Novel compounds for use as cbp / pa300 inhibitors and pharmaceutical compositions for preventing or treating cancer, inflammatory disorders or autoimmune diseases comprising the same as an active ingredient

Abstract

The present application provides a novel compound for use as a CBP / p300 inhibitor, a preparation method thereof, isomers, pharmaceutically acceptable salts, hydrates or solvates thereof, and a pharmaceutical composition for preventing or treating cancer, an inflammatory disorder or an autoimmune disease, the pharmaceutical composition comprising at least one of the above as an active ingredient.

Description

Technical Field

[0001] This application claims priority to Korean Patent Application No. 2024-0007503, filed on January 17, 2024, the entire disclosure of which is incorporated herein by reference. This disclosure relates to a novel compound used as a CBP / p300 inhibitor, and a pharmaceutical composition containing said compound as an active ingredient for the prevention or treatment of cancer, inflammatory disorders, or autoimmune diseases. Background Technology

[0002] CBP [CREB (cyclic AMP response element binding protein) binding protein] and its paralog p300 are transcriptional coactivators composed of multiple functional domains, including a histone acetyltransferase (HAT) domain and a bromide domain (BRD) domain. CBP and p300 are major epigenetic regulators that recognize and induce histone lysine acetylation at specific chromatin loci, such as enhancers and promoters, thereby regulating the expression of various genes.

[0003] Given their high structural similarity and functional redundancy, overexpression or mutation of CBP and p300 (often referred to as CBP / p300) is associated with a variety of diseases, particularly malignancies. For example, CBP and p300 bind to chromatin via BRD and HAT, and acetylate histones at enhancer sites of oncogenes, thereby relaxing chromatin structure and allowing the assembly of transcriptional proteins, including RNA polymerase II. As a result, tumor cells increase the expression of oncogenes such as MYC and IRF4, leading to tumor formation and growth. Repression of the HAT domain results in an overall reduction of acetylation, which is crucial for transcription, and acts in the same way not only on tumor cells but also on normal cells, especially stem cells. Therefore, it has been reported that securing a therapeutic window is difficult and that toxicity may be induced; thus, these concerns are expected to be overcome through strategies involving bromodomain inhibitors.

[0004] Therefore, various studies have been conducted to develop inhibitors that selectively inhibit the bromodomain of CBP / p300 and reduce the transcription of activated oncogenes in tumor cells. For example, CCS1477, a CBP / p300 bromodomain inhibitor developed by CellCentric, is undergoing a phase 1b / 2a clinical trial for the treatment of hematologic malignancies and advanced drug-resistant prostate cancer, and various CBP / p300 activity modulators are also disclosed in patent documents 1 to 3 below.

[0005] However, the development of effective and selective therapeutics targeting CBP / p300 remains a challenging task. Therefore, there is a need to develop more chemically-based CBP / p300 inhibitors.

[0006] [Patent Document 1] WO2018073587

[0007] [Patent Document 2] WO2019191667

[0008] [Patent Document 3] WO2017205538 Summary of the Invention

[0009] Technical goals

[0010] The purpose of this disclosure is to provide a novel compound for use as a CBP / p300 inhibitor.

[0011] Another object of this disclosure is to provide isomers of the said compound, pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof.

[0012] Another object of this disclosure is to provide a pharmaceutical composition for the prevention or treatment of cancer, inflammatory disorders or autoimmune diseases, comprising at least one of the compound, its isomers, its pharmaceutically acceptable salts, its hydrates and its solvates as an active ingredient.

[0013] Technical solution

[0014] To address the aforementioned task, according to one aspect of this disclosure, a compound represented by formula I is provided: <Formula I>

[0015] in

[0016] n is an integer from 0 to 3, where if n is an integer of 2 or greater, then R is the same or different, and R is independently NR. a R b SO2NHR c OR d CONR e R f Halogen, cyano, amidine, imine, C 1-8 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 5- to 13-membered heteroaryl, 3- to 14-membered heterocyclic alkyl, or 4- to 9-membered heterocyclic alkenyl, and R a To R f Each is independently selected from hydrogen and C. 1-4 Alkyl, C 3-10 cycloalkyl and C 6-10 Aryl, and

[0017] Z is C 1-8 Alkyl, C 3-10 cycloalkyl, C 1-5Haloalkyl, C 6-10 aryl, 5- to 13-membered heteroaryl, or 3- to 14-membered heterocyclic alkyl, Among them, R, R a To R f Both Z and I are either substituted by or unsubstituted by the base group I.

[0018] Another aspect of this disclosure relates to isomers of the above-mentioned compounds, pharmaceutically acceptable salts thereof, their hydrates or solvates thereof.

[0019] Another aspect of this disclosure relates to a pharmaceutical composition for the prevention or treatment of cancer, inflammatory disorders, or autoimmune diseases, said composition comprising at least one of the above-described compounds, their isomers, their pharmaceutically acceptable salts, their hydrates, and their solvates as an active ingredient.

[0020] Effect

[0021] According to this disclosure, the compounds represented by Formula I have been found to have excellent CBP / p300 inhibitory activity. Therefore, the compounds represented by Formula I of this disclosure, isomers of the compounds, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof, and pharmaceutical compositions comprising at least one of them as active ingredients may be used to inhibit, for example, prevent or treat cancer, inflammatory disorders or autoimmune diseases.

[0022] The effects of this disclosure are not limited to those described above, and are to be understood to include all effects that can be inferred from the configuration of the invention as described in the specification or claims of this disclosure. Detailed Implementation

[0023] In the following description, to aid in understanding this disclosure, it will be described in more detail. In this context, the terms or words used in this specification and claims should not be construed as limited to their ordinary or dictionary meaning, but rather as meaning and concepts consistent with the technical spirit of this disclosure, the principle being that the inventor can appropriately define the concepts of the terms to best interpret his own invention.

[0024] This disclosure provides a compound represented by the following formula I: <Formula I>

[0025] in

[0026] n can be an integer from 0 to 3, where if n is an integer of 2 or greater, then R can be the same or different, and R can be NR independently. a R b SO2NHR c OR d CONRe R f Halogen, cyano, amidine, imine, C 1-8 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 5- to 13-membered heteroaryl, 3- to 14-membered heterocyclic alkyl, or 4- to 9-membered heterocyclic alkenyl, and R a To R f Each can be independently selected from hydrogen and C. 1-4 Alkyl, C 3-10 cycloalkyl and C 6-10 Aryl, and Z can be C 1-8 Alkyl, C 3-10 cycloalkyl, C 1-5 Haloalkyl, C 6-10 aryl, 5- to 13-membered heteroaryl or 3- to 14-membered heterocyclic alkyl, wherein R, R a To R f Z can be substituted by or remain unsubstituted by the substituted base set I: Substituent group I: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 3-20 Carbon rings, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted C 6-30 aryl, substituted or unsubstituted 3 to 30-membered heterocycles, substituted or unsubstituted C 1-10 Alkoxy, substituted or unsubstituted C 2-10 Alkenyl group, substituted or unsubstituted C 3-10 Cycloalkoxy, substituted or unsubstituted C 6-30 Aryloxy group, substituted or unsubstituted 3- to 30-membered heterocyclic oxy group, substituted or unsubstituted C 1-10 Alkyl ketones, substituted or unsubstituted C 2-10 alkenyl ketones, substituted or unsubstituted C 3-10 Cycloalkyl ketones, substituted or unsubstituted C 6-30 Aryl ketones, substituted or unsubstituted 3- to 30-membered heterocyclic ketones, substituted or unsubstituted C 1-10 alkylthio, substituted or unsubstituted C 2-10 Thylene, substituted or unsubstituted C 3-10 Cyclothio, substituted or unsubstituted C 6-30 Aryl thiols, substituted or unsubstituted 3- to 30-membered heterocyclic thiols, aldehydes, carboxyl groups, halogens, substituted or unsubstituted C groups 1-10 Halogenated alkyl groups, hydroxyl groups, substituted or unsubstituted amino groups, imine groups, cyano groups, nitro groups, amide groups, thiols, sulfones, and phosphoric acids. Where C 1-10The alkyl portion may be intercalated with a heteroatom group selected from -O-, -S-, -SO-, -SO2-, and -NR. g -(R) g It is hydrogen or substituted or unsubstituted C 1-10 Alkyl groups, -N=, =N-, -POR g -and-PO4R g - and the heterocyclic moiety may include at least one of S, N, P and O as a cyclic atom.

[0027] In this specification, matters concerning R also apply to R1, , and .

[0028] Throughout this specification, the concepts defined by Formula I are used. Unless otherwise specified, these definitions apply to terms used individually or as part of a larger group throughout this specification. Unless otherwise defined, terms and abbreviations used herein have their original meanings.

[0029] In this specification, the term "substituted" may mean that the hydrogen atom bonded to each substituent listed in the compound or group of substituents is replaced and bonded by any substituent. In this case, there is no limitation on the position to be substituted, as long as the position is where a hydrogen atom bonded to each substituent listed in the compound or group of substituents is present, i.e., where the hydrogen atom can be replaced by a substituent. If two or more positions are substituted, the two or more substituents may be the same as or different from each other. In contrast, "unsubstituted" may mean that no hydrogen atom bonded to a carbon atom is replaced by any substituent.

[0030] Any substituent suitable for “substitution” may be suitably selected from the substituents listed in the group of substituents described herein, but the range of substituents that can be used for substitution is not limited to the group of substituents described herein.

[0031] If a substituent is not described or mentioned separately in the chemical formula described in this specification, it can be assumed that hydrogen is bonded, and in some cases, depending on the cyclizing element of the heterocycle, the substituent may not be present.

[0032] In this specification, the term "halogen" includes, but is not limited to, fluorine, chlorine, bromine, and iodine, for example.

[0033] In this specification, the term "amino" is intended to cover monovalent primary amines, monovalent secondary amines, and monovalent tertiary amines. That is, an amino group refers to both a monovalent group in which two hydrogen atoms are bonded to a nitrogen atom and a monovalent group in which at least one hydrogen atom is replaced by another substituent. In the foregoing, the group in which two hydrogen atoms are bonded to the nitrogen atom can be an unsubstituted amino group, and the group in which at least one hydrogen atom is replaced by another substituent can be a substituted amino group. Furthermore, for dialkylamino groups, the alkyl moiety can be the same or different.

[0034] In this specification, the term "imine or imino" is intended to cover monovalent primary ketone imines (-C(=NH)R) i-1 ), secondary ketone imine (-C(N=R) i-2 )R i-1 Primary aldehyde imines (-C(=NH)H) and secondary aldehyde imines (-C(=NR)H) i-1 )H), where R i-1 and R i-2 Each can be independent of, but is not limited to, C. 1-10 Alkyl, C 2-10 alkenyl, C 3-10 Carbon ring, C 3-10 cycloalkyl, C 6-30 Aryl, 3 to 30-membered heterocyclic or C 1-10 Halogenated alkyl groups, and each of them may be substituted or unsubstituted, but is not limited thereto.

[0035] In this specification, the term "alkyl" itself, or as part of another substituent, means a straight-chain or branched monovalent hydrocarbon (i.e., C14) having a specified number of carbon atoms. 1-10 (meaning 1 to 10 carbon atoms), unless otherwise stated.

[0036] Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methyl-butyl, 1-ethyl-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 1-methylhexyl, n-octyl, tert-octyl, 1-methylheptyl, 2-ethylhexyl, 2-propylpentyl, n-nonyl, 2,2-dimethylheptyl, 1-ethyl-propyl, 1,1-dimethyl-propyl, isohexyl, 2-methylpentyl, 4-methylhexyl, and 5-methylhexyl, but these are non-limiting examples and the scope of this disclosure is not limited thereto.

[0037] In this specification, the term "cycloalkyl" means a monovalent aliphatic carbon ring in which a hydrogen atom is missing from any position among the carbon atoms constituting the ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 3-methylcyclopentyl, 2,3-dimethylcyclopentyl, cyclohexene-3-methylcyclohexyl, 4-methylcyclohexyl, 2,3-dimethylcyclohexyl, 3,4,5-trimethylcyclohexyl, 4-tert-butylcyclohexyl, cycloheptyl, and cyclooctyl.

[0038] In this specification, the term "aryl" refers to a polyunsaturated, usually aromatic, hydrocarbon ring, wherein the aryl group can be monocyclic or polycyclic. Polycyclic forms include those in which only aromatic hydrocarbon rings are fused and those in which aliphatic hydrocarbon rings are fused with aromatic hydrocarbons. Examples of aryl groups include monocyclic aryl groups such as phenyl, biphenyl, terphenyl, and tetraphenyl, and polycyclic aryl groups such as naphthyl, anthraceneyl, phenanthryl, pyrene, and benzo[a]pyrene.

[0039] In this specification, the term "heterocyclic" refers to a ring comprising one to five heteroatoms other than carbon (i.e., O, N, P, and S) that are cyclic atoms together with carbon. Here, heterocyclic rings can be aromatic, aliphatic, monocyclic, or polycyclic, and include, but are not limited to, thiophene, furanyl, pyrrole, imidazolyl, and thiazolyl groups. azole group, Diazolyl, pyridyl, bipyridyl, pyrimidinyl, triazinyl, triazolyl, pyridazinyl, pyridopyrimidinyl, pyridopyrazinyl, pyrazenopyrazinyl, isozynyl The groups are azole and thiadiazole, but the scope of this disclosure is not limited thereto.

