), and C1-C6 alkyl substituted with a halogen atom. 10 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S-(C1-C6 alkyl), and C1-C6 alkyl substituted with a halogen atom. 10 alkyl.

[0044] In some preferred embodiments, each R is independently selected from the group consisting of a halogen atom, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S-(C1-C6 alkyl), and C1-C6 alkyl substituted with a halogen atom.

[0045] In some more preferred embodiments, each R is independently selected from the group consisting of a halogen atom, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -S-(C1-C3 alkyl), and C1-C6 alkyl substituted with a halogen atom.

[0046] In the present application, the halogen atom is selected from the group consisting of F, Cl, Br, and I.

[0047] In some preferred embodiments, the substituted or unsubstituted benzyl group is selected from the group consisting of: benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-ethylbenzyl, 4-propylbenzyl, 4-isopropylbenzyl, 4-tert-butylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4-ethoxybenzyl, 4-methylthiobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-iodobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-trifluoromethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,3-dimethylbenzyl, 2,4-dimethylbenzyl, 3,4-dimethylbenzyl, 2,6-dimethylbenzyl, 4-n-butylbenzyl, 4-isobutylbenzyl, 2,3-difluorobenzyl, and 3,4-difluorobenzyl.

[0048] In a second aspect, the present application provides the following compounds or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof:

[0049]

[0050]

[0051]

[0052]

[0053] In a third aspect, the present application provides a pharmaceutical composition comprising at least one compound according to the first aspect or the second aspect, or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof, and one or more pharmaceutically acceptable carriers.

[0054] In a fourth aspect, the present application provides a pharmaceutical preparation comprising at least one compound according to the first aspect or the second aspect, or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof, or a pharmaceutical composition according to the third aspect.

[0055] In a fifth aspect, the present application provides use of a compound according to the first aspect or the second aspect, or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof, or a pharmaceutical composition according to the third aspect, or a pharmaceutical preparation according to the fourth aspect, in the preparation of an HDAC inhibitor.

[0056] In a sixth aspect, the present application provides use of the compound according to the first aspect or the second aspect, or the pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof, or the pharmaceutical composition according to the third aspect, or the pharmaceutical preparation according to the fourth aspect in the preparation of a medicament; the medicament is selected from the group consisting of an anti-tumor drug, an anti-inflammatory drug, an autoimmune disease drug and an Alzheimer's disease drug.

[0057] In a seventh aspect, the present application provides the compound according to the first aspect or the second aspect, or the pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof, or the pharmaceutical composition according to the third aspect, or the pharmaceutical preparation according to the fourth aspect for use in the prevention and / or treatment of tumors, inflammation, autoimmune diseases and / or Alzheimer's disease.

[0058] In an eighth aspect, the present application provides a method for preventing and / or treating tumors, inflammation, autoimmune diseases and / or Alzheimer's disease, comprising the step of: administering a prophylactically and / or therapeutically effective amount of the compound according to the first aspect or the second aspect, or the pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof, or the pharmaceutical composition according to the third aspect, or the pharmaceutical preparation according to the fourth aspect to an individual in need thereof.

[0059] In some embodiments, the tumor described in the present application is selected from the group consisting of leukemia, colorectal cancer, lung cancer, breast cancer, cervical cancer, melanoma and gastric cancer.

[0060] Effects of the invention

[0061] The present application provides a novel benzimidazole small molecule inhibitor (compound) targeting HDAC, which has excellent HDAC inhibitory activity. The compound of the present application can inhibit HDAC6 and / or HDAC1 at high intensity, and exhibits significant anti-tumor cell proliferation activity, which is comparable to or superior to the marketed drug SAHA, and can be used for preparing a drug for treating malignant tumors targeting HDAC, and has very broad application prospects. Moreover, the compound of the present application, while inhibiting HDAC6 at high intensity, exhibits excellent HDAC6 selectivity. Pharmacodynamic experiments show that the compound involved in the present application can be used as a therapeutic drug for tumors, autoimmune diseases, inflammation and / or Alzheimer's disease. DETAILED DESCRIPTION

[0062] Before further describing the present application, it should be understood that the present application is not limited to the specific embodiments described herein; it should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0063] [Term Definition]

[0064] Unless otherwise indicated, the following terms have the following meanings in the present application.

[0065] In the present application, the numerical range indicated by "numerical value A to numerical value B" means a range including the end point numerical values A, B.

[0066] In the present application, when "room temperature" is used, the temperature can be 15 to 30°C, or 15 to 25°C, for example, 20°C.

[0067] The term "independently" means that at least two groups (or ring systems) having the same or similar value range exist in a structure, and can have the same or different meaning in a specific case. For example, substituent X and substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0068] The term "substituted" means that one or more (e.g., 1, 2, 3, 4, or 5) atoms (e.g., hydrogen atoms) or atom groups (e.g., triflate group) of the designated group are replaced with other atoms or atom groups, provided that the designated group meets the valence requirement in the current case and forms a stable compound after substitution. The combination of substituents and / or variables is only allowed when the combination can form a stable compound. If a substituent is described as "optionally substituted", the substituent can be unsubstituted or substituted. If a first substituent is described as optionally substituted by one or more of a list of second substituents, one or more hydrogen atoms in the first substituent can be replaced individually or independently by one or more of the list of second substituents, or not replaced.

[0069] The term "oxo" means "=O".

[0070] The term "alkyl" means a straight-chain or branched-chain aliphatic hydrocarbon group that is a monovalent radical. For example, the term "C1-C6alkyl" as used herein means an alkyl group having from 1 to 6 carbon atoms. Common alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, and the like. The term "alkylene" means the divalent form of "alkyl". 1-10 The term "alkyl" means an alkyl group having 1 to 10 carbon atoms. Common alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, and the like. The term "alkylene" means the divalent form of "alkyl".

[0071] The term "alkoxy" means "-O-alkyl", "alkyl" having the above definition. The term "alkyleneoxy" means the divalent form of "alkoxy", i.e. "-O-alkyl-".

[0072] The term "alkylamino" means "-NH-alkyl", "alkyl" having the above definition. The term "alkyleneamino" means the divalent form of "alkylamino", i.e. "-NH-alkyl-".

[0073] The term "alkoxycarbonyl" means "-C(=O)-O-alkyl", "alkyl" having the above definition. The term "alkyleneoxycarbonyl" means the divalent form of "alkoxycarbonyl", i.e. "-C(=O)-O-alkyl-".

[0074] The term "amido" means "-NH-C(=O)-alkyl", "alkyl" having the above definition. The term "amido" means the divalent form of "amido", i.e. "-NH-C(=O)-alkyl-".

[0075] The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, "alkyl" having the above definition.

[0076] The term "haloalkoxy" means an alkoxy group substituted with one or more halogen atoms, "alkoxy" having the above definition.

[0077] The term "halogen atom" or "halogen" means F, Cl, Br or I.

