Novel compounds used as CBP / P300 inhibitors and pharmaceutical compositions containing them as active ingredients for the prevention or treatment of cancer, inflammatory disorders, or autoimmune diseases.

Abstract

The present invention provides a novel compound for use as a CBP / p300 inhibitor, a method for its preparation, an isomer thereof, a pharmaceutically acceptable salt thereof, its hydrate thereof or a solvate thereof, and a pharmaceutical composition for the prevention or treatment of cancer, inflammatory disorders or autoimmune diseases, said pharmaceutical composition comprising at least one of these substances as an active ingredient.

Description

Technical Field

[0001] This application claims priority to Korean Patent Application No. 2024-0007499, 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, one aspect of this disclosure relates to a compound represented by the following formula I: <Formula I>

[0015] in

[0016] X is C or N. 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. R is C independently. 1-7 Alkyl, C 3-7 cycloalkyl, C 1-5 Haloalkyl, C 6-10 Aryl, 5- to 9-membered heteroaryl, 3- to 14-membered heterocyclic alkyl, 4- to 9-membered heterocyclic alkenyl, halogen, cyano, carbonyl, formaldehyde oxime, NR a R b SO2NHR c CONR d R e CO2R f , NHCOR g OR h And R a To R f Each is independently selected from hydrogen and C. 1-5 Alkyl, C 3-7 cycloalkyl, C 1-4Haloalkyl, C 6-10 Aryl, halogen, carbonyl, and Boc groups, Q represents hydrogen, C represents... 1-7 Alkyl or C 3-7 cycloalkyl, A is hydrogen, C 1-8 Alkyl, C 2-8 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, C 6-10 Aryl, 3- to 16-membered heterocyclic alkyl, 3- to 16-membered heterocyclic alkenyl, 5- to 9-membered heteroaryl, halogen, carbonyl, NR i R j OR k And R i To R k Each is independently selected from hydrogen and C. 1-8 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl, and Boc groups, and Z is C 1-8 Alkyl, C 3-7 cycloalkyl, C 6-10 Aryl, 5- to 13-membered heteroaryl, or 3- to 8-membered heterocyclic alkyl, Among them, R, R a To R k Q, A, and Z are either substituted by or unsubstituted by the substituted group I.

[0017] Another aspect of this disclosure relates to isomers of the above-mentioned compounds, pharmaceutically acceptable salts thereof, their hydrates or solvates thereof.

[0018] 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.

[0019] Effect

[0020] 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.

[0021] 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

[0022] 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.

[0023] This disclosure may provide a compound represented by the following formula I: <Formula I>

[0024] Where X can be C or N, n can be an integer from 0 to 3, and if n is an integer of 2 or greater, then R can be the same or different, and R can be C independently. 1-7 Alkyl, C 3-7 cycloalkyl, C 1-5 Haloalkyl, C 6-10 Aryl, 5- to 9-membered heteroaryl, 3- to 14-membered heterocyclic alkyl, 4- to 9-membered heterocyclic alkenyl, halogen, cyano, carbonyl, formaldehyde oxime, NR a R b SO2NHR c CONR d R e CO2R f , NHCOR g OR h And R a To R f Each can be independently selected from hydrogen and C. 1-5 Alkyl, C 3-7 cycloalkyl, C 1-4 Haloalkyl, C 6-10 Aryl, halogen, carbonyl, and Boc groups, where Q can be hydrogen or C. 1-7 Alkyl or C 3-7 cycloalkyl, where A can be hydrogen or C 1-8 Alkyl, C 2-8 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, C 6-10 Aryl, 3- to 16-membered heterocyclic alkyl, 3- to 16-membered heterocyclic alkenyl, 5- to 9-membered heteroaryl, halogen, carbonyl, NR i R j OR kAnd R i To R k Each can be independently selected from hydrogen and C. 1-8 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl, and Boc group, wherein Z can be C 1-8 Alkyl, C 3-7 cycloalkyl, C 6-10 aryl, 5 to 13-membered heteroaryl or 3 to 8-membered heterocyclic alkyl, wherein R, R a To R k Q, A, and Z can each be substituted by the substituted base group I or remain unsubstituted.

[0025] Substituent group I: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2-10 Alkyne, 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, substituted or unsubstituted carbonyl groups, 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, wherein C 1-10 The alkyl portion may be intercalated with a heteroatom group selected from -O-, -S-, -SO-, -SO2-, and -NR. m -(R) m It is hydrogen or substituted or unsubstituted C 1-10Alkyl groups, -N=, =N-, -POR m -and-PO4R m - and the heterocyclic moiety may include at least one of S, N, P and O as a cyclic atom.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] In this specification, the term "alkynyl" can be straight-chain or branched. Alynyl groups include, for example, ethynyl and trimethylsilylethynyl, but are not limited to these.

[0034] 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, cyclohexyl, cyclohexene, 3-methylcyclohexyl, 4-methylcyclohexyl, 2,3-dimethylcyclohexyl, 3,4,5-trimethylcyclohexyl, 4-tert-butylcyclohexyl, cycloheptyl, and cyclooctyl.

[0035] In this specification, the term "cycloalkenyl" refers to a cyclic hydrocarbon having a double bond. Examples of cycloalkenyl include, but are not limited to, cyclohexenyl. In this specification, the term "aryl" refers to a ring containing multiple unsaturated rings, typically aromatic hydrocarbon rings, 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, anthracene, phenanthryl, pyrene, and benzo[a]pyrene.

[0036] 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.

[0037] 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[] Azolyl, benzothiophene, quinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, isoquinolinyl, thiophene, acridineyl, indazole, carbazole, benzimidazolyl, benzocarbazole, benzofuranyl, benzothiophene, dibenzothiophene, pyrazolopyrimidineyl The diazolyl or azidoindolyl groups are used, but the scope of this disclosure is not limited thereto.

[0038] In this specification, the term "heterocyclic alkyl" refers to 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 1, 1 to 2, or 1 to 3. For example, they may include, but are not limited to, piperazinyl, piperazin-diketone, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, and thiomorpholinyl dimethyl ether. Zincyl, oxazaspiroheptyl, hexahydrofuranopyrrole, oxazabicycloheptyl, imidazoalkyl, imidazolidinone, lactamyl, tetrahydropyranyl, tetrahydrofuranyl, diazabicyclooctyl, oxaindolyl, benzo[] Azinone, oxetane, azirone, or diazaspirooctyl.

[0039] In this specification, the term "heterocyclic alkenyl" means an unsaturated hydrocarbon containing one or more heteroatoms selected from O, N, P, and S as cyclic atoms to form 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, tetrahydropyridyl, dihydropyrazinyl, and dihydroquinoline.

[0040] In this specification, the term "halogen" includes, for example, fluorine, chlorine, bromine, or iodine, but is not limited thereto.

[0041] 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, hydrogen, substituted or unsubstituted C. 1-10 Alkyl, C 2-10 alkenyl, substituted or unsubstituted 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, each of which is defined as described above.

[0042] In this specification, the term "Boc group" refers to the tert-butoxycarbonyl protecting group.

[0043] 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.

[0044] 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.

[0045] In this specification, the terms "carbocyclic" and "of a carbocyclic ring" refer to a ring in which the cyclic atoms 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.

[0046] 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.

[0047] 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, 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.

[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, 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.

[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, -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.

[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, 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.

[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, 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.

[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, 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 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 Substituents represented by )”, where R P It can be, but is not limited to, substituted or unsubstituted 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.

[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, 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.

[0056] In one implementation, R, R a To R k Q, A, and Z can each be substituted by the substituent group I-1 or remain unsubstituted.

[0057] Substituent group I-1: substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-5 alkenyl, substituted or unsubstituted C 2-7 Alkyne, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-5 Halogenated alkyl, substituted or unsubstituted C 6-8Aryl, substituted or unsubstituted carbonyl, substituted or unsubstituted 3- to 9-membered heterocyclic alkyl, halogen, cyano, Boc group, OR p1 NR p2 R p3 CONR p4 R p5 , NHCOR p6 or CO2R p7 , where R p1 To R p7 It can be hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted propenyl, substituted or unsubstituted methanesulfonate, substituted or unsubstituted carbonyl, and Boc group, each independently.

[0058] In one embodiment, the compound of formula I may be represented by either formula I-1 or I-2: <Formula I-1>

[0059] <Formula I-2>

[0060] n, R, Q, A, and Z can be the same as those defined above.

[0061] In one embodiment, the compound of formula I-1 may be represented by either formula I-1-1 or I-1-2: <Formula I-1-1>

[0062] <Formula I-1-2>

[0063] Where A 2 It can be C 1-8 Alkyl, C 2-8 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, C 6-10 Aryl, 3- to 16-membered heterocyclic alkyl, 5- to 9-membered heteroaryl, halogen, carbonyl, NR i R j OR k It is either substituted by or unsubstituted by the substituent group I, and R i To R k , n, R, Q and Z can be the same as those defined above.

[0064] In one implementation, A 2It can be chlorine, hydroxyl, substituted or unsubstituted carbonyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted butyl, substituted or unsubstituted propenyl, substituted or unsubstituted butenyl, trimethylsilylethynyl, ethynyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclohexenyl, substituted or unsubstituted cyclohexanone, substituted or unsubstituted phenyl, substituted or unsubstituted azacyclobutane, substituted or unsubstituted pyrroleyl, substituted or unsubstituted piperazine, substituted or unsubstituted Substituted pyridyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperidinone, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted azircyclopropane, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydropyridyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted thiomorpholinium dioxide, substituted or unsubstituted oxazaspiroheptyl, substituted or unsubstituted hexahydrofuranopyrroleyl, substituted or unsubstituted oxazabicycloheptyl, substituted or unsubstituted pyrazolyl, NR i R j OR k , where R i To R k It can be hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted butyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclohexylmethyl, substituted or unsubstituted oxacyclobutyl, substituted or unsubstituted dimethyl The compounds are oxazolidinone, substituted or unsubstituted cyclohexanone methyl, substituted or unsubstituted phenyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted tetrahydropyranyl.

[0065] In one implementation, A 2 The atom bonded to the 2-oxo-benzimidazole of the parent nucleus can be C, or a heteroatom such as N or O. For example, if A 2 If A is a substituted or unsubstituted azacyclobutane, a substituted or unsubstituted azacyclopropane, a substituted or unsubstituted pyrroleyl, a substituted or unsubstituted piperazine, a substituted or unsubstituted piperidinyl, a substituted or unsubstituted morpholinyl, a substituted or unsubstituted thiomorpholinyl, a substituted or unsubstituted thiomorpholin dioxide, a substituted or unsubstituted oxazaspiroheptyl, a substituted or unsubstituted hexahydrofuranopyrrole, or a substituted or unsubstituted oxazabicycloheptyl, then A 2 The 2-oxo-benzimidazole of the parent nucleus can be linked via N.

[0066] In one embodiment, the compound of formula I-2 may be represented by either formula I-2-1 or I-2-2: <Formula I-2-1>

[0067] <Formula I-2-2>

[0068] Where A 2 , n, R, Q and Z can be the same as those defined above.

[0069] In one embodiment, the compound of formula I-1-1 can be represented by either formula I-1-1-1 or I-1-1-2: <Formula I-1-1-1>

[0070] <Formula I-1-1-2>

[0071] Where R 111 R 211 and R 311 Each can be C independently 1-5 Alkyl, C 1-3 Haloalkyl, C 6-8 Aryl, 5- to 7-membered heteroaryl, halogen, cyano, carbonyl, CONR d R e or CO2R f It can be substituted by or unsubstituted by the base set I, and R d To R f Q and Z can be the same as defined above.

[0072] In one implementation, R 111 R 211 and R 311 Each of these can be independently methyl, propyl, CF2H, phenyl, pyrazolyl, bromine, fluorine, cyano, aldehyde, or CONR. d R e or CO2R f , where R d To R f Each can be independently hydrogen or substituted or unsubstituted methyl groups, and R 111 and R 211 They can be substituted independently by the substituted base group I-1-1 or remain unsubstituted.

[0073] Substituent group I-1-1: substituted or unsubstituted C 1-3 Alkyl, halogen, ORp1 NR p2 R p3 CONR p4 R p5 or NHCOR p6 , where R p1 To R p6 Each can be hydrogen, substituted or unsubstituted methyl, or substituted or unsubstituted propyl, independently.

[0074] In one embodiment, the compound of formula I-1-2 can be represented by any of the following formulas I-1-2-1 to I-1-2-3: <Formula I-1-2-1>

[0075] <Formula I-1-2-2>

[0076] <Formula I-1-2-3>

[0077] Where A 2 It can be the same as defined above, R 112 and R 212 Each can be C independently 1-5 Alkyl, C 3-7 cycloalkyl, C 1-5 Haloalkyl, C 6-10 Aryl, 5- to 9-membered heteroaryl, 3- to 14-membered heterocyclic alkyl, 4- to 9-membered heterocyclic alkenyl, halogen, cyano, carbonyl, formaldehyde oxime, NR a R b SO2NHR c CONR d R e CO2R f , NHCOR g OR h , where R 112 and R212 Each can be substituted by or remain unsubstituted by the base set I, and R a To R h Q and Z can be the same as defined above.

[0078] In one implementation, R 112 and R 212 Each of these can be independently methyl, cyclopropyl, CF3, CF2H, CFH2, phenyl, azole, pyrazol, thiazolyl, pyridinyl diazole, imidazole, triazole, lactam, hydroxyindole, quinolinone, dihydroquinolinone, benzo[] Phosphone group, dihydropyranyl group, fluorine, chlorine, bromine, cyano group, aldehyde, formaldehyde oxime, NR a R b SO2NHR c CONR d R e CO2R f , NHCOR g OR h , where R a To R h Each of these can be independently hydrogen, substituted or unsubstituted methyl, CF2H, CF3, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted carbonyl, or a Boc group, and R 112 and R 212 They can be substituted independently by the substituted base group I-1-2 or remain unsubstituted.

[0079] Substituent group I-1-2: substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 3-5 cycloalkyl, substituted or unsubstituted C 1-5 alkenyl, substituted or unsubstituted C 1-4 Halogenated alkyl groups, halogens, 4- to 8-membered heterocyclic alkyl groups, OR p1 NR p2 R p3 CONR p4 R p5 or NHCOR p6 , where R p1 To R p6 Each can be hydrogen, substituted or unsubstituted methyl, or substituted or unsubstituted carbonyl.

[0080] In one embodiment, the compound of formula I-2-1 may be represented by either formula I-2-1-1 or I-2-1-2: <Formula I-2-1-1>

[0081] <Formula I-2-1-2>

[0082] Where R 221 and R 312 Each can be C independently 6-9 Aryl, 5- to 9-membered heteroaryl, halogen or CONR d R e , where R 221 and R312 Each can be substituted by or remain unsubstituted by the base set I, and R d To R e Q and Z can be the same as defined above.

[0083] In one implementation, R 221 and R 312 Each can be independently phenyl, pyrazolyl, bromine, or CONR. d R e , where R d To R e Each can be independently hydrogen or substituted or unsubstituted methyl groups, and R 221 and R 312 They can be substituted independently by the substituted base group I-1-3 or remain unsubstituted.

[0084] Substituent group I-1-3: substituted or unsubstituted C 1-3 Alkyl, halogen or CONR p4 R p5 , where R p4 To R p5 Each can be hydrogen or a substituted or unsubstituted methyl group, independently.

[0085] In one embodiment, the compound of formula I-2-2 can be represented by either formula I-2-2-1 or I-2-2-2: <Formula I-2-2-1>

[0086] <Formula I-2-2-2>

[0087] Where A 2 It can be the same as defined above, R 222 and R 322 Each can be an independent 5- to 9-membered heteroaryl group, of which R 222 and R 322 Each can be substituted by or unsubstituted by the base set I, and Q and Z can be the same as defined above.

[0088] In one implementation, R 222 and R 322 Each can be either a pyrazolyl group or a thiazolyl group, where R 222 and R 322 They can be substituted independently by the substituted group I-1-4 or remain unsubstituted.

[0089] Substituent group I-1-4: substituted or unsubstituted C 1-3Alkyl or substituted or unsubstituted C 1-3 Halogenated alkyl groups.

[0090] In one embodiment, Q can be hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl.

[0091] In one embodiment, Z may be substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted butyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted phenyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thiophene, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted oxacyclobutane.

[0092] In one embodiment, the compound may be selected from any of the compounds listed in Table 2 below.

[0093] 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.

[0094] 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.

[0095] This disclosure also provides isomers of the compound represented by Formula I, pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] In this specification, the term "hydrate" refers to a compound in which water (H2O) is bonded to another compound.

[0104] 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.

[0105] 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.

[0106] In one embodiment, the cancer may be an AR-expressing cancer, a tumor carrying a CBP or p300 loss-of-function mutation, or a cancerous disease with CBP and / or p300 functional activation.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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 sessions. 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 said composition.

[0112] 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.

[0113] The present disclosure will be described in more detail below by way of preparation examples, embodiments, and experimental examples. However, the embodiments and experimental examples below are intended to illustrate the present disclosure, and the scope of the present disclosure is not limited thereto.

[0114] Compounds having the structure of Formula I can be synthesized by the following method.

[0115] <Reaction I>

[0116] <Reaction II>

[0117] <Reaction III>

[0118] <Reaction IV>

[0119] 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.)

[0120] 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).

[0121] Each starting material was a known compound, synthesized from literature or purchased commercially.

[0122] intermediate synthesis method

[0123] Preparation of Intermediate I-1: 5-Amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0124] Step 1) Preparation of 5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0125] 4-Nitrophenyl-1,2-diamine (10 g, 65.3 mmol) was dissolved in tetrahydrofuran (365 mL) and cooled to 0 °C. 1,1'-carbonyldiimidazole (21 g, 130.6 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was distilled 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).

[0126] 1 H-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).

[0127] Step 2: Preparation of 1,3-dimethyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0128] The 5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (4.9 g, 27.5 mmol) obtained in step 1 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 iodomethane (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).

[0129] 1¹H-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).

[0130] Step 3: Preparation of 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0131] The 1,3-dimethyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (3.5 g, 16.9 mmol) obtained in step 2 was dissolved in ethyl acetate (50 mL) and methanol (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 distilled 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)

[0132] 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).

[0133] Intermediate I-2 (Synthetic Method IA): Preparation of 6-amino-4-chloro-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0134] Step 1: Preparation of 3-chloro-5-nitrobenzene-1,2-diamine

[0135] Sodium sulfide pentahydrate (3.95 g, 37.2 mmol) and sulfur (1.194 g, 37.2 mmol) were added to a solution of water (25 mL) and ethanol (6 mL), and the mixture was stirred at 100 °C for 15 min. Over 10 min, a mixture of 2-chloro-4,6-dinitroaniline (5.4 g, 24.82 mmol) and ammonium chloride (1.991 g, 37.2 mmol) dissolved in ethanol (50 mL) and water (25 mL) was added dropwise to the reaction solution. The reaction solution was stirred at 65 °C for 1 h. Then, 6 N sodium hydroxide (12.41 mL, 74.5 mmol) was added dropwise over 10 min, and the mixture was stirred at 65 °C for 1 h. The reaction solution was cooled to 0 °C, and over 20 min, 6 N hydrochloric acid (11.5 mL, 69 mmol) and water (25 mL) were added. The reaction solution was stirred at 0 °C for 40 min, and the suspension was filtered. The filter cake was washed with water and ethanol and dried under nitrogen to give a yellow solid. (4 g, 21.32 mmol, 86% yield)

[0136] 1 ¹H-NMR (500 MHz, chloroform-d) δ 7.88 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 4.47 (s, 2H), 3.69–3.48 (m, 2H).