[0040] In this specification, the term "heterocyclic alkyl" means a partially or fully saturated hydrocarbon containing one or more heteroatoms selected from O, N, P, and S as cyclic atoms, forming a monocyclic or fused ring. Preferably, the heteroatoms can be one, one to two, or one to three. For example, they may include, but are not limited to, piperazinyl, piperazin-diketone, piperidinyl, pyrrolyl, morpholinyl, imidazoalkyl, imidazolidinone, lactamyl, tetrahydropyranyl, tetrahydrofuranyl, diazabicyclooctyl, and diazaspirooctyl.

[0041] In this specification, the term "heterocyclic alkenyl" means an unsaturated hydrocarbon comprising one or more heteroatoms selected from O, N, P, and S as cyclizing atoms to form a monocyclic or fused ring. Preferably, the heteroatoms may be one, one to two, or one to three. For example, they may include, but are not limited to, tetrahydropyridyl.

[0042] In this specification, the term "heteroaryl" refers to an aromatic heterocycle, which can be monocyclic or polycyclic. Polycyclic includes not only forms in which multiple aromatic rings are fused together, but also forms in which aromatic and aliphatic rings are fused together. Examples of heteroaryl groups include pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, and others. azole group, iso Azolyl, thiazolyl, tetrazolyl, isothiazolyl, furanyl, thiophene, pyridyl, N-oxypyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzo[] The group name may be azole, benzothiophene, quinolino, quinazolino, quinoxalino, phthalazino, isoquinolino, thiophene, acridine, indazole, carbazole, benzimidazol, benzocarbazole, benzofuran, benzothiophene, dibenzothiophene, pyrazolopyrimidinyl, or azaindole, but the scope of this disclosure is not limited thereto.

[0043] In this specification, the term "alkenyl" can be straight-chain or branched. Alkenyl groups include, for example, vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl or 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, and 1,1-dimethyl-2-propenyl. 1,2-Dimethyl-1-propenyl, 1,2-Dimethyl-2-propenyl, 1-Ethyl-1-propenyl, 1-Ethyl-2-propenyl, 1-Hexenyl, 2-Hexenyl, 3-Hexenyl, 4-Hexenyl, 5-Hexenyl, 1-Methyl-1-pentenyl, 2-Methyl-1-pentenyl, 3-Methyl-1-pentenyl, 4-Methyl-1-pentenyl, 1-Methyl-2-pentenyl, 2-Methyl-2-pentenyl, 3-Methyl-2-pentenyl, 4-Methyl-2-pentenyl, 1-Methyl-3-pentenyl, 2-Methyl-3-pentenyl, 3-Methyl-3-pentenyl, 4-Methyl-3-pentenyl, 1-Methyl-4-pentenyl, 2-Methyl -4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl The following are included, but not limited to: 1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, and 5-decenyl.

[0044] In this specification, the terms "carbocyclic" and "of a carbocyclic ring" mean a ring in which the atoms forming the ring are composed of carbon atoms. Carbocyclic rings can be aliphatic or aromatic, saturated or unsaturated, monocyclic or polycyclic. Polycyclic rings can be fused, bridged, or spirocyclic. Monocyclic carbocyclic rings can have 3 to 17 carbon atoms, particularly 3 to 14 carbon atoms, more particularly 3 to 10 carbon atoms, and especially particularly 3 to 7 carbon atoms.

[0045] In this specification, the term "alkoxy" refers to a substituent having an oxygen bonded to an alkyl group, and can be a straight chain, branched chain, or cyclic chain. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, isopropyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, neopentoxy, isopentoxy, n-hexyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, n-octoxy, n-nonoxy, n-decoxy, benzoxy, p-methylbenzoxy, and their monohalogenated and polyhalogenated variants.

[0046] In this specification, the term "oxygen group" refers to a group that can be converted from "-OR". 氧基 " represents the substituent, where R 氧基 It can be, but is not limited to, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 3-10 Carbon rings, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 6-30 aryl, substituted or unsubstituted 3 to 30-membered heterocycles, or substituted or unsubstituted C 1-10 Halogenated alkyl groups.

[0047] In this specification, the term "carbonyl" can be derived from "-C(=O)R". car " represents the substituent, where R car It can be, but is not limited to, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 3-10 Carbon rings, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 6-30 aryl, substituted or unsubstituted 3 to 30-membered heterocycles, or substituted or unsubstituted C 1-10 Haloalkyl groups, each of which is defined as described above. A "carbonyl" group may be referred to as a "ketone" and may also be referred to as an "alkyl ketone" depending on its substituents and bonding sites.

[0048] In this specification, the term "thio" can be derived from "-SR". 硫代 " represents the substituent, where R 硫代 It can be, but is not limited to, substituted or unsubstituted C.1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 3-10 Carbon rings, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 6-30 aryl, substituted or unsubstituted 3 to 30-membered heterocycles, or substituted or unsubstituted C 1-10 Halogenated alkyl groups.

[0049] In this specification, the term "halogenated alkyl" is synonymous with "halogenated alkyl" and "halogen-substituted alkyl," and may refer to an alkyl group in which any hydrogen atom is replaced by any halogen atom. For example, -CF3, -CF2H, -CH2Cl, -CH2CF3, and -C(Cl2)CF3 are haloalkyl groups, but the scope of this disclosure is not limited thereto.

[0050] In this specification, the term "amide" is a substituent that can be represented by, for example, RC(=O)-NR'R'', where R, R', and R'' are each, but not limited to, hydrogen, substituted, or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 3-10 Carbon rings, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 6-30 aryl, substituted or unsubstituted 3 to 30-membered heterocycles, or substituted or unsubstituted C 1-10 Halogenated alkyl groups, but not limited to them.

[0051] In this specification, the term "sulfonyl" refers to a group that can be formed by "-S(=O)2R". s1 " represents the substituent, where R s1 It can be, but is not limited to, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 3-10 Carbon rings, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 6-30 aryl, substituted or unsubstituted 3 to 30-membered heterocycles, or substituted or unsubstituted C 1-10 Halogenated alkyl groups.

[0052] In this specification, the term "thioamide" refers to an amino acid that can be produced by the reaction of "-C(=S)NR". ta 2”, "-C(=S)NHR" ta The substituents represented by "" and "-C(=S)NH2", where R ta They are independent of each other, and each can be, but is not limited to, a substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 3-10Carbon rings, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 6-30 aryl, substituted or unsubstituted 3 to 30-membered heterocycles, or substituted or unsubstituted C 1-10 Halogenated alkyl groups.

[0053] In this specification, the term "sulfinyl" refers to a group that can be formed by "-S(=O)R". s2 " represents the substituent, where R s2 It can be, but is not limited to, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 3-10 Carbon rings, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 6-30 aryl, substituted or unsubstituted 3 to 30-membered heterocycles, or substituted or unsubstituted C 1-10 Haloalkyl groups, and each of them as defined above. The sulfinyl group can also be used interchangeably with "thiocarbonyl," and in R... s2 In the case of an alkyl group, it can also be called an alkyl thiocarbonyl group in a narrow sense.

[0054] In this specification, the term "phosphoric acid" refers to phosphoric acid that can be formed by "-OP(=O)(OH)2" or "-OP(=O)(OH)(OR)2". P The substituent is represented by )”, where R P It can be, but is not limited to, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 3-10 Carbon rings, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 6-30 aryl, substituted or unsubstituted 3 to 30-membered heterocycles, or substituted or unsubstituted C 1-10 Halogenated alkyl groups.

[0055] In this specification, the term "ester" can be derived from "-OC(=O)R". 酯 " represents the substituent, where R 酯 It can be, but is not limited to, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 3-10 Carbon rings, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 6-30 aryl, substituted or unsubstituted 3 to 30-membered heterocycles, or substituted or unsubstituted C 1-10 Halogenated alkyl groups.

[0056] In one implementation, R, R a To Rf A and Z can each be substituted by the base set I-1 or remain unsubstituted.

[0057] Substituent group I-1: substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, hydroxyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-4 Halogenated alkyl, substituted or unsubstituted C 6-8 Aryl, substituted or unsubstituted 3- to 8-membered heteroaryl, substituted or unsubstituted cyano, substituted or unsubstituted amino, substituted or unsubstituted amide, aldehyde, halogen, CO2R p1 , NHCOR p2 NHCO2R p3 or NHSO2R p4 , where R p1 To R p4 Each is independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted butyl, or substituted or unsubstituted phenyl.

[0058] In one embodiment, the compound represented by formula I can be represented by formula I-1: <Formula I-1>

[0059] in

[0060] R 1 It can be NR a R b SO2NHR c OR d CONR e R f Halogen, cyano or imine, and can be substituted or unsubstituted with substituent group I, and R a To R f Z can be the same as defined above.

[0061] Unless otherwise specified, matters relating to R in this specification shall also apply to R. 1 .

[0062] In one implementation, R 1 It can be NR a R b SO2NHR c OR d CONR e R f , bromine, cyano or amidine, wherein R a To Rf Each of these can be independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, or substituted or unsubstituted phenyl, and R 1 It can be substituted by or not substituted by the base set I-1-1: Substituent group I-1-1: substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl and hydroxyl groups.

[0063] In one embodiment, the compound of formula I can be represented by formula I-2: <Formula I-2>

[0064] in It can be a C5 cycloalkyl, a 5-membered heteroaryl, or a 5-membered heterocycloalkyl, where m can be an integer from 0 to 3, and if m is an integer of 2 or greater, then R A They can be the same or different, and R A C can be substituted or unsubstituted. 1-6 Alkyl, substituted or unsubstituted C 1-4 Halogenated alkyl, substituted or unsubstituted cyano, substituted or unsubstituted amide, substituted or unsubstituted amino or aldehyde.

[0065] Unless otherwise specified, matters relating to R in this specification shall apply equally to all matters relating to R. .

[0066] In one implementation method It can be furanyl, iso azole group, Diazolone, pyrazol, thiophene, triazol, thiazolyl, or thiazoline.

[0067] In one implementation, Z can be the same as described above.

[0068] In one embodiment, the compound of formula I can be represented by formulas I-3: <Formula I-3>

[0069] in It can be a C5 cycloalkyl, C6 aryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, or 6-membered heterocycloalkenyl, and p can be an integer from 0 to 3, where if p is an integer of 2 or greater, then R B They can be the same or different, and R BC can be substituted or unsubstituted. 1-5 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted amides, substituted or unsubstituted amino groups, halogens, cyano groups, hydroxyl groups, aldehydes, CO2R h , NHCOR i NHCO2R j or NHSO2R k , where R h To R k Each can be hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted butyl, or substituted or unsubstituted phenyl, independently.

[0070] Unless otherwise specified, matters relating to R in this specification shall apply equally to all matters relating to R. .

[0071] In one implementation method It can be phenyl, pyridone, pyridyl, pyrimidinyl, piperidinyl, or tetrahydropyridyl.

[0072] In one implementation, Z can be the same as described above.

[0073] In one embodiment, the compound of formula I can be represented by formulas I-4: <Formula I-4>

[0074] in

[0075] q can be an integer from 0 to 3, where if q is an integer of 2 or greater, then R C They can be the same or different. It can be C9 cycloalkyl, C 10 cycloalkyl, C9 aryl, C 10 Aryl, 9-membered heteroaryl, 10-membered heteroaryl, 9-membered heterocyclic alkyl or 10-membered heterocyclic alkyl, and R C C can be substituted or unsubstituted. 1-8 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, halogen, or cyano groups.

[0076] Unless otherwise specified, matters relating to R in this specification shall apply equally to all matters relating to R. .

[0077] In one implementation method It can be benzimidazolyl, benzodioxanepentyl, benzodioxanehexyl or dihydrobenzofuranyl.

[0078] In one implementation, Z can be the same as described above.

[0079] In one implementation, q can be 0.

[0080] In one embodiment, Z can be methyl, ethyl, propyl, butyl, cyclopropyl, cyclohexyl, trifluoromethyl, phenyl, furanyl, imidazolyl, or isopropyl. azole group, Z can be substituted with or without the following groups: azole, pyrazol, pyrrole, thiazolyl, thiophene, pyridinyl, pyrimidinyl, azaindolyl, indolyl, piperidinyl, tetrahydropyranyl, lactamyl, or tetrahydronaphthyl, and Z can be substituted with or without the substituent group I-1-2: Substituent group I-1-2: substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-3 Halogenated alkyl, halogen, hydroxyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 6-8 Aryl, substituted or unsubstituted 3- to 8-membered heteroaryl, substituted or unsubstituted cyano, substituted or unsubstituted amino, substituted or unsubstituted amide, CO2R l or NHCO2R m , where R l and R m Each is independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted butyl, or substituted or unsubstituted phenyl.

[0081] In one embodiment, the compound represented by Formula I may be selected from any of the compounds in Table 1 below.

[0082] In one embodiment, the compound represented by Formula I can be used as a CBP / p300 inhibitor. In this specification, CBP / p300 may refer to CBP and / or p300. CBP refers to CREB (cyclic AMP response element binding protein) binding protein, and p300 refers to a paralog of CBP.