[0078] The term "aryl" means a monocyclic, bicyclic or tricyclic aromatic carbocyclic ring system containing the indicated number of carbon atoms, "aryl" being a monovalent group. Examples of aryl groups can include phenyl, naphthyl, anthryl, phenanthryl or pyrenyl, among others.

[0079] The term "arylene" is the divalent form of "aryl".

[0080] The term "heteroaryl" means an aromatic monocyclic or polycyclic ring system containing the indicated number of ring atoms, at least one of which is a heteroatom and the remainder of which are carbon, the heteroatoms being independently selected from O, N or S, the number of heteroatoms being preferably 1, 2 or 3, "heteroaryl" being a monovalent group. Examples of heteroaryl groups include furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phtalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophtalazinyl, among others.

[0081] The term "heteroarylene" is the divalent form of "heteroaryl".

[0082] The term "aralkyl" means "aryl-alkyl-" which is a monovalent group, "aryl" and "alkyl" having the above definitions.

[0083] The term "aralkyl" means "aryl-alkyl-" which is a monovalent group, "aryl" and "alkyl" having the above definitions.

[0084] The term "aralkyl" means "aryl-alkyl-" which is a monovalent group, "aryl" and "alkyl" having the above definitions.

[0085] The term "aralkyl" means "aryl-alkyl-" which is a monovalent group, "aryl" and "alkyl" having the above definitions.

[0086] The term "alicyclic" means a non-aromatic, monocyclic, bicyclic or polycyclic (including fused, bridged or spirocyclic) saturated or partially unsaturated ring structure composed only of carbon and hydrogen atoms having the specified number of ring atoms. When the "alicyclic" is a bicyclic or polycyclic fused partially unsaturated ring structure, at least one ring is not aromatic. In the present invention, the "alicyclic" is preferably in monocyclic form, or in bicyclic or polycyclic fused form.

[0087] The term "alicyclic" means a non-aromatic, monocyclic, bicyclic or polycyclic (including fused, bridged or spirocyclic) saturated or partially unsaturated ring structure composed only of carbon and hydrogen atoms having the specified number of ring atoms. When the "alicyclic" is a bicyclic or polycyclic fused partially unsaturated ring structure, at least one ring is not aromatic. In the present invention, the "alicyclic" is preferably in monocyclic form, or in bicyclic or polycyclic fused form.

[0088] The term "heterocycle" means a non-aromatic, monocyclic, bicyclic or polycyclic (including fused, bridged or spirocyclic) saturated or partially unsaturated ring structure having the specified number of ring atoms composed of carbon atoms and one or more heteroatoms such as N, O and S. When the "heterocycle" is bicyclic or polycyclic and the number of ring heteroatoms is greater than or equal to 2, the ring heteroatoms can be located on one ring or on different rings. When the "heterocycle" is a bicyclic or polycyclic fused partially unsaturated ring structure, at least one ring is not aromatic. In the present invention, the "heterocycle" is preferably in monocyclic form, or in bicyclic or polycyclic fused form.

[0089] The term "heterocycle" means a non-aromatic, monocyclic, bicyclic or polycyclic (including fused, bridged or spirocyclic) saturated or partially unsaturated ring structure having the specified number of ring atoms composed of carbon atoms and one or more heteroatoms such as N, O and S. When the "heterocycle" is bicyclic or polycyclic and the number of ring heteroatoms is greater than or equal to 2, the ring heteroatoms can be located on one ring or on different rings. When the "heterocycle" is a bicyclic or polycyclic fused partially unsaturated ring structure, at least one ring is not aromatic. In the present invention, the "heterocycle" is preferably in monocyclic form, or in bicyclic or polycyclic fused form.

[0090] The term "heterocycle" means a non-aromatic, monocyclic, bicyclic or polycyclic (including fused, bridged or spirocyclic) saturated or partially unsaturated ring structure having the specified number of ring atoms composed of carbon atoms and one or more heteroatoms such as N, O and S. When the "heterocycle" is bicyclic or polycyclic and the number of ring heteroatoms is greater than or equal to 2, the ring heteroatoms can be located on one ring or on different rings. When the "heterocycle" is a bicyclic or polycyclic fused partially unsaturated ring structure, at least one ring is not aromatic. In the present invention, the "heterocycle" is preferably in monocyclic form, or in bicyclic or polycyclic fused form.

[0091] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable, irritating, allergic or otherwise inappropriate. The substance used for salt formation can be an acid or a base, wherein the acid includes an inorganic acid or an organic acid which can form a salt with a basic group in the compound of the present invention; the base includes an inorganic base or an organic base which can form a salt with an acidic group in the compound of the present invention.

[0092] Unless otherwise specified, all compounds of the present application encompass all possible isomers, such as stereoisomers and tautomers (e.g., enol and keto forms). Stereoisomers in the present application include optical isomers (e.g., enantiomers, diastereomers, epimers), cis and trans isomers (e.g., Z- and E-forms), conformers. In addition, single stereoisomers or tautomers, as well as mixtures of stereoisomers and tautomers are within the scope of the present application.

[0093] The term "optical isomer" refers to a stable isomer capable of rotating the plane of plane-polarized light as a result of having at least one chiral element (including chiral centers, chiral axes, chiral planes, etc.) that results in a non-superimposable mirror image. Because of the presence of asymmetric centers and other chemical structures in the compounds of the present application that can lead to stereoisomers, the present application also includes these stereoisomers and mixtures thereof. Because the compounds of the present application and salts thereof include asymmetric carbon atoms, they can exist in single stereoisomer, racemic, enantiomeric and diastereomeric mixtures. The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of one another. The term "diastereomers" or "diastereomers" refers to optical isomers that are not mirror images of one another. The term "racemic mixture" or "racemate" refers to a mixture containing equal amounts of a single pair of enantiomeric isomers (i.e., an equimolar mixture of two R and S enantiomeric isomers).

[0094] The term "cis and trans isomers" refers to stereoisomers that result from the orientation of atoms (or groups) on either side of a double bond or ring system due to their different positions relative to a reference plane; in cis isomers, the atoms (or groups) are on the same side of the double bond or ring system, in trans isomers, the atoms (or groups) are on opposite sides of the double bond or ring system. Unless otherwise indicated, all cis and trans isomer forms of the compounds of the present application are within the scope of the present application.

[0095] The term "conformers" or "rotamers" refers to different spatial arrangements of atoms or groups due to single bond rotations, for example, cyclohexane has two conformers, boat and chair. Unless otherwise indicated, all conformer forms of the compounds of the present application are within the scope of the present application.

[0096] The term "tautomer" also referred to as "tautomeric form" refers to structural isomers that can interconvert by a low energy barrier. If tautomerization is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, prototropic tautomers (or proton-shift tautomers) include, but are not limited to, interconversions by proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imidol isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the application are within the scope of the application.