[0137] Step 2: Preparation of 4-chloro-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0138] The 3-chloro-5-nitrobenzene-1,2-diamine (4 g, 21.32 mmol) obtained in step 1 was dissolved in dimethylformamide (80 mL), and 1,1'-carbonyldiimidazole (5.19 g, 32.0 mmol) was added at room temperature. The mixture was stirred at room temperature for 18 hours. The reaction solution was cooled to 0 °C, water (80 mL) and 6 N hydrochloric acid (10.7 mL) were added, and the mixture was stirred for 30 minutes. The suspension was filtered, the filter cake was washed with methyl tert-butyl ether, and dried under nitrogen purging to give the title compound (3.6 g, 16.86 mmol, 79% yield).

[0139] 1 H-NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 1.8 Hz, 1H), 7.70-7.66 (m,1H).

[0140] Step 3: Preparation of 4-chloro-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0141] The 4-chloro-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (7.2 g, 33.7 mmol) obtained in step 2 was dissolved in dimethylformamide (100 mL), and potassium carbonate (13.98 g, 101 mmol) and methyl iodoforme (8.39 mL, 135 mmol) were added. The reaction solution was stirred for 3 hours. After cooling the mixture to 0 °C, water (100 mL) was added, and the product was stirred for 20 minutes. The solid formed during the reaction was filtered off, washed with water, and finally washed with methyl tert-butyl ether and dried under nitrogen to give the title compound (5.9 g, 24.42 mmol, 72.4% yield).

[0142] 1 H-NMR (500 MHz, DMSO-d6) δ 8.07 (d, J = 1.8 Hz, 1H), 8.03-8.00 (1H), 3.66 (s, 3H), 3.43 (s, 3H).

[0143] Step 4: Preparation of 6-amino-4-chloro-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0144] Add 3 g (12.42 mmol) of 4-chloro-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one and stannous chloride dihydrate (8.40 g, 37.2 mmol) obtained in step 3 to ethanol (30 mL), and stir under reflux at 70 °C for 5 h. Cool the reaction solution to room temperature, add water (40 mL), and add 40–60 mL of 6 N sodium hydroxide at 0 °C to adjust the pH of the solution to approximately 10–12. After stirring for 20 min, extract the organic layer with ethyl acetate and wash with brine. The solid obtained by concentration under reduced pressure was used in subsequent reactions without further purification. (2.7 g, 12.76 mmol, 100% yield)

[0145] 1 ¹H-NMR (500 MHz, chloroform-d) δ 6.38 (s, 1H), 6.22 (s, 1H), 3.66 (s, 3H), 3.59 (s, 2H), 3.33 (s, 3H).

[0146] Preparation of intermediate I-4 (synthetic method IB): 6-amino-1,3-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0147] Step 1: Preparation of 4-(3,6-dihydro-2H-pyran-4-yl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0148] To 1,4-two 4-Chloro-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound of step 3 of synthetic method IA, 1.2 g, 4.97 mmol) was added to an alkane (20 mL), followed by the addition of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (1.148 g, 5.46 mmol), potassium carbonate (1.373 g, 9.93 mmol), XPhos Pd G2 (0.195 g, 0.248 mmol), and XPhos (0.237 g, 0.497 mmol), and then bubbled under nitrogen for 5 min. The reaction solution was stirred at 90 °C for 18 h under nitrogen. After cooling the reaction solution to room temperature, water was added, the product was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was concentrated under reduced pressure and separated by MPLC to obtain the title compound.

[0149] 1 ¹H-NMR (500 MHz, chloroform-d) δ 7.85 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 5.86 (s, 1H), 4.35 (t, J = 2.6 Hz, 2H), 3.99 (t, J = 5.3 Hz, 2H), 3.56–3.52 (3H), 3.51 (s, 3H), 2.46 (d, J = 2.1 Hz, 2H)

[0150] Step 2: Preparation of 6-amino-1,3-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0151] Add 1.45 g (5.01 mmol) of 4-(3,6-dihydro-2H-pyran-4-yl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one obtained in step 1 to methanol (2 mL), and add 0.352 g (2.506 mmol) of dihydroxypalladium. Stir the solution at 60 °C for 4 hours under hydrogen atmosphere. Filter the reaction solution through a diatomaceous earth pad and concentrate the filtrate under reduced pressure. The resulting material was used in subsequent reactions without further purification.

[0152] 1 H-NMR (500 MHz, DMSO-d6) δ 6.26 (s, 1H), 6.20 (s, 1H), 4.78 (s, 2H), 3.99-3.84 (m, 2H), 3.49 (d, J = 11.0 Hz, 4H), 3.19 (s, 3H), 1.74-1.59 (m,4H).

[0153] Intermediate I-8 (Synthetic Method IC): Preparation of 6-amino-1,3-dimethyl-4-(propylamino)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0154] Step 1: Preparation of 1,3-dimethyl-6-nitro-4-(propylamino)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0155] 6-Amino-4-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-3, 100 mg, 0.350 mmol) and propyl-1-amine (0.057 mL, 0.699 mmol) were reacted with tris(diphenylmethylacetone)dipalladium(0) (28.5 mg, 0.035 mmol), Xantphos (60.7 mg, 0.105 mmol), and cesium carbonate (297 mg, 1.398 mmol) in toluene (3.5 mL) and stirred at 100 °C for 18 hours. The reaction product was diluted with ethyl acetate, washed with water, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (66 mg, 0.250 mmol, 71.4% yield).

[0156] Step 2: Preparation of 6-amino-1,3-dimethyl-4-(propylamino)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0157] The 1,3-dimethyl-6-nitro-4-(propylamino)-1,3-dihydro-2H-benzo[d]imidazol-2-one (66 mg, 0.250 mmol) obtained in step 1 and stannous chloride dihydrate (169 mg, 0.749 mmol) were added to ethanol (1 mL) and stirred at 60 °C for 18 hours. After quenching the reaction with 1 N sodium hydroxide, the organic layer was extracted with ethyl acetate, washed thoroughly with water, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by MPLC to give the title compound (50 mg, 0.213 mmol, 85% yield).

[0158] 1 H-NMR (500 MHz, DMSO-d6) δ 5.74 (s, 2H), 4.76 (t, J = 5.6 Hz, 1H), 4.63 (s, 2H), 3.48 (s, 3H), 3.13 (s, 3H), 2.93 (dd, J = 13.0, 6.9 Hz, 2H), 1.60 (p, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0159] Preparation of intermediate I-12: 6-amino-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0160] Step 1: Preparation of N1-methyl-5-nitrobenzene-1,2-diamine

[0161] 4-Nitrophenyl-1,2-diamine (1.53 g, 9.99 mmol) and potassium carbonate (2.76 g, 19.98 mmol) were reacted with iodomethane (0.625 mL, 9.99 mmol) in a solution of dimethylformamide (15 mL) and stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed once with water, twice with brine, and dehydrated over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to give the title compound (720 mg, 4.31 mmol, 43.1% yield).

[0162] 1 H-NMR (500 MHz, DMSO-d6) δ 7.50 (d, 1H), 7.11 (s, 1H), 6.56 (s, 1H), 6.12 (br s, 2H), 5.20 (s, 1H), 2.79 (d, 3H); LC / MS: 168 (M+H)

[0163] Step 2: Preparation of 1-methyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0164] The N1-methyl-5-nitrobenzene-1,2-diamine (720 mg, 4.31 mmol) obtained in step 1 was dissolved in tetrahydrofuran (30 mL), and 1,1'-carbonyldiimidazole (838 mg, 5.17 mmol) was added. The product was stirred at 80 °C for 6 hours and then stirred at room temperature for 3 days. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was precipitated by grinding with ethyl acetate and dried to give the title compound (614 mg, 3.18 mmol, 73.8% yield).

[0165] 1 H-NMR (500 MHz, DMSO-d6) δ 11.63 (br s, 1H), 8.01 (d, 1H), 7.99 (s,1H), 7.15 (d, 1H), 3.78 (s, 3H); LC / MS: 192 (MH).

[0166] Step 3: Preparation of 6-amino-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0167] Using 1-methyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (400 mg, 2.071 mmol) obtained in step 2 as the starting material, the title compound was obtained in a manner similar to step 3 of the synthesis of intermediate I-1. (331 mg, 2.028 mmol, 98% yield)

[0168] LC / MS: 164 (M+H).

[0169] Preparation of Intermediate I-13 (Synthetic Method ID): 6-Amino-1,3-dimethyl-4-(pyrrolidone-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0170] Step 1: Preparation of 1,3-dimethyl-6-nitro-4-(pyrrolidone-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0171] The title compound was obtained using 6-amino-4-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-3, 300 mg, 1.049 mmol) and pyrrolidine (0.086 mL, 1.049 mmol) in a manner similar to step 1 of synthetic method IC. (160 mg, 0.579 mmol, 55.2% yield)

[0172] Step 2: Preparation of 6-amino-1,3-dimethyl-4-(pyrrolidone-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0173] The 1,3-dimethyl-6-nitro-4-(pyrrolidone-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (131 mg, 0.474 mmol) obtained in step 1 was reacted with palladium / carbon (50.5 mg, 0.047 mmol) in methanol (1.2 mL) and ethyl acetate (1.2 mL) under hydrogen atmosphere for 18 hours. After the reaction was complete, the product was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (110 mg, 0.474 mmol, 94% yield).

[0174] 1 H-NMR (500 MHz, chloroform-d) δ 6.26 (br s, 1H), 6.10 (br s, 1H), 3.61 (s,3H), 3.54 (br s, 2H), 3.33 (s, 3H), 3.11 (br s, 2H), 3.02 (br s, 2H), 2.01(br s, 2H), 1.93(br s, 2H).

[0175] Intermediate I-18 (Synthetic Method IE): Preparation of 6-amino-4-isopropoxy-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0176] Step 1: Preparation of 4-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0177] To dissolve in 1,4-di A solution of 4-bromo-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (15 g, 52.4 mmol) and potassium hydroxide (3.53 g, 62.9 mmol) in alkyl (300 mL) was supplemented with tris(diphenylmethylacetone)dipalladium(O) (4.80 g, 5.24 mmol) and 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (t-BuXPhos) (4.45 g, 10.5 mmol), and nitrogen was purged. The mixture was then stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature and filtered. The filtered solid was eluted with 1,4-didimethylamine. Wash with alkane. Concentrate the filtrate under reduced pressure and purify the residue by column chromatography to give the title compound. (5 g, 21.7 mmol, 41.4% yield)

[0178] 1 ¹H-NMR (400 MHz, chloroform-d) δ 10.75 (s, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 3.53 (s, 3H), 3.35 (s, 3H); LC / MS: 224 (M+H).

[0179] Step 2: Preparation of 4-isopropoxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0180] 2-Iodopropane (0.549 mL, 5.50 mmol) was added to a solution of 4-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.116 g, 5.0 mmol) and potassium carbonate (0.829 g, 6.00 mmol) dissolved in acetonitrile (25.00 mL), and the mixture was stirred at 82 °C for 10 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (1.065 g, 4.01 mmol, 80% yield).

[0181] 1¹H-NMR (500 MHz, chloroform-d) δ 7.64 (s, 1H), 7.59 (s, 1H), 4.79–4.74 (m, 1H), 3.71 (s, 3H), 3.48 (s, 3H), 1.46 (d, J = 5.8 Hz, 6H); LC / MS: 266 (M+H)

[0182] Step 3: Preparation of 6-amino-4-isopropoxy-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0183] The title compound was obtained using 4-isopropoxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.06 g, 4.00 mmol) obtained in step 2 as the starting material, in a manner similar to step 2 of synthetic method ID. (812 mg, 3.45 mmol, 86% yield)

[0184] 1 ¹H-NMR (500 MHz, chloroform-d) δ 6.04 (s, 1H), 5.98 (s, 1H), 4.57–4.50 (m, 1H), 3.56 (d, J = 7.6 Hz, 5H), 3.31 (s, 3H), 1.36 (d, J = 6.1 Hz, 6H); LC / MS: 236 (M+H).

[0185] Preparation of intermediate I-24: 4-acetyl-6-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0186] Step 1: Preparation of 4-(1-ethoxyvinyl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0187] To 1,4-two 4-Bromo-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (400 mg, 1.398 mmol) was added to an alkyl group (6 mL), followed by the addition of tributyl(1-ethoxyvinyl)stanane (0.566 mL, 1.678 mmol) and bis(triphenylphosphine)palladium(II) dichloride (49.1 mg, 0.070 mmol). The solution was bubbled with nitrogen for 5 minutes. The reaction solution was stirred at 90 °C for 18 hours under nitrogen. Water and 1 N hydrochloric acid were added to the reaction solution, and the product was extracted twice 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 (218.8 mg, 0.789 mmol, 56.4% yield).

[0188] 1 ¹H-NMR (500 MHz, chloroform-d) δ 8.03 (s, 1H), 7.85 (s, 1H), 4.51 (s, 1H), 4.41 (s, 1H), 3.98 (q, J = 6.9 Hz, 2H), 3.53 (s, 3H), 3.51 (s, 3H), 1.42 (t, J = 6.9 Hz, 3H).

[0189] Step 2: Preparation of 4-acetyl-6-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0190] The title compound was obtained using 4-(1-ethoxyvinyl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (125 mg, 0.451 mmol) obtained in step 1 as the starting material, in a manner similar to step 2 of synthetic method IC. (73.5 mg, 0.335 mmol, 74.4% yield)

[0191] 1 ¹H-NMR (500 MHz, chloroform-d) δ 6.68 (s, 1H), 6.49 (s, 1H), 3.67 (s, 2H), 3.42–3.35 (6H), 2.62 (s, 3H); LC / MS: 220 (M+H).

[0192] Intermediate I-43 (Synthetic Method IF): Preparation of 6-amino-1,3-dimethyl-4-(pyridin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0193] Step 1: Preparation of 1,3-dimethyl-6-nitro-4-(pyridin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0194] To 1,4-two Alkane (150 mL) and water (25 mL) were reacted with 4-bromo-1,3-dimethyl-6-nitro-1,3-benzodiazol-2-one (5 g, 17.48 mmol) and pyridin-4-ylboronic acid (4.30 g, 34.95 mmol), followed by tetrakis(triphenylphosphine)palladium (2.02 g, 1.748 mmol) and sodium carbonate (7.41 g, 69.91 mmol), and stirred at 100 °C for 24 h. The reaction solution was cooled to room temperature, filtered, and washed with dichloromethane. The filtrate was washed with brine, the organic layer was dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound was obtained by separation by MPLC (3 g, 9.97 mmol, 57.06% yield).

[0195] LC / MS: 285 (M+H).

[0196] Step 2: Preparation of 6-amino-1,3-dimethyl-4-(pyridin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0197] The title compound was obtained using 1,3-dimethyl-6-nitro-4-(pyridin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2.5 g, 8.79 mmol) obtained in step 1 as the starting material, in a manner similar to step 2 of synthetic method ID. (1.5 g, 5.69 mmol, 64.73% yield)

[0198] 1 H-NMR (400 MHz, DMSO-d6) δ 8.69-8.53 (m, 2H), 7.50-7.29 (m, 2H), 6.44(d, J = 2.1 Hz, 1H), 6.16 (d, J = 2.1 Hz, 1H), 4.99 (s, 2H), 3.26 (s, 3H),2.82 (s, 3H).

[0199] Preparation of Intermediate I-50: 1-Bromo-2-(difluoromethyl)-4-fluoro-5-nitrobenzene

[0200] Step 1: Preparation of methyl 2,2-dimethylpropionic acid (2-bromo-5-fluorophenyl) ester

[0201] (2-Bromo-5-fluorophenyl)methanol (200 g, 0.976 mol) and triethylamine (370.7 mL, 2.93 mol) were dissolved in dichloromethane (3 L), and then trimethylacetyl chloride (141.15 g, 1.17 mol) was slowly added dropwise under nitrogen at 0 °C. The reaction solution was stirred at room temperature for 2 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 MPLC to give the title compound (144 g, 0.498 mol, 51.1% yield).

[0202] Step 2: Preparation of (2-bromo-5-fluoro-4-nitrophenyl)methanol

[0203] The methyl 2,2-dimethylpropionic acid (2-bromo-5-fluorophenyl) ester obtained in step 1 (160 g, 553.36 mmol) was dissolved in sulfuric acid (1.6 L), and potassium nitrate (67.13 g, 664.03 mmol) was slowly added dropwise under nitrogen at 0 °C. The reaction solution was stirred at 0 °C for 3 hours. After the reaction was complete, ice water was poured into the reaction solution, 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 (50 g, 199.98 mmol, 36.14% yield).

[0204] Step 3: Preparation of 2-bromo-5-fluoro-4-nitrobenzaldehyde

[0205] The (2-bromo-5-fluoro-4-nitrophenyl)methanol (40 g, 159.99 mmol) obtained in step 2 was dissolved in dichloromethane (500 mL), and Dess-Martin (135.71 g, 319.97 mmol) was slowly added dropwise under nitrogen at 0 °C. The reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, a saturated aqueous solution of sodium thiosulfate was added at room temperature, 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 (30.8 g, 124.2 mmol, 77.63% yield).

[0206] 1 H-NMR (400 MHz, DMSO-d6) δ 10.16 (d, J = 2.6 Hz, 1H), 8.55 (d, J =6.5 Hz, 1H), 7.93 (d, J = 10.8 Hz, 1H).

[0207] Step 4: Preparation of 1-bromo-2-(difluoromethyl)-4-fluoro-5-nitrobenzene

[0208] The 2-bromo-5-fluoro-4-nitrobenzaldehyde (31.5 g, 127 mmol) obtained in step 3 was dissolved in dichloromethane (300 mL), and then diethylaminosulfur trifluoride (35.2 mL, 267 mmol) was added at 0 °C. The reaction solution was stirred for 4 hours. After the reaction was complete, water was slowly added at 0 °C to terminate the reaction, and the organic layer was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (32.4 g, 120 mmol, 94% yield).

[0209] 1 ¹H-NMR (500 MHz, chloroform-d) δ 8.33 (d, J = 6.7 Hz, 1H), 7.64 (d, J = 10.4 Hz, 1H), 6.87 (t, J = 54.0 Hz, 1H).

[0210] Preparation of intermediate I-51: 1-bromo-2-(difluoromethoxy)-4-fluoro-5-nitrobenzene

[0211] Step 1: Preparation of 1-bromo-2-(difluoromethoxy)-4-fluorobenzene

[0212] 2-Bromo-5-fluorophenol (25 g, 130.89 mmol) was dissolved in dimethylformamide, followed by the slow addition of sodium carbonate (27.75 g, 261.78 mmol) at room temperature, and then the slow addition of 2-chloro-2,2-difluoroacetic acid (25.62 g, 196.34 mmol). The reaction solution was stirred at room temperature under nitrogen for 3 hours. 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 to give the title compound (16.6 g, 68.85 mmol, 52.62% yield).

[0213] Step 2: Preparation of 1-bromo-2-(difluoromethoxy)-4-fluoro-5-nitrobenzene

[0214] The 1-bromo-2-(difluoromethoxy)-4-fluorobenzene (7.8 g, 32.36 mmol) obtained in step 1 was dissolved in sulfuric acid, and potassium nitrate (4.58 g, 45.31 mmol) was added stepwise at -10 °C. The reaction solution was stirred at 0 °C for 3 hours under nitrogen atmosphere. After the reaction was complete, ice was added to terminate the reaction. Water was added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (5.1 g, 17.80 mmol, 55.10% yield).

[0215] 1 ¹H-NMR (400 MHz, chloroform-d) δ 8.40 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 11.0 Hz, 1H), 6.71 (t, 1H).

[0216] Preparation of intermediate I-52: 1-bromo-4-fluoro-5-nitro-2-(trifluoromethoxy)benzene

[0217] Step 1: Preparation of 2-fluoro-1-nitro-4-(trifluoromethoxy)benzene and 4-fluoro-1-nitro-2-(trifluoromethoxy)benzene

[0218] Using 1-fluoro-3-(trifluoromethoxy)benzene (15 g, 83.29 mmol) as the starting material, a mixture of the two title compounds was obtained in a manner similar to step 2 of the synthesis of intermediate I-51. (12.1 g, 53.72 mmol, 64.54% yield)

[0219] LC / MS: 226 (M+H).