[0083] CBP / p300 induces histone H3 lysine 27 acetylation (H3K27ac) at the promoters, enhancers, and superenhancers of target genes, and simultaneously activates gene transcription by recognizing acetylated histones via BRD. Based on the overexpression of CBP / p300 in cancer cells and drug-resistant cancer cells, oncogene transcription is activated, and cancer cell proliferation, survival, tumor formation, metastasis, immune evasion, or drug resistance are induced. Therefore, it is necessary to inhibit the overexpression of CBP / p300 in cancer cells, etc. The use of compounds represented by Formula I as CBP / p300 inhibitors in this specification may imply that the compounds possess the inhibitory activity against CBP / p300 overexpression as described above. The compounds represented by Formula I of this disclosure can, for example, reduce H3K27ac and downregulate oncogene transcription, thereby inducing cancer cell growth inhibition and apoptosis in vivo, activating immune responses, overcoming drug resistance, and inhibiting tumor progression. For example, the compounds represented by Formula I of this disclosure can also, for example, enhance the anticancer efficacy of chemotherapy, radiotherapy, and epigenetic anticancer agents by inhibiting BRD.

[0084] This disclosure also provides isomers of the compound represented by Formula I, pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof.

[0085] In this specification, the term "isomer" may include enantiomers, their diastereomers, their tautomers, and their geometric isomers. In this specification, enantiomers refer to two stereoisomers of a compound that are non-superimposed mirror images of each other.

[0086] In this specification, a diastereomer is a stereoisomer having two or more chiral centers, whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical procedures such as electrophoresis and chromatography.

[0087] In this specification, geometric isomers refer to cis and trans forms, in which atoms or groups of the same type are located on the same side of the double bond, while in the trans form, atoms or groups of the same type are located on opposite sides of the double bond.

[0088] In this specification, tautomers or tautomer forms refer to structural isomers with different energies that are compatible through low energy barriers. For example, proton tautomers (also referred to as proton tautomers) include interconversions via proton transfer, including keto-enol and imine-enamine isomerization. Atomic tautomers include interconversions via the retransfer of some bonding electrons.

[0089] In this specification, any atoms present in the compounds disclosed herein may exist in any naturally occurring isotopic form. For example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine may be... 2 H(“D”), 3 H, 11 C 12 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 32 P, 33 P, 35 S, 18 F, 36 Cl、 123 I and 125 I.

[0090] In this specification, the term "acceptable salt" means a salt of an active compound prepared with an acid or base, depending on the specific substituents of the compound described herein. If the compound according to this disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound in a neutral state with a sufficient amount of the desired base in the absence of a solvent or in the presence of a suitable inert solvent.

[0091] Acceptable salts include, for example, alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; ammonium salts; aliphatic amine salts, such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, or procaine salts; aralkylamine salts, such as N,N-diphenylmethylethylenediamine salts; heterocyclic aromatic amine salts, such as pyridine salts, methylpyridine salts, quinoline salts, or isoquinoline salts; quaternary ammonium salts, such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts, or tetrabutylammonium salts; and basic amino acid salts, such as arginine salts or lysine salts. Salts can be, for example, inorganic salts, such as hydrochlorides, sulfates, nitrates, phosphates, carbonates, bicarbonates, or perchlorates; organic salts, such as acetates, propionates, lactates, malates, fumarates, tartrates, malates, fumarates, citrates, ascorbic acid, or formic acid; sulfonates, such as methanesulfonates, thiosulfates, benzenesulfonates, or p-toluenesulfonates; and acidic amino acid salts, such as aspartate or glutamate.

[0092] In this specification, the term "hydrate" refers to a compound in which water (H2O) is bonded to another compound.

[0093] In this specification, the term "solvent" refers to an aggregate or complex of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0094] This disclosure also provides a pharmaceutical composition for the prevention or treatment of cancer, inflammatory disorders or autoimmune diseases, comprising at least one of the compound represented by Formula I, its isomers, its pharmaceutically acceptable salts, its hydrates and its solvates as active ingredients.

[0095] In one embodiment, the cancer may be a cancer dependent on the oncogene MYC, a tumor carrying a loss-of-function mutation of CBP or p300, or a cancerous disease with activated CBP and / or p300 function.

[0096] In one embodiment, the cancer may be selected from one or more of hematologic malignancies, prostate cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer, and melanoma.

[0097] In one embodiment, the cancer may be selected from acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, craniopharyngioma, and cystadenocarcinoma. Diffuse large B-cell lymphoma, dysplastic changes, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocytosis, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, pedunculated tumor, heavy chain disease head and neck cancer, hemangioblastoma, hepatocellular carcinoma, hormone-insensitive prostate. Cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphoendothelial sarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, midline NUT carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer Ovarian cancer, pancreatic cancer, papillary gland cancer, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland cancer, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial malformation, sweat gland cancer, thyroid cancer, Waldenström macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor, one or more of these.

[0098] In one embodiment, the inflammatory disorder or autoimmune disease may be selected from Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous dermatitis, chronic obstructive pulmonary disease, Crohn's disease, dermatitis, eczema, giant cell arteritis, fibrosis, glomerulonephritis, hepatic vascular occlusion, hepatitis, hypophysitis, immunodeficiency syndrome, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, aortitis, toxic shock, thyroiditis, type 1 diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis, or more of these.

[0099] In one embodiment, the pharmaceutical composition may further comprise a pharmaceutically acceptable diluent or carrier. Specifically, the pharmaceutical compositions of this disclosure may comprise a pharmaceutically acceptable carrier and may be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, topical preparations, suppositories, and sterile injectable solutions according to common methods. The pharmaceutically acceptable carrier may include lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil. Furthermore, the carrier may include diluents or excipients, such as fillers, weighting agents, binders, wetting agents, disintegrants, and surfactants. Oral solid dosage forms may include tablets, pills, powders, granules, and capsules, and may contain one or more excipients, such as starch, calcium carbonate, sucrose or lactose, and gelatin, and may contain lubricants such as magnesium stearate and talc. Oral liquid dosage forms may include suspensions, solutions, emulsions, and syrups, and may contain diluents such as water and liquid paraffin, wetting agents, sweeteners, flavoring agents, and preservatives. Parenteral dosage forms may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories, and the non-aqueous solvents and suspensions may contain propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As suppository bases, Witepsol, polyethylene glycol, Tween 61, cocoa butter, lauryl butter, glycerin gelatin, etc., can be used.

[0100] In one embodiment, the dosage of the compound represented by Formula I, its isomers, its pharmaceutically acceptable salts, its hydrates, or its solvates included in the pharmaceutical compositions of this disclosure varies depending on the patient's condition, weight, disease severity, drug form, route of administration, and time of administration, but can be suitably selected by those skilled in the art. For example, the compound represented by Formula I or its pharmaceutically acceptable salts may be administered at a dose of 0.0001 to 1000 mg / kg daily, preferably 0.01 to 1000 mg / kg, and said administration may be once daily or divided into several doses. Furthermore, the pharmaceutical compositions of this disclosure may contain 0.001 to 90% by weight of the compound represented by Formula I or its pharmaceutically acceptable salts, based on the total weight of the composition.

[0101] In one embodiment, the pharmaceutical compositions of this disclosure can be administered to mammals, such as rats, mice, livestock, and humans, via various routes, such as oral, intraperitoneal, rectal or intravenous, intramuscular, subcutaneous, intrauterine, or intraventricular injection.

[0102] The present disclosure will be described in more detail below by way of preparation examples, embodiments, and experimental examples. However, the preparation examples, embodiments, and experimental examples below are intended to illustrate the present disclosure, and the scope of the present disclosure is not limited thereto.

[0103] Compounds having the structure of Formula I can be synthesized by the following method.

[0104]

[0105] The compounds prepared in the preparation examples and embodiments were analyzed as follows: Nuclear magnetic resonance (NMR) spectroscopy was performed on a Bruker 500 MHz or Jeol 400 MHz spectrometer. Mass spectrometry was performed using LC / MS (Agilent 1260infinity II / Agilent Infinity Lab LC / MSD, API-ES mode, UV detection at 220 nm / 254 nm). (Column: ZORBAX RRHT StableBond C18, 2.1 x 50 mm, 1.8 μm, 80 Å, mobile phase: water / acetonitrile / formic acid (30 / 70 / 0.1%), isocratic elution for 3 min.)

[0106] In addition, the compounds were purified using medium-pressure liquid chromatography (MPLC, CombiFlash Nextgen 300+) or preparative HPLC (Thermo Ultimate 3000 with diode array detector, UV detection: 215 nm, 254 nm, 280 nm). The preparative HPLC conditions were as follows: (column: Phenomenex Luna, 10 μm, C18(2), 100 Å, 250 x 21.20 mm), mobile phase A: water / 0.1% trifluoroacetic acid, mobile phase B: acetonitrile / 0.1% trifluoroacetic acid, gradient elution for 30 min, A:B = 75:25-65:35).

[0107] Each starting material was a known compound, synthesized from literature or purchased commercially.

[0108] The compounds prepared in the preparation examples and embodiments were analyzed as follows: Nuclear magnetic resonance (NMR) spectroscopy was performed on a Bruker 500 MHz or Jeol 400 MHz spectrometer. Mass spectrometry was performed using LC / MS (Agilent 1260infinity II / Agilent Infinity Lab LC / MSD, API-ES mode, UV detection at 220 nm / 254 nm). (Column: ZORBAX RRHT StableBond C18, 2.1 x 50 mm, 1.8 μm, 80 Å, mobile phase: water / acetonitrile / formic acid (30 / 70 / 0.1%), isocratic elution for 3 min.)

[0109] In addition, the compounds were purified using medium-pressure liquid chromatography (MPLC, CombiFlash Nextgen 300+) or preparative HPLC (Thermo Ultimate 3000 with diode array detector, UV detection: 215 nm, 254 nm, 280 nm). The preparative HPLC conditions were as follows: (column: Phenomenex Luna, 10 μm, C18(2), 100 Å, 250 x 21.20 mm), mobile phase A: water / 0.1% trifluoroacetic acid, mobile phase B: acetonitrile / 0.1% trifluoroacetic acid, gradient elution for 30 min, A:B = 75:25-65:35).

[0110] Each starting material was a known compound, synthesized from literature or purchased commercially.

[0111] intermediate synthesis method

[0112] Preparation of Intermediate I-1: 5-Amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0113] Step 1) Preparation of 5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0114] 4-Nitrophenyl-1,2-diamine (10 g, 65.3 mmol) was dissolved in tetrahydrofuran (365 mL) and cooled to 0 °C, then 1,1-carbonylimidazole (21 g, 130.6 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting solid was washed with diethyl ether, 1 N hydrochloric acid, and water. The solid was dried under vacuum to give the title compound (9.59 g, 53.5 mmol, 82% yield).

[0115] 1H NMR (500 MHz, DMSO-d6) δ 11.43 (s, 1H), 11.20 (s, 1H), 7.94 (dd, J= 8.6, 2.3 Hz, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H)

[0116] Step 2) Preparation of 1,3-dimethyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0117] 5-Nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (4.9 g, 27.5 mmol) was dissolved in dimethylformamide (70 mL) and cooled to 0 °C. Sodium hydride (60%, dispersed in mineral oil, 4.4 g, 110 mmol) was added stepwise, followed by methyl iodine (11.7 g, 5.13 mL, 83.0 mmol). The reaction solution was stirred at 60 °C for 2 hours, and then water was added to terminate the reaction. The reaction solution was diluted with ethyl acetate and washed with 0.1 N hydrochloric acid and brine. The organic layer was distilled under reduced pressure, and the resulting solid was washed with hexane and dried under vacuum to give the title compound (4.95 g, 23.4 mmol, 87% yield).

[0118] 1 ¹H NMR (500 MHz, chloroform-d) δ 8.12 (dd, J = 8.6, 2.2 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 3.50 (s, 3H), 3.49 (s, 3H)

[0119] Step 3) Preparation of 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0120] 1,3-Dimethyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (3.5 g, 16.9 mmol) was dissolved in ethyl acetate / methanol (50 mL / 50 mL), and palladium / carbon (10 wt%, 0.7 g) was added. After replacing the reaction system with hydrogen using a hydrogen balloon, the reaction solution was stirred under hydrogen conditions for 3 hours. After the reaction was complete, the reaction solution was filtered through a diatomaceous earth pad to remove the catalyst. The filtrate was concentrated under reduced pressure to give the title compound, which could be used in subsequent reactions without further purification (2.79 g, 15.7 mmol, 93% yield).

[0121] 1 H NMR (500 MHz, DMSO-d6) δ 6.78 (d, J = 8.2 Hz, 1H), 6.35 (d, J = 2.0Hz, 1H), 6.31 (dd, J = 8.2, 2.1 Hz, 1H), 4.77 (s, 2H), 3.22 (s, 3H), 3.21 (s,3H)

[0122] Preparation of intermediate I-2: 4-fluoro-N-methyl-3-nitrobenzenesulfonamide

[0123] 4-Fluoro-3-nitrobenzenesulfonyl chloride (1.076 g, 4.49 mmol) was dissolved in dichloromethane (8.98 mL), and methylamine (2 M, in tetrahydrofuran, 5.6 mL, 11.23 mmol) was slowly added dropwise at 0 °C. The reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to give the title compound (533 mg, 2.276 mmol, 50.7% yield).