[0097] The term "hydrate" refers to a substance formed by the combination of a compound of the application, or a pharmaceutically acceptable salt thereof, with water through non-covalent intermolecular forces. The term "hydrate" includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.

[0098] The term "deuterated compound" refers to a compound formed by replacing a hydrogen atom in the structure with a deuterium atom.

[0099] The term "prodrug" refers to a derivative of a compound of the application that, upon administration to a patient, is capable of providing directly or indirectly a compound of the application. Particularly preferred are derivatives or prodrugs that increase the bioavailability of a compound of the application when administered to a patient (e.g., are more readily absorbed into the blood), or that facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the application are within the scope of the application, and various prodrug forms are well known in the art.

[0100] In order to make the objects, technical solutions and advantages of the present application clearer, the embodiments of the present application are described in detail below in conjunction with the examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present application, and should not be regarded as limiting the scope of the present application.

[0101] The experimental methods described in the embodiments of the present application all adopt conventional methods unless otherwise specified; the reagents and materials used are purchased from conventional biochemical reagents unless otherwise specified.

[0102] The synthesis routes of the compounds 1-30 of the present application are shown in Route I:

[0103]

[0104] Reaction conditions:

[0105] a is: sodium bisulfite, ethanol, rt;

[0106] b is: (R) m substituted benzyl bromide, cesium carbonate, acetone, rt;

[0107] c is: hydroxylamine, NaOH, MeOH, rt.

[0108] The synthetic route of compounds 34-63 of the present application is shown in Route II:

[0109]

[0110] Reaction conditions:

[0111] d is: EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride), HOBt (1-hydroxybenzotriazole), DIEA (N,N-diisopropylethylamine), THF (tetrahydrofuran), rt;

[0112] e is: hydrochloric acid, methanol, 65 °C;

[0113] f is: (R) m substituted benzyl bromide, cesium carbonate, acetone, rt;

[0114] g is: hydroxylamine, NaOH, MeOH, rt.

[0115] The synthetic route of compounds 64-93 of the present application is shown in Route III:

[0116]

[0117] Reaction conditions:

[0118] h is: (R) m substituted benzyl bromide, sodium tert-butoxide, ethanol, rt;

[0119] i is: sodium cyanoborohydride, 1,2-dichloroethane, reflux;

[0120] j is: hydroxylamine, NaOH, MeOH, rt.

[0121] The synthetic route of compounds 94-121 of the present application is shown in Route IV:

[0122]

[0123] Reaction conditions:

[0124] k is: NMP (N-methyl pyrrolidone), 80 °C;

[0125] l is: iron powder, ammonium chloride, ethanol, water, reflux;

[0126] m is: chloroacetic acid, hydrochloric acid, 100 °C;

[0127] n is: methyl p-aminobenzoate, potassium iodide, ethanol, 80 °C;

[0128] o is: hydroxylamine, NaOH, MeOH, rt.

[0129] Example

[0130] Example 1 : Synthesis of 4-(l-benzyl-lH-benzimidazol-2-yl)-N- hydroxybenzamide (Compound 1)

[0131]

[0132] First step: In a dry 100 mL single necked round bottom flask, add p- formylbenzoate (13.4 mmol, 2.20 g), aqueous sodium bisulfite (20 mL, 40% wt) and ethanol (15 mL), stir the reaction at room temperature for 1 hour. Then add 1,2-phenylenediamine (13.4 mmol, 2.20 g) and warm the reaction to reflux overnight. After the reaction is complete, cool to room temperature, pour the reaction into ice water, filter and wash with water and dry under vacuum to give intermediate 31 (3.40 g, yield: 100%).

[0133] Second step: In a dry 50 mL single necked round bottom flask, add intermediate 31 (2.0 mmol, 0.51 g) and add acetone (10 mL) and cesium carbonate (4.0 mmol, 1.3 g), then add benzyl bromide (4.0 mmol, 0.68 g) dropwise to the reaction, stir at room temperature for 3 hours, TLC shows no starting material remaining, filter to give intermediate 1a (0.58 g, yield: 85%).

[0134] Third step: Add intermediate 1a (1.0 mmol, 0.34 g) to a 25 mL reaction flask under ice water bath conditions, add methanol (0.1 M), NaOH powder (10 mmol, 10.0 eq), aqueous NH2OH (10 mmol, 10.0 eq), stir at room temperature for 2 hours, filter the mixture, TLC shows no intermediate 1a remaining, stop the reaction. Add 10 mL water to the reaction, adjust to pH = 6-7 with 1 M HCI, stir at room temperature for 30 min, suction filter, filter cake is dried under reduced pressure at 50 °C, wash with dichloromethane / methanol several times, filter to give white pure product solid Compound 1 (153.5 mg, yield 43%).

[0135] 1H NMR (600 MHz, DMSO-d6) δ 11.43 - 11.25 (m, 1H), 9.15 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.78 - 7.73 (m, 1H), 7.54 - 7.48 (m, 1H), 7.34 - 7.21 (m, 5H), 6.99 (d, J = 7.5 Hz, 2H), 5.62 (s, 2H).

[0136] 13 C NMR (151 MHz, DMSO-d6) δ 164.0, 152.9, 143.1, 137.3, 136.5, 134.2, 133.1, 129.5, 129.3, 128.0, 127.7, 126.6, 123.5, 122.9, 119.9, 111.7, 48.0.

[0137] Compound 2-30 was prepared according to the similar synthetic procedure as Example 1 using the corresponding starting materials.

[0138] Example 2: Synthesis of N-hydroxy-4-[1-(4-methylbenzyl)-1H-benzimidazol-2- yl]benzamide (Compound 4)

[0139]

[0140] Compound 2-30 was prepared according to the similar synthetic procedure as Example 1 using the corresponding starting materials.

[0141] 1 H NMR (600 MHz, DMSO-d6) δ 11.43 - 11.25 (m, 1H), 9.15 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.78 - 7.73 (m, 1H), 7.54 - 7.48 (m, 1H), 7.34 - 7.21 (m, 5H), 6.99 (d, J = 7.5 Hz, 2H), 5.62 (s, 2H).

[0142] 13 C NMR (151 MHz, DMSO-d6) δ 164.0, 152.9, 143.1, 137.3, 136.5, 134.2, 133.1, 129.5, 129.3, 128.0, 127.7, 126.6, 123.5, 122.9, 119.9, 111.7, 48.0.

[0143] Example 3: Synthesis of N-hydroxy-4-[l-(4-ethylbenzyl)-lH-benzimidazol-2- yl]benzamide (Compound 5)

[0144]

[0145] Following a similar synthetic procedure as in Example 1, except that in the second step, intermediate 31 and 4-ethylbenzyl bromide were used as starting materials, and the other steps were the same as in Example 1.

[0146] 1 H NMR (600 MHz, DMSO-d6) δ 11.46 - 11.23 (m, 1H), 9.16 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.78 - 7.66 (m, 1H), 7.58 - 7.45 (m, 1H), 7.26 (dq, J = 7.9, 5.6, 3.9 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 6.91 (d, J = 7.7 Hz, 2H), 5.58 (s, 2H), 2.56 - 2.51 (m, 2H), 1.11 (t, J = 7.5 Hz, 3H).