[0220] Step 2: Preparation of 1-bromo-4-fluoro-5-nitro-2-(trifluoromethoxy)benzene and 1-bromo-2-fluoro-5-nitro-4-(trifluoromethoxy)benzene

[0221] A mixture of 2-fluoro-1-nitro-4-(trifluoromethoxy)benzene and 4-fluoro-1-nitro-2-(trifluoromethoxy)benzene obtained in step 1 (15 g, 66.64 mmol) and sulfuric acid (3 mL) was dissolved in trifluoroacetic acid (150 mL), followed by the gradual and slow addition of N-bromosuccinimide (35.58 g, 199.91 mmol) at room temperature. The reaction solution was stirred at 80 °C for 18 hours. 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, concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography to give a mixture of the two title compounds (10.2 g, 33.72 mmol, 50.6% yield).

[0222] 1 ¹H-NMR (400 MHz, chloroform-d) δ 8.33 (d, J = 7.7 Hz, 1H), 8.23 ​​(d, J = 6.7 Hz, 1H), 7.30–7.16 (m, 2H); LC / MS: 304 (M+H) (mixture of isomers).

[0223] Preparation of intermediate I-53: 2-bromo-5-fluoro-4-nitrophenol

[0224] 1-Bromo-4-fluoro-2-methoxy-5-nitrobenzene (5 g, 20 mmol) was dissolved in 1,2-dichloroethane (100 mL), and then boron tribromide (7.51 g, 30 mmol) was added at 0 °C. The reaction solution was stirred at 60 °C for 18 hours under nitrogen atmosphere. After the reaction was complete, ice and water were 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 (2.3 g, 9.82 mmol, 49.1% yield).

[0225] 1 H-NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 13.0 Hz, 1H).

[0226] Preparation of intermediate I-54: 1-(benzylmethyloxy)-2-bromo-5-fluoro-4-nitrobenzene

[0227] Benzyl bromide (0.214 mL, 1.80 mmol) was added to a solution of 2-bromo-5-fluoro-4-nitrophenol (intermediate I-53, 354 mg, 1.50 mmol), potassium carbonate (415 mg, 3.00 mmol), and potassium iodide (24.9 mg, 0.15 mmol) dissolved in acetone (6.00 mL), and the mixture was stirred at 56 °C for 18 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (456 mg, 1.40 mmol, 93% yield).

[0228] 1 ¹H-NMR (500 MHz, chloroform-d) δ 8.39 (d, J = 7.9 Hz, 1H), 7.46–7.37 (m, 5H), 6.80 (d, J = 12.2 Hz, 1H), 5.24 (s, 2H); LC / MS: 326 (M+H).

[0229] Preparation of intermediate I-55: 4-(2,4-difluoro-5-nitrophenyl)-1-methyl-1H-pyrazole

[0230] Bromo-2,4-difluoro-5-nitrobenzene (3 g, 12.61 mmol), 1-methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (3.67 g, 17.65 mmol), tetrakis(triphenylphosphine)palladium (0.728 g, 0.630 mmol), and sodium carbonate (2.67 g, 25.2 mmol) were prepared in a 1,4-difluoro-5-nitrobenzene atmosphere. The reaction mixture was stirred at 90 °C for 18 hours in a solvent of alkane (40 mL) and water (10 mL). The product was diluted in ethyl acetate, washed with water, dehydrated over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound. (2.75 g, 11.5 mmol, 91% yield)

[0231] 1 H-NMR (500 MHz, chloroform-d) δ 8.30 (t, J = 7.71 Hz, 1H), 7.87 (s, 1H),7.81 (s, 1H), 7.10 (t, J = 10.22 Hz, 1H), 3.99 (s, 3H); LC / MS: 240 (M+H).

[0232] Preparation of intermediate I-56: ((2,4-difluoro-5-nitrophenyl)ethynyl)trimethylsilane

[0233] 1-Bromo-2,4-difluoro-5-nitrobenzene (213 mg, 0.895 mmol), bis(triphenylphosphine)palladium(II) dichloride (62.8 mg, 0.090 mmol), cuprous(I) iodide (25.6 mg, 0.134 mmol), and triethylamine (624 μL, 4.48 mmol) were dissolved in toluene (4.8 mL), followed by the addition of ethynyltrimethylsilane (371 μL, 2.69 mmol). The reaction solution was stirred at room temperature for 7 hours. 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 to give the title compound (197 mg, 0.772 mmol, 86% yield).

[0234] 1 H-NMR (500 MHz, chloroform-d) δ 8.25 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 9.3 Hz, 1H), 0.28 (s, 9H).

[0235] Intermediate I-57: 5-(2,4-difluoro-5-nitrophenyl)-3-methyl-1,2,4- Preparation of diazoles

[0236] Step 1: Preparation of 2,4-difluoro-5-nitrobenzoic acid

[0237] Methyl 2,4-difluoro-5-nitrobenzoate (1 g, 4.61 mmol) was dissolved in tetrahydrofuran (10 mL) and water (5 mL), and lithium hydroxide (0.221 g, 9.21 mmol) was slowly 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 and diluted with ethyl acetate. The pH of the reaction solution was adjusted to 5–6 with 1 N hydrochloric acid solution, 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 to give the title compound, which could be used directly in subsequent steps without further purification. (955 mg, 4.70 mmol, 100% yield)

[0238] 1 H-NMR (500 MHz, DMSO-d6) δ 13.86 (s, 1H), 8.61 (t, J = 7.8 Hz, 1H), 7.87 (t, J = 10.8 Hz, 1H).

[0239] Step 2: 5-(2,4-difluoro-5-nitrophenyl)-3-methyl-1,2,4- Preparation of diazoles

[0240] 2,4-Difluoro-5-nitrobenzoic acid (200 mg, 0.99 mmol) and N-hydroxyacetamidine (76 mg, 0.99 mmol) obtained in step 1 were dissolved in ethyl acetate (2.5 mL), triethylamine (0.4 mL, 2.95 mmol) was added, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane 2,4,6-trioxide (50 wt%, in ethyl acetate, 5 mL, 2.46 mmol) was slowly added. The reaction solution was stirred at 80 °C for 18 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 aqueous sodium bicarbonate solution and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (68.8 mg, 0.285 mmol, 29.0% yield).

[0241] 1 ¹H-NMR (500 MHz, chloroform-d) δ 8.92 (t, J = 7.2 Hz, 1H), 7.28 (t, J = 9.6 Hz, 1H), 2.49 (s, 3H).

[0242] Preparation of intermediate I-58: 2,2-dimethyl-3-oxopropionitrile

[0243] Step 1: Preparation of 3-hydroxy-2,2-dimethylpropionitrile

[0244] Sodium borohydride (8.93 g, 235.96 mmol) was dissolved in methanol (100 mL) and stirred at 0 °C for 5 min. Methyl 2-cyano-2,2-dimethylacetate (10 g, 78.65 mmol) was slowly added over 5 min at 0 °C. The reaction solution was stirred at room temperature for 18 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, water and dichloromethane were added, and the organic layer was extracted. The organic layer was washed with a saturated aqueous ammonium chloride solution, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (6.4 g, 64.6 mmol, 82.1% yield).

[0245] 1H-NMR (400 MHz, DMSO-d6) δ 5.43 (t, J = 5.7 Hz, 1H), 3.36 (d, J = 5.4Hz, 2H), 1.23 (s, 6H).

[0246] Step 2: Preparation of 2,2-dimethyl-3-oxopropionitrile

[0247] Oxaloyl chloride (8.25 mL, 96.84 mmol) was dissolved in dichloromethane (80 mL), and then dimethyl sulfoxide (8.60 mL, 121.05 mmol) was added under nitrogen at -78 °C. 3-hydroxy-2,2-dimethylpropionitrile (8 g, 80.7 mmol), obtained in step 1, was slowly added at -78 °C. The reaction solution was stirred under nitrogen at -78 °C for 40 min. Triethylamine (56.09 mL, 403.5 mmol) was slowly added over 5 min at -78 °C. The reaction solution was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, water and ethyl acetate were added, and the organic layer was extracted. The organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound, which could be used directly in subsequent steps without further purification. (4 g, 41.16 mmol, 51.0% yield)

[0248] 1 H-NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 1.32-1.00 (m, 6H).

[0249] In addition, intermediates synthesized in a similar manner as described above and their synthesis methods are listed in Table 1.

[0250] [Table 1]

[0251] The commonly used synthesis methods in each embodiment are described below.

[0252] Example 1 (Synthesis Method A): Preparation of 3-(7-chloro-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-sulfonamide

[0253] Step 1: Preparation of 3-fluoro-N-methyl-4-nitrobenzenesulfonamide

[0254] A solution of 3-fluoro-4-nitrobenzenesulfonyl chloride (10 g, 41.7 mmol) dissolved in dichloromethane (100 mL) was cooled to 0 °C, and then a methylamine solution (2 M, in tetrahydrofuran, 52.2 mL, 104 mmol) was slowly added dropwise, followed by stirring at room temperature for 2 hours. After the reaction was complete, the methylamine salt was filtered off and washed with dichloromethane. The residue was concentrated under reduced pressure and used in subsequent reactions without further purification. (11.4 g, 48.6 mmol, 100% yield)

[0255] 1 ¹H-NMR (400 MHz, chloroform-d) δ 8.26–8.14 (m, 2H), 7.80 (t, J = 9.3 Hz, 2H), 4.56 (s, 1H), 2.83–2.74 (m, 3H).

[0256] Step 2: Preparation of 3-((7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methyl-4-nitrobenzenesulfonamide

[0257] 6-Amino-4-chloro-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-2, 0.43 g 2.05 mmol) and 3-fluoro-N-methyl-4-nitrobenzenesulfonamide (0.4 g 1.71 mmol) obtained in step 1 were added to 1,4-di... The mixture was added to 10 mL of alkylene and diisopropylethylamine (0.6 mL, 3.42 mmol), and then stirred at 80 °C for 18 hours. The reaction product was concentrated under reduced pressure, and the resulting solid was washed with dichloromethane and methanol and filtered. The filter cake was washed with methanol, dried under nitrogen, and used in subsequent reactions without further purification. (430 mg, 0.73 mmol, 59% yield)

[0258] Step 3: Preparation of 4-amino-3-((7-chloro-1,3-dimethyl-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methylbenzenesulfonamide

[0259] The 3-((7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methyl-4-nitrobenzenesulfonamide (430 mg, 1.01 mmol) and iron (169 mg, 3.03 mmol) obtained in step 2 were added to methanol (6 mL) and water (3 mL), and ammonium chloride (270 mg, 5.05 mmol) was added. The reaction solution was then stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, ethyl acetate (30 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through a diatomaceous earth mat, the filtrate was washed with brine, and water was removed with anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and purified by MPLC to give the title compound (220 mg, 0.56 mmol, 55% yield).

[0260] 1 H-NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.02 (m, 2H), 6.96 (m, 1H), 6.90 (m, 1H), 6.73(s, 1H), 6.14(m, 1H), 4.41(d, J = 6.5 Hz, 2H), 3.57 (s,3H), 3.27(s, 3H), 2.37 (d, J = 5 Hz, 3H).

[0261] Step 4: Preparation of 3-(7-chloro-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-sulfonamide

[0262] Copper(II) acetate (92 mg, 0.51 mmol) was added to a solution of 4-amino-3-((7-chloro-1,3-dimethyl-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methylbenzenesulfonamide (200 mg, 0.51 mmol) and 6-methyl-1H-indole-3-carboxaldehyde (80 mg, 0.51 mmol) obtained in step 3, dissolved in acetic acid (7 mL). The solution was stirred at 80 °C for 3 hours. The reaction solution was cooled to room temperature, water and 1 N sodium hydroxide were added, and the organic layer was extracted with ethyl acetate and washed with brine. The organic layer was concentrated under reduced pressure and separated by MPLC to give the title compound (16 mg, 0.03 mmol, 5.92% yield).

[0263] 1 H-NMR (500 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.49 (d, 1H), 8.12 (s, 1H), 7.62 (m, 2H), 7.43 (s, 1H), 7.37 (m, 1H), 7.25 (m, 2H), 7.08 (d, 1H), 6.68 (d, 1H), 3.73 (s, 3H), 3.35 (s, 3H), 2.43 (s, 6H).

[0264] Examples 3 and 4 (Synthesis Method B): Preparation of methyl 6-bromo-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-carboxylate and methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-5-carboxylate

[0265] Step 1: Preparation of methyl 2-bromo-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-4-nitrobenzoate

[0266] 5-Amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-1, 0.637 g, 3.60 mmol) was dissolved in 1,4-dimethylamino-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-1, 0.637 g, 3.60 mmol) The reaction mixture was placed in alkyl (9 mL) and methyl 2-bromo-5-fluoro-4-nitrobenzene (1 g, 3.60 mmol) and diisopropylethylamine (0.942 mL, 5.40 mmol) were added. The reaction solution was stirred at 100 °C 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 MPLC to give the title compound (1.5 g, 3.45 mmol, 96% yield).

[0267] 1 H-NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.33 (s, 1H), 7.24 (s, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1H), 7.05 (dd, J = 8.2, 1.8Hz, 1H), 3.76 (s, 3H), 3.31 (s, 3H).

[0268] Step 2: Preparation of methyl 4-amino-2-bromo-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)benzoate

[0269] Methyl 2-bromo-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-4-nitrobenzene (1.5 g, 3.45 mmol) obtained in step 1 was dissolved in ethanol (11.50 mL) and water (5.70 mL), followed by the addition of iron (1.155 g, 20.68 mmol) and ammonium chloride (0.221 g, 4.14 mmol). The reaction solution was stirred at 100 °C for 2 hours. After the reaction was complete, the product was filtered through a diatomaceous earth filter and concentrated, then purified by MPLC to give the title compound (1.3 g, 3.21 mmol, 93% yield).

[0270] 1 H-NMR (500 MHz, DMSO-d6) δ 7.51 (s, 1H), 7.03-6.98 (m, 3H), 6.66-6.60 (m, 2H), 3.67 (s, 3H), 3.28 (s, 3H), 3.24 (s, 3H).

[0271] Step 3: Preparation of methyl 6-bromo-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-carboxylate (Example 3)

[0272] 1-Methyl-1H-imidazol-5-carboxaldehyde (54.3 mg, 0.494 mmol) and methyl 4-amino-2-bromo-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)benzoate (200 mg, 0.494 mmol), obtained in step 2, were dissolved in acetic acid (8.2 mL), followed by the addition of copper(II) acetate (90 mg, 0.494 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 to give the title compound (102 mg, 0.206 mmol, 41.7% yield).

[0273] 1 ¹H-NMR (500 MHz, chloroform-d) δ 8.09 (s, 1H), 7.56 (brs, 1H), 7.51 (s, 1H), 7.16–7.08 (m, 2H), 6.92 (s, 1H), 6.47 (br s, 1H), 4.17 (s, 3H), 3.88 (s, 3H), 3.53 (s, 3H), 3.41 (s, 3H).

[0274] Step 4: Preparation of methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-5-carboxylate (Example 4)

[0275] The methyl 6-bromo-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-carboxylate (102 mg, 0.206 mmol), (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (48.7 mg, 0.247 mmol), and tripotassium phosphate (87 mg, 0.412 mmol) obtained in step 3 were dissolved in 1,4-di... The [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane adduct (16.82 mg, 0.021 mmol) was added to alkyl (0.8 mL) and water (0.2 mL). The reaction solution was stirred at 100 °C for 3 h 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 residue was purified by MPLC and PTLC to give the title compound (111 mg, 0.196 mmol, 95% yield).

[0276] 1 H-NMR (500 MHz, chloroform-d) δ 8.12 (t, J = 8.1 Hz, 1H), 7.73 (s, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.17-7.12 (m, 3H), 6.96(s, 1H), 6.83-6.80 (m, 1H), 6.47 (s, 1H), 4.17 (s, 3H), 3.59 (s, 3H), 3.52(s, 3H), 3.41 (s, 3H), 3.05 (d, J = 4.3 Hz, 3H); LC / MS: 568 (M+H).

[0277] Example 6 (Synthesis Method C): Preparation of 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile

[0278] Step 1: Preparation of 4-amino-2-bromo-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)benzonitrile

[0279] The title compound was obtained using 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-1, 56 mg, 0.316 mmol) and 5-fluoro-4-nitrobenzenenitrile (77 mg, 0.316 mmol) as starting materials, in a manner similar to steps 1 and 2 of synthetic method B. (70.5% yield after two steps)

[0280] Step 2: Preparation of 4-amino-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)benzonitrile

[0281] The 4-amino-2-bromo-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)benzonitrile (78 mg, 0.210 mmol), potassium carbonate (57.9 mg, 0.419 mmol), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (52.3 mg, 0.251 mmol) obtained in step 1 were dissolved in 1,4-dioxaborhexacyclopentan-2-yl)amino)benzonitrile (78 mg, 0.210 mmol), potassium carbonate (57.9 mg, 0.419 ... The [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane adduct (17.11 mg, 0.021 mmol) was added to alkyl (0.8 mL) and water (0.2 mL). 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 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 (54 mg, 0.145 mmol, 69.0% yield).

[0282] 1 H-NMR (500 MHz, methanol-d4) δ 8.02 (s, 1H), 7.84 (s, 1H), 7.25 (s, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J = 7.0 Hz, 1H), 6.69 (dd, J = 8.5, 1.8 Hz, 1H), 6.64 (d, J = 1.8 Hz, 1H), 6.58 (s, 2H), 3.95 (s, 3H), 3.39 (s, 3H), 3.35 (s, 3H).

[0283] Step 3: Preparation of 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile

[0284] The title compound was obtained using 4-amino-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)benzonitrile (27 mg, 0.072 mmol) and 1-methyl-1H-imidazol-5-carboxaldehyde (7.96 mg, 0.072 mmol) obtained in step 2 as starting materials, in a manner similar to step 3 of synthetic method B. (19 mg, 0.041 mmol, 56.7% yield)

[0285] 1 H-NMR (400 MHz, methanol-d4) δ 8.06 (s, 1H), 7.90 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 7.49 (s, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 1.8 Hz,1H), 7.20 (dd, J = 8.2, 1.8 Hz, 1H), 6.51 (s, 1H), 4.11 (s, 3H), 3.96 (s,3H), 3.49 (s, 3H), 3.40 (s, 3H).

[0286] Example 7 (Synthesis Method D): Preparation of 5-[6-(hydroxymethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0287] Methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylate (Example 5, 300 mg, 0.550 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0 °C. Diisobutylaluminum hydride (DIBAL-H) ​​(1 M, in tetrahydrofuran, 2.2 mL, 2.2 mmol) was slowly added. The reaction solution was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate and washed with water and brine. Anhydrous sodium sulfate was added to the organic layer to remove water, and the mixture was then filtered. The filtrate was concentrated under reduced pressure and purified by MPLC to give the title compound (125 mg, 0.242 mmol, 43.9% yield).

[0288] 1H-NMR (400 MHz, DMSO-d6) δ 11.11(s, 1H), 8.52 (d, 1H), 7.96 (d, 1H),7.72 (d, 2H), 7.46 (m, 2H), 7.22 (m, 2H), 7.12 (s, 1H), 7.04 LC / MS: 518 (M+H).

[0289] Example 8 (Synthesis Method E): Preparation of 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxaldehyde

[0290] 5-[6-(hydroxymethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 7, 100 mg, 0.193 mmol) was dissolved in dichloromethane (1 mL), and manganese dioxide (33.6 mg, 0.386 mmol) was added. The reaction solution was stirred at 45 °C for 4 hours. The reaction solution was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure. The title compound was purified by MPLC (90 mg, 0.193 mmol, 90.0% yield).