[0124] 1 ¹H-NMR (400 MHz, chloroform-d) δ 8.55 (dd, J = 6.9, 2.3 Hz, 1H), 8.16–8.13 (m, 1H), 7.51–7.47 (m, 1H), 5.10–5.07 (m, 1H), 2.71 (d, J = 5.0 Hz, 3H)

[0125] Preparation of intermediate I-3: 4-fluoro-N-methyl-3-nitrobenzamide

[0126] 4-Fluoro-3-nitrobenzoic acid (2 g, 10.8 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.69 g, 14.1 mmol) were dissolved in dichloromethane (30 mL), and methylamine (2 M, in tetrahydrofuran, 5.4 mL, 10.8 mmol) was slowly added dropwise at 0 °C. The reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, the solution was cooled to 0 °C, water was added, and the organic layer was extracted with dichloromethane. The organic layer was washed with 1 N sodium hydroxide aqueous solution and brine, and concentrated under reduced pressure. The product was used in subsequent reactions without further purification. (1.8 g, 9.08 mmol, 84% yield)

[0127] 1H-NMR (500 MHz, chloroform-d) δ 8.47 (dd, J = 6.9, 2.3 Hz, 1H), 8.14 (qd,J = 4.3, 2.4 Hz, 1H), 7.41 (dd, J = 10.1, 8.8 Hz, 1H), 6.21 (s, 1H), 3.08 (d,J = 4.9 Hz, 3H)

[0128] Intermediate I-4 (Synthetic Method IA): Preparation of 3-amino-4-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-methylbenzenesulfonamide

[0129] Step 1) Preparation of 4-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methyl-3-nitrobenzenesulfonamide

[0130] 4-Fluoro-N-methyl-3-nitrobenzenesulfonamide (intermediate I-2, 533 mg, 2.276 mmol) was dissolved in 1,4-di(2 ... The reaction mixture was placed in an alkyl group (5.5 mL), and then 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-1, 403 mg, 2.276 mmol) and N,N-diisopropylethylamine (994 µl, 5.69 mmol) were added. The reaction solution was stirred at 110 °C for 18 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the resulting solid was washed with dichloromethane and methanol without further purification to obtain the title compound (846 mg, 2.161 mmol, 95% yield).

[0131] 1 ¹H-NMR (400 MHz, chloroform-d) δ 9.80 (s, 1H), 8.74 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.07–7.03 (m, 3H), 6.90 (s, 1H), 4.40–4.39 (m, 1H), 3.47 (s, 3H), 3.43 (s, 3H), 2.70 (d, J = 5.0 Hz, 3H)

[0132] Step 2) Preparation of 3-amino-4-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methylbenzenesulfonamide

[0133] The compound 4-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methyl-3-nitrobenzenesulfonamide (846 mg, 2.161 mmol) obtained above was dissolved in ethanol (10 mL), and stannous(II) chloride dihydrate (1.463 g, 6.48 mmol) was added. The reaction solution was stirred at 90 °C for 18 hours. After the reaction was complete, 1 N sodium hydroxide aqueous solution was added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to give the title compound (610 mg, 1.688 mmol, 78% yield).

[0134] 1 H-NMR (400 MHz, DMSO-d6) δ 7.34 (brs, 1H), 7.15 (s, 1H), 7.09-7.04(m, 2H), 7.00-6.94 (m, 2H), 6.88 (d, J = 1.8 Hz, 1H), 6.80 (dd, J = 8.2, 1.8Hz, 1H), 3.31 (s, 3H), 3.28 (s, 3H), 2.38 (d, J = 3.7 Hz, 3H)

[0135] Preparation of Intermediate I-5 (Synthetic Method IB): 5-Bromo-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one

[0136] Step 1) Preparation of 5-((4-bromo-2-nitrophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0137] The title compound was obtained using 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-1, 2.85 g, 16.07 mmol) and 4-bromo-1-fluoro-2-nitrobenzene (2 mL, 16.07 mmol) in a manner similar to step 1 of synthetic method IA. (3 g, 7.95 mmol, 49.5% yield)

[0138] 1H-NMR (500 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.59-7.56 (m, 1H), 7.22-7.19 (m, 2H), 7.04-7.02 (m, 1H), 6.94 (d, J = 9.2 Hz,1H), 3.35 (s, 3H), 3.31 (s, 3H)

[0139] Step 2) Preparation of 5-((2-amino-4-bromophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0140] The title compound was obtained using the compound 5-((4-bromo-2-nitrophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (3 g, 7.95 mmol) obtained above, in a manner similar to step 2 of synthetic method IA. (2.4 g, 6.91 mmol, 87% yield)

[0141] 1 H-NMR (400 MHz, DMSO-d6) δ 6.96 (d, J = 8.2 Hz, 1H), 6.92 (s, 1H), 6.87-6.85 (m, 2H), 6.62-6.59 (m, 2H), 6.56 (dd, J = 8.2, 1.8 Hz, 1H), 5.04(s, 2H), 3.27 (s, 3H), 3.23 (s, 3H), LC / MS: 347 349 (M+H)

[0142] Step 3) Preparation of 5-bromo-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one

[0143] The compounds 5-((2-amino-4-bromophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (450 mg, 1.296 mmol) and 1-methyl-1H-imidazol-5-carboxaldehyde (143 mg, 1.296 mmol) obtained above were dissolved in acetic acid (1 mL), and then copper acetate (118 mg, 0.648 mmol) was added. The reaction solution was stirred at 80 °C for 30 min. After the reaction was complete, water and 1 N sodium hydroxide aqueous solution were added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to give the title compound (337 mg, 0.771 mmol, 59.5% yield).

[0144] 1 ¹H-NMR (500 MHz, chloroform-d) δ 7.95 (s, 1H), 7.61 (s, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.12–7.06 (m, 2H), 6.94–6.91 (m, 2H), 6.57 (s, 1H), 4.14 (s, 3H), 3.51 (s, 3H), 3.39 (s, 3H)

[0145] Intermediate I-6 (Synthetic Method IC): Preparation of 3′-amino-4′-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-[1,1′-biphenyl]-4-carboxamide

[0146] Step 1) Preparation of 4′-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-3′-nitro-[1,1′-biphenyl]-4-carboxamide

[0147] 5-((4-bromo-2-nitrophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (the compound from step 1 of synthetic method IB, 353 mg, 0.936 mmol), (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (203 mg, 1.029 mmol) and tripotassium phosphate (397 mg, 1.872 mmol) were dissolved in 1,4-di... The reaction mixture was prepared in alkyl (4 mL) and water (1 mL), and then 1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane adduct (76 mg, 0.094 mmol) was added. The reaction solution was stirred at 100 °C for 3 hours under nitrogen. After the reaction was complete, water was added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was washed with ethanol and used in subsequent reactions without further purification. (438 mg, 0.565 mmol, 60.4% yield)

[0148] 1 H-NMR (500 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.46 (s, 1H), 8.22 (m, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.72-7.59 (m, 3H), 7.24-7.22 (m, 2H), 7.09 (s, 1H),7.07 (s, 1H), 3.36 (s, 3H), 3.32 (s, 3H), 2.79 (d, J = 4.3 Hz, 3H)

[0149] Step 2) Preparation of 3'-amino-4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide

[0150] The title compound was obtained using the compound 4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-3'-nitro-[1,1'-biphenyl]-4-carboxamide (254 mg, 0.565 mmol) obtained above, in a manner similar to step 2 of synthetic method IA. (228 mg, 0.446 mmol, 79% yield)

[0151] 1H-NMR (500 MHz, DMSO-d6) δ 8.17-8.16 (m, 1H), 7.68 (t, J = 7.9 Hz,1H), 7.47-7.41 (m, 2H), 7.10 (s, 1H), 7.06 (s, 1H), 7.04-6.99 (m, 2H), 6.92(d, J = 8.2 Hz, 1H), 6.74 (s, 1H), 6.68 (d, J = 8.2 Hz, 1H), 4.90 (s, 2H), 3.29 (s, 3H), 3.26 (s, 3H), 2.79 (d, J = 4.6 Hz, 3H), LC / MS: 420 (M+H)

[0152] Preparation of Intermediate I-7: ((4-fluoro-3-nitrophenyl)ethynyl)trimethylsilane

[0153] 4-Bromo-1-fluoro-2-nitrobenzene (4.4 g, 20 mmol), bis(triphenylphosphine)palladium(II) dichloride (1.4 g, 2 mmol), and copper iodide (0.570 g, 3 mmol) were dissolved in toluene (66 mL) and water (33 mL), followed by the addition of trimethylsilylacetylene (4.2 mL, 30 mmol). The reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and then water and ethyl acetate were added to extract the organic layer. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to give the title compound (4.13 g, 17.4 mmol, 87% yield).

[0154] 1 H NMR (500 MHz, chloroform-d) δ 8.14 (dd, J = 7.1, 2.1 Hz, 1H), 7.68 (ddd,J = 8.6, 4.2, 2.2 Hz, 1H), 7.23 (dd, J = 10.5, 8.6 Hz, 1H), 0.26 (s, 9H)

[0155] Example Synthesis Method

[0156] Example 1 (Synthesis Method A): Preparation of 1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(3-methylimidazol-4-yl)benzimidazol-5-sulfonamide

[0157] 3-Amino-4-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methylbenzenesulfonamide (intermediate I-4, 42.3 mg, 0.117 mmol) and 1-methyl-1H-imidazol-5-carboxaldehyde (12.9 mg, 0.117 mmol) were dissolved in acetic acid (5.3 mL), followed by the addition of copper acetate (21.28 mg, 0.117 mmol). The reaction solution was stirred at 85 °C for 1 hour. After the reaction was complete, water and a 1 N sodium hydroxide aqueous solution were added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC and PTLC to give the title compound (21 mg, 0.047 mmol, 39.7% yield).

[0158] 1 H-NMR (400 MHz, methanol-d4) δ 8.25 (d, J = 1.4 Hz, 1H), 7.82 (brs, 1H), 7.74 (dd, J = 8.5, 1.6 Hz, 1H), 7.38-7.35 (m, 2H), 7.31 (d, J = 8.2 Hz, 1H),7.22 (dd, J = 8.2, 1.8 Hz, 1H), 6.56 (brs, 1H), 4.10 (s, 3H), 3.50 (s, 3H),3.40 (s, 3H), 2.53 (s, 3H)

[0159] Example 3 (Synthesis Method B): Preparation of 1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(3-phenylimidazol-4-yl)benzimidazol-5-sulfonamide

[0160] 3-Amino-4-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methylbenzenesulfonamide (intermediate I-4, 50 mg, 0.138 mmol), 1-phenyl-1H-imidazol-5-carboxylic acid (26.0 mg, 0.138 mmol) and N,N-diisopropylethylamine (0.031 mL, 0.180 mmol) were dissolved in ethyl acetate (3.2 mL), and then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane 2,4,6-trioxide (50% wt, in ethyl acetate, 0.107 mL, 0.180 mmol) and acetic acid (78 µl, 1.38 mmol) were added. The mixture was then stirred at 90 °C for 48 hours. After the reaction was complete, 1 N sodium hydroxide aqueous solution was added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to give the title compound. (10 mg, 0.019 mmol, 14.07% yield)

[0161] 1 H-NMR (500 MHz, chloroform-d) δ 7.85 (d, J = 8.5 Hz, 1H), 7.76 (dd, J =8.2, 1.5 Hz, 1H), 7.68 (s, 1H), 7.63 (s, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.21(s, 1H), 7.15-7.12 (m, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.89-6.83 (m, 3H), 6.79(dd, J = 8.2, 1.8 Hz, 1H), 6.62 (d, J = 1.8 Hz, 1H), 3.51 (s, 3H), 3.37 (s,3H), 2.62 (d, J = 5.2 Hz, 3H)

[0162] Example 7 (Synthesis Method C): Preparation of 1,3-dimethyl-5-[2-(3-methylimidazol-4-yl)-5-phenyl-benzimidazol-1-yl]benzimidazol-2-one

[0163] 5-Bromo-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one (intermediate I-5, 37.9 mg, 0.087 mmol), phenylboronic acid (12.68 mg, 0.104 mmol), and tripotassium phosphate (36.8 mg, 0.173 mmol) were dissolved in 1,4-dimethyldimethylphenyl ether. The reaction mixture was prepared in alkyl (0.8 mL) and water (0.2 mL). The 1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane adduct (7.08 mg, 8.67 µmol) was added. The reaction solution was stirred at 100 °C for 4 hours under nitrogen atmosphere. After the reaction was complete, water was added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to give the title compound (30 mg, 0.069 mmol, 80% yield).

[0164] 1 H-NMR (500 MHz, chloroform-d) δ 8.05 (s, 1H), 7.68-7.66 (m, 2H), 7.51-7.44(m, 4H), 7.34 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.12 (s, 2H),6.96 (s, 1H), 6.47 (s, 1H), 4.17 (s, 3H), 3.51 (s, 3H), 3.40 (s, 3H), LC / MS: 434 (M+H)

[0165] Examples 8 and 13 (Synthesis Method D): Preparation of 5-[5-bromo-2-(6-methyl-1H-indol-3-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one and 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-yl]piperidine-1-carboxylic acid tert-butyl ester

[0166] Step 1) Preparation of 5-[5-bromo-2-(6-methyl-1H-indol-3-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 8)

[0167] The title compound was obtained using 5-((2-amino-4-bromophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (the compound from step 2 of synthetic method IB, 250 mg, 0.720 mmol) and 6-methyl-1H-indole-3-carboxaldehyde (114.6 mg, 0.720 mmol), in a manner similar to step 3 of synthetic method IB. (280 mg, 0.576 mmol, 80.0% yield)

[0168] 1 H-NMR (400MHz, DMSO-d6) δ 11.19 (s, 1H), 8.47 (d, 1H), 7.93 (s, 1H), 7.47 (m, 2H), 7.42 (d, 1H), 7.22 (m, 2H), 7.05 (d, 1H), 6.96 (m, 1H), 6.51(d, 1H), 3.46 (s, 3H), 3.34 (s, 3H), 2.42 (s, 3H), LC / MS: 486, 488 (M+H)

[0169] Step 2) Preparation of tert-butyl 4-(1',3'-dimethyl-2-(6-methyl-1H-indol-3-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazolium]-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0170] The title compound was obtained using the compound 5-[5-bromo-2-(6-methyl-1H-indol-3-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 8, 300 mg, 0.617 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (191 mg, 0.617 mmol) in the same manner as described in synthetic method C. (267 mg, 0.454 mmol, 73.5% yield)

[0171] Step 3) Preparation of tert-butyl piperidine-1-carboxylate (Example 13)

[0172] The compound tert-butyl 4-(1′,3′-dimethyl-2-(6-methyl-1H-indol-3-yl)-2′-oxo-2′,3′-dihydro-1′H-[1,5′-biphenyl[d]imidazolium]-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.340 mmol) obtained above was dissolved in methanol / tetrahydrofuran (2:1), and then palladium / carbon (36 mg, 0.340 mmol) was added. The reaction solution was stirred at room temperature under hydrogen atmosphere for 2 hours. After the reaction was complete, the reaction solution was passed through a diatomaceous earth filter, the filtrate was concentrated and purified by MPLC to give the title compound (175 mg, 0.296 mmol, 87.0% yield).