[0147] 13 C NMR (151 MHz, DMSO-d6) δ 163.9, 152.8, 143.5, 143.1, 136.5, 134.5, 134.2, 133.1, 129.5, 128.7, 127.8, 126.6, 123.4, 122.8, 119.9, 111.7, 55.4, 47.8, 28.2, 15.9.

[0148] Example 4: Synthesis of 4-[l-(3-fluorobenzyl)-lH-benzimidazol-2-yl]-N- hydroxybenzamide (Compound 13)

[0149]

[0150] Following a similar synthetic procedure as in Example 1, except that in the second step, intermediate 31 and 3-fluorobenzyl bromide were used as starting materials, and the other steps were the same as in Example 1.

[0151] 1H NMR (600 MHz, DMSO-d6) δ 11.36 (s, 1H), 9.16 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.76 (dt, J = 7.9, 3.2 Hz, 1H), 7.57 - 7.48 (m, 1H), 7.38 - 7.19 (m, 3H), 7.08 (td, J = 8.6, 2.7 Hz, 1H), 6.86 (d, J = 9.9 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 5.64 (s, 2H).

[0152] 13 C NMR (151 MHz, DMSO-d6) δ 163.9, 163.5, 161.9, 152.9, 143.1, 140.3, 140.2, 136.4, 134.3, 132.9, 131.44, 131.39, 129.5, 127.8, 123.6, 123.0, 122.54, 122.52, 120.0, 115.0, 114.8, 113.7, 113.6, 111.6, 47.5.

[0153] Example 5: Synthesis of 4-[1-(4-chlorobenzyl)-1H-benzimidazol-2-yl]-N- hydroxybenzamide (Compound 15)

[0154]

[0155] Following a similar synthetic procedure as in Example 1, except that in the second step, intermediate 31 and 4-chlorobenzyl bromide were used as starting materials, and the other steps were the same as in Example 1.

[0156] 1 H NMR (600 MHz, DMSO-d6) δ 11.36 (s, 1H), 9.16 (s, 1H), 7.92 - 7.85 (m, 2H), 7.81 (d, J = 8.3 Hz, 2H), 7.78 - 7.71 (m, 1H), 7.55 - 7.46 (m, 1H), 7.38 - 7.32 (m, 2H), 7.31 - 7.22 (m, 2H), 7.01 (d, J = 8.5 Hz, 2H), 5.62 (s, 2H).

[0157] 13 C NMR (151 MHz, DMSO-d6) δ 152.8, 143.1, 136.39, 136.35, 134.3, 132.9, 132.6, 129.5, 129.3, 128.5, 127.8, 123.6, 123.0, 119.9, 111.6, 55.4, 47.4.

[0158] Example 6: Synthesis of 4-[l-(4-bromobenzyl)-lH-benzimidazol-2-yl]-N- hydroxybenzamide (Compound 28)

[0159]

[0160] Following a similar synthetic procedure as in Example 1, except that in the second step, intermediate 31 and 4-bromobenzyl bromide were used as starting materials, and the other steps were the same as in Example 1.

[0161] 1 H NMR (600 MHz, DMSO-d6) δ 11.35 (s, 1H), 9.15 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.78 - 7.69 (m, 1H), 7.49 (ddt, J = 11.1, 9.1, 2.0 Hz, 3H), 7.27 (td, J = 7.4, 6.6, 3.7 Hz, 2H), 6.95 (d, J = 8.2 Hz, 2H), 5.60 (s, 2H).

[0162] 13 C NMR (151 MHz, DMSO-d6) δ 163.9, 152.8, 143.1, 136.8, 136.4, 134.3, 132.9, 132.2, 129.5, 128.8, 127.8, 123.6, 123.0, 121.1, 119.9, 111.6, 55.4, 47.4.

[0163] Example 7: Synthesis of 4-[l-(4-iodobenzyl)-lH-benzimidazol-2-yl]-N- hydroxybenzamide (Compound 16)

[0164]

[0165] Following a similar synthetic procedure as in Example 1, except that in the second step, intermediate 31 and 4-iodobenzyl bromide were used as starting materials, and the other steps were the same as in Example 1.

[0166] 1 H NMR (600 MHz, DMSO-d6) δ 11.34 (s, 1H), 9.15 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.77 - 7.70 (m, 1H), 7.69 - 7.61 (m, 2H), 7.52 - 7.45 (m, 1H), 7.32 - 7.22 (m, 2H), 6.80 (d, J = 8.1 Hz, 2H), 5.58 (s, 2H).

[0167] 13 C NMR (151 MHz, DMSO-d6) δ 163.7, 152.9, 143.1, 138.0, 137.2, 136.4, 132.6, 129.4, 128.9, 127.6, 123.5, 122.9, 119.9, 111.6, 94.0, 47.5.

[0168] Example 8: Synthesis of N-hydroxy-4-[1-(4-trifluoromethylbenzyl)-1H- benzimidazol-2-yl]benzamide (Compound 19)

[0169]

[0170] By the similar synthetic method as Example 1, except that intermediate 31 and 4- trifluoromethylbenzyl bromide were used as starting materials in the second step, and other steps were the same as Example 1.

[0171] 1 H NMR (600 MHz, DMSO-d6) δ 11.35 (s, 1H), 9.16 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 8.3 Hz, 2H), 7.79 - 7.73 (m, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.50 (dd, J = 7.1, 2.0 Hz, 1H), 7.34 - 7.24 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 5.74 (s, 2H).

[0172] 13 C NMR (151 MHz, DMSO-d6) δ 163.9, 152.9, 143.2, 142.1, 136.4, 134.3, 132.8, 129.5, 128.7, 128.5, 127.8, 127.4, 126.3, 126.24, 126.22, 126.19, 125.5, 123.7, 123.1, 120.0, 111.6, 55.4, 49.1, 47.6.

[0173] Example 9: Synthesis of N-hydroxy-4-[(1-benzyl-1H-benzimidazol-2-yl)methyl]benzamide (Compound 34)

[0174]

[0175] First step: In a dry 100 mL single necked round bottom flask, add o-phenylenediamine (11.0 mmol, 1.19 g, 1.1 eq), 2-(4-methoxycarbonylphenyl)acetic acid (10.0 mmol, 1.94 g) and tetrahydrofuran (30 mL) in sequence, then add condensing agent EDCI (2.3 g, 12.0 mmol), HOBt (1.62 g, 12.0 mmol) and DIEA (2.58 g, 20.0 mmol), and react at room temperature overnight. Filter the reaction solution with water to obtain intermediate 32 (2.6 g, yield: 92%).