[0291] 1 H-NMR (400 MHz, chloroform-d) δ 10.22 (s, 1H), 8.59 (d, 1H), 8.21 (m, 1H), 7.88 (d, 1H), 7.74 (d, 1H), 7.68 (s, 1H), 7.55 (d, 1H), 7.24 (m, 3H), 7.03 (s, 1H), 6.64 (d, 1H), 4.05 (s, 3H), 3.57 (s, 3H), 3.42 (s, 3H), 2.51 (s, 3H); LC / MS: 516 (M+H).

[0292] Example 9: Preparation of 5-[6-(difluoromethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0293] 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxaldehyde (Example 8, 90 mg, 0.175 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Diethylaminosulfur trifluoride (98 mg, 0.61 mmol) was slowly added. The reaction solution was stirred at room temperature for 12 hours. A saturated sodium bicarbonate solution was added to the reaction solution, and the product was extracted with dichloromethane. Anhydrous sodium sulfate was added to the collected organic layer to remove water, and the mixture was then filtered. The filtrate was concentrated under reduced pressure and purified by MPLC to give the title compound (15 mg, 0.028 mmol, 16.0% yield).

[0294] 1 H-NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.53 (d, 1H), 7.92 (d, 1H), 7.79 (s, 1H), 7.67 (d, 1H), 7.50 (m, 2H), 7.28 (d, 1H), 7.22 (d, 2H), 7.07(m, 2H), 6.54 (d, 1H), 3.94 (s, 3H), 3.47 (s, 3H), 3.36 (s, 3H), 2.43 (s, 3H); LC / MS: 538 (M+H).

[0295] Example 10 (Synthesis Method F): Preparation of 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylic acid

[0296] Methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylate (Example 5, 20 mg, 0.037 mmol) was dissolved in methanol (1 mL), and 1 N sodium hydroxide (0.11 mL, 0.11 mmol) was slowly added. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was neutralized with 1 N hydrochloric acid. The reaction solution was diluted with water and extracted with ethyl acetate. Anhydrous sodium sulfate was added to the organic layer to remove water and the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by MPLC to give the title compound. (11 mg, 21 μmol, 56.5% yield)

[0297] 1 H-NMR (400 MHz, methanol-d4) δ 8.00 (d, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.65 (s, 1H), 7.60 (m, 1H), 7.45 (m, 2H), 7.38 (d, 1H), 7.29 (m, 1H), 7.12(d, 1H), 7.06 (s, 1H), 3.98 (s, 3H), 3.55 (s, 3H), 3.35 (s, 3H), 2.47 (s, 3H); LC / MS: 532 (M+H).

[0298] Example 12 (Synthesis Method G): Preparation of 5-[6-(1-hydroxy-1-methyl-ethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one

[0299] Methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylate (Example 5, 30 mg, 0.055 mmol) was dissolved in tetrahydrofuran (1 mL), and methylmagnesium bromide (3 M, in diethyl ether, 0.055 mL, 0.165 mmol) was slowly added. The reaction solution was stirred at room temperature for 24 hours. Ice was added to the reaction solution, and the product was diluted with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. Anhydrous sodium sulfate was added to the organic layer to remove water, and then the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by MPLC to give the title compound (4.3 mg, 0.0079 mmol, 14.3% yield).

[0300] 1 H-NMR (400 MHz, chloroform-d) δ 8.39 (m, 2H), 7.66 (d, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.21 (m, 1H), 7.15 (m, 2H), 7.08 (d, 1H), 6.98(s, 1H), 6.54 (s, 1H), 4.01 (s, 3H), 3.78 (s, 1H), 3.54 (s, 3H), 3.38 (s,3H), 2.47 (s, 3H), 1.53 (s, 6H); LC / MS: 546 (M+H).

[0301] Example 26 (Synthesis Method H): Preparation of 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-N-methyl-2-(3-methylimidazol-4-yl)benzimidazol-5-carboxamide

[0302] 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-5-carboxylic acid (Example 22, 78 mg, 0.141 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (40.5 mg, 0.211 mmol), and hydroxybenzotriazole (32.4 mg, 0.211 mmol) were dissolved in dimethylformamide (1.4 mL), and then methylamine (2 M, in tetrahydrofuran, 176 μL, 0.352 mmol) was added. The reaction solution was stirred at room temperature for 6 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, concentrated under reduced pressure, and the residue was purified by MPLC to give the title compound. (54 mg, 0.095 mmol, 67.6% yield)

[0303] 1H-NMR (500 MHz, chloroform-d) δ 8.15 (t, J = 8.1 Hz, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.27-7.24 (m, 1H),7.14-7.09 (m, 2H), 6.95 (s, 1H), 6.82-6.78 (m, 1H), 6.47 (s, 1H), 5.36 (d, J= 4.9 Hz, 1H), 4.17 (s, 3H), 3.52 (s, 3H), 3.41 (s, 3H), 3.06 (d, J = 4.9 Hz,3H), 2.69 (d, J = 4.9 Hz, 3H).

[0304] Example 47 (Synthesis Method I): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0305] Step 1: Preparation of 6-((4-bromo-5-fluoro-2-nitrophenyl)amino)-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0306] 6-Amino-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-10, 47 mg, 0.179 mmol) and 1-bromo-2,4-difluoro-5-nitrobenzene (42.6 mg, 0.179 mmol) were dissolved in 1,4-di... The mixture was added dropwise to alkylene (2.00 mL) and diisopropylethylamine (0.064 mL, 0.358 mmol) and stirred at 100 °C for 18 hours. The reaction solution was diluted in dichloromethane, washed with water, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (77.6 mg, 0.162 mmol, 90% yield).

[0307] 1H-NMR (500 MHz, chloroform-d) δ 9.54 (s, 1 H), 8.51 (s, 1 H), 6.79 (dd, 3H), 3.92 (br. s., 4 H), 3.79 (s, 3 H), 3.42 (s, 3H), 3.01 (s, 4H).

[0308] Step 2: Preparation of 5-bromo-6-fluoro-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-7'-morpholino-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one

[0309] The 6-((4-bromo-5-fluoro-2-nitrophenyl)amino)-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one] (77.6 mg, 0.162 mmol) obtained in step 1 and sodium dithionite (99 mg, 0.485 mmol) were stirred at 90 °C for 1 hour with 1-methyl-1H-imidazol-5-carboxaldehyde (175 mg, 0.162 mmol) in dimethyl sulfoxide (2.3 mL) and water (0.23 mL). The reaction was terminated by adding 25% ammonia after diluting the reaction solution with water and ethyl acetate. The organic layer was washed with water, dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (48 mg, 0.162 mmol, 55% yield).

[0310] 1 H-NMR (500 MHz, chloroform-d) δ 8.01 (d, 1H), 7.53 (s, 1H), 6.88 (d, 1H), 6.84 (s, 1H), 6.74 (s, 1H), 6.45 (s, 1H), 4.16 (s, 3 H), 3.89 (br, s, 4H), 3.83 (s, 3H), 3.40 (s, 3H), 2.97 (s, 4H).

[0311] Step 3: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0312] The title compound was obtained using 5-bromo-6-fluoro-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-7'-morpholino-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one (7.5 mg, 0.014 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (4.04 mg, 0.019 mmol) obtained in step 2 as starting materials, in a manner similar to step 4 of synthetic method B. (0.8 mg, 0.014 mmol, 10.6% yield)

[0313] 1 H-NMR (500 MHz, chloroform-d) δ 7.92 (s, 1H), 7.79 (br. s., 1H), 7.53 (s,1H), 6.87 (s, 2H), 6.77 (s, 1H), 6.46 (s, 1H), 4.18 (s, 3H), 3.99 (s, 3H), 3.83 (s, 3H), 3.40 (s, 3H), 2.98 (br. s., 4H); LC / MS: 542 (M+H).

[0314] Example 49 (Synthesis Method J): Preparation of 1-ethyl-5-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-3-methylbenzimidazol-2-one

[0315] Potassium carbonate (23.43 mg, 0.170 mmol) and bromoethane (6.33 μL, 0.085 mmol) were added to a solution of 5-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-3-methyl-1H-benzimidazol-2-one (Example 48, 25 mg, 0.057 mmol) dissolved in dimethylformamide (2 mL), and the mixture was stirred at room temperature for 3 days. The reaction product was diluted with ethyl acetate and water, and the separated aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by PTLC to give the title compound (17.6 mg, 0.037 mmol, 66.2% yield).

[0316] 1H-NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.10 (d, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.45-7.42 (m, 2H), 7.18 (d, 1H), 6.98 (d, 1H), 6.37 (s, 1H), 4.05 (s, 3H), 3.99-3.97 (m, 2H), 3.91 (s, 3H), 3.35 (s, 3H), 1.29 (t, 3H); LC / MS: 471 (M+H).

[0317] Example 54 (Synthesis Method K): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropenyl-1,3-dimethylbenzimidazol-2-one

[0318] 4-chloro-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 53, 30 mg, 0.061 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhexacyclopentane (20.54 mg, 0.122 mmol) and 2 M sodium carbonate aqueous solution (0.122 mL, 0.244 mmol) were added to 1,4-di-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 53, 30 mg, 0.061 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhexacyclopentane (20.54 mg, 0.122 mmol), and 2 M sodium carbonate aqueous solution (0.122 mL, 0.244 mmol) Alkane (1 mL) was added and stirred for 5 minutes while bubbling under nitrogen. Tetra(triphenylphosphine)palladium(0) (7.06 mg, 6.11 μmol) was added to the reaction solution, and the mixture was stirred at 90 °C for 18 hours under nitrogen. After the reaction was complete, water was added, the product was extracted with ethyl acetate, the organic layer was washed with brine and concentrated under reduced pressure. The title compound was purified by MPLC and PTLC. (26 mg, 0.052 mmol, 86% yield)

[0319] 1H-NMR (500 MHz, chloroform-d) δ 8.12-7.98 (m, 2H), 7.83 (s, 1H), 7.08-6.75(m, 4H), 6.72 (s, 1H), 5.44 (s, 1H), 5.10 (s, 1H), 4.40 (s, 3H), 4.04 (s, 3H), 3.60 (s, 3H), 3.45 (s, 3H), 2.16 (s, 3H); LC / MS: 497 (M+H).

[0320] Example 58 (Synthesis Method L): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethylbenzimidazol-2-one

[0321] 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropenyl-1,3-dimethyl-benzimidazol-2-one (Example 54, 30 mg, 0.060 mmol) and carbon-supported palladium hydroxide (21.21 mg, 0.030 mmol) were added to ethanol (1 mL) / methanol (1 mL) and stirred at 50 °C for 18 hours under hydrogen balloon pressure. The reaction solution was filtered through a diatomaceous earth pad to remove the catalyst. The product was concentrated under reduced pressure and separated by MPLC and PTLC to give the title compound. (18 mg, 0.036 mmol, 59.8% yield)

[0322] 1 H-NMR (500 MHz, chloroform-d) δ 7.95 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 7.02 (s, 1H), 6.84 (d, J = 10.4 Hz, 1H), 6.77 (s,1H), 6.45 (s, 1H), 4.23-4.12 (3H), 3.98 (s, 3H), 3.77 (s, 3H), 3.75-3.65 (m,1H), 3.39 (s, 3H), 1.33 (d, J = 6.7 Hz, 6H); LC / MS: 499(M+H).

[0323] Example 59 (Synthesis Method M): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethylbenzimidazol-2-one

[0324] Step 1: Preparation of 6-((4-bromo-5-fluoro-2-nitrophenyl)amino)-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0325] The title compound was obtained using 6-amino-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-14, 235 mg, 1.003 mmol) and 1-bromo-2,4-difluoro-5-nitrobenzene (239 mg, 1.003 mmol) as starting materials in a manner similar to step 1 of synthetic method B. (378 mg, 0.836 mmol, 83% yield)

[0326] 1 H-NMR (500 MHz, chloroform-d) δ 9.52 (s, 1H), 8.49 (d, J = 8.9 Hz, 1H), 6.83 (d, J = 13.4 Hz, 1H), 6.37 (s, 1H), 6.33 (s, 1H), 3.83 (s, 1H), 3.77 (s,3H), 3.63-3.59 (m, 1H), 3.39 (s, 3H), 1.29 (d, J = 7.9 Hz, 6H); LC / MS: 452,454 (M+H).

[0327] Step 2: Preparation of 6-((5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)amino)-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0328] The title compound was obtained using 6-((4-bromo-5-fluoro-2-nitrophenyl)amino)-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (701 mg, 1.550 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (387 mg, 1.860 mmol) obtained in step 1 as starting materials, in a manner similar to step 4 of synthetic method B. (487 mg, 1.074 mmol, 69.3% yield)

[0329] 1 H-NMR (500 MHz, chloroform-d) δ 9.49 (s, 1H), 8.42 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 6.82 (d, J = 13.1 Hz, 1H), 6.38 (s, 1H), 6.34 (s, 1H), 3.95 (s, 3H), 3.75 (s, 3H), 3.61-3.59 (m, 1H), 3.37 (s, 3H), 1.27 (d, J= 6.1 Hz, 6H); LC / MS: 454 (M+H).

[0330] Step 3: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethylbenzimidazol-2-one

[0331] The 6-((5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)amino)-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (358 mg, 0.789 mmol) and sodium dithionite (412 mg, 2.368 mmol) obtained in step 2 were reacted with 1-methyl-1H-imidazol-5-carboxaldehyde (87 mg, 0.789 mmol) in ethanol (11.8 mL) and water (3.93 mL) and stirred at 90 °C for 1 hour. The reaction was terminated with 25% ammonia. The reaction product was diluted with ethyl acetate, washed with water, dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (263 mg, 0.512 mmol, 64.9% yield).

[0332] 1H-NMR (500 MHz, chloroform-d) δ 7.94 (d, J = 6.1 Hz, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.51 (s, 1H), 6.88 (d, J = 10.4 Hz, 1H), 6.62 (s, 1H), 6.39 (d,J = 7.6 Hz, 2H), 4.17 (s, 3H), 3.98 (s, 3H), 3.90 (d, J = 7.0 Hz, 1H), 3.81(s, 3H), 3.54-3.52 (m, 1H), 3.35 (s, 3H), 1.22 (d, J = 6.1 Hz, 6H); LC / MS: 514 (M+H).

[0333] Example 60 (Synthetic Method N): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(propylamino)benzimidazol-2-one

[0334] To 1,4-two Alkane (1 mL) was added with 4-chloro-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 53, 38 mg, 0.077 mmol) and sodium tert-butoxide (22.32 mg, 0.232 mmol), and propan-1-amine (0.025 mL, 0.310 mmol) and PEPPSI-iPr catalyst (5.26 mg, 7.74 μmol). The mixture was stirred at 120 °C for 40 min using a microwave. Water was added to the reaction solution, the product was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The title compound was obtained by separation by MPLC and PTLC (14 mg, 0.027 mmol, 35.2% yield).

[0335] 1H-NMR (500 MHz, chloroform-d) δ 7.94 (d, J = 6.1 Hz, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 6.88 (d, J = 10.4 Hz, 1H), 6.62 (s, 1H), 6.41 (s,1H), 6.37 (s, 1H), 4.16 (s, 3H), 3.98 (s, 3H), 3.82 (s, 3H), 3.35 (s, 3H), 3.03 (t, J = 7.0 Hz, 2H), 1.74-1.59 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H); LC / MS: 514 (M+H).

[0336] Example 97: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-hydroxy-1,3-dimethylbenzimidazol-2-one

[0337] 1,4-dimethylbenzimidazol-2-one (Example 53, 25 mg, 0.050 mmol), tris(diphenylmethylacetone)dipalladium(O) (2.289 mg, 2.500 μmol), 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (5.89 mg, 10.00 μmol), and potassium hydroxide (8.42 mg, 0.150 mmol) were added to a reaction vessel containing 4-chloro-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one (Example 53, 25 mg, 0.050 mmol), tris(diphenylmethylacetone)dipalladium(O) (2.289 mg, 2.500 μmol), 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (5.89 mg, 10.00 μmol), and potassium hydroxide (8.42 mg, 0.150 mmol). Alkane (0.10 mL) and water (0.10 mL) were added, nitrogen was purged, and the mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature, acidified with 1 N hydrochloric acid, and extracted with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (2.3 mg, 4.87 μmol, 9.7% yield).

[0338] 1¹H-NMR (500 MHz, chloroform-d) δ 7.88 (d, J = 7.0 Hz, 2H), 7.75 (s, 1H), 7.61 (s, 1H), 6.77 (d, J = 11.6 Hz, 2H), 6.49 (s, 1H), 6.35 (s, 1H), 4.13 (s, 3H), 3.97 (s, 3H), 3.79 (s, 3H), 3.34 (s, 3H); LC / MS: 473 (M+H).

[0339] Example 99 (Synthesis Method O): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-propoxy-benzimidazol-2-one

[0340] 1,4-dimethylbenzimidazol-2-one (Example 53, 49 mg, 0.100 mmol), tris(diphenylmethylacetone)dipalladium(O) (4.57 mg, 4.99 μmol), 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (11.75 mg, 0.020 mmol), and potassium hydroxide (16.80 mg, 0.299 mmol) were added to a reaction vessel containing 4-chloro-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one (Example 53, 49 mg, 0.100 mmol), tris(diphenylmethylacetone)dipalladium(O) (4.57 mg, 4.99 μmol), 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (11.75 mg, 0.020 mmol), and potassium hydroxide (16.80 mg, 0.299 mmol). Alkane (0.10 mL) and water (0.10 mL) were added, nitrogen was introduced, and the mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature, cetyltrimethylammonium bromide (3.6 mg, 9.98 μmol) and 1-bromopropane (0.018 mL, 0.200 mmol) were added, and the reaction mixture was stirred at 100 °C for another 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (16.1 mg, 0.031 mmol, 31.3% yield).

[0341] 1H-NMR (500 MHz, chloroform-d) δ 7.94 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 6.85 (d, J = 10.4 Hz, 1H), 6.61 (d, J = 7.0 Hz,2H), 6.54 (s, 1H), 4.17 (s, 3H), 3.98 (s, 3H), 3.95 (t, J = 6.1 Hz, 2H), 3.75(s, 3H), 3.38 (s, 3H), 1.85 (td, J = 13.6, 6.5 Hz, 2H), 1.07 (t, J = 7.3 Hz,3H); LC / MS: 515 (M+H).

[0342] Example 107: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[isopropyl(methyl)amino]-1,3-dimethyl-benzimidazol-2-one

[0343] A solution of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one (Example 59, 29 mg, 0.056 mmol) dissolved in 0.565 mL of 1,2-dichloroethane was added with formaldehyde (37 wt% aqueous solution, 0.021 mL, 0.282 mmol), acetic acid (0.016 mL, 0.282 mmol), and sodium triacetoxyborohydride (35.9 mg, 0.169 mmol), and stirred at room temperature for 24 hours. The reaction was terminated by adding saturated aqueous sodium bicarbonate solution, and the product was extracted with dichloromethane. The resulting organic layer was washed with brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound. (7 mg, 0.013 mmol, 23.5% yield)

[0344] 1H-NMR (500 MHz, chloroform-d) δ 7.95 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 6.86 (s, 1H), 6.83 (d, J = 10.7 Hz, 1H), 6.69 (s,1H), 6.50 (s, 1H), 4.16 (s, 3H), 3.98 (s, 3H), 3.79 (s, 3H), 3.38 (s, 3H),3.34-3.29 (m, 1H), 2.64 (s, 3H), 1.11 (d, J = 4.6 Hz, 6H); LC / MS: 528 (M+H).