[0173] 1 H-NMR (400MHz, DMSO-d6) δ 11.10 (s, 1H), 8.48 (d, 1H), 7.58 (s, 1H), 7.46 (m, 2H), 7.19 (m, 2H), 7.03 (m, 2H), 6.92 (d, 1H), 6.49 (s, 1H), 4.12(brs, 2H), 3.45 (s, 3H), 3.32 (s, 3H), 2.84 (m, 3H), 2.42 (s, 3H), 1.85 (m,2H), 1.61 (m, 2H), 1.44 (s, 9H), LC / MS: 591 (M+H)

[0174] Example 14 (Synthesis Method E): Preparation of 1,3-dimethyl-5-[2-(6-methyl-1H-indol-3-yl)-5-(4-piperidinyl)benzimidazol-1-yl]benzimidazol-2-one

[0175] 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-yl]piperidin-1-carboxylic acid tert-butyl ester (Example 13, 170 mg, 0.288 mmol) was dissolved in dichloromethane, and then trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then neutralized with saturated sodium bicarbonate solution. The organic layer was extracted with ethyl acetate, washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (105 mg, 0.214 mmol, 74.4% yield).

[0176] 1H-NMR (400MHz, DMSO-d6) δ 11.11 (d, 1H), 8.48 (d, 1H), 7.57 (s, 1H), 7.42 (m, 2H), 7.20 (m, 2H), 7.05 (m, 2H), 6.93 (d, 1H), 6.50 (d, 1H), 3.45(s, 3H), 3.34 (s, 3H), 3.19 (m, 3H), 2.80 (m, 3H), 2.42 (s, 3H), 1.86 (m,2H), 1.72 (m, 2H), 1.44 (s, 9H), LC / MS 491 (M+H)

[0177] Example 15: Preparation of 5-(1-ethylpiperidin-4-yl)-1',3'-dimethyl-2-(6-methyl-1H-indol-3-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazolium]-2'-one carbamate

[0178] 1,3-Dimethyl-5-[2-(6-methyl-1H-indol-3-yl)-5-(4-piperidinyl)benzimidazol-1-yl]benzimidazol-2-one (Example 14, 30 mg, 0.061 mmol) was dissolved in acetonitrile, followed by the addition of bromoethane (8 mg, 0.073 mmol) and potassium carbonate (17 mg, 0.122 mmol). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (16 mg, 0.031 mmol, 50.4% yield).

[0179] 1 H-NMR (400MHz, DMSO-d6) δ 11.11 (d, 1H), 8.48 (d, 1H), 8.20 (s, 1H), 7.59 (s, 1H), 7.42 (m, 2H), 7.20 (m, 2H), 7.07 (m, 2H), 6.92 (d, 1H), 6.49(d, 1H), 3.45 (s, 3H), 3.36 (s, 3H), 3.14 (m, 4H), 2.68 (m, 1H), 2.42 (s,3H), 2.24 (m 2H), 1.88 (m, 4H), 1.11 (t, 3H); LC / MS: 519 (M+H)

[0180] Example 20 (Synthesis Method F): Preparation of 1,3-dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(1-piperidinyl)benzimidazol-1-yl]benzimidazol-2-one

[0181] 5-Bromo-1'3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazole]-2'-one (intermediate I-5, 58.2 mg, 0.133 mmol), piperidine (131 µl, 1.331 mmol), and potassium tert-butoxide (59.7 mg, 0.532 mmol) were dissolved in toluene (0.9 mL), followed by the addition of di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (5.65 mg, 0.013 mmol) and tris(diphenylmethylacetone)dipalladium(0) (6.09 mg, 6.65 µmol). The reaction solution was stirred at 110 °C for 18 hours under nitrogen atmosphere. After the reaction was complete, the reaction solution was passed through a diatomaceous earth filter, the filtrate was concentrated and purified by PTLC to obtain the title compound. (1.3 mg, 0.003 mmol, 2.2% yield)

[0182] 1H-NMR (500 MHz, methanol-d4) δ 7.76 (s, 1H), 7.35 (s, 1H), 7.32 (d, J =8.2 Hz, 1H), 7.27 (s, 1H), 7.17-7.09 (m, 3H), 6.61 (s, 1H), 3.97 (s, 3H), 3.50 (s, 3H), 3.40 (s, 3H), 3.17-3.15 (m, 4H), 1.82-1.77 (m, 4H), 1.64-1.59 (m, 3H).

[0183] Example 30 (Synthesis Method G): Preparation of 5-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-N-methylpyridine-2-carboxamide

[0184] Compounds 5-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazol]-5-yl)pyridinecarboxylic acid (45 mg, 0.094 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (27.0 mg, 0.141 mmol), and 1-hydroxybenzotriazole hydrate (21.56 mg, 0.141 mmol) obtained by synthetic method H were dissolved in dimethylformamide (1 mL), and methylamine (2 M, in tetrahydrofuran, 117 µl, 0.235 mmol) was slowly added. The reaction solution was stirred at room temperature for 18 hours. After the reaction was complete, water was added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by PTLC to give the title compound. (5 mg, 10.15 µmol, 10.82% yield)

[0185] 1 H-NMR (500 MHz, chloroform-d) δ 8.84 (d, J = 1.8 Hz, 1H), 8.28 (d, J = 8.2Hz, 1H), 8.10-8.07 (m, 2H), 8.04-8.01 (m, 1H), 7.54 (s, 1H), 7.50 (dd, J =8.5, 1.5 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.16-7.09 (m, 2H), 6.97 (s, 1H), 6.47 (s, 1H), 4.19 (s, 3H), 3.53 (s, 3H), 3.42 (s, 3H), 3.07 (d, J = 5.2 Hz, 3H)

[0186] Example 44 (Synthesis Method H): Preparation of 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]benzoic acid

[0187] Methyl 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]benzoate (Example 43, 22 mg, 0.045 mmol) was dissolved in methanol (0.2 mL) and water (0.1 mL), and then lithium hydroxide hydrate (18.74 mg, 0.447 mmol) was added. The reaction solution was stirred at 50 °C for 5 hours. After the reaction was complete, the reaction solution was neutralized with 1 N hydrochloric acid aqueous solution. Ethyl acetate was added and the organic layer was extracted. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by PTLC to give the title compound (5.6 mg, 0.012 mmol, 26.2% yield).

[0188] LC / MS: 479 (M+H)

[0189] Example 58: Preparation of 5-[5-[4-(hydroxymethyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0190] Methyl 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]benzoate (Example 43, 22 mg, 0.045 mmol) was dissolved in tetrahydrofuran (0.4 mL), and lithium aluminum hydride (1 M, in tetrahydrofuran, 0.089 mL, 0.089 mmol) was slowly added at 0 °C. The reaction solution was stirred at room temperature for 4 hours. The reaction was terminated by slow addition of water at 0 °C, and the reaction solution was filtered. Water and ethyl acetate were added to the filtrate, and the organic layer was extracted. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to give the title compound (10.5 mg, 0.023 mmol, 50.6% yield).

[0191] 1 ¹H-NMR (500 MHz, chloroform-d) δ 8.03 (s, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.53 (s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.12–7.10 (m, 3H), 6.95 (s, 1H), 6.46 (s, 1H), 4.75 (s, 2H), 4.17 (s, 3H), 3.52 (s, 3H), 3.40 (s, 3H)

[0192] Example 71: Preparation of 1,3-dimethyl-5-[2-(3-methylimidazol-4-yl)-5-phenoxy-benzimidazol-1-yl]benzimidazol-2-one

[0193] 5-Bromo-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one (intermediate I-5, 19.8 mg, 0.045 mmol) was dissolved in 1,4-dimethyl ... The reaction mixture was added to alkyl (1.4 mL), followed by the addition of phenol (12.78 mg, 0.136 mmol), cesium carbonate (88.6 mg, 0.272 mmol), dimethylglycine (8.74 µl, 0.09 mmol), and copper iodide (7.77 mg, 0.042 mmol). The reaction solution was stirred at 110 °C for 18 hours. After the reaction was complete, the reaction solution was passed through a diatomaceous earth filter, the filtrate was concentrated, and purified by PTLC to give the title compound (5.3 mg, 0.012 mmol, 26.0% yield).

[0194] 1 H-NMR (500 MHz, chloroform-d) δ 7.51 (s, 1H), 7.46 (s, 1H), 7.34-7.31 (m,2H), 7.12 (s, 2H), 7.08 (t, J = 7.5 Hz, 1H), 7.04-7.02 (m, 4H), 6.96 (s, 1H), 6.45 (s, 1H), 4.14 (s, 3H), 3.52 (s, 3H), 3. 41 (s, 3H), LC / MS: 451 (M+H)

[0195] Example 84 (Synthesis Method I): Preparation of 4-[2-cyclopropyl-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide

[0196] 3'-Amino-4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide (intermediate I-6, 30 mg, 0.072 mmol) and cyclopropaneformaldehyde (5.01 mg, 0.072 mmol) were dissolved in ethanol (1 mL) and acetic acid (0.1 mL), followed by the addition of copper acetate (6.50 mg, 0.036 mmol). The reaction solution was stirred at 80 °C for 30 min. After the reaction was complete, water and a 1 N sodium hydroxide aqueous solution were added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to give the title compound (22.7 mg, 0.048 mmol, 67.6% yield).

[0197] 1 H-NMR (500 MHz, chloroform-d) δ 8.15 (t, J = 8.2 Hz, 1H), 7.92 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 13.7 Hz,1H), 7.21 (d, J = 8.2 Hz, 1H), 7.15-7.13 (m, 2H), 7.08 (s, 1H), 6.81-6.77 (m,1H), 3.51 (s, 3H), 3.46 (s, 3H), 3.04 (d, J = 4.9 Hz, 3H), 1.86-1.81 (m, 1H),1.36-1.33 (m, 2H), 1.06-1.02 (m, 2H), LC / MS: 470 (M+H)

[0198] Example 87 (Synthesis Method J): 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-iso Preparation of 5-yl-benzimidazol-5-yl]-2-fluoro-N-methylbenzamide

[0199] 3'-amino-4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide (intermediate I-6, 27.8 mg, 0.066 mmol), iso... Azoxyl-5-carboxylic acid (8.24 mg, 0.073 mmol) and N,N-diisopropylethylamine (0.013 mL, 0.073 mmol) were dissolved in ethyl acetate (0.8 mL), and 2,4,6-tripropyl-1,3,5,2,4,6-triphosphacyclohexane 2,4,6-trioxide (50% wt, in ethyl acetate, 0.197 mL, 0.331 mmol) was added. The reaction solution was stirred in a microwave at 110 °C for 30 min. After the reaction was complete, the reaction solution was diluted with water, 1 N sodium hydroxide aqueous solution was added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to give the title compound (18.9 mg, 0.038 mmol, 57.4% yield).

[0200] 1 H-NMR (500 MHz, chloroform-d) δ 8.24 (s, 1H), 8.18 (t, J = 8.2 Hz, 1H), 8.09 (s, 1H), 7.57-7.52 (m, 2H), 7.39-7.36 (m, 1H), 7.23-7.21 (m, 1H), 7.18-7.14 (m, 2H), 7.04 (s, 1H), 6.82-6.79 (m, 1H), 6.46 (s, 1H), 3.53 (s, 3H), 3.43 (s, 3H), 3.05 (d, J = 4.9 Hz, 3H), LC / MS 497 (M+H)

[0201] Example 100 (Synthesis Method K): Preparation of 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-thienyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide

[0202] 4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-3'-nitro-[1,1'-biphenyl]-4-carboxamide (the compound from step 1 of synthetic method IC, 20.3 mg, 0.045 mmol)) was dissolved in dimethyl sulfoxide (0.5 mL), followed by the addition of thiophene-2-carboxaldehyde (5.07 mg, 0.045 mmol) and sodium hyposulfite (23.59 mg, 0.136 mmol). The reaction solution was stirred at 90 °C for 18 hours. After the reaction was complete, water and an aqueous solution of ammonium hydroxide were added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to give the title compound (13.6 mg, 0.027 mmol, 58.9% yield).