[0176] Second step: Dissolve intermediate 32 (1.42 g, 5.0 mmol) in methanol (20 mL), add hydrochloric acid (15 mL) and heat to 65 °C, and react for 6 hours. After the reaction is completed, filter to obtain intermediate 33 (1.03 g, yield: 78%).

[0177] Third step: Add intermediate 33 (0.28 g, 1.0 mmol) to a dry 50 mL single necked round bottom flask, and add acetone (10 mL) and cesium carbonate (0.65 g, 2.0 mmol), then add benzyl bromide (2.0 mmol, 0.34 g) dropwise to the above reaction solution, and react at room temperature for 3 hours. TLC detection shows that there is no raw material left. Remove the acetone, add 20 mL of water, extract with ethyl acetate (20 mL x 3), combine the organic phases, add an appropriate amount of anhydrous sodium sulfate, dry and remove water, remove the ethyl acetate solvent by rotary evaporation under reduced pressure, and purify by column chromatography to obtain intermediate 34a (256.6 mg, yield: 72%).

[0178] Fourth step: Add intermediate 34a (178 mg, 0.5 mmol) to a reaction flask at 0 °C, add methanol (0.1 M), NaOH powder (5 mmol, 10.0 eq), and NH2OH aqueous solution (5 mmol, 10.0 eq), stir at room temperature for 30 min, filter the mixture, and TLC detection shows that there is no intermediate 34a left. Stop the reaction. Add 10 mL of water to the reaction solution, adjust to pH = 6-7 with 1M HCl, stir at room temperature for 30 min, suction filter, dry the filter cake by rotary evaporation under reduced pressure at 50 °C, and purify by column chromatography to obtain white pure product solid compound 34 (106 mg, yield: 59%).

[0179] 1H NMR (600 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.01 (s, 1H), 7.65 (d, J = 7.9 Hz, 2H), 7.62 - 7.54 (m, 1H), 7.44 - 7.36 (m, 1H), 7.32 (d, J = 7.9 Hz, 2H), 7.25 (dd, J = 12.5, 7.1 Hz, 3H), 7.22 - 7.12 (m, 2H), 7.03 (d, J = 7.4 Hz, 2H), 5.49 (s, 2H), 4.33 (s, 2H).

[0180] 13 C NMR (151 MHz, DMSO-d6) δ 153.8, 142.9, 140.5, 137.3, 135.8, 131.6, 129.4, 129.1, 128.0, 127.5, 127.1, 122.5, 122.1, 119.2, 111.0, 46.8, 33.3.

[0181] Example 10: Synthesis of N-hydroxy-4-[(l-(2,4,6-trimethylbenzyl)-lH- benzimidazol-2-yl)methyl]benzamide (Compound 36)

[0182]

[0183] Following a similar synthetic procedure as in Example 9, except that in the third step, intermediate 33 and 2,4,6-trimethylbenzyl bromide were used as starting materials, and the other steps were the same as in Example 9.

[0184] 1 H NMR (600 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.05 (s, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 7.8 Hz, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.96 (t, J = 7.7 Hz, 1H), 6.86 (s, 2H), 6.70 (d, J = 8.2 Hz, 1H), 5.39 (s, 2H), 4.32 (s, 2H), 2.22 (s, 3H), 2.00 (s, 6H).

[0185] 13 C NMR (151 MHz, DMSO-d6) δ 154.1, 142.8, 137.7, 137.6, 135.6, 129.8, 129.2, 129.1, 127.3, 122.2, 121.6, 119.2, 110.9, 43.8, 33.8, 21.0, 20.1.

[0186] Example 11: Synthesis of N-hydroxy-4-[(l-(4-propylbenzyl)-lH- benzimidazol-2-yl)methyl]benzamide (Compound 50)

[0187]

[0188] Following a similar synthetic procedure as in Example 9, except that in the third step, intermediate 33 and 4-bromobenzyl bromide were used as starting materials, and the other steps were the same as in Example 9.

[0189] 1 H NMR (600 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.05 (s, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.9 Hz, 2H), 7.22 - 7.10 (m, 2H), 6.96 (d, J = 8.0 Hz, 2H), 5.47 (s, 2H), 4.31 (s, 2H).

[0190] 13 C NMR (151 MHz, DMSO-d6) δ 153.8, 142.9, 136.7, 135.6, 132.0, 129.3, 129.3, 127.4, 122.6, 122.2, 121.0, 119.3, 110.9, 46.2, 33.2.

[0191] Example 12: Synthesis of N-hydroxy-4-[(l-(4-methoxybenzyl)-lH- benzimidazol-2-yl)methyl]benzamide (Compound 51)

[0192]

[0193] Following a similar synthetic procedure as in Example 9, except that in the third step, intermediate 33 and 3-trifluoromethylbenzyl bromide were used as starting materials, and the other steps were the same as in Example 9.

[0194] 1 H NMR (600 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.05 (s, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.9 Hz, 2H), 7.22 - 7.10 (m, 2H), 6.96 (d, J = 8.0 Hz, 2H), 5.47 (s, 2H), 4.31 (s, 2H).

[0190] 13 C NMR (151 MHz, DMSO-d6) δ 153.8, 142.9, 136.7, 135.6, 132.0, 129.3, 129.3, 127.4, 122.6, 122.2, 121.0, 119.3, 110.9, 46.2, 33.2.

[0191] Example 12: Synthesis of N-hydroxy-4-[(l-(4-methoxybenzyl)-lH- benzimidazol-2-yl)methyl]benzamide (Compound 51)

[0192]

[0193] Following a similar synthetic procedure as in Example 9, except that in the third step, intermediate 33 and 3-trifluoromethylbenzyl bromide were used as starting materials, and the other steps were the same as in Example 9.

[0194] 1 H NMR (600 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.05 (s, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.9 Hz, 2H), 7.22 - 7.10 (m, 2H), 6.96 (d, J = 8.0 Hz, 2H), 5.47 (s, 2H), 4.31 (s, 2H).

[0195] 13 C NMR (151 MHz, DMSO-d6) δ 164.3, 153.8, 142.9, 140.4, 138.7, 135.6, 131.5, 130.9, 130.2, 130.0, 129.8, 129.6, 129.2, 127.4, 125.3, 124.67, 124.65, 123.59, 123.56, 123.5, 122.7, 122.3, 119.3, 110.8, 46.3, 33.1.

[0196] Example 13: Synthesis of N-hydroxy-4-[(l-(3-fluorobenzyl)-lH- benzimidazol-2-yl)methyl]benzamide (Compound 56)

[0197]

[0198] By the similar synthetic method as in Example 9, except that in the third step, intermediate 33 and 3-fluorobenzyl bromide were used as starting materials, and the other steps were the same as in Example 9.

[0199] 1 H NMR (600 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.65 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 7.1 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.29 (t, J = 7.6 Hz, 3H), 7.22 - 7.12 (m, 2H), 7.05 (t, J = 8.6 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 5.52 (s, 2H), 4.33 (s, 2H).