[0345] Example 116 (Synthetic Method P): Preparation of 6-[6-fluoro-2-(1-methylcyclopropyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethylbenzimidazol-2-one

[0346] Step 1: Preparation of 6-((2-amino-5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one)

[0347] The title compound was synthesized using 6-amino-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-23, 540 mg, 2.463 mmol) and 1-bromo-2,4-difluoro-5-nitrobenzene (310 μL, 2.463 mmol) as starting materials, in a manner similar to steps 1 and 2 of synthetic method C. (50.9% yield after two steps)

[0348] 1 H-NMR (500 MHz, chloroform-d) δ 7.77 (s, 1H), 7.69 (s, 1H), 6.95 (d, J =7.3 Hz, 1H), 6.85 (d, J = 12.2 Hz, 1H), 6.63 (s, 1H), 6.42 (s, 1H), 3.94 (s, 3H), 3.65 (s, 3H), 3.62-3.57 (m, 1H), 3.34 (s, 3H), 1.31 (d, J = 6.7 Hz, 6H); LC / MS: 409 (M+H).

[0349] Step 2: Preparation of 6-[6-fluoro-2-(1-methylcyclopropyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethylbenzimidazol-2-one

[0350] The 6-((2-amino-5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (39 mg, 0.095 mmol), 1-methylcyclopropane-1-carboxylic acid (10.51 mg, 0.105 mmol), and diisopropylethylamine (0.033 mL, 0.191 mmol) obtained in step 1 were dissolved in ethyl acetate (1 mL), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane 2,4,6-trioxide (50 wt%, in ethyl acetate, 0.284 mL, 0.477 mmol) was added. The reaction solution was stirred at 110 °C for 3 hours using a microwave. 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. (8.3 mg, 0.018 mmol, 18.40% yield)

[0351] 1 H-NMR (500 MHz, chloroform-d) δ 7.85-7.84 (m, 2H), 7.72 (s, 1H), 7.11 (s,1H), 6.89 (s, 1H), 6.83 (d, J = 10.4 Hz, 1H), 3.96 (s, 3H), 3.76 LC / MS: 473 (M+H).

[0352] Example 118: Preparation of 6-[6-fluoro-2-(3-methyloxetane-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethylbenzimidazol-2-one

[0353] (3-Methyloxetane-3-yl)methanol (15.00 mg, 0.147 mmol) was dissolved in ethyl acetate (0.5 mL) and dimethyl sulfoxide (0.25 mL), and then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphazenecyclohexane 2,4,6-trioxide (50 wt%, in ethyl acetate, 0.131 mL, 0.220 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, 6-((2-amino-5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (the compound from step 1 of synthetic method P, 30 mg, 0.073 mmol) was added, and stirring was continued for 1 hour. 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. (11.3 mg, 0.023 mmol, 31.5% yield)

[0354] 1 H-NMR (400 MHz, chloroform-d) δ 7.90 (d, J = 6.4 Hz, 1H), 7.87 (s, 1H), 7.74 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.79-6.76 (m, 2H), 5.22(d, J = 5.9 Hz, 2H), 4.27-4.26 (m, 2H), 3.97 (s, 3H), 3.76 (s, 3H), 3.73-3.68(m, 1H), 3.43 (s, 3H), 1.76 (s, 3H), 1.34 (d, J = 6.9 Hz, 6H); LC / MS: 489 (M+H).

[0355] Example 122: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-trimethylsilylethynyl)benzimidazol-2-one

[0356] Step 1: Preparation of 4-bromo-6-((5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0357] 6-Amino-4-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-3, 100 mg, 0.390 mmol) and 4-(2,4-difluoro-5-nitrophenyl)-1-methyl-1H-pyrazole (intermediate I-55, 112 mg, 0.469 mmol) were reacted with anhydrous potassium fluoride (85 mg, 0.586 mmol) in dimethylformamide (1.5 mL) at 160 °C for 4 h using a microwave. The reaction product was diluted with ethyl acetate, washed with water, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (75.4 mg, 0.159 mmol, 40.6% yield).

[0358] 1 H-NMR (500 MHz, chloroform-d) δ 9.46 (br, s, 1 H), 8.43 (d, J=7.78 Hz, 1H), 7.82(s, 1 H), 7.71 (s, 1 H), 7.17 (s, 1 H), 6.85 (s, 1 H), 6.75 (d, J=12.97 Hz, 1H), 3.97 (s, 3H), 3.79 (s, 3H), 3.43 (s, 3H).

[0359] Step 2: Preparation of 7'-bromo-6-fluoro-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one

[0360] The 4-bromo-6-((5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (75.4 mg, 0.159 mmol), 1-methyl-1H-imidazol-5-carboxaldehyde (17.5 mg, 0.159 mmol), and sodium sulfate (83 mg, 0.476 mmol) obtained in step 1 were reacted in dimethyl sulfoxide (1 mL, 0.786 mmol) at 90 °C for 3 h. The reaction product was quenched with 25% ammonium hydroxide, diluted in ethyl acetate, washed with water, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (35.4 mg, 0.066 mmol, 41.7% yield).

[0361] 1 H-NMR (500 MHz, chloroform-d) δ 7.96(d, 2H) 7.79(s, 1H) 7.54(s, 1H) 6.89(s, 1H) 6.86(d, 1H) 6.55(s, 1H) 4.17(s, 1H) 3.99(s, 1H) 3.86 (s, 3H) 3.41 (s, 3H); LC / MS: 535, 537 (M+H).

[0362] Step 3: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-trimethylsilylethynyl)benzimidazol-2-one

[0363] The 7'-bromo-6-fluoro-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazol]-2'-one (50 mg, 0.093 mmol) obtained in step 2 was dissolved in dimethylformamide (1 mL), and ethynyltrimethylsilane (0.026 mL, 0.187 mmol), cuprous iodide (I) (1.779 mg, 9.34 μmol), triethylamine (0.130 mL, 0.934 mmol), and bis(triphenylphosphine)palladium dichloride (II) (6.56 mg, 9.34 μmol) were added. The reaction solution was stirred at 100 °C for 18 hours. The reaction solution was cooled to room temperature, water and ethyl acetate were added, the organic layer was extracted, and then washed with brine. The organic layer was concentrated under reduced pressure and purified by MPLC and PTLC to give the title compound. (17 mg, 0.031 mmol, 32.9% yield)

[0364] 1H-NMR (500 MHz, chloroform-d) δ 7.94 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.18 (s, 1H), 6.85 (s, 1H), 6.82 (d, J = 10.4 Hz, 1H), 6.53 (s, 1H), 4.20-4.13 (3H), 4.02-3.94 (3H), 3.86 (s, 3H), 3.41-3.35(3H), 0.30-0.22 (9H); LC / MS: 553 (M+H).

[0365] Example 123: Preparation of 4-ethynyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0366] 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-trimethylsilylethynyl)benzimidazol-2-one (Example 122, 14 mg, 0.025 mmol) was added to tetrahydrofuran (0.5 mL), followed by the addition of tetra-n-butylammonium fluoride (1 M, in tetrahydrofuran, 0.076 mL, 0.076 mmol). The reaction solution was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the organic layer was extracted with ethyl acetate and washed with brine. Water was removed with anhydrous magnesium sulfate. The solution was filtered, concentrated under reduced pressure, and purified by PTLC to give the title compound (9.7 mg, 0.020 mmol, 80% yield).

[0367] 1 H-NMR (500 MHz, chloroform-d) δ 7.95 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.21 (s, 1H), 6.90 (s, 1H), 6.83 (d, J = 10.4 Hz,1H), 6.56-6.49 (1H), 4.16 (s, 3H), 3.98 (s, 3H), 3.90-3.81 (3H), 3.40 (s,3H), 3.36 (s, 1H); LC / MS: 481 (M+H).

[0368] Example 125: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-hydroxyethyl)-1,3-dimethyl-benzimidazol-2-one

[0369] 4-Acetyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 124, 20 mg, 0.040 mmol) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.2 mL), and sodium borohydride (3.04 mg, 0.080 mmol) was added at 0 °C. The reaction solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the organic layer was extracted with ethyl acetate and then concentrated under reduced pressure. The title compound was purified by PTLC (20 mg, 0.040 mmol, 100% yield).

[0370] 1 H-NMR (500 MHz, chloroform-d) δ 7.94 (d, J = 6.4 Hz, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.49 (s, 1H), 7.28 (s, 1H), 6.87 (s, 1H), 6.83 (d, J = 10.4 Hz,1H), 6.43 (s, 1H), 5.55 (q, J = 6.1 Hz, 1H), 4.14 (s, 3H), 3.97 (s, 3H), 3.77(s, 3H), 3.44-3.36 (3H), 1.59 (d, J = 6.4 Hz, 3H); LC / MS: 501 (M+H).

[0371] Example 126: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-hydroxy-1-methyl-ethyl)-1,3-dimethyl-benzimidazol-2-one

[0372] Add 4-acetyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 124, 25 mg, 0.050 mmol) to tetrahydrofuran (0.5 mL). Cool the product to 0 °C and add methylmagnesium bromide (3.4 M, in methyltetrahydrofuran, 0.074 mL, 0.251 mmol). Stir the reaction solution at room temperature for 18 hours. Add water to the reaction solution, and extract the organic layer with ethyl acetate, then concentrate under reduced pressure. Purify by PTLC to give the title compound (11.5 mg, 0.022 mmol, 44.6% yield).

[0373] 1 H-NMR (500 MHz, chloroform-d) δ 7.95 (d, J = 6.4 Hz, 1H), 7.90 (s, 1H), 7.77 (s, 1H), 7.51 (s, 1H), 7.04 (s, 1H), 6.90 (s, 1H), 6.83 (d, J = 10.4 Hz, 1H), 6.43 (s, 1H), 4.16 (s, 3H), 3.98 (s, 3H), 3.96 (s, 3H), 3.41 (s, 3H), 2.85 (br, 1H), 1.71 (s, 6H); LC / MS: 515 (M+H).

[0374] Example 128 (Synthesis Method Q): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-methoxyethyl)-1,3-dimethyl-benzimidazol-2-one

[0375] 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-hydroxyethyl)-1,3-dimethyl-benzimidazol-2-one (Example 125, 22 mg, 0.044 mmol) was dissolved in tetrahydrofuran (0.5 mL). The product was cooled to 0 °C, and sodium hydride (60% dispersed in mineral oil, 2.64 mg, 0.066 mmol) was added. The solution was stirred for 10 min, and then iodomethane (0.027 mL, 0.440 mmol) was added, followed by stirring at room temperature for 18 h. Water was added to the reaction solution, and the organic layer was extracted with ethyl acetate and washed with brine. The organic layer was concentrated under reduced pressure and purified by PTLC to give the title compound (6 mg, 0.012 mmol, 26.5% yield).

[0376] 1 H-NMR (500 MHz, chloroform-d) δ 7.96 (d, J = 6.7 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.17 (s, 1H), 6.88 (s, 1H), 6.85 (d, J = 10.4 Hz,1H), 6.44 (s, 1H), 5.10-4.93 (m, 1H), 4.16 (s, 3H), 3.98 (s, 3H), 3.82-3.69(3H), 3.42 (s, 3H), 3.26 (s, 3H), 1.54 (d, J = 6.1 Hz, 3H); LC / MS: 515 (M+H).

[0377] Example 130 (Synthetic Method R): Preparation of 4-isopropyl-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one

[0378] Step 1: Preparation of 6-((4-bromo-2-nitro-5-(trifluoromethyl)phenyl)amino)-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0379] A solution of 6-amino-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (121 mg, 0.550 mmol), 1-bromo-4-iodo-5-nitro-2-(trifluoromethyl)benzene (198 mg, 0.500 mmol), tris(diphenylmethylacetone)dipalladium(O) (11.45 mg, 0.013 mmol), xanthos (28.9 mg, 0.050 mmol), and potassium tert-butoxide (67.3 mg, 0.600 mmol) dissolved in toluene (1.000 mL) was stirred at 80 °C for 18 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound. (192 mg, 0.394 mmol, 79% yield)

[0380] 1 H-NMR (500 MHz, chloroform-d) δ 9.51 (s, 1H), 8.52 (s, 1H), 7.48 (s, 1H), 6.92 (s, 1H), 6.71 (s, 1H), 3.71 (s, 3H), 3.69-3.64 (m, 1H), 3.41 (s, 3H), 1.32 (d, J = 6.7 Hz, 6H); LC / MS: 487, 489 (M+H).

[0381] Step 2: Preparation of 4-isopropyl-1,3-dimethyl-6-((4-(1-methyl-1H-pyrazol-4-yl)-2-nitro-5-(trifluoromethyl)phenyl)amino)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0382] The title compound was obtained using 6-((4-bromo-2-nitro-5-(trifluoromethyl)phenyl)amino)-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (146 mg, 0.300 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (94 mg, 0.450 mmol) obtained in step 1, in a manner similar to step 4 of synthetic method B. (125.3 mg, 0.257 mmol, 86% yield)

[0383] 1H-NMR (500 MHz, chloroform-d) δ 9.50 (s, 1H), 8.23 ​​(s, 1H), 7.57 (s, 1H), 7.54 (s, 1H), 7.47 (s, 1H), 6.96 (s, 1H), 6.75 (s, 1H), 3.97 (s, 3H), 3.72(s, 3H), 3.70-3.64 (m, 1H), 3.41 (s, 3H), 1.33 (d, J = 6.7 Hz, 6H); LC / MS: 489(M+H).

[0384] Step 3: Preparation of 4-isopropyl-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one

[0385] The mixture of 4-isopropyl-1,3-dimethyl-6-((4-(1-methyl-1H-pyrazol-4-yl)-2-nitro-5-(trifluoromethyl)phenyl)amino)-1,3-dihydro-2H-benzo[d]imidazol-2-one (19.3 mg, 0.040 mmol) and sodium dithionite (20.64 mg, 0.119 mmol) obtained in step 2, dissolved in ethanol (0.3 mL) and water (0.1 mL), was stirred at 90 °C. After confirming the depletion of the starting material by TLC (approximately 30 min), 1-methyl-1H-imidazol-5-carboxaldehyde (4.35 mg, 0.040 mmol) was added, and the mixture was stirred at 90 °C for 18 h. The reaction mixture was cooled to room temperature, quenched with 25% ammonia, diluted with water, and extracted with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound. (15.5 mg, 0.028 mmol, 71.5% yield)

[0386] 1H-NMR (500 MHz, chloroform-d) δ 7.81 (s, 1H), 7.63 (s, 1H), 7.54 (s, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.03 (s, 1H), 6.78 (s, 1H), 6.48 (s, 1H), 4.19(s, 3H), 3.99 (s, 3H), 3.79 (s, 3H), 3.76-3.71 (m, 1H), 3.40 (s, 3H), 1.33(d, J = 6.4 Hz, 6H); LC / MS: 549 (M+H).

[0387] Example 146 (Synthetic Method S): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1-piperidinyl)benzimidazol-2-one

[0388] 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-trimethylsilylethynyl)benzimidazol-2-one (the compound synthesized in step 2 of Example 122, 0.03 g, 0.056 mmol), piperidine (0.022 mL, 0.224 mmol), tris(diphenylmethylacetone)dipalladium(0) (4.58 mg, 0.006 mmol), xanthos (9.73 mg, 0.017 mmol), and cesium carbonate (0.055 g, 0.168 mmol) were stirred in toluene (3 mL) at 100 °C for 18 hours. The reaction product was diluted with ethyl acetate, washed with water, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound. (8.4 mg, 0.016 mmol, 27.8% yield)

[0389] 1H-NMR (500 MHz, chloroform-d) δ 7.96 (d, J = 5.80 Hz, 1H), 7.92 (s., 1H), 7.79 (s., 2H), 7.52 (s., 2H), 6.85 (s, 1H), 6.87 (s, 1H), 6.69 (s., 1H), 6.50(s., 1H), 4.17 (s., 4H), 3.99 (br. s., 3H), 3.83 (br. s., 3H), 3.38 (br. s.,3H), 1.76 (br. s., 4H), 1.26 (br. s., 6H); LC / MS: 540 (M+H).

[0390] Example 178 (Synthetic Method T): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-piperidinyl)benzimidazol-2-one

[0391] Add 4-[6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylic acid tert-butyl ester (Example 174, 190 mg, 0.297 mmol) to tetrahydrofuran (3 mL) and methanol (1 mL), and add hydrochloric acid (4 M, in 1,4-di... In an alkane (0.742 mL, 2.97 mmol), the reaction solution was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC to give the title compound (150 mg, 0.278 mmol, 94% yield).

[0392] 1H-NMR (500 MHz, chloroform-d) δ 7.95 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 7.00 (s, 1H), 6.83 (d, J = 13.7 Hz, 2H), 6.41 (s,1H), 4.16 (s, 3H), 3.99 (s, 3H), 3.76 (s, 3H), 3.40 (s, 4H), 3.24 (d, J =11.9 Hz, 2H), 2.79 (d, J = 12.2 Hz, 2H), 1.90 (d, J = 16.5 Hz, 2H), 1.70 (br,2H); LC / MS: 540 (M+H).

[0393] Example 188 (Synthesis Method U): Preparation of 4-(1-acetyl-4-piperidinyl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one

[0394] 4-[6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylic acid tert-butyl ester (Example 174, 30 mg, 0.056 mmol) was dissolved in dichloromethane (1 mL), and acetyl chloride (4.35 μL, 0.061 mmol) and pyridine (5.40 μL, 0.067 mmol) were added at 0 °C. The reaction solution was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the organic layer was extracted with dichloromethane and then concentrated under reduced pressure. The title compound was obtained by separation by MPLC and PTLC. (17 mg, 0.029 mmol, 52.6% yield)

[0395] 1H-NMR (400 MHz, chloroform-d) δ 7.95 (d, J = 6.9 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J = 2.7 Hz, 1H), 7.51 (s, 1H), 6.93-6.90 (m, 1H), 6.86 (dd, J = 6.4,1.8 Hz, 1H), 6.81 (d, J = 10.5 Hz, 1H), 6.36 (d, J = 3.7 Hz, 1H), 4.82 (d, J= 13.3 Hz, 1H), 4.17 (s, 3H), 3.98 (s, 4H), 3.78 (s, 3H), 3.50 (d, J = 11.9Hz, 1H), 3.41 (s, 3H), 3.24-3.18 (m, 1H), 2.67-2.62 (m, 1H), 2.09 (s, 3H),1.96 (t, J = 14.2 Hz, 2H), 1.67 (d, J = 12.8 Hz, 2H); LC / MS: 582 (M+H).

[0396] Example 189 (Synthesis Method V): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1-methyl-4-piperidinyl)benzimidazol-2-one

[0397] 4-[6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylic acid tert-butyl ester (Example 174, 50 mg, 0.093 mmol) was added to acetonitrile (1 mL), and formaldehyde (37 wt% aqueous solution, 15.90 mg, 0.185 mmol), sodium triacetoxyborohydride (29.5 mg, 0.139 mmol), and acetic acid (5.56 mg, 0.093 mmol) were added. The reaction solution was stirred at room temperature for 5 hours. 1 N sodium hydroxide was added to adjust the pH to approximately 9–11, and the organic layer was extracted with dichloromethane. The collected organic layer was concentrated under reduced pressure and separated and purified by PTLC to give the title compound. (18 mg, 0.033 mmol, 35.1% yield)

[0398] 1H-NMR (400 MHz, chloroform-d) δ 7.95 (d, J = 6.9 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.51 (s, 1H), 6.99 (d, J = 2.1 Hz, 1H), 6.86-6.83(m, 2H), 6.40 (s, 1H), 4.15 (s, 3H), 3.98 (s, 3H), 3.75 (s, 3H), 3.41 (s,3H), 3.28-3.24 (m, 1H), 3.10-3.04 (m,2H), 2.36 (s, 3H), 2.18 (s, 2H), 1.90 (s, 4H); LC / MS: 554 (M+H).