[0203] 1 H-NMR (500 MHz, chloroform-d) δ 8.18 (t, J = 8.2 Hz, 1H), 8.06 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.39-7.36 (m, 2H), 7.20-7.16 (m, 2H), 7.10 (d, J = 8.5 Hz, 1H), 7.03 (s, 1H), 6.98 (d, J = 3.7 Hz,1H), 6.94-6.93 (m, 1H), 6.81-6.78 (m, 1H), 3.54 (s, 3H), 3.43 (s, 3H), 3.06(d, J = 4.6 Hz, 3H), LC / MS 512 (M+H)

[0204] Example 124: Preparation of 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-isopropyl-benzimidazol-5-yl]-2-fluoro-N-methylbenzamide

[0205] Methyl 2-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-5-[3-fluoro-4-(methylcarbamoyl)phenyl]benzimidazol-2-yl]-2-methylpropionate (Example 123, 33 mg, 0.062 mmol) was dissolved in methanol (0.24 mL) and water (0.8 mL), and then lithium hydroxide hydrate (13.07 mg, 0.312 mmol) was added. The reaction solution was stirred at 45 °C for 6 hours. After the reaction was complete, the reaction solution was neutralized with 1 N hydrochloric acid aqueous solution. Dichloromethane was added and the organic layer was extracted. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by PTLC to give the title compound (3.1 mg, 6.01 µmol, 9.65% yield).

[0206] 1 H-NMR (500 MHz, chloroform-d) δ 8.18 (t, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 14.0 Hz,1H), 7.16-7.09 (m, 3H), 6.97 (s, 1H), 6.80-6.76 (m, 1H), 3.53 (s, 3H), 3.46(s, 3H), 3.12-3.08 (m, 1H), 3.06 (d, J = 4.6 Hz, 3H), 1.38 (d, J = 6.7 Hz, 6H), LC / MS: 472 (M+H)

[0207] Example 128 (Synthesis Method L): Preparation of 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-[2-methyl-3-(1-methylpyrazol-4-yl)phenyl]benzimidazol-5-yl]-2-fluoro-N-methylbenzamide

[0208] 4-[2-(3-bromo-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide (Example 127, 30 mg, 0.050 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (12.52 mg, 0.060 mmol) and tripotassium phosphate (21.28 mg, 0.100 mmol) were dissolved in 1,4-dioxaborhexacyclopentan-2-yl)-2-fluoro-N-methyl-benzamide (Example 127, 30 mg, 0.050 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (12.52 mg, 0.060 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (Example 127, 30 mg, 0.05 ... The reaction mixture was prepared in alkyl (1 mL) and water (0.250 mL), and 1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane adduct (4.09 mg, 5.01 µmol) was added. The reaction solution was stirred at 100 °C for 18 hours under nitrogen. After the reaction was complete, water was added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to give the title compound (24 mg, 0.040 mmol, 80% yield).

[0209] 1 H-NMR (500 MHz, chloroform-d) δ 8.17 (t, J = 8.2 Hz, 1H), 8.09 (s, 1H), 7.57-7.53 (m, 2H), 7.50 (s, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 7.38 (s, 1H),7.33 (d, J = 7.3 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.17-7.14 (m, 1H), 7.00-6.95 (m, 2H), 6.88-6.84 (m, 1H), 6.83 (s, 1H), 3.93 (s, 3H), 3.42 (s, 3H), 3.31 (s, 3H), 3.04 (d, J = 4.3 Hz, 3H), 2.22 (s, 3H), LC / MS: 600 (M+H)

[0210] Example 132: Preparation of 4-[2-[3-[2-(dimethylamino)ethylamino]-2-methyl-phenyl]-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide

[0211] 4-[2-(3-bromo-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide (Example 127, 52.3 mg, 0.044 mmol), N1,N1-dimethylethyl-1,2-diamine (5.17 µl, 0.048 mmol), rac-[1,1'-binaphthyl]-2,2'-diylbis(diphenylphosphine) (27.2 mg, 0.044 mmol), and potassium tert-butoxide (9.81 mg, 0.087 mmol) were dissolved in toluene (0.8 mL), and tris(diphenylmethylacetone)dipalladium(0) (4.00 mg, 4.37 µmol) was added. The reaction solution was stirred at 100 °C for 48 hours under nitrogen atmosphere. After the reaction was complete, water was added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to give the title compound. (9.2 mg, 0.015 mmol, 34.8% yield)

[0212] 1 H-NMR (500 MHz, chloroform-d) δ 8.19 (t, J = 8.2 Hz, 1H), 8.09 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.43-7.38 (m, 2H), 7.09-7.06 (m, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.84-6.80(m, 2H), 6.73 (d, J = 7.6 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 3.47 (s, 3H), 3.42 LC / MS: 606 (M+H)

[0213] Example 142: Preparation of 4-[2-(3,5-dimethylimidazol-4-yl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide

[0214] 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(4-fluorophenyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide (Example 141, 10 mg, 0.020 mmol) was dissolved in tetrahydrofuran (0.5 mL). Then, 1,4-diazabicyclo[5,4,0]undec-7-ene (5.92 µl, 0.040 mmol) and methyl iodine (2.454 µl, 0.040 mmol) were added. The reaction solution was stirred at 50 °C for 4 hours. After the reaction was complete, water was added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride aqueous solution and brine, dehydrated on anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by PTLC to give the title compound (1.4 mg, 2.67 µmol, 13.62% yield).

[0215] 1 H-NMR (500 MHz, chloroform-d) δ 8.22 (t, J = 7.9 Hz, 1H), 8.12 (s, 1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.48-7.42 (m, 3H), 7.05-7.02 (m, 1H), 6.97 (d, J= 8.2 Hz, 1H), 6.82 (s, 1H), 6.79-6.77 (m, 1H), 3.65 (s, 3H), 3.49 (s, 3H), 3.47 (s, 3H), 3.38 (s, 3H), 3.07 (s, 3H), LC / MS: 524 (M+H)

[0216] Example 145 (Synthetic Method M): Preparation of 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(trifluoromethyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide

[0217] 3'-Amino-4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide (intermediate I-6, 60 mg, 0.054 mmol) was dissolved in trifluoroacetic acid (1 mL), and the reaction solution was stirred at 90 °C for 18 h. The reaction solution was then stirred at 100 °C for 3 h. After the reaction was complete, the reaction solution was diluted with water, 1N sodium hydroxide aqueous solution was added at 0 °C, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (19.2 mg, 0.039 mmol, 71.0% yield).

[0218] 1 H-NMR (500 MHz, chloroform-d) δ 8.23-8.20 (m, 1H), 8.15 (s, 1H), 7.63 (d,J = 8.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 13.4 Hz, 1H), 7.20-7.13 (m, 3H), 7.04 (s, 1H), 6.80-6.77 (m, 1H), 3.53 (s, 3H), 3.46 (s, 3H), 3.07 (d, J = 3.0Hz, 3H), LC / MS: 498 (M+H)

[0219] Example 152: Preparation of 4-[2-(3-cyano-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide

[0220] 4-[2-(3-bromo-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide (Example 127, 12 mg, 0.020 mmol) was dissolved in anhydrous dimethylformamide (0.8 mL), followed by the addition of zinc dicyanocyanate (23.54 mg, 0.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (11.59 mg, 0.01 mmol). The reaction solution was stirred at 130 °C for 10 hours using a microwave. After the reaction was complete, the reaction solution was diluted with water, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to give the title compound (4.8 mg, 8.81 µmol, 44.0% yield).

[0221] 1 H-NMR (500 MHz, chloroform-d) δ 8.22 (t, J = 8.0 Hz, 1H), 8.12 (s, 1H), 7.67 (d, J = 17.7 Hz, 1H), 7.60-7.57 (m, 3H), 7.45-7.40 (m, 2H), 7.30 (d, J =8.5 Hz, 1H), 6.98-6.97 (m, 1H), 6.92-6.90 (m, 1H), 6.81-6.78 (m, 2H), 3.46(s, 3H), 3.36 (s, 3H), 3.07 (d, J = 5.5 Hz, 3H), 2.46 (s, 3H), LC / MS: 545 (M+H)

[0222] Example 156: Preparation of 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(1-methoxy-1-methyl-ethyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide

[0223] 2-Methoxy-2-methylprop-1-ol (26.6 mg, 0.256 mmol) was dissolved in ethyl acetate (1 mL) and dimethyl sulfoxide (0.5 mL), and then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane 2,4,6-trioxide (50% wt, in ethyl acetate, 0.277 mL, 0.465 mmol) was added at 0 °C. The reaction solution was stirred at room temperature for 2 hours. After the oxidation of the alcohol was complete, 3'-amino-4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide (intermediate I-6, 195 mg, 0.232 mmol) was added and stirring was continued for 3 hours. After the reaction was complete, water and a saturated aqueous sodium bicarbonate solution were added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to give the title compound. (4.8 mg, 9.57 µmol, 4.12% yield)

[0224] 1 H-NMR (500 MHz, chloroform-d) δ 8.18 (t, J = 8.0 Hz, 1H), 8.07 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 13.7 Hz,1H), 7.16-7.14 (m, 1H), 7.11-7.09 (m, 1H), 7.01 (m, 2H), 6.80-6.77 (m, 1H),3.51 (s, 3H), 3.44 (s, 3H), 3.16 (s, 3H), 3.06 (d, J = 3.0 Hz, 3H), 1.65 (d,J = 21.1 Hz, 6H), LC / MS: 502 (M+H)

[0225] Example 158: Preparation of N'-hydroxy-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazolium]-5-formamidin

[0226] 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazolium]-5-carboxynitrile (Example 157, 100.0 mg, 0.2608 mmol) was dissolved in dimethylformamide (1 mL), and then a 3 N hydroxylamine solution (1 mL) was added. The reaction solution was stirred at 50 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and no further purification was required to obtain the title compound. (97.0 mg, 0.2329 mmol, 89% yield)

[0227] 1H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.89 (s, 2H), 8.10 (s,1H), 7.82 (s, 1H), 7.80 (s, 2H), 7.64 (dd, J = 8.7, 1.3 Hz, 1H), 7.43 (d, J =1.9 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.18 (dd, J = 8.2, 2.0 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.36 (s, 1H), 4.05 (d, J = 3.6 Hz, 3H), 3.43 (s, 3H),3.33 (s, 3H)

[0228] Example 159: 3-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazol]-5-yl)-1,2,4- Preparation of diazole-5(2H)-one

[0229] N'-hydroxy-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazole]-5-formamidin (Example 158, 20.0 mg, 0.048 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.022 mL, 0.1441 mmol) were dissolved in dimethylformamide (0.5 mL), and 1,1'-carbonyldiimidazole (16.0 mg, 0.096 mmol) was added. The reaction solution was stirred at 80 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative HPLC to give the title compound (2.5 mg, 5.651 µmol, 12% yield).

[0230] 1 H NMR (500 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.25 (d, J = 1.0 Hz, 1H), 8.14 (s, 1H), 7.76 (dd, J = 8.5, 1.4 Hz, 1H), 7.48 (d, J = 1.7 Hz, 1H), 7.39(d, J = 8.2 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.23 (dd, J = 8.2, 1.7 Hz,1H), 6.55 (s, 1H), 4.10 (s, 3H), 3.43 (s, 3H), 3.33 (s, 3H)

[0231] Example 163: Preparation of 5-(4,5-dihydrothiazol-2-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one

[0232] 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazolium]-5-carboxynitrile (Example 157, 38.0 mg, 0.09911 mmol) was dissolved in methanol (1 mL), and then 2-aminoethyl-1-thiol (38.0 mg, 0.4956 mmol) was added. The reaction solution was stirred at 80 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by MPLC to give the title compound (0.0135 g, 0.03044 mmol, 31% yield).

[0233] 1 H NMR (500 MHz, chloroform-d) δ 8.26 (d, J = 0.8 Hz, 1H), 7.86 (dd, J =8.5, 1.4 Hz, 1H), 7.52 (s, 1H), 7.15 – 7.10 (m, 2H), 7.07 (d, J = 8.5 Hz,1H), 6.95 (s, 1H), 6.44 (s, 1H), 4.49 (t, J = 8.2 Hz, 2H), 4.18 (s, 3H), 3.52(s, 3H), 3.45 (t, J = 8.2 Hz, 2H), 3.41 (s, 3H)

[0234] Example 164 (Synthetic Method O): Preparation of ethyl acetate 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazol]-5-yl)-1H-1,2,3-triazol-1-yl)

[0235] Step 1) Preparation of 5-ethynyl-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one

[0236] The title compound was obtained using ((4-fluoro-3-nitrophenyl)ethynyl)trimethylsilane (intermediate I-7, 4.1 g, 17.4 mmol) and 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-1, 3.08 g, 17.4 mmol) in a manner similar to that of synthetic method IB. (13.5% yield after 3 steps)

[0237] 1 H NMR (500 MHz, chloroform-d) δ 7.97 (s, 1H), 7.60 (s, 1H), 7.37 (dd, J =8.3, 1.3 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.08 (dd, J = 8.1, 1.1 Hz, 1H),7.00 (d, J = 8.3 Hz, 1H), 6.93 (s, 1H), 6.48 (s, 1H), 4.15 (s, 3H), 3.52 (s,3H), 3.40 (s, 3H), 3.07 (s, 1H)

[0238] Step 2) Preparation of ethyl acetate 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazol]-5-yl)-1H-1,2,3-triazol-1-yl) (Example 164)

[0239] The compound 5-ethynyl-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one (1 g, 2.6 mmol), sodium ascorbate (0.051 g, 0.26 mmol), and copper iodide (0.098 g, 0.52 mmol) obtained above were dissolved in methanol (18 mL) and water (9 mL), and then ethyl azide (0.670 g, 5.2 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (0.5140 g, 1.005 mmol, 39% yield).