[0200] 13 C NMR (151 MHz, DMSO-d6) δ 163.5, 161.9, 153.8, 142.9, 140.2, 140.1, 135.7, 131.2, 131.1, 129.2, 127.3, 124.0, 123.0, 122.6, 122.2, 119.3, 114.8, 114.7, 114.0, 113.8, 110.9, 46.3, 33.2.

[0201] Example 14: Synthesis of N-hydroxy-4-[[(l-benzyl-lH-benzimidazol-2- yl)amino]methyl]benzamide (Compound 64)

[0202]

[0203] First step: In a dry 100 mL single necked round bottom flask, add 2-aminobenzimidazole (1.33 g, 10.0 mmol) and dissolve in ethanol (20 mL), then add sodium tert-butoxide (0.96 g, 10.0 mmol), add benzyl bromide (1.7 g, 10.0 mmol) drop by drop under stirring, let the reaction proceed at room temperature for 20 hours. TLC test shows no starting material left, add water to the reaction mixture and filter to get intermediate 64a (1.63 g, yield: 73%).

[0204] Second step: Add intermediate 64a (223.5 mg, 1.0 mmol) to a 50 mL single necked round bottom flask, add 1,2-dichloroethane (10 mL), add methyl p-formylbenzoate (197 mg, 1.2 mmol) to the reaction mixture, heat to 85 °C and reflux for 5 hours, cool to room temperature, then add sodium cyanoborohydride (157.2 mg, 2.5 mmol) and let the reaction proceed at room temperature overnight. Add 20 mL water to the mixture, extract with ethyl acetate (20 mL x 3), combine the organic phase, add an appropriate amount of anhydrous sodium sulfate, dry and remove water, remove the ethyl acetate solvent by rotary evaporation under reduced pressure, and purify by column chromatography to obtain intermediate 64b (yield: 57%).

[0205] Third step: Add intermediate 64b (186 mg, 0.5 mmol) to the reaction flask at 0 °C, add methanol (0.1 M), NaOH powder (5 mmol, 10.0 eq), NH2OH aqueous solution (5 mmol, 10.0 eq), stir at room temperature for 30 min, filter the mixture, TLC test shows no intermediate 64b left, terminate the reaction. Add 10 mL water to the reaction mixture, adjust to pH = 6-7 with 1 M HCl, stir at room temperature for 30 min, suction filter, dry the filter cake by rotary evaporation under reduced pressure at 50 °C, purify by column chromatography to obtain white pure product solid compound 64. (119 mg, yield: 64%).

[0206] 1 H NMR (600 MHz, DMSO) δ 11.15 (s, 1H), 8.99 (s, 1H), 7.67 (d, J = 7.8 Hz, 2H), 7.48 (t, J = 6.1 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.17 (dd, J = 8.1, 3.7 Hz, 3H), 7.10 (d, J = 7.8 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 5.33 (s, 2H), 4.65 (d, J = 5.8 Hz, 2H).

[0207] 13C NMR (151 MHz, DMSO) δ 164.6, 155.1, 144.2, 143.0, 137.5, 135.2, 131.7, 129.0, 127.8, 127.4, 127.3, 127.25, 121.0, 119.0, 115.7, 108.4, 45.9, 44.9, 40.5.

[0208] Example 15: Synthesis of N-hydroxy-4-[[(1 -(4-ethylbenzyl)-1 H- benzimidazol-2-yl)amino]methyl]benzamide (Compound 68)

[0209]

[0210] Prepared by a similar synthetic procedure to Example 14, except that 4- ethylbenzyl bromide was used as the starting material in the first step, and the other steps were the same as Example 14.

[0211] 1 H NMR (600 MHz, DMSO) δ 11.19 (s, 1 H), 9.16 - 8.89 (m, 1 H), 7.66 (d, J = 7.9 Hz, 2H), 7.49 (t, J = 6.1 Hz, 1 H), 7.38 (d, J = 7.9 Hz, 2H), 7.16 (dd, J = 15.7, 7.8 Hz, 3H), 7.13 - 7.06 (m, 3H), 6.93 (t, J = 7.5 Hz, 1 H), 6.86 (t, J = 7.5 Hz, 1 H), 5.27 (s, 2H), 4.64 (d, J = 5.8 Hz, 2H), 2.55 (q, J = 7.6 Hz, 2H), 1.13 (t, J = 7.6 Hz, 3H).

[0212] 13 C NMR (151 MHz, DMSO) δ 164.8, 155.0, 144.1, 143.5, 142.8, 135.0, 134.6, 131.6, 128.4, 127.4, 127.2, 121.0, 119.1, 115.6, 108.4, 45.8, 44.7, 28.3, 16.1.

[0213] Example 16: Synthesis of N-hydroxy-4-[[(1 -(4-methoxybenzyl)-1 H- benzimidazol-2-yl)amino]methyl]benzamide (Compound 73)

[0214]

[0215] Prepared by a similar synthetic procedure to Example 14, except that 4- methoxybenzyl bromide was used as the starting material in the first step, and the other steps were the same as Example 14.

[0216] 1 H NMR (600 MHz, DMSO) δ 11.19 (s, 1H), 9.12 - 8.97 (m, 1H), 7.67 (d, J = 7.9 Hz, 2H), 7.50 (t, J = 6.1 Hz, 1H), 7.39 (d, J = 7.9 Hz, 2H), 7.15 (td, J = 13.9, 7.7 Hz, 4H), 6.94 (t, J = 7.5 Hz, 1H), 6.88 (dd, J = 8.3, 3.4 Hz, 3H), 5.24 (s, 2H), 4.65 (d, J = 5.8 Hz, 2H), 3.71 (s, 3H).

[0217] 13 C NMR (151 MHz, DMSO) δ 159.0, 154.9, 144.1, 142.8, 135.0, 131.6, 129.3, 128.9, 127.4, 127.3, 121.0, 119.1, 115.6, 114.4, 108.5, 55.6, 45.8, 44.4.

[0218] Example 17: Synthesis of N-hydroxy-4-[[(l-benzyl-lH-benzimidazol-2-yl)methyl]amino] benzamide (Compound 94)

[0219]

[0220] First Step: In a dry 100 mL single-necked round-bottom flask, add o-fluoronitrobenzene (1.41 g, 10.0 mmol) and benzylamine (2.14 g, 20.0 mmol), then add solvent NMP (30 mL), and warm the reaction liquid to 80 °C, and react for 4 hours. After the reaction is completed, add 20 mL of water, extract with ethyl acetate (20 mL x 3), combine the organic phases, add an appropriate amount of anhydrous sodium sulfate, dry and remove water, remove the ethyl acetate solvent by rotary evaporation under reduced pressure, and purify by column chromatography to obtain intermediate 94a (yield: 79%).