[0399] Example 191: 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,2,4-] Preparation of [diazol-3-yl]benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one

[0400] Step 1: Preparation of 5-bromo-2-(tert-butyl)-6-fluoro-7'-(isopropylamino)-1',3'-dimethyl-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazolium]-2'-one

[0401] The title compound was obtained using 6-amino-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-14, 474 mg, 2.023 mmol) and 1-bromo-2,4-difluoronitrobenzene (481 mg, 2.023 mmol) as starting materials, in a manner similar to steps 1 and 2 of synthetic method I. (33.5% yield after two steps)

[0402] 1 H-NMR (500 MHz, chloroform-d) δ 7.93 (d, J = 5.8 Hz, 1H), 6.61 (d, J = 8.2Hz, 1H), 6.42 (s, 1H), 6.40-6.34 (m, 1H), 3.80 (s, 3H), 3.59-3.50 (m, 1H), 3.37 (s, 3H), 1.39 (s, 9H), 1.28-1.16 (m, 6H); LC / MS: 488, 490 (M+H).

[0403] Step 2: Preparation of 2-(tert-butyl)-6-fluoro-7'-(isopropylamino)-1',3'-dimethyl-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazolium]-5-carboxynitrile

[0404] The 5-bromo-2-(tert-butyl)-6-fluoro-7'-(isopropylamino)-1',3'-dimethyl-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazole]-2'-one (50 mg, 0.102 mmol) obtained in step 1 was dissolved in anhydrous dimethylformamide (1 mL), followed by the addition of zinc dicyanocyanate (36.1 mg, 0.307 mmol) and tetrakis(triphenylphosphine)palladium (11.83 mg, 10.24 μmol). The reaction solution was stirred at 100 °C for 18 hours under a nitrogen balloon. 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 to give the title compound (44 mg, 0.101 mmol, 99% yield).

[0405] 1 H-NMR (500 MHz, chloroform-d) δ 7.92 (d, 1H), 6.60 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.93 (s, 1H), 3.78 (s, 3H), 3.53 (s, 1H), 3.34 (s, 3H), 1.38(s, 9H), 1.23 (t, 6H); LC / MS: 435 (M+H).

[0406] Step 3: 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,2,4-] Preparation of [diazol-3-yl]benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one

[0407] The 2-(tert-butyl)-6-fluoro-7'-(isopropylamino)-1',3'-dimethyl-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazole]-5-carboxynitrile (44 mg, 0.101 mmol) and potassium carbonate (28.0 mg, 0.203 mmol) obtained in step 2 were dissolved in ethanol (1 mL), and then an aqueous solution of hydroxylamine (0.012 mL, 0.203 mmol) was added. The reaction solution was stirred at 80 °C for 18 hours. After confirming the disappearance of the starting material, the solvent was removed by concentration under reduced pressure, and the product was dissolved in pyridine (1.0 mL), and acetic anhydride (10.73 μL, 0.111 mmol) was added. The reaction solution was stirred at 80 °C for 3 hours. 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. (8.5 mg, 0.017 mmol, 17.08% yield)

[0408] 1 H-NMR (500 MHz, chloroform-d) δ 8.45-8.42 (m, 1H), 6.69-6.66 (m, 1H), 6.46(s, 1H), 6.39 (s, 1H), 3.80 (s, 3H), 3.57-3.52 (m, 1H), 3.38 (s, 3H), 2.67 (s, 3H), 1.42 (s, 9H), 1.25 (d, J = 5.8 Hz, 6H); LC / MS: 492 (M+H).

[0409] Example 192 (Synthesis Method W): 6-[2-tert-butyl-6-fluoro-5-(3-methyl-1,2,4-] Preparation of [diazol-5-yl]benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one

[0410] Using 6-amino-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-14, 42.8 mg, 0.182 mmol) and 5-(2,4-difluoro-5-nitrophenyl)-3-methyl-1,2,4- The title compound was obtained using diazole (intermediate I-57, 40 mg, 0.166 mmol) as the starting material, in a manner similar to steps 1 and 2 of synthetic method I. (23.5% yield after two steps)

[0411] 1 H-NMR (500 MHz, chloroform-d) δ 8.45 (s, 1H), 6.68 (d, J = 16.5 Hz, 1H), 6.45 (s, 1H), 6.38 (s, 1H), 3.80 (s, 3H), 3.55-3.53 (m, 1H), 3.37 (s, 3H), 2.49 (s, 3H), 1.41 (s, 9H), 1.24 (s, 6H); LC / MS: 492 (M+H).

[0412] Example 219 (Synthetic Method X): Preparation of 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-methoxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0413] 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one (Example 218, 25 mg, 0.044 mmol) was added to tetrahydrofuran (0.5 mL), followed by the addition of sodium hydride (2.61 mg, 0.065 mmol) at 0 °C. After stirring for 30 min, iodomethane (0.027 mL, 0.436 mmol) was added, and the mixture was stirred at room temperature for 18 h. Water was added to the reaction solution, and the organic layer was extracted with ethyl acetate and washed with brine. The organic layer was concentrated under reduced pressure and separated by PTLC to give the title compound (7 mg, 0.012 mmol, 27.3% yield).

[0414] 1 H-NMR (500 MHz, chloroform-d) δ 7.81 (s, 1H), 7.66 (s, 1H), 7.54 (s, 2H), 7.48 (s, 1H), 6.88-6.58 (m, 3H), 6.56 (s, 1H), 4.19 (s, 3H), 4.01 (s, 3H), 3.86-3.80 (2H), 3.78 (s, 3H), 3.69 (d, J = 7.0 Hz, 2H), 3.37 (s, 3H), 3.24(s, 3H), 1.60 (s, 3H); LC / MS: 588(M+H).

[0415] Example 243 (Synthesis Method Y): Preparation of 6-[2-tert-butyl-5-(2-methylthiazolyl-5-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0416] Step 1: Preparation of 6-((4-bromo-2-nitro-5-(trifluoromethyl)phenyl)amino)-4-(3-hydroxy-3-methylazacyclobutane-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0417] The title compound was obtained using 6-amino-4-(3-hydroxy-3-methylazacyclobutan-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-29, 13.12 g, 50 mmol) and 1-bromo-4-iodo-5-nitro-2-(trifluoromethyl)benzene (21.77 g, 55.0 mmol) as starting materials in a manner similar to step 1 of synthetic method R. (15.64 g, 29.5 mmol, 59.0% yield)

[0418] 1 H-NMR (500 MHz, chloroform-d) δ 9.46 (s, 1H), 8.51 (s, 1H), 7.45 (s, 1H), 6.54 (s, 1H), 6.48 (s, 1H), 3.78 (dd, J = 12.4, 7.5 Hz, 4H), 3.71 (s, 3H), 3.37 (s, 3H), 2.01 (s, 1H), 1.67 (s, 3H); LC / MS: 530, 532 (M+H).

[0419] Step 2: Preparation of 5-bromo-2-(tert-butyl)-7'-(3-hydroxy-3-methylazacyclobutane-1-yl)-1',3'-dimethyl-6-(trifluoromethyl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazolium]-2'-one

[0420] Using 6-((4-bromo-2-nitro-5-(trifluoromethyl)phenyl)amino)-4-(3-hydroxy-3-methylazacyclobutan-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (135 mg, 0.255 mmol) and neopentanal (55.3 μL, 0.509 mmol) obtained in step 1 as starting materials, the title compound (28 mg, 0.049 mmol, 19.4% yield) was obtained in a manner similar to step 3 of synthetic method R.

[0421] 1 H-NMR (500 MHz, chloroform-d) δ 8.11 (s, 1H), 7.15 (s, 1H), 6.62 (s, 1H), 6.54 (s, 1H), 3.83-3.77 (m, 4H), 3.77(s, 3H), 3.40 (s, 3H), 1.68 (s, 3H), 1.38 (s, 9H); LC / MS: 566, 568 (M+H).

[0422] Step 3: Preparation of 6-[2-tert-butyl-5-(2-methylthiazolyl-5-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0423] The title compound was obtained using 5-bromo-2-(tert-butyl)-7'-(3-hydroxy-3-methylazacyclobutane-1-yl)-1',3'-dimethyl-6-(trifluoromethyl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazole]-2'-one (15 mg, 0.026 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)thiazole (8.94 mg, 0.040 mmol) as starting materials in a manner similar to step 4 of synthetic method B. (4.6 mg, 7.87 μmol, 29.7% yield)

[0424] 1H-NMR (500 MHz, chloroform-d) δ 7.84 (s, 1H), 7.55 (s, 1H), 7.21 (s, 1H), 6.64 (s, 1H), 6.57 (s, 1H), 3.83-3.78 (m, 4H), 3.78 (s, 3H), 3.40 (s, 3H), 2.75 (s, 3H), 2.11 (s, 1H), 1.68 (s, 3H), 1.39 (s, 9H); LC / MS: 585 (M+H).

[0425] Example 244: Preparation of 6-[5-(1-cyclopropylpyrazol-4-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0426] 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1H-pyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one (Example 230, 6.8 mg, 0.013 mmol), cyclopropylboronic acid (4.43 mg, 0.052 mmol), pyridine (10.4 μL, 0.129 mmol), and triethylamine (9.0 μL, 0.064 mmol) were dissolved in tetrahydrofuran (0.8 mL), and copper(II) acetate (7.02 mg, 0.039 mmol) was added. The reaction solution was stirred at 100 °C for 1 hour under a nitrogen balloon. After the reaction was complete, the reaction solution was diluted with ethyl acetate, then passed through a diatomaceous earth filter, and the filtrate was concentrated. The residue was purified by PTLC to give the title compound. (1.5 mg, 2.64 μmol, 20.50% yield)

[0427] 1H-NMR (500 MHz, chloroform-d) δ 7.95 (d, J = 6.7 Hz, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 6.85 (m, 2H), 6.76 (s, 1H), 6.45 (s, 1H), 4.17(s, 3H), 3.88 (s, 4H), 3.82 (s, 3H), 3.65-3.68 (m, 1H), 3.39 (s, 3H), 2.97(s, 4H), 2.36-2.33 (m, 2H), 2.30-2.28 (m, 2H); LC / MS: 568 (M+H).

[0428] Example 261: Preparation of 6-[2-tert-butyl-6-(methoxymethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0429] 6-[2-tert-butyl-6-(hydroxymethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one (Example 260, 15 mg, 0.028 mmol) was added to tetrahydrofuran (0.3 mL) and cooled to 0 °C. Sodium hydride (60% dispersed in mineral oil, 1.699 mg, 0.042 mmol) was then added. After stirring for 30 minutes, iodomethane (0.018 mL, 0.283 mmol) was added to the reaction solution. 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 ethyl acetate and washed with brine. The organic layer was concentrated under reduced pressure and purified by MPLC and PTLC to give the title compound (11.5 mg, 0.021 mmol, 74.7% yield).

[0430] 1H-NMR (400 MHz, chloroform-d) δ 7.80 (s, 1H), 7.65 (d, J = 0.9 Hz, 1H), 7.55 (s, 1H), 6.90 (t, J = 1.6 Hz, 2H), 6.80 (d, J = 2.3 Hz, 1H), 4.37 (s,2H), 3.98 (s, 3H), 3.90 (s, 4H), 3.83 (s, 3H), 3.41 (s, 3H), 3.34 (s, 3H), 3.00-2.96 (m, 4H), 1.38 (s, 9H); LC / MS: 544 (M+H).

[0431] Example 262: Preparation of 6-[2-tert-butyl-6-(fluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0432] 6-[2-tert-butyl-6-(hydroxymethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one (Example 260, 15 mg, 0.028 mmol) was added to dichloromethane (0.5 mL), followed by dropwise addition of diethylaminosulfur trifluoride (0.011 mL, 0.085 mmol) at 0 °C. The reaction solution was stirred at 0 °C for 2 hours. Water and a saturated sodium bicarbonate solution were added to the reaction solution, and the organic layer was extracted with dichloromethane and washed with brine. The organic layer was concentrated under reduced pressure and separated by MPLC to give the title compound (7.5 mg, 0.014 mmol, 49.8% yield).

[0433] 1 H-NMR (400 MHz, chloroform-d) δ 7.86 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 6.94 (d, J = 2.7 Hz, 1H), 6.91 (d, J = 1.8 Hz, 1H), 6.80 (d, J = 1.8 Hz, 1H), 5.39 (s, 1H), 5.27 (s, 1H), 3.99 (s, 3H), 3.90 (s, 4H), 3.84 (s, 3H), 3.42 (s, 3H), 2.99 (s, 4H), 1.39 (s, 9H); LC / MS: 532(M+H).

[0434] Example 272: Preparation of methyl 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazol-5-carboxylate

[0435] The title compound was obtained using 6-amino-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-10, 133 mg, 0.507 mmol) and methyl 2,4-difluoro-5-nitrobenzene (100 mg, 0.461 mmol) as starting materials, in a manner similar to steps 1 and 2 of synthetic method I. (68.9% yield after two steps)

[0436] 1 H-NMR (500 MHz, chloroform-d) δ 8.36 (d, J = 5.5 Hz, 1H), 6.85 (s, 1H), 6.76 (s, 1H), 6.50 (d, J = 12.8 Hz, 1H), 3.91 (s, 4H), 3.87 (s, 3H), 3.79 (s, 3H), 3.40 (s, 3H), 2.96 (s, 4H), 1.35 (s, 9H); LC / MS: 496 (M+H).

[0437] Example 273: Preparation of 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazol-5-carboxylic acid

[0438] Methyl 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazol-5-carboxylate (Example 272, 160 mg, 0.323 mmol) was dissolved in methanol (2 mL) and water (1 mL), and then lithium hydroxide hydrate (135 mg, 3.23 mmol) was added. The reaction solution was stirred at 50 °C for 1 hour. After the reaction was complete, the reaction was terminated with 1 N hydrochloric acid aqueous solution, and the pH of the reaction solution was adjusted to 5-6. 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 PTLC to give the title compound.

[0439] 1H-NMR (500 MHz, chloroform-d) δ 8.51 (d, J = 6.1 Hz, 1H), 6.88 (s, 1H), 6.79 (s, 1H), 6.54 (d, J = 10.4 Hz, 1H), 3.90 (s, 4H), 3.83 (s, 3H), 3.42 (s, 3H), 2.99 (s, 4H), 1.38 (s, 9H); LC / MS: 482 (M+H).

[0440] Example 274 (Synthesis Method Z): Preparation of 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-N-methyl-benzimidazol-5-carboxamide

[0441] 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazol-5-carboxylic acid (Example 273, 35 mg, 0.073 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (20.90 mg, 0.109 mmol), and hydroxybenzotriazole (16.70 mg, 0.109 mmol) were dissolved in dichloromethane (0.8 mL), and then methylamine (2 M, in tetrahydrofuran, 0.109 mL, 0.218 mmol) was 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 MPLC and PTLC to give the title compound. (35.6 mg, 0.072 mmol, 99% yield)

[0442] 1 H-NMR (500 MHz, chloroform-d) δ 8.55 (d, J = 6.7 Hz, 1H), 6.87 (s, 1H), 6.77 (s, 1H), 6.73 (d, J = 11.6 Hz, 1H), 6.50 (d, J = 12.2 Hz, 1H), 3.90 (s,4H), 3.82 (s, 3H), 3.41 (s, 3H), 3.04 (d, J = 4.3 Hz, 3H), 2.99 (s, 4H), 1.37(s, 9H); LC / MS: 495 (M+H).

[0443] Example 288: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-hydroxy-1,3-dimethylbenzimidazol-2-one

[0444] Palladium / carbon (10 wt%, 41.2 mg, 0.039 mmol) was added to a solution of 4-benzyloxy-6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 286, 221 mg, 0.387 mmol) dissolved in ethyl acetate (0.968 mL) and methanol (0.968 mL). The reaction mixture was subjected to three hydrogen / vacuum exchanges to fully fill the interior of the reaction vessel with hydrogen, and stirred at room temperature for 4 hours in the presence of a hydrogen balloon. The reaction mixture was passed through diatomaceous earth and filtered, eluting with dichloromethane. The filtrate was concentrated under reduced pressure, and the resulting residue was used in subsequent reactions without further purification. (156 mg, 0.325 mmol, 84% yield)

[0445] 1 H-NMR (500 MHz, chloroform-d) δ 7.62 (s, 1H), 7.47 (s, 1H), 7.34 (s, 1H), 7.17 (s, 1H), 6.67-6.45 (m, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.41 (s, 3H), 1.31 (s, 9H); LC / MS: 481 (M+H).

[0446] Example 290 (Synthetic Method AA): Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(3-methylpyrazol-1-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0447] Step 1: Preparation of 5-bromo-2-(tert-butyl)-6-(difluoromethyl)-7'-(3-hydroxy-3-methylazacyclobutane-1-yl)-1',3'-dimethyl-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazolium]-2'-one

[0448] The title compound was obtained using 6-amino-4-(3-hydroxy-3-methylazacyclobutan-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-29, 180 mg, 0.686 mmol) and 1-bromo-2-(difluoromethyl)-4-fluoro-5-nitrobenzene (intermediate I-50, 185 mg, 0.686 mmol) as starting materials, in a manner similar to steps 1 and 2 of synthetic method I. (24.4% yield after two steps)

[0449] 1 H-NMR (400 MHz, chloroform-d) δ 8.01 (s, 1H), 7.13 (s, 1H), 6.97 (t, J =55.3 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), 6.58 (d, J = 1.8 Hz, 1H), 3.82 (dd, J= 11.2, 7.1 Hz, 4H), 3.76 (s, 3H), 3.38 (s, 3H), 1.69 (s, 3H), 1.37 (s, 9H); LC / MS: 548, 550 (M+H).

[0450] Step 2: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(3-methylpyrazol-1-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0451] The 5-bromo-2-(tert-butyl)-6-(difluoromethyl)-7'-(3-hydroxy-3-methylazacyclobutane-1-yl)-1',3'-dimethyl-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazole]-2'-one (32 mg, 0.058 mmol) obtained in step 1 was dissolved in toluene (0.8 mL). (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.84 μL, 0.012 mmol), 3-methyl-1H-pyrazole (9.58 mg, 0.117 mmol), potassium carbonate (16.13 mg, 0.117 mmol), and cuprous iodide (I) (0.556 mg, 2.92 μmol) were added. The mixture was stirred in a microwave at 150 °C for 8 h. 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. (1.5 mg, 2.73 μmol, 4.68% yield)

[0452] 1 H-NMR (500 MHz, chloroform-d) δ 7.75 (s, 1H), 7.57 (s, 1H), 7.21 (s, 1H), 6.92 (t, J = 55.5 Hz, 1H), 6.66 (s, 1H), 6.58 (s, 1H), 6.25 (s, 1H), 3.83-3.80 (m, 4H), 3.78 (s, 3H), 3.41 (s, 3H), 2.37 (s, 3H), 2.04 (s, 3H), 1.68(s, 3H), 1.39 (s, 9H); LC / MS: 550 (M+H).

[0453] Example 292: 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,3,4-] Preparation of [diazol-2-yl]benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0454] Step 1: Preparation of N'-acetyl-2-(tert-butyl)-6-fluoro-1',3'-dimethyl-7'-morpholino-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazolium]-5-formylhydrazine

[0455] 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazol-5-carboxylic acid (Example 273, 42.3 mg, 0.088 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (25.3 mg, 0.132 mmol), and hydroxybenzotriazole (20.18 mg, 0.132 mmol) were dissolved in dimethylformamide (1 mL), and acetylhydrazine (19.52 mg, 0.264 mmol) was 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, concentrated under reduced pressure, and the residue was purified by MPLC to give the title compound (44 mg, 0.082 mmol, 9% yield).

[0456] 1 H-NMR (500 MHz, chloroform-d) δ 9.47 (q, J = 6.4 Hz, 1H), 9.33 (s, 1H), 8.52 (d, J = 6.7 Hz, 1H), 6.86 (s, 1H), 6.77 (s, 1H), 6.56 (d, J = 11.6 Hz,1H), 3.90 (s, 4H), 3.82 (s, 3H), 3.42 (s, 3H), 2.99 (s, 4H), 2.14 (s, 3H), 1.37 (s, 9H); LC / MS: 538 (M+H).