[0240] 1H NMR (500 MHz, chloroform-d) δ 8.23 ​​(d, J = 0.9 Hz, 1H), 7.96 (s, 1H), 7.86 (dd, J = 8.4, 1.5 Hz, 1H), 7.57 (s, 1H), 7.14 (s, 1H), 7.13 (s, 3H),6.97 (s, 1H), 6.49 (s, 1H), 5.24 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.18 (s,3H), 3.53 (s, 3H), 3.42 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H)

[0241] Example 165: Preparation of 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazol]-5-yl)-1H-1,2,3-triazol-1-yl)acetic acid

[0242] Ethyl 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazol]-5-yl)-1H-1,2,3-triazol-1-yl) (Example 164, 0.510 g, 0.9970 mmol) was dissolved in methanol / tetrahydrofuran (2:3), followed by the addition of 1 M aqueous lithium hydroxide solution (2.991 mL, 2.991 mmol). The reaction solution was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, water was added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure without further purification to give the title compound. (0.4387 g, 0.9073 mmol, 91% yield)

[0243] 1 ¹H NMR (500 MHz, methanol-d⁴) δ 8.33 (s, 1H), 8.26 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.27 – 7.19 (m, 2H), 6.61 (s, 1H), 5.04 (s, 2H), 4.06 (s, 3H), 3.52 (s, 3H), 3.42 (s, 3H)

[0244] Example 167 (Synthetic Method P): Preparation of 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazol]-5-yl)-1H-1,2,3-triazol-1-yl)-N-methylacetamide

[0245] 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazol]-5-yl)-1H-1,2,3-triazol-1-yl)acetic acid (Example 165, 43.5 mg, 0.09 mmol) and methylamine (2 M, in tetrahydrofuran, 0.0585 mL, 0.117 mmol) were dissolved in dimethylformamide (0.45 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.0419 g, 0.27 mmol), 1-hydroxybenzotriazole hydrate (0.0365 g, 0.27 mmol), and N,N-diisopropylethylamine (0.047 mL, 0.27 mmol) were added. The reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, water was added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound. (5.8 mg, 0.0117 mmol, 13% yield)

[0246] 1 H NMR (500 MHz, chloroform-d) δ 8.23 ​​(d, J = 1.0 Hz, 1H), 7.94 (s, 1H), 7.82 (dd, J = 8.4, 1.5 Hz, 2H), 7.57 (s, 1H), 7.13 (dd, J = 12.6, 5.3 Hz,2H), 6.95 (d, J = 1.7 Hz, 1H), 6.46 (d, J = 0.8 Hz, 1H), 6.14 (s, 1H), 5.12(s, 2H), 4.18 (s, 3H), 3.54 (s, 3H), 3.41 (s, 3H), 2.85 (d, J = 4.9 Hz, 3H)

[0247] Examples 2, 4-6, 9-12, 16-19, 21-29, 31-43, 45-57, 59-70, 72-83, 85, 86, 88-99, 101-123, 125-127, 129-131, 133-141, 143, 144, 146-151, 153-155, 157, 160-162, 166 and 168-176

[0248] The synthesis was performed using the same synthesis method as the representative embodiments described above.

[0249] Specifically, Examples 2, 4, 6, 10, and 11 were prepared similarly using synthesis method A; Examples 5, 12, and 16 were prepared similarly using synthesis method B; Examples 9, 17 to 19, 21 to 29, 31 to 43, 45, 47 to 57, 59 to 69, 73 to 83, 86, 160 to 162, and 172 to 176 were prepared similarly using synthesis method C; Example 157 was prepared similarly using synthesis method D; Examples 16, 93, and 154 were prepared similarly using synthesis method E; Example 70 was prepared similarly using synthesis method F; Example 72 was prepared similarly using synthesis method G; Example 46 was prepared similarly using synthesis method H; and Examples 85, 89 to 91, 9 ... Examples 4, 96, 97, 99, 101 to 103, 106 to 109, 112 and 113 were prepared similarly by synthesis method I; Examples 88, 92, 95, 98, 110, 111 and 129 were prepared similarly by synthesis method J; Examples 104, 105, 114 to 123, 125 to 127, 130, 133 to 141, 143, 144, 147 to 151, 153 and 155 were prepared similarly by synthesis method K; Example 131 was prepared similarly by synthesis method L; Example 146 was prepared similarly by synthesis method M; Example 166 was prepared similarly by synthesis method O; and Examples 168 to 171 were prepared similarly by synthesis method P.

[0250] The structure and name, NMR, LC / MS and synthesis method of each compound synthesized from the examples are described in Table 1 below.

[0251] [Table 1]

[0252] Experimental Example 1. CBP Inhibitory Activity

[0253] The inhibitory activity of CBP was measured using time-resolved fluorescence resonance energy transfer (TR-FRET) experiments to verify the activity of the CBP bromine domain.

[0254] The assays were performed in a final volume of 14 μl, optimized based on the CREBBP Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay Kit (BPS Bioscience, catalog 32619) to maximize the assay window. The TR-FRET fluorescent acceptor and Tb donor were diluted in assay buffer containing 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (hereinafter referred to as assay buffer, BPS Bioscience, catalog 33012), and 3 μl of each solution was transferred to all wells of a white low-capacity 384-well plate (Corning, catalog 4513). 2 μl of 4X Ac-H4 peptide (final concentration 85 nM) was transferred to the high control and test wells. Ten concentrations of each compound were prepared by sequentially diluting 3-fold from the highest concentration in dimethyl sulfoxide solvent. Each concentration of the compound was then diluted in assay buffer to prepare a solution of the diluted compound at a concentration 4-fold higher than the final concentration. Dispense 2 μl of each compound or dimethyl sulfoxide prepared in this manner into the assay plate to achieve a final test concentration ranging from a minimum of 0.5 μM to a maximum of 10 μM (final dimethyl sulfoxide concentration of 1%). Add 6 μL of 1X assay buffer to the low control wells and 2 μl to the high control and test wells. Then, add 2 μl of 4X CBP BRD protein (final concentration 7.5 nM, BPSbioscience, catalog number 31128) to initiate the PPI reaction. Incubate the plate at room temperature for 2 hours, then measure the signal. The TR-FRET signal was measured using an EnVision multi-label plate reader (PerkinElmer; Mirror LNACE / DELFIA Dual / Bias).

[0255] For data analysis, values ​​for each well were obtained using the TR-FRET ratio ((signal 665 nm / signal 615 nm) x 20000). Data analysis was performed using the TR-FRET ratio ((signal 665 nm / signal 615 nm) x 20000). Data were reported as the percentage of inhibition compared to the control wells according to the following equation: % activity = ((FRET compound – FRET low av) / (FRET high av – FRET low av)) x 100. IC50 analysis was determined using a standard 4-parameter curve fitting algorithm based on GraphPad Prism 7.0 (GraphPad Software Inc., La Jolla, CA, USA). All data are expressed as mean ± standard error of mean (SEM).

[0256] Experimental Example 2. BRD4 Inhibitory Activity

[0257] The inhibitory activity of BRD4 was measured using time-resolved fluorescence resonance energy transfer (TR-FRET) experiments to verify the activity of the bromine domain of BRD4.

[0258] The assays were performed in a final volume of 14 μl, optimized based on the CREBBP Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay Kit (BPS Bioscience, catalog 32613) to maximize the assay window. The TR-FRET fluorescent acceptor and Tb donor were diluted in assay buffer (hereinafter referred to as assay buffer, BPS Bioscience, catalog 33012) containing 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid, and 3 μl of each solution was transferred to all wells of a white low-capacity 384-well plate (Corning, catalog 4513). 2 μl of 4X Ac-H4 peptide (final concentration 15 nM) was transferred to the high control and test wells. Ten concentration points of each compound were prepared by sequentially diluting 3-fold from the highest concentration in dimethyl sulfoxide solvent. Each concentration of the compound was then diluted in assay buffer to prepare a diluted compound solution 4-fold higher than the final concentration. Dispense 2 μl of each compound or dimethyl sulfoxide prepared in this manner into the assay plate to achieve a final assay concentration ranging from a minimum of 0.5 μM to a maximum of 10 μM (final dimethyl sulfoxide concentration of 1%). Add 6 μL of 1X assay buffer to the low control wells and 2 μl to the high control and test wells. Then, add 2 μl of 4X BRD4 (BD1) protein (final concentration 7.5 nM, BPSbioscience, catalog number 31040) to initiate the PPI reaction. Incubate the plate at room temperature for 2 hours, then measure the signal. TR-FRET signals were measured using an EnVision multi-label plate reader (PerkinElmer; Mirror LNACE / DELFIA Dual / Bias). For data analysis, the value for each well was obtained using the TR-FRET ratio ((signal 665 nm / signal 615 nm) x 20000). Data analysis was performed using the TR-FRET ratio ((signal 665 nm / signal 615 nm) x 20000). Data were reported as a percentage of inhibition compared to the control wells according to the following equation: % activity = ((FRET compound – FRET low av) / (FRET high av – FRET low av)) x 100. IC50 analysis was determined by standard 4-parameter curve fitting using the algorithm of GraphPad Prism 7.0 (GraphPad Software Inc., La Jolla, CA, USA). All data are expressed as mean ± standard error of mean (SEM).

[0259] The results from Experiments 1 and 2 are shown in Tables 2 and 3 below.

[0260] In Tables 2 and 3 below, activity values ​​of 0 to 500 nM are indicated as “+++”, values ​​greater than 500 and less than or equal to 5 μM are indicated as “++”, and values ​​greater than 5 μM are indicated as “+”.

[0261] [Table 2]

[0262] [Table 3]

Claims

1. A compound represented by formula I: <Formula I> in n is an integer from 0 to 3, where if n is an integer of 2 or greater, then R is the same or different, and R is independently NR. a R b SO2NHR c OR d CONR e R f Halogen, cyano, amidine, imine, C 1-8 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 5- to 13-membered heteroaryl, 3- to 14-membered heterocyclic alkyl, or 4- to 9-membered heterocyclic alkenyl, and R a To R f Each is independently selected from hydrogen and C. 1-4 Alkyl, C 3-10 cycloalkyl and C 6-10 Aryl, and Z is C 1-8 Alkyl, C 3-10 cycloalkyl, C 1-5 Haloalkyl, C 6-10 aryl, 5- to 13-membered heteroaryl, or 3- to 14-membered heterocyclic alkyl, Among them, R, R a To R f Z and each of them are either substituted by or unsubstituted by the base group I: Substituent group I: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 3-20 Carbon rings, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted C 6-30 aryl, substituted or unsubstituted 3 to 30-membered heterocycles, substituted or unsubstituted C 1-10 Alkoxy, substituted or unsubstituted C 2-10 Alkenyl group, substituted or unsubstituted C 3-10 Cycloalkoxy, substituted or unsubstituted C 6-30 Aryloxy group, substituted or unsubstituted 3- to 30-membered heterocyclic oxy group, substituted or unsubstituted C 1-10 Alkyl ketones, substituted or unsubstituted C 2-10 alkenyl ketones, substituted or unsubstituted C 3-10 Cycloalkyl ketones, substituted or unsubstituted C 6-30 Aryl ketones, substituted or unsubstituted 3- to 30-membered heterocyclic ketones, substituted or unsubstituted C 1-10 alkylthio, substituted or unsubstituted C 2-10 Thylene, substituted or unsubstituted C 3-10 Cyclothio, substituted or unsubstituted C 6-30 Aryl thiols, substituted or unsubstituted 3- to 30-membered heterocyclic thiols, aldehydes, carboxyl groups, halogens, substituted or unsubstituted C groups 1-10 Halogenated alkyl groups, hydroxyl groups, substituted or unsubstituted amino groups, imine groups, cyano groups, nitro groups, amide groups, thiols, sulfones, and phosphoric acids. Where C 1-10 The alkyl portion is intercalated with a heteroatom group selected from -O-, -S-, -SO-, -SO2-, and -NR. g -(R) g It is hydrogen or substituted or unsubstituted C 1-10 Alkyl groups, -N=, =N-, -POR g -and-PO4R g - and the heterocyclic portion contains at least one of S, N, P and O as a cyclic atom.

2. The compound according to claim 1, wherein R, R a To R f Z is either substituted by or unsubstituted by the base set I-1: Substituent group I-1: substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, hydroxyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-4 Halogenated alkyl, substituted or unsubstituted C 6-8 Aryl, substituted or unsubstituted 3- to 8-membered heteroaryl, substituted or unsubstituted cyano, substituted or unsubstituted amino, substituted or unsubstituted amide, aldehyde, halogen, CO2R p1 , NHCOR p2 NHCO2R p3 or NHSO2R p4 , where R p1 To R p4 Each is independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted butyl, or substituted or unsubstituted phenyl.

3. The compound according to claim 1, wherein the compound of formula I is represented by formula I-1: <Formula I-1> in R 1 It is NR a R b SO2NHR c OR d CONR e R f Halogen, cyano or imine, and either substituted or unsubstituted with substituent group I, and R a To R f Z is the same as defined in claim 1.