[0221] Second Step: In a dry 100 mL single-necked round-bottom flask, add intermediate 94a (457 mg, 2.0 mmol) and dissolve with ethanol: water (4: 1), then add reducing agent iron powder (1.0 g, 16.0 mmol) and ammonium chloride (0.11 g, 2.0 mmol), warm the reaction liquid to 78 °C, and react under reflux conditions for 8 hours. After the reaction is completed, remove the ethanol by rotary evaporation, filter with water to obtain intermediate 94b (yield: 87%).

[0222] Step 3: To a dry 50 mL single necked round bottom flask, was added intermediate 94b (0.99 g, 5.0 mmol) and 5 M hydrochloric acid (10 mL), to the reaction was added chloroacetic acid (7.5 mmol), the reaction was heated to 100 °C and stirred for 8 h under reflux condition. Upon completion of the reaction, the reaction was neutralized with sodium hydroxide solution, extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography to yield intermediate 94c (yield: 69%).

[0223] Step 4: To a dry 50 mL single necked round bottom flask, was added intermediate 94c (256.7 mg, 1.0 mmol), potassium iodide (166 mg, 1.0 mmol) and ethanol (10 mL), to the reaction was added methyl p-aminobenzoate (0.3 g, 2.0 mmol), the reaction was heated to 80 °C and stirred for 24 h under reflux condition. Upon completion of the reaction, the reaction was diluted with water and extracted with dichloromethane, the organic layers were combined, concentrated under reduced pressure and purified by column chromatography to yield intermediate 94d (yield: 52%).

[0224] Step 5: To a reaction flask was added intermediate 94d (185.7 mg, 0.5 mmol) at 0 °C, to the reaction was added methanol (0.1 M), NaOH powder (5 mmol, 10.0 eq), aqueous NH2OH (5 mmol, 10.0 eq), the reaction was stirred at room temperature for 30 min, the mixture was filtered, TLC monitoring showed no remaining intermediate 94d, the reaction was stopped. To the reaction was added water 10 mL, 1 M HC1 was added to adjust the pH to 6-7, the reaction was stirred at room temperature for 30 min, suction filtered, the filter cake was dried under reduced pressure at 50 °C, purified by column chromatography to yield white pure product solid compound 94 (114 mg, 61%).

[0225] 1 H NMR (600 MHz, DMSO) δ 10.78 (s, 1H), 8.69 (s, 1H), 7.69 - 7.60 (m, 1H), 7.55 - 7.47 (m, 2H), 7.45 - 7.36 (m, 1H), 7.35 - 7.23 (m, 3H), 7.23 - 7.15 (m, 2H), 7.16 - 7.08 (m, 2H), 6.83 (t, J = 5.6 Hz, 1H), 6.74 - 6.63 (m, 2H), 5.59 (s, 2H), 4.58 (d, J = 5.6 Hz, 2H).

[0226] 13C NMR (151 MHz, DMSO) δ 165.3, 152.6, 151.1, 142.5, 137.3, 136.1, 129.2, 128.6, 128.0, 127.3, 122.8, 122.1, 120.6, 119.4, 111.9, 111.0, 46.8, 40.7.

[0227] Example 18: Synthesis of N-hydroxy-4-[[(l-(2-fluorobenzyl)-lH- benzimidazol-2-yl)methyl]amino]benzamide (Compound 105)

[0228]

[0229] It was prepared by a similar synthetic procedure as in Example 17, except that 2- fluorobenzyl bromide was used as the starting material in the first step, and the other steps were the same as in Example 17.

[0230] 1 H NMR (600 MHz, DMSO) δ 10.78 (s, 1H), 8.69 (s, 1H), 7.68 - 7.61 (m, 1H), 7.55 - 7.46 (m, 2H), 7.42 - 7.37 (m, 1H), 7.33 (tdd, J = 7.5, 5.3, 1.7 Hz, 1H), 7.29 - 7.21 (m, 1H), 7.21 - 7.14 (m, 2H), 7.04 (td, J = 7.5, 1.2 Hz, 1H), 6.83 (td, J = 7.8, 1.8 Hz, 1H), 6.79 (t, J = 5.6 Hz, 1H), 6.72 - 6.62 (m, 2H), 5.65 (s, 2H), 4.61 (d, J = 4.6 Hz, 2H).

[0231] 13 C NMR (151 MHz, DMSO) δ 165.3, 161.2, 159.6, 152.7, 151.1, 142.3, 135.9, 131.4, 130.3, 130.2, 129.11, 129.08, 128.6, 125.2, 125.1, 124.0, 123.9, 122.9, 122.3, 120.6, 119.4, 116.1, 115.9, 111.9, 110.8, 41.5, 40.7.

[0232] Example 1: Assay of the inhibitory activity of the compounds of the present application on HDAC1 and HDAC6 enzymes

[0233] The enzymatic inhibitory activity of the target molecules was assayed using the HDAC1 / 6 Fluorometric Kit, according to the following procedure:

[0234] HDAC1 / 6 fluorescent detection kit purchased from BPS Bioscience, HDAC substrate and enzyme were diluted to the specified concentration with HDAC buffer, and then the target compound and positive control were prepared into a series of different concentrations. In a 96-well plate, add 5 μL HDAC substrate, 5 μL BSA (1 mg / mL), 30 μL buffer, 5 μL different concentrations of compound or positive control (SAHA), 5 μL enzyme solution, 37°C incubation for 30 min. Then add 50 μL HDAC developer containing Trichostatin A (2X), incubate at room temperature for 15 min. The fluorescence intensity (excitation wavelength: 360 nm, emission wavelength: 460 nm) was measured using Varioskan LUX microplate reader. Three independent experiments were performed, and the half-inhibitory concentration (IC 50 ) of the compound was calculated using GraphPad Prism 8.0.

[0235] Table 1 Inhibition of HDAC1 and HDAC6 by compounds of the present application

[0236] Compound HDAC1 IC 50 (nM) HDAC6 IC 50 (nM) Example 1 D A Example 2 D A Example 5 D B Example 8 C A Example 10 D A Example 12 C A Example 13 C A Example 15 C A Example 17 C A SAHA B B

[0237] Note: A: IC 50 ≤ 10 nM, B: 10 nM < IC 50 ≤ 100 nM, C: IC 50 : 100 nM < IC 50 ≤ 500 nM, D: IC 50 > 500 nM.

[0238] From the data in Table 1, it can be seen that the compounds of the present application have obvious inhibitory effect on HDAC1 and HDAC6, and show good selectivity for HDAC6.

[0239] Example 2: Anti-proliferative activity of compounds of the present application on tumor cells

[0240] The CCK-8 method was used to evaluate the anti-proliferative activity of the compounds of the present application on human promyelocytic leukemia cell line HL-60, colorectal cancer cell line HCT-116, breast cancer cell lines MCF-7 and MDA-MB-231, and cervical cancer cell line Hela. All cell lines were cultured in complete medium containing 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin. The cells in the logarithmic growth phase were digested, counted, and inoculated in a 96-well plate (5 × 10 3 μL CCK-8 reagent was added to each well, incubated at 37°C for 1-3 h, and the absorbance was measured at 450 nm. All experiments were repeated three times, and the IC50 Values were obtained by calculation with GraphPad Prism 8.0 software.