[0457] Step 2: 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,3,4-] Preparation of [diazol-2-yl]benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0458] The N'-acetyl-2-(tert-butyl)-6-fluoro-1',3'-dimethyl-7'-morpholino-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazole]-5-carboxylhydrazide (41 mg, 0.076 mmol) obtained in step 1 was dissolved in tetrahydrofuran (0.8 mL), and then Burgess reagent (72.6 mg, 0.306 mmol) was added. The reaction solution was stirred at 100 °C for 2 hours. 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 to give the title compound (30 mg, 0.058 mmol, 76% yield).

[0459] 1 H-NMR (500 MHz, chloroform-d) δ 8.32 (d, J = 5.8 Hz, 1H), 6.88 (s, 1H), 6.79 (s, 1H), 6.62 (d, J = 10.1 Hz, 1H), 3.88 (s, 4H), 3.81 (s, 3H), 3.41 (s, 3H), 2.98 (s, 4H), 2.61 (s, 3H), 1.36 (s, 9H); LC / MS: 520 (M+H).

[0460] Example 299: Preparation of (5E)-2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxaldehyde oxime

[0461] 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxaldehyde (Example 285, 12 mg, 0.023 mmol) was added to methanol (0.5 mL), along with hydroxylamine hydrochloride (1.738 mg, 0.025 mmol) and potassium carbonate (3.46 mg, 0.025 mmol). The mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the organic layer was extracted with ethyl acetate. The collected organic layer was concentrated under reduced pressure and purified by MPLC to give the title compound (11.1 mg, 0.020 mmol, 90% yield).

[0462] 1H-NMR (500 MHz, chloroform-d) δ 8.34 (s, 1H), 7.77 (s, 1H), 7.57-7.53(1H), 7.39 (s, 1H), 7.32-7.28 (1H), 6.91-6.84 (1H), 6.78 (s, 1H), 4.00-3.96(3H), 3.89 (s, 4H), 3.82 (s, 3H), 3.40 (s, 3H), 2.98 (s, 4H), 1.38 (s, 9H); LC / MS: 543 (M+H).

[0463] Example 300: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(6-chloropyrimidin-4-yl)oxy-1,3-dimethyl-benzimidazol-2-one

[0464] The reaction solution containing 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-hydroxy-1,3-dimethyl-benzimidazol-2-one (Example 288, 15 mg, 0.031 mmol), 4,6-dichloropyrimidine (5.12 mg, 0.034 mmol), and potassium carbonate (12.94 mg, 0.094 mmol) dissolved in dimethylformamide (0.312 mL) was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (8.9 mg, 0.015 mmol, 48.1% yield).

[0465] 1 H-NMR (500 MHz, chloroform-d) δ 8.57 (s, 1H), 7.77 (s, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 7.26 (s, 1H), 7.12 (s, 1H), 6.94 (s, 1H), 6.90 (s, 1H), 6.68(t, J = 55.5 Hz, 1H), 3.99 (s, 3H), 3.52 (s, 3H), 3.47 (s, 3H), 1.43 (s, 9H); LC / MS: 593 (M+H).

[0466] Example 301 (Synthesis Method AB): Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-methoxyphenoxy)-1,3-dimethyl-benzimidazol-2-one

[0467] A 4 Å molecular sieve was added to a solution of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-hydroxy-1,3-dimethyl-benzimidazol-2-one (Example 288, 15 mg, 0.031 mmol), (4-methoxyphenyl)boronic acid (14.2 mg, 0.094 mmol), and copper(II) acetate (5.67 mg, 0.031 mmol) dissolved in dichloromethane (1.56 mL), and the mixture was stirred at room temperature for 10 min. Triethylamine (26.1 μL, 0.187 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 18 h after allowing air to pass through the reaction vessel. The reaction mixture was diluted with dichloromethane and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to give the title compound. (15.2 mg, 0.026 mmol, 83% yield)

[0468] 1 H-NMR (400 MHz, chloroform-d) δ 7.73 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 7.17 (s, 1H), 7.00 (d, J = 9.1 Hz, 2H), 6.86 (d, J = 9.1 Hz, 2H), 6.80-6.52(m, 2H), 6.51 (d, J = 1.8 Hz, 1H), 3.98 (s, 3H), 3.76 (s, 3H), 3.74 (s, 3H), 3.45 (s, 3H), 1.35 (s, 9H); LC / MS: 587 (M+H).

[0469] Example 307: Preparation of 6-[2-tert-butyl-6-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0470] 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,3,4- [diazol-2-yl]benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one (Example 292, 17 mg, 0.033 mmol) was dissolved in acetic acid (0.6 mL), followed by the addition of ammonium acetate (50.4 mg, 0.654 mmol). The reaction solution was stirred at 150 °C for 12 hours using a microwave. 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 PTLC to give the title compound. (8 mg, 0.015 mmol, 47.1% yield)

[0471] 1 H-NMR (500 MHz, chloroform-d) δ 8.64 (s, 1H), 6.89 (s, 1H), 6.80 (s, 1H), 6.60 (d, J = 11.3 Hz, 1H), 3.91 (s, 4H), 3.83 (s, 3H), 3.42 (s, 3H), 3.00 (s,4H), 2.52 (s, 3H), 1.39 (s, 9H); LC / MS: 519 (M+H).

[0472] Example 311: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1,1-dioxo-1,4-thiazinyl-4-yl)-1,3-dimethyl-benzimidazol-2-one

[0473] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-thiomorpholino-benzimidazol-2-one (Example 298, 8.6 mg, 0.015 mmol) and 3-chlorobenzoic acid (15.33 mg, 0.068 mmol) were stirred in chloroform (1 mL) at 10–15 °C for 3 hours. The reaction was terminated with saturated aqueous sodium bicarbonate solution. The reaction product was diluted with ethyl acetate, washed with water, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (6 mg, 0.010 mmol, 66.0% yield).

[0474] 1H-NMR (500 MHz, chloroform-d) δ 7.80 (s, 1H), 7.62 (s, 1H), 7.50 (s, 1H), 7.14 (s, 1H), 6.99 (d, J = 1.68 Hz, 1H), 6.88 (d, J = 1.53 Hz, 1H), 6.68 (t,1H), 4.01 (s, 3H), 3.84 (s, 3H), 3.55 (br. s., 4H), 3.50-3.36 (m, 5H), 3.16 (br. s., 2H); LC / MS: 598 (M+H).

[0475] Example 315: Preparation of 6-[2-tert-butyl-6-fluoro-5-(1-methyltriazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0476] Step 1: Preparation of 6-((4-ethynyl-5-fluoro-2-nitrophenyl)amino)-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0477] Using 6-amino-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-10, 362 mg, 1.379 mmol) and ((2,4-difluoro-5-nitrophenyl)ethynyl)trimethylsilane (intermediate I-56, 320 mg, 1.253 mmol) as starting materials, a mixture of the two title compounds was obtained in the same manner as step 1 of synthetic method I. (202 mg, 0.475 mmol, 37.9% yield)

[0478] Example 315-1A: 1 H-NMR (500 MHz, chloroform-d) δ 9.65 (s, 1H), 8.43 (d, J =7.0 Hz, 1H), 6.77 (s, 1H), 6.69 (s, 1H), 6.65 (d, J = 11.0 Hz, 1H), 3.90 (s,4H), 3.76 (s, 3H), 3.40 (s, 3H), 3.22 (s, 1H), 2.98 (s, 4H); LC / MS: 426 (M+H).

[0479] Example 315-1B: 1H-NMR (500 MHz, chloroform-d) δ 9.63 (s, 1H), 8.40 (d, J =7.0 Hz, 1H), 6.79 (s, 1H), 6.70 (s, 1H), 6.63 (d, 1H), 3.90 (s, 4H), 3.76 (s,3H), 3.40 (s, 3H), 2.98 (s, 4H), 0.25 (s, 9H).

[0480] Step 2: Preparation of 2-(tert-butyl)-5-ethynyl-6-fluoro-1',3'-dimethyl-7'-morpholinyl-1',3'-dihydro-2'H-[1,5'-benzo[d]imidazolium]-2'-one and 2-(tert-butyl)-6-fluoro-1',3'-dimethyl-7'-morpholinyl-5-((trimethylsilyl)ethynyl)-1',3'-dihydro-2'H-[1,5'-benzo[d]imidazolium]-2'-one

[0481] Using a mixture of 6-((4-ethynyl-5-fluoro-2-nitrophenyl)amino)-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one and 6-((5-fluoro-2-nitro-4-((trimethylsilyl)ethynyl)phenyl)amino)-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one (202 mg, 0.475 mmol) and neopentaldehyde (155 μL, 1.424 mmol) as starting materials, a mixture of the two title compounds was obtained in the same manner as in step 2 of synthetic method I. (83 mg, 0.180 mmol, 37% yield)

[0482] Example 315-2A: 1 H-NMR (500 MHz, chloroform-d) δ 7.87 (d, J = 5.8 Hz, 1H), 6.86 (s, 1H), 6.76 (s, 1H), 6.49 (d, J = 8.9 Hz, 1H), 3.89 (s, 4H), 3.81 (s,3H), 3.41 (s, 3H), 3.25 (s, 1H), 2.98 (s, 4H), 1.36 (s, 9H); LC / MS: 462 (M+H).

[0483] Example 315-2B: 1H-NMR (500 MHz, chloroform-d) δ 7.80 (d, J = 5.8 Hz, 1H), 6.85 (s, 1H), 6.75 (s, 1H), 6.44 (d, J = 8.9 Hz, 1H), 3.89 (s, 4H), 3.80 (s,3H), 3.40 (s, 3H), 2.97 (s, 4H), 1.34 (s, 9H), 0.25 (s, 9H); LC / MS: 534 (M+H).

[0484] Step 3: Preparation of 2-(tert-butyl)-5-ethynyl-6-fluoro-1',3'-dimethyl-7'-morpholino-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazolium]-2'-one

[0485] The mixture of 2-(tert-butyl)-5-ethynyl-6-fluoro-1',3'-dimethyl-7'-morpholinyl-1',3'-dihydro-2'H-[1,5'-benzo[d]imidazolium]-2'-one and 2-(tert-butyl)-6-fluoro-1',3'-dimethyl-7'-morpholinyl-5-((trimethylsilyl)ethynyl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazolium]-2'-one (83 mg, 0.156 mmol) obtained in step 2 was dissolved in tetrahydrofuran (0.8 mL), and then tetra-n-butylammonium fluoride (1 M, in tetrahydrofuran, 0.311 mL, 0.311 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed by concentration under reduced pressure and diluted with ethyl acetate. Water was added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound. (61 mg, 0.132 mmol, 85% yield)

[0486] 1 H-NMR (500 MHz, chloroform-d) δ 7.85 (d, J = 5.2 Hz, 1H), 6.85 (s, 1H), 6.76 (s, 1H), 6.48 (d, J = 8.9 Hz, 1H), 3.88 (s, 4H), 3.80 (s, 3H), 3.39 (s, 3H), 3.24 (s, 1H), 2.97 (s, 4H), 1.34 (s, 9H); LC / MS: 462 (M+H).

[0487] Step 4: Preparation of 2-(tert-butyl)-6-fluoro-1',3'-dimethyl-7'-morpholino-5-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazolium]-2'-one

[0488] The 2-(tert-butyl)-5-ethynyl-6-fluoro-1',3'-dimethyl-7'-morpholino-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazole]-2'-one (32 mg, 0.069 mmol) obtained in step 3 was dissolved in dimethylformamide (0.8 mL), and cuprous iodide (I) (2.64 mg, 0.014 mmol) and diisopropylethylamine (0.012 mL, 0.069 mmol) were added. After 5 minutes, (azidomethyl)trimethylsilane (0.051 mL, 0.347 mmol) was added, and the reaction solution was stirred at room temperature for 8 hours. 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, concentrated under reduced pressure, and the residue was purified by MPLC to give the title compound. (29 mg, 0.049 mmol, 70.8% yield)

[0489] 1 H-NMR (500 MHz, chloroform-d) δ 8.62 (d, J = 6.1 Hz, 1H), 7.72 (s, 1H), 6.89 (s, 1H), 6.79 (s, 1H), 6.53 (d, J = 10.1 Hz, 1H), 3.93 (s, 2H), 3.89 (s, 4H), 3.81 (s, 3H), 3.41 (s, 3H), 2.99 (s, 4H), 1.37 (s, 9H), 0.17 (s, 9H); LC / MS: 591 (M+H).

[0490] Step 5: Preparation of 6-[2-tert-butyl-6-fluoro-5-(1-methyltriazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0491] The title compound was obtained using 2-(tert-butyl)-6-fluoro-1',3'-dimethyl-7'-morpholino-5-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazole]-2'-one (29 mg, 0.049 mmol) obtained in step 4 as the starting material, in a manner similar to step 3 above. (23 mg, 0.044 mmol, 90% yield)

[0492] 1 H-NMR (500 MHz, chloroform-d) δ 8.62 (s, 1H), 7.83 (s, 1H), 6.89 (s, 1H), 6.79 (s, 1H), 6.54 (d, J = 10.1 Hz, 1H), 4.13 (s, 3H), 3.89 (s, 4H), 3.81 (s,3H), 3.41 (s, 3H), 2.98 (s, 4H), 1.36 (s, 9H); LC / MS: 519 (M+H).

[0493] Example 317 (Synthetic Method AC): Preparation of 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0494] N-[2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl]carbamate (Example 316, 160 mg, 0.260 mmol) was dissolved in dichloromethane (2 mL), and hydrochloric acid (4 M, in 1,4-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl) was added. In alkane, 0.651 mL (2.60 mmol). The reaction solution was stirred at room temperature for 1 hour. The pH of the reaction solution was adjusted to 10 by adding 1 N sodium hydroxide, and the reaction solution was extracted with dichloromethane. The organic layer was concentrated under reduced pressure and used in subsequent reactions without further purification. (120 mg, 0.233 mmol, 90% yield)

[0495] 1H-NMR (400 MHz, chloroform-d) δ 7.67 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 6.91 (d, J = 1.8 Hz, 1H), 6.80 (d, J = 1.8 Hz, 1H), 6.15 (s, 1H), 3.97 (s, 3H), 3.91 (s, 4H), 3.82 (s, 3H), 3.65 (s, 2H), 3.41 (s, 3H), 2.99 (s, 4H), 1.36 (s, 9H); LC / MS: 515 (M+H).

[0496] Example 318 (Synthetic Method AD): Preparation of 6-[2-tert-butyl-6-(methylaminomethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0497] 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxaldehyde (Example 285, 20 mg, 0.038 mmol) was added to dichloroethane (0.5 mL), along with methylamine (2 M, in tetrahydrofuran, 0.038 mL, 0.076 mmol), acetic acid (2.170 μL, 0.038 mmol), and sodium triacetoxyborohydride (10.44 mg, 0.049 mmol). The reaction solution was stirred at room temperature for 4 hours. After the reaction was complete, water and 1 N sodium hydroxide were added to adjust the pH to 9–11, and the organic layer was extracted with dichloromethane. The collected organic layer was concentrated under reduced pressure and separated by PTLC to give the title compound (7 mg, 0.013 mmol, 34.0% yield).

[0498] 1H-NMR (400 MHz, chloroform-d) δ 7.75 (s, 1H), 7.63 (s, 1H), 7.56 (s, 1H), 6.90 (d, J = 1.8 Hz, 1H), 6.85 (s, 1H), 6.80 (d, J = 1.4 Hz, 1H), 3.98 (s,3H), 3.91 (s, 4H), 3.83 (s, 3H), 3.80-3.73 (m, 2H), 3.42 (s, 3H), 2.99 (s,4H), 2.36 (s, 3H), 2.23 (s, 1H), 1.37 (s, 9H); LC / MS: 543 (M+H).

[0499] Example 321: Preparation of N-[2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl]acetamide

[0500] 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one (Example 317, 30 mg, 0.058 mmol) was added to dichloromethane (1 mL), along with acetyl chloride (4.16 μL, 0.058 mmol) and diisopropylethylamine (0.020 mL, 0.117 mmol). The mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the organic layer was extracted with dichloromethane and then concentrated under reduced pressure. The title compound was purified by MPLC (22.3 mg, 0.040 mmol, 68.7% yield).

[0501] 1 H-NMR (400 MHz, chloroform-d) δ 7.70 (s, 1H), 7.66 (s, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 6.90 (d, J = 1.8 Hz, 1H), 6.80 (d, J = 1.8 Hz, 1H), 4.01 (s, 3H), 3.89 (s, 4H), 3.82 (s, 3H), 3.40 (s, 3H), 2.99 (d, J = 4.6Hz, 4H), 2.05 (s, 3H), 1.37 (s, 9H); LC / MS: 557 (M+H).

[0502] Example 325 (Synthetic Method AE): Preparation of 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxecyclobutane-3-ylmethoxy)benzimidazol-2-one

[0503] Step 1: Preparation of 7'-(benzylmethyloxy)-2-(tert-butyl)-6-fluoro-1',3'-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazolium]-2'-one

[0504] The title compound was obtained using 6-amino-4-(benzylmethyloxy)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4.53 g, 16 mmol), 1-bromo-2,4-difluoro-5-nitrobenzene (3.81 g, 16.00 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (2.70 g, 13.00 mmol), and neopentanal (2.12 mL, 19.50 mmol) as starting materials, in a manner similar to synthetic method M. (2.71 g, 5.03 mmol, 52% yield after three steps)

[0505] 1 H-NMR (400 MHz, chloroform-d) δ 7.91 (d, J = 6.4 Hz, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.38-7.34 (m, 5H), 6.65 (s, 2H), 6.50 (d, J = 10.5 Hz, 1H), 5.19 (d, J = 12.3 Hz, 1H), 5.11 (d, J = 11.9 Hz, 1H), 3.96 (s, 3H), 3.75 (s,3H), 3.41 (s, 3H), 1.31 (s, 9H); LC / MS: 539 (M+H).

[0506] Step 2: Preparation of 2-(tert-butyl)-6-fluoro-7'-hydroxy-1',3'-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazolium]-2'-one

[0507] The title compound was obtained using 7'-(benzylmethyloxy)-2-(tert-butyl)-6-fluoro-1',3'-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazole]-2'-one (2.478 g, 4.6 mmol) obtained in step 1 as the starting material, in a manner similar to the synthesis in Example 288. (2.04 g, 4.55 mmol, 99% yield)

[0508] 1 H-NMR (400 MHz, chloroform-d) δ 7.75 (s, 1H), 7.74 (d, J = 6.4 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 6.52 (d, J = 1.4 Hz, 1H), 6.46 (d, J = 10.1 Hz,1H), 6.13 (s, 1H), 3.94 (s, 3H), 3.84 (s, 3H), 3.40 (s, 3H), 1.26 (s, 9H); LC / MS: 449 (M+H).

[0509] Step 3: Preparation of 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxetane-3-ylmethoxy)benzimidazol-2-one

[0510] 3-(bromomethyl)oxetane (9.06 mg, 0.060 mmol) was added to a solution of 2-(tert-butyl)-6-fluoro-7'-hydroxy-1',3'-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazole]-2'-one (27.0 mg, 0.060 mmol) and cesium carbonate (23.5 mg, 0.072 mmol) dissolved in dimethylformamide (0.300 mL), and the mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (26.7 mg, 0.051 mmol, 86% yield).

[0511] 1H-NMR (500 MHz, chloroform-d) δ 7.92 (d, J = 6.7 Hz, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 6.70 (s, 1H), 6.65 (s, 1H), 6.56 (d, J = 10.4 Hz, 1H), 4.94-4.91 (m, 2H), 4.64 (t, J = 6.1 Hz, 2H), 4.26-4.20 (m, 2H), 3.96 (s, 3H), 3.74(s, 3H), 3.52-3.46 (m, 1H), 3.42 (s, 3H), 1.39-1.42 (9H); LC / MS: 519 (M+H).