4. The compound according to claim 3, wherein... R 1 It is NR a R b SO2NHR c OR d CONR e R f , bromine, cyano or amidine, Where R a To R f Each is independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, or substituted or unsubstituted phenyl, and R 1 Substituted by or unsubstituted group I-1-1: Substituent group I-1-1: substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl and hydroxyl groups.

5. The compound according to claim 1, wherein the compound of formula I is represented by formulas I-2: <Formula I-2> in It is a C5 cycloalkyl, a 5-membered heteroaryl, or a 5-membered heterocycloalkyl. m is an integer from 0 to 3, where if m is an integer of 2 or greater, then R A Same or different, and R A Is it substituted or unsubstituted C? 1-6 Alkyl, substituted or unsubstituted C 1-4 Halogenated alkyl groups, substituted or unsubstituted cyano groups, substituted or unsubstituted amide groups, substituted or unsubstituted amino groups, or aldehydes, and Z is the same as that defined in claim 1.

6. The compound according to claim 5, wherein... It is furanyl, iso azole group, Diazolone, pyrazol, thiophene, triazol, thiazolyl, or thiazoline.

7. The compound according to claim 1, wherein the compound of formula I is represented by formulas I-3: <Formula I-3> in It is a C5 cycloalkyl, C6 aryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, or 6-membered heterocycloalkenyl. p is an integer from 0 to 3, where if p is an integer of 2 or greater, then R B Same or different, and R B Is it substituted or unsubstituted C? 1-5 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted amides, substituted or unsubstituted amino groups, halogens, cyano groups, hydroxyl groups, aldehydes, CO2R h , NHCOR i NHCO2R j or NHSO2R k , where R h To R k Each is independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted butyl, or substituted or unsubstituted phenyl, and Z is the same as that defined in claim 1.

8. The compound according to claim 7, wherein It is phenyl, pyridone, pyridyl, pyrimidinyl, piperidinyl, or tetrahydropyridyl.

9. The compound according to claim 1, wherein the compound of formula I is represented by formulas I-4: <Formula I-4> in q is an integer from 0 to 3, where if q is an integer of 2 or greater, then R C Same or different, It is a C9 cycloalkyl group, C 10 cycloalkyl, C9 aryl, C 10 aryl, 9-membered heteroaryl, 10-membered heteroaryl, 9-membered heterocyclic alkyl or 10-membered heterocyclic alkyl, R C Is it substituted or unsubstituted C? 1-8 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, halogen, or cyano groups, and Z is the same as that defined in claim 1.

10. The compound according to claim 9, wherein... It is benzimidazolyl, benzodioxanepentyl, benzodioxanehexyl or dihydrobenzofuranyl, and q is 0.

11. The compound according to claim 1, wherein... Z represents methyl, ethyl, propyl, butyl, cyclopropyl, cyclohexyl, trifluoromethyl, phenyl, furanyl, imidazolyl, and isopropyl. azole group, Azolyl, pyrazolyl, pyrroleyl, thiazolyl, thiophene, pyridyl, pyrimidinyl, azaindolyl, indolyl, piperidinyl, tetrahydropyranyl, lactamyl, or tetrahydronaphthyl, and Z is either substituted by the substituted group set I-1-2 or unsubstituted: Substituent group I-1-2: substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-3 Halogenated alkyl, halogen, hydroxyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 6-8 Aryl, substituted or unsubstituted 3- to 8-membered heteroaryl, substituted or unsubstituted cyano, substituted or unsubstituted amino, substituted or unsubstituted amide, CO2R l or NHCO2R m , where R l and R m Each is independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted butyl, or substituted or unsubstituted phenyl.

12. The compound according to claim 1, wherein it is selected from any one of the following groups: 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(3-methylimidazol-4-yl)benzimidazol-5-sulfonamide; 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-sulfonamide; 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(3-phenylimidazol-4-yl)benzimidazol-5-sulfonamide; 2-[3-(3,4-difluorophenyl)imidazol-4-yl]-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-benzimidazol-5-sulfonamide; 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-oxo-2-piperidinyl)benzimidazol-5-sulfonamide; 2-(6-bromo-1H-indol-3-yl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-benzimidazol-5-sulfonamide; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-phenyl-benzimidazol-1-yl]benzimidazol-2-one; 5-[5-bromo-2-(6-methyl-1H-indol-3-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-5-[2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzimidazol-2-one; 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-carboxamide; 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(3-methylimidazol-4-yl)benzimidazol-5-carboxamide; 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-oxo-2-piperidinyl)benzimidazol-5-carboxamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-yl]piperidine-1-carboxylic acid tert-butyl ester; 1,3-Dimethyl-5-[2-(6-methyl-1H-indol-3-yl)-5-(4-piperidinyl)benzimidazol-1-yl]benzimidazol-2-one; 5-(1-Ethylpiperidin-4-yl)-1',3'-dimethyl-2-(6-methyl-1H-indol-3-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazole]-2'-ketocarboxylate; 1',3'-Dimethyl-2-(6-methyl-1H-indol-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzis[d]imidazole]-2'-ketocarboxylate; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]benzimidazol-1-yl]benzimidazol-2-one; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-methyl-pyrazole-3-carboxynitrile; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(1-piperidinyl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(4-pyridyl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(4-methyl-2-thienyl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(3-pyridyl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-pyrimidin-5-yl-benzimidazol-1-yl]benzimidazol-2-one; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 5-[5-(2-methoxyphenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 2-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]benzonitrile; 5-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]pyridine-2-carboxylic acid methyl ester; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(2-pyridyl)benzimidazol-1-yl]benzimidazol-2-one; 5-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-N-methylpyridine-2-carboxamide; 5-[5-(2-fluorophenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(3-fluorophenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(4-fluorophenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(2-fluoro-4-pyridyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(3-methoxyphenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(1-methyl-2-oxo-4-pyridyl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(1-methyl-6-oxo-3-pyridyl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(2-methyl-4-pyridyl)benzimidazol-1-yl]benzimidazol-2-one; 5-[5-(2-methoxy-4-pyridinyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(2-oxo-1H-pyridin-4-yl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(6-oxo-1H-pyridin-3-yl)benzimidazol-1-yl]benzimidazol-2-one; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]methyl benzoate; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]benzoic acid; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluorobenzoate; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluorobenzoic acid; 5-[5-(4-methoxyphenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; N-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; 2-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]pyrazol-1-yl]acetamide; 5-[5-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]benzimidazol-1-yl]benzimidazol-2-one; 5-[5-[1-(2,2-difluoroethyl)pyrazol-4-yl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]benzamide; 5-[5-(2-amino-4-pyridyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-3-yl)benzimidazol-1-yl]benzimidazol-2-one; 5-[5-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-[4-(hydroxymethyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(3-hydroxyphenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(4-hydroxyphenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(3-fluoro-4-hydroxy-phenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 5-[5-(4-aminophenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(6-amino-3-pyridyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 5-[5-(2-aminopyrimidin-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 2-Chloro-4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-N,N-dimethylbenzamide; 5-[5-(3-aminophenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 3-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-N-methylbenzamide; N-[3-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; 5-[5-anilino-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-phenoxy-benzimidazol-1-yl]benzimidazol-2-one; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2,6-difluoro-N-methylbenzamide; 5-[5-[3-(dimethylamino)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; N-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-phenyl]acetamide; N-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]methanesulfonamide; 5-[5-(3,5-dimethoxyphenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; N-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]tert-butyl carbamate; N-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]benzamide; 5-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 3-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-4-fluoro-N-methylbenzamide; 5-[5-[4-(dimethylamino)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(2-aminothiazo-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 5-[5-(1H-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-[2-Cyclopropyl-1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-phenyl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 1,3-Dimethyl-5-[5-[4-(methylamino)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]benzimidazol-2-one; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-iso] [[5-yl-benzimidazol-5-yl]-2-fluoro-N-methylbenzamide;] 4-[2-cyclohexyl-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(4-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-5-[3-fluoro-4-(methylcarbamoyl)phenyl]benzimidazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(4-piperidinyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-tetrahydropyran-4-yl-benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[2-(cyclohexylmethyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[2-benzylmethyl-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-thiazolyl-5-yl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-furanyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(1-methylpyrrolo-2-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-thienyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(o-tolyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2,3-dimethylphenyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2- [[Azol-4-yl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide;] 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(1H-imidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(1-methylpyrazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-thiazolyl-4-yl-benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2- [[5-yl-benzimidazol-5-yl]-2-fluoro-N-methylbenzamide;] 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-thienyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-furanyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-methyl-3-thienyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-methyl-3-furanyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-[3-(trifluoromethyl)phenyl]benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-tetrahydronaphth-5-yl-benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(4-methyl-3-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-methyl-3-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(5-methyl-3-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(4-amino-3-pyridyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(m-tolyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[2-(3-chlorophenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[2-(2,3-dichlorophenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-fluoro-2-methyl-phenyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-pyrimidin-5-yl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 2-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-5-[3-fluoro-4-(methylcarbamoyl)phenyl]benzimidazol-2-yl]-2-methylpropionate; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-isopropyl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-hydroxy-3-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-hydroxy-4-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[2-(3-bromo-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-[2-methyl-3-(1-methylpyrazol-4-yl)phenyl]benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[2-[2-(dimethylamino)ethyl]-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[2-(3-cyclopropyl-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-[3-[2-(dimethylamino)ethylamino]-2-methyl-phenyl]-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-[2-methyl-3-(trifluoromethyl)phenyl]benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-fluorophenyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[2-(2-chlorophenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-[2-(trifluoromethyl)phenyl]benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methoxy-2-methyl-phenyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-methoxyphenyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methoxyphenyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(4-fluorophenyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(4-methyl-1H-imidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(3,5-dimethylimidazol-4-yl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[2-(2,3-dimethylimidazol-4-yl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[2-tert-butyl-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(trifluoromethyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-methyl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-methoxy-3-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[2-(2-anilino-1,1-dimethyl-2-oxo-ethyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-methylpyrazol-3-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[2-(2-amino-3-pyridyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; N-[1-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-5-[3-fluoro-4-(methylcarbamoyl)phenyl]benzimidazol-2-yl]-1-methyl-ethyl]tert-butyl carbamate; 4-[2-(3-cyano-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(1-cyano-1-methyl-ethyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(1-amino-1-methyl-ethyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(2-chloro-3-pyridyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(1-methoxy-1-methyl-ethyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazolium]-5-carboxynitrile; N'-Hydroxy-1',3'-Dimethyl-2-(1-Methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazol]-5-formamidin; 3-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazol]-5-yl)-1,2,4- Diazole-5(2H)-one; 5-(2,3-dihydrobenzo[b][1,4]di) (1,3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one; 5-(2,3-dihydrobenzofuran-5-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one; 5-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazol]-5-yl)furan-2-carboxaldehyde; 5-(4,5-dihydrothiazolyl-2-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one; 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazol]-5-yl)-1H-1,2,3-triazol-1-yl)ethyl acetate; 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazol]-5-yl)-1H-1,2,3-triazol-1-yl)acetic acid; 5-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one; 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazol]-5-yl)-1H-1,2,3-triazol-1-yl)-N-methylacetamide; 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazol]-5-yl)-1H-1,2,3-triazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide; 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-5-(1-(2-oxo-2-(piperidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one; 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-5-(1-(2-morpholino-2-oxoethyl)-1H-1,2,3-triazol-4-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one; N-Benzyl-2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazol]-5-yl)-1H-1,2,3-triazol-1-yl)acetamide; 5-(3,5-dimethylisocyanate) 1,3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one; 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-5-(5-methylfuran-2-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one; 5-(benzo[d][1,3]dioxacyclopenten-5-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one; 5-(furan-3-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one; and 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-5-(1-methyl-1H-pyrazol-5-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one.

13. The compound according to claim 1, which is used as a CBP / p300 inhibitor.

14. An isomer of the compound according to claim 1, a pharmaceutically acceptable salt thereof, its hydrate or a solvate thereof.

15. A pharmaceutical composition for the prevention or treatment of cancer, inflammatory disorders, or autoimmune diseases, said composition comprising at least one of the compound of claim 1, its isomer, its pharmaceutically acceptable salt, its hydrate, and its solvate as an active ingredient.

16. The pharmaceutical composition of claim 15, wherein the cancer is a cancer dependent on the oncogene MYC, a tumor carrying a loss-of-function mutation of CBP or p300, or a cancer with activated CBP and / or p300 function.

17. The pharmaceutical composition according to claim 15, wherein the cancer is selected from one or more of hematologic malignancies, prostate cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer, and melanoma.

18. The pharmaceutical composition according to claim 15, wherein the cancer is selected from acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colon cancer, and cranial cancer. Pharyngoductoma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic changes, embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocytosis, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, pedunculated tumor, heavy chain disease head and neck cancer, hemangioblastoma, hepatocellular carcinoma, hormone insensitivity. Prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphoendothelial sarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, midline NUT carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma One or more of the following: ovarian cancer, pancreatic cancer, papillary gland cancer, papillary carcinoma, pineal gland tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland cancer, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial malformation, sweat gland cancer, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

19. The pharmaceutical composition of claim 15, wherein the inflammatory disorder or autoimmune disease is selected from Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous dermatitis, chronic obstructive pulmonary disease, Crohn's disease, dermatitis, eczema, giant cell arteritis, fibrosis, glomerulonephritis, hepatic vascular occlusion, hepatitis, hypophysitis, immunodeficiency syndrome, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, aortitis, toxic shock, thyroiditis, type 1 diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis, or more thereof.

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