[0241] Table 2 Anti-proliferation activity IC of compounds of the present application against tumor cells 50 (μM)

[0242]

[0243] Note: A: IC 50 ≤1 μM, B: IC 50 : 1 < IC 50 ≤5 μM, C: 5 < IC 50 ≤20 μM, D: IC 50 >20 μM.

[0244] From the data in Table 2, it can be seen that the compounds of the present application exhibit significant anti-proliferation activity against tumor cells.

[0245] In summary, the benzimidazole derivatives of the present application have good application prospects as novel HDACs inhibitors in the field of malignant tumor treatment.

[0246] Other compounds in the present application have similar anti-proliferation effects as the listed compounds, but should not be limited to the understanding that the compounds of the present application only have the above beneficial effects.

[0247] It should be noted that the specific embodiments in the present application are for illustration only and should not be construed as limiting the scope of the present application. Furthermore, it should be understood that after reading the content involved in the present application, those skilled in the art can make various modifications or modifications to the present application, and such equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof: wherein, A1and A3are each independently selected from CR' and N; A2is selected from CR3and N; A4is selected from CR2and N; X is selected from CR' and N; R2and R3, if present, are each independently selected from the group consisting of H, hydroxyl, a halogen atom (selected from the group consisting of F, Cl, Br, and I), C1-C6alkoxy, C1-C6alkylamino, C1-C6alkoxycarbonyl, substituted or unsubstituted C1-C6acylamino, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered cycloaliphatic, substituted or unsubstituted 3-12 membered heterocyclyl, and substituted or unsubstituted benzyl; and 10 R2and R3, if present, are each independently selected from the group consisting of H, hydroxyl, a halogen atom (selected from the group consisting of F, Cl, Br, and I), C1-C6alkoxy, C1-C6alkylamino, C1-C6alkoxycarbonyl, substituted or unsubstituted C1-C6acylamino, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered cycloaliphatic, substituted or unsubstituted 3-12 membered heterocyclyl, and substituted or unsubstituted benzyl; and 12 R2and R3, if present, are each independently selected from R1is selected from the group consisting of H, C1-C6alkoxy, C1-C6alkylamino, C1-C6alkoxycarbonyl, substituted or unsubstituted C1-C6acylamino, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered cycloaliphatic, substituted or unsubstituted 3-12 membered heterocyclyl, and substituted or unsubstituted benzyl; 10 R1is selected from the group consisting of H, C1-C6alkoxy, C1-C6alkylamino, C1-C6alkoxycarbonyl, substituted or unsubstituted C1-C6acylamino, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered cycloaliphatic, substituted or unsubstituted 3-12 membered heterocyclyl, and substituted or unsubstituted benzyl; 12 R1is selected from the group consisting of H, C1-C6alkoxy, C1-C6alkylamino Y is absent or selected from C1-C6alkylene, CR'2, NH, C1-C6alkyleneoxy, C1-C6alkylenamino, C1-C6alkyleneoxycarbonyl and substituted or unsubstituted C1-C6alkylimido; said substitution means that one or more hydrogen atoms of a group are each independently replaced by R: Z is absent or selected from C1-C6alkylene, substituted or unsubstituted C 6-14 substituted or unsubstituted C1-C6alkylene, substituted or unsubstituted C 7-12 substituted or unsubstituted C1-C6alkylene, substituted or unsubstituted C If present, each R' is independently selected from H, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkoxycarbonyl, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C6-C 12 aryl, substituted or unsubstituted 5-12-membered heteroaryl, substituted or unsubstituted 3-12-membered alicyclic, substituted or unsubstituted 3-12-membered heterocyclic and substituted or unsubstituted benzyl; said compound is of Formula (II): Each R is independently selected from halogen, oxo, carboxyl, hydroxyl, amino, nitro, cyano, C1-C 10 Alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S-(C1-C6 alkyl), C1-C6 alkylamino, C1-C6 alkoxycarbonyl, C1-C6 amide, C6-C 10 Aryl, five-membered heteroaryl and six-membered heteroaryl, and C1-C substituents thereof. 10 Alkyl, C6-C 10 Aryl, five-membered heteroaryl and six-membered heteroaryl; preferably C1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkylamino.

2. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug, or isomer thereof, wherein, wherein R1, X, Y and Z are as defined in claim 1. said compound is of Formula (III):

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug, or isomer thereof, wherein, wherein R1and Y are as defined in claim 1.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof, wherein, preferably, R1is substituted or unsubstituted benzyl. R1is selected from substituted or unsubstituted C6-C 12 unsubstituted 3-12 membered heterocyclyl, and substituted or unsubstituted benzyl; said compound is of Formula (IV):

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug, or isomer thereof, wherein, wherein Y and R are as defined in claim 1; and m is selected from an integer from 0 to 4, preferably from 0 to 3.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof, wherein, Y is absent or selected from C1-C6alkylene, NH, C1-C6alkyleneoxy, C1-C6alkylenamino, C1-C6alkyleneoxycarbonyl and substituted or unsubstituted C1-C6alkylimido; preferably, Y is absent or selected from C1-C6alkylene and C1-C6alkylenamino.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof, wherein, said substitution means that 1, 2, 3, 4 or 5 hydrogen atoms of a group are each independently replaced by R:

8. The following compounds or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof: each R is independently selected from a halogen atom, a C1-C6alkyl group, a C1-C6alkoxy group, a C1-C6haloalkoxy group, a -S-(C1-C6alkyl) group, and a C1-C6alkyl group substituted with a halogen atom. 10 a C1-C6alkyl group, a C1-C6alkoxy group, a C1-C6haloalkoxy group, a -S-(C1-C6alkyl) group, and a C1-C6alkyl group substituted with a halogen atom. 10 a C1-C6alkyl group, a C1-C6alkoxy group, a C1-C6haloalkoxy 9. A pharmaceutical composition comprising at least one compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof, and one or more pharmaceutically acceptable carriers.

10. A pharmaceutical preparation comprising at least one compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof, or a pharmaceutical composition according to claim 9.

11. Use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof, or a pharmaceutical composition according to claim 9, or a pharmaceutical preparation according to claim 10, for the manufacture of an HDAC inhibitor. ​ 12. Use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, hydrate, deuteride, prodrug or isomer thereof, or a pharmaceutical composition according to claim 9, or a pharmaceutical preparation according to claim 10, in the manufacture of a medicament; the medicament selected from the group consisting of an anti-tumor medicament, an anti-inflammatory medicament, an autoimmune disease medicament and an Alzheimer's disease medicament. Preferably, the tumor is selected from the group consisting of leukemia, colorectal cancer, lung cancer, breast cancer, cervical cancer, melanoma and gastric cancer.

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