[0512] Example 326 (Synthetic Method AF): Preparation of 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(1-methyl-4-piperidinyl)oxy]benzimidazol-2-one

[0513] To a solution of 2-(tert-butyl)-6-fluoro-7'-hydroxy-1',3'-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazole]-2'-one (compound of step 2 of synthetic method AE, 22.0 mg, 0.050 mmol) dissolved in anhydrous tetrahydrofuran (0.500 mL), 1-methylpiperidin-4-ol (6.91 mg, 0.060 mmol) and triphenylphosphine (19.7 mg, 0.075 mmol) were added. The reaction mixture was cooled to 0 °C, diisopropyl azodicarbonate (14.6 μL, 0.075 mmol) was added, and the product was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound. (15.9 mg, 0.029 mmol, 58.3% yield)

[0514] 1H-NMR (500 MHz, chloroform-d) δ 7.92 (d, J = 6.7 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J = 2.1 Hz, 1H), 6.64 (d, J = 1.5 Hz, 1H), 6.61 (d, J = 1.5 Hz, 1H),6.56 (d, J = 10.4 Hz, 1H), 4.37 (s, 1H), 3.96 (s, 3H), 3.75 (s, 3H), 3.41 (s,3H), 2.68 (s, 2H), 2.34-2.29 (m, 5H), 2.05 (t, J = 6.9 Hz, 3H), 1.95-1.87 (m,3H), 1.41-1.39 (9H); LC / MS: 546 (M+H).

[0515] Examples 331 and 332: Synthesis of 6-[2-tert-butyl-6-(methylamino)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one and 6-[2-tert-butyl-6-(dimethylamino)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0516] 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one (Example 317, 30 mg, 0.058 mmol) was added to 1,2-dichloroethane (0.5 mL), along with formaldehyde (37 wt% aqueous solution, 4.34 μL, 0.058 mmol), acetic acid (3.34 μL, 0.058 mmol), and sodium triacetoxyborohydride (16.06 mg, 0.076 mmol). The mixture was stirred at room temperature for 3 hours. When the reaction was complete, water and 1 N sodium hydroxide were added to adjust the pH to 9–11, and the organic layer was extracted with dichloromethane. The collected organic layers were concentrated under reduced pressure and separated by PTLC to obtain two title compounds: Example 331 (7 mg, 0.013 mmol, 22.71% yield) and Example 332 (5 mg, 0.009 mmol, 15.9% yield).

[0517] Example 331: 1H-NMR (400 MHz, chloroform-d) δ 7.63 (s, 1H), 7.56 (s, 1H), 7.48(s, 1H), 6.92 (d, J = 1.4 Hz, 1H), 6.82 (d, J = 1.4 Hz, 1H), 5.92 (s, 1H), 3.98 (s, 3H), 3.90 (s, 4H), 3.84 (s, 3H), 3.42 (s, 3H), 2.99 (s, 4H), 2.66 (s, 3H), 1.35 (s, 9H); LC / MS: 529 (M+H).

[0518] Example 332: 1 H-NMR (400 MHz, chloroform-d) δ 7.90 (s, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 6.46 (s, 1H), 3.96 (s, 3H), 3.92 (s, 4H), 3.84 (s, 3H), 3.43 (s, 3H), 3.00 (s, 4H), 2.53 (s, 6H), 1.35 (s, 9H); LC / MS: 543 (M+H).

[0519] Example 333: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(3-chloro-2-hydroxy-2-methyl-propyl)amino]-1,3-dimethyl-benzimidazol-2-one

[0520] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one (Example 183, 100 mg, 0.18 mmol) was added to dichloromethane (2 mL), and hydrochloric acid (4 M, in 1,4-di ... The solution was mixed in 0.045 mL (0.18 mmol) with an alkane and stirred for 1 hour. The reaction solution was concentrated under reduced pressure and separated by MPLC to give the title compound.

[0521] 1H-NMR (500 MHz, chloroform-d) δ 7.78 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.22 (s, 1H), 6.67 (t, J = 55.7 Hz, 1H), 6.53 (s, 1H), 6.42 (s, 1H), 4.70 (s,1H), 3.99 (s, 3H), 3.84 (s, 3H), 3.76-3.56 (m, 2H), 3.40 (s, 3H), 3.23 (d, J= 5.8 Hz, 1H), 3.13 (t, J = 5.6 Hz, 1H), 2.70 (s, 1H), 1.42 (s, 9H); LC / MS: 586 (M+H).

[0522] Example 338 (Synthetic Method AG): Preparation of 6-[2-tert-butyl-6-hydroxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0523] Palladium / carbon (10 wt%, 7.6 mg, 7.10 μmol) was added to a solution of 6-[6-benzoxy-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one (Example 337, 43 mg, 0.071 mmol) dissolved in methanol (0.355 mL). The reaction mixture was subjected to three hydrogen / vacuum exchanges to fully fill the reaction vessel with hydrogen, and stirred at room temperature for 4 hours in the presence of a hydrogen balloon. The reaction mixture was passed through diatomaceous earth and filtered, eluting with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was purified by PTLC to give the title compound (31 mg, 0.060 mmol, 85% yield).

[0524] 1H-NMR (500 MHz, chloroform-d) δ 7.74 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 6.64 (d, J = 1.8 Hz, 1H), 6.59 (d, J = 1.8 Hz, 1H), 6.36 (s, 1H), 3.98 (s, 3H), 3.81-3.73 (m, 7H), 3.37 (s, 3H), 1.67 (s, 3H), 1.36 (s, 9H); LC / MS: 516 (M+H).

[0525] Example 339: Preparation of [2-tert-butyl-3-[7-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl]acetate

[0526] Pyridine (5.02 μL, 0.062 mmol) was added to a solution of 6-[2-tert-butyl-6-hydroxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one (Example 338, 16 mg, 0.031 mmol) dissolved in dichloromethane (0.155 mL). The reaction mixture was cooled to 0 °C, acetyl chloride (3.31 μL, 0.047 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture to terminate the reaction, and the product was extracted with ethyl acetate. The resulting organic layer was washed with brine, dehydrated on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (7.7 mg, 0.014 mmol, 44.5% yield).

[0527] 1 H-NMR (500 MHz, chloroform-d) δ 7.84 (s, 1H), 7.70 (s, 1H), 7.53 (s, 1H), 6.68 (d, J = 1.8 Hz, 1H), 6.61 (d, J = 1.8 Hz, 1H), 6.58 (s, 1H), 3.95 (s,3H), 3.82-3.73 (m, 7H), 3.39 (s, 3H), 2.20 (s, 3H), 2.06 (s, 1H), 1.68 (s,3H), 1.38 (s, 9H); LC / MS: 558 (M+H).

[0528] Example 342: 6-[2-tert-butyl-6-fluoro-5-(2-methyl)] Preparation of [[5-yl]benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one]

[0529] 2-(tert-butyl)-5-ethynyl-6-fluoro-1',3'-dimethyl-7'-morpholino-1',3'-dihydro-2'H-[1,5'-biphenyl[d]imidazolium]-2'-one (the compound from step 3 synthesized in Example 315, 33 mg, 0.071 mmol) was dissolved in acetonitrile (0.8 mL), and then triphenylphosphine gold(I) bis(trifluoromethanesulfonyl)imide (14.80 mg, 0.093 mmol) was added. The reaction solution was stirred at 60 °C for 18 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by PTLC to give the title compound (18.2 mg, 0.035 mmol, 49.1% yield).

[0530] 1 H-NMR (500 MHz, chloroform-d) δ 8.11 (d, J = 6.4 Hz, 1H), 7.27 (s, 1H), 6.88 (d, J = 1.8 Hz, 1H), 6.78 (d, J = 1.8 Hz, 1H), 6.56 (d, J = 10.4 Hz,1H), 3.90 (s, 4H), 3.82 (s, 3H), 3.42 (s, 3H), 3.00-2.98 (m, 4H), 2.55 (s,3H), 1.38 (s, 9H); LC / MS: 519 (M+H).

[0531] Examples 345 and 346: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-vinylpyrazole-4-yl)benzimidazol-1-yl]-4-[3-(dimethylamino)-3-methyl-azacyclobutane-1-yl]-1,3-dimethyl-benzimidazol-2-one and 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-[2-(dimethylamino)ethyl]pyrazole-4-yl]benzimidazol-1-yl]-4-[3-(dimethylamino)-3-methyl-azacyclobutane-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0532] Step 1: Preparation of 1-(2-(tert-butyl)-6-(difluoromethyl)-1',3'-dimethyl-5-(1-(2-((methanesulfonyl)oxy)ethyl)-1H-pyrazol-4-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazolium]-7'-yl)-3-methylazacyclobutane-3-ylmethanesulfonate

[0533] After dissolving 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-hydroxyethyl)pyrazol-4-yl]benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one (Example 313, 42.4 mg, 0.073 mmol) in dichloromethane (0.8 mL), methanesulfonyl chloride (0.0165 mL, 0.219 mmol) and triethylamine (0.051 mL, 0.366 mmol) were added at 0 °C. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, water and dichloromethane were added, 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. (54.2 mg, 0.074 mmol, 100% yield)

[0534] 1 H-NMR (400 MHz, chloroform-d) δ 7.75 (s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.19 (s, 1H), 6.79-6.51 (m, 3H), 4.63 (t, J = 4.8 Hz, 2H), 4.50 (t, J = 4.8Hz, 2H), 4.16-4.11 (m, 2H), 3.93-3.87 (m, 2H), 3.75 (s, 3H), 3.39 (s, 3H), 3.04 (s, 3H), 2.87 (s, 3H), 1.99 (s, 3H), 1.37 (s, 9H); LC / MS: 735 (M+H).

[0535] Step 2: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-vinylpyrazole-4-yl)benzimidazol-1-yl]-4-[3-(dimethylamino)-3-methyl-azacyclobutane-1-yl]-1,3-dimethyl-benzimidazol-2-one and 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-[2-(dimethylamino)ethyl]pyrazole-4-yl]benzimidazol-1-yl]-4-[3-(dimethylamino)-3-methyl-azacyclobutane-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0536] After dissolving 1-(2-(tert-butyl)-6-(difluoromethyl)-1',3'-dimethyl-5-(1-(2-((methanesulfonyl)oxy)ethyl)-1H-pyrazol-4-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazolium]-7'-yl)-3-methylazacyclobutane-3-yl methanesulfonate (27 mg, 0.037 mmol) in acetonitrile (0.8 mL), dimethylamine (0.022 mL, 0.044 mmol) and cesium carbonate (17.93 mg, 0.055 mmol) were added. The reaction solution was stirred at 80 °C for 18 hours. 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 obtain the title compound.

[0537] Example 345: 1 H-NMR (500 MHz, chloroform-d) δ 7.81 (s, 1H), 7.75 (s, 1H), 7.72(s, 1H), 7.22 (s, 1H), 7.10 (dd, J = 15.9, 8.9 Hz, 1H), 6.78-6.56 (m, 2.15 (s, 6H), 1.43 (s, 3H), 1.39(s, 9H); LC / MS: 589 (M+H).

[0538] Example 346: 1H-NMR (500 MHz, chloroform-d) δ 7.79 (s, 1H), 7.63 (s, 1H), 7.61(s, 1H), 7.20 (s, 1H), 6.79-6.57 (m, 3H), 4.30 (t, J = 6.7 Hz, 2H), 3.77 (s,3H), 3.75-3.70 (m, 2H), 3.62-3.57 (m, 2H), 3.39 (s, 3H), 2.85 (t, J = 6.6 Hz,2H), 2.32 (s, 6H), 2.15 (s, 6H), 1.43 (s, 3H), 1.39 (s, 9H); LC / MS: 634 (M+H).

[0539] Example 347: Preparation of [1-[6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-morpholinylethyl)pyrazol-4-yl]benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3-methyl-azacyclobutane-3-yl]methanesulfonate

[0540] 1-(2-(tert-butyl)-6-(difluoromethyl)-1',3'-dimethyl-5-(1-(2-((methanesulfonyl)oxy)ethyl)-1H-pyrazol-4-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-biphenyl[d]imidazolium]-7'-yl)-3-methylazacyclobutane-3-yl methanesulfonate (the compound from step 1 of Examples 345 and 346, 27 mg, 0.037 mmol) was dissolved in morpholine (0.5 mL, 5.80 mmol) and stirred at room temperature for 18 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, water and ethyl acetate were 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 MPLC and PTLC to give the title compound. (16.5 mg, 0.023 mmol, 61.9% yield)

[0541] 1H-NMR (500 MHz, chloroform-d) δ 7.79 (s, 1H), 7.64 (s, 1H), 7.61 (s, 1H), 7.20 (s, 1H), 6.79-6.57 (m, 3H), 4.32 (s, 2H), 4.18-4.13 (m, 2H), 3.91 (dd, J= 22.4, 8.4 Hz, 2H), 3.76 (s, 3H), 3.71 (s, 4H), 3.40 (s, 3H), 3.05 (s, 3H),2.88 (s, 2H), 2.52 (s, 4H), 2.01 (s, 3H), 1.39 (s, 9H); LC / MS: 727 (M+H).

[0542] Example 348: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-morpholinylethyl)pyrazol-4-yl]benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0543] [1-[6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-morpholinylethyl)pyrazol-4-yl]benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3-methyl-azacyclobutane-3-yl]methanesulfonate (Example 347, 7.4 mg, 10.18 μmol) was dissolved in dimethyl sulfoxide (0.3 mL), and 1 M triethylammonium acetate aqueous solution (0.015 mL, 0.015 mmol) was added. The mixture was then stirred at 60 °C for 18 hours. 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 PTLC to give the title compound (3.5 mg, 5.39 μmol, 53.0% yield).

[0544] 1H-NMR (500 MHz, chloroform-d) δ 7.79 (s, 1H), 7.63 (s, 1H), 7.62 (s, 1H), 7.21 (s, 1H), 6.79-6.57 (m, 3H), 4.31 (t, J = 6.3 Hz, 2H), 3.83-3.76 (m, 7H), 3.70 (t, J = 4.4 Hz, 4H), 3.40 (s, 3H), 2.86 (t, J = 6.3 Hz, 2H), 2.51 (s, 4H), 1.68 (s, 3H), 1.39 (s, 9H); LC / MS: 649 (M+H).

[0545] Example 357: Preparation of 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(2,3-dihydroxy-2-methyl-propyl)amino]-1,3-dimethyl-benzimidazol-2-one

[0546] N-[2-tert-butyl-3-[7-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl]carbamate (Example 343, 36 mg, 0.059 mmol) and trifluoroacetic acid (0.031 mL, 0.468 mmol) were stirred in dichloromethane (0.3 mL) for 1 hour. After diluting the reaction solution with dichloromethane (3 mL), a saturated aqueous solution of sodium bicarbonate was added dropwise at 0 °C. The reaction solution was extracted with dichloromethane, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (1 mg, 0.002 mmol, 3.3% yield).

[0547] 1H-NMR (500 MHz, chloroform-d) δ 7.67 (s, 1H), 7.59 (br. s., 1H), 7.54 (s,1H), 6.50 (s, 1H), 6.40 (s, 1H), 6.17 (d, J = 2.59 Hz, 1H), 5.03 (br. s.,1H), 4.03-3.92 (m, 4H), 3.86-3.79 (m, 3H), 3.77-3.72 (m, 2H), 3.70-3.62 (m,2H), 3.44-3.34 (m, 4H), 3.21-3.14 (m, 1H), 3.12-3.05 (m, 1H), 1.46-1.35 (m,9H), 1.30 (d, J = 1.83 Hz, 3H); LC / MS: 533 (M+H).

[0548] Example 359 (Synthetic Method AH): Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidinyl)benzimidazol-2-one

[0549] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1,3-dimethyl-benzimidazol-2-one (Example 361, 220 mg, 0.363 mmol) was dissolved in tetrahydrofuran (1.8 mL), and then 1 M hydrochloric acid (2.54 mL, 2.54 mmol) was added. The reaction was carried out at room temperature for 18 hours. The reaction solution was neutralized with aqueous sodium hydroxide solution, diluted with ethyl acetate, washed with water, dehydrated on anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to give the title compound (141 mg, 0.251 mmol, 69.1% yield).

[0550] 1H-NMR (500 MHz, chloroform-d) δ 7.80 (s, 1H), 7.61 (s, 1H), 7.49 (s, 1H), 7.18 (s, 1H), 6.92 (d, J = 1.68 Hz, 1H), 6.84 (d, J = 1.68 Hz, 1H), 6.68 (t,1H), 4.00 (s, 3H), 3.96-3.88 (m, 3H), 3.54 (br. s., 1H), 3.50 (br. s., 1H), 3.48-3.40 (m, 3H), 3.14 (br. s., 2H), 2.84 (br. s., 2H), 2.53 (br. s., 2H), 1.48-1.32 (m, 9H); LC / MS: 562 (M+H).

[0551] Example 362 (Synthetic Method AI): Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one

[0552] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidinyl)benzimidazol-2-one (Example 359, 22 mg, 0.039 mmol) was stirred in ethanol (0.2 mL) and sodium borohydride (2.67 mg, 0.071 mmol) was added at 0 °C, followed by stirring for 2 hours. The reaction was terminated with a saturated aqueous solution of ammonium chloride, and the reaction solution was diluted with ethyl acetate, washed with water, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (9.7 mg, 0.017 mmol, 43.9% yield).

[0553] 1H-NMR (500 MHz, chloroform-d) δ 7.79 (s, 1H), 7.61 (s, 1H), 7.49 (s, 1H), 7.19 (s, 1H), 6.77 (d, J = 1.68 Hz, 1H), 6.68 (t, 1H), 4.00 (s, 3H), 3.84 (s,3H), 3.75 (br. s., 1H), 3.42 (s, 3H), 3.19 (br. s., 2H), 2.75 (br. s., 2H), 2.12-2.06 (m, 2H), 1.87-1.76 (m, 3H), 1.72-1.64 (m, 1H); LC / MS: 564 (M+H).

[0554] Example 366: 4-[[[6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]amino]methyl]-4-methyl- Preparation of 2-oxazolidinone

[0555] N-[1-[6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3-methyl-azacyclobutane-3-yl]carbamate (Example 364, 28 mg, 0.043 mmol) was dissolved in dichloromethane (0.3 mL), and trifluoroacetic acid (33 μL, 0.432 mmol) was added. The reaction solution was stirred at room temperature for 4 hours. After the reaction was complete, 1 N sodium hydroxide aqueous solution and ethyl acetate were 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 MPLC and PTLC to give the title compound (16.3 mg, 0.028 mmol, 63.7% yield).

[0556] 1H-NMR (500 MHz, chloroform-d) δ 7.78 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.68-6.56 (m, 2H), 6.41 (s, 1H), 5.35 (d, J = 11.9Hz, 1H), 4.52-4.45 (m, 1H), 4.33-4.32 (m, 1H), 4.17 (d, J = 8.9 Hz, 1H), 3.99(s, 3H), 3.81 (s, 3H), 3.40 (s, 3H), 3.19-3.08 (m, 2H), 1.47 (s, 3H), 1.41 (s, 9H); LC / MS: 593 (M+H).

[0557] Example 375 (Synthetic Method AJ): Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one

[0558] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidinyl)benzimidazol-2-one (Example 359, 30 mg, 0.053 mmol) was stirred in tetrahydrofuran (0.4 mL) at 0 °C, and methyl magnesium bromide (3 M, in diethyl ether, 0.036 mL, 0.107 mmol) was added dropwise at the same temperature, followed by stirring at room temperature for 1 hour. The reaction was quenched with water, the organic layer was extracted with dichloromethane, dehydrated on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (11.7 mg, 0.020 mmol, 37.9% yield).

[0559] 1H-NMR (500 MHz, chloroform-d) δ 7.79 (s, 1H), 7.62 (s, 1H), 7.49 (s, 1H), 7.20 (s, 1H), 6.93 (br. s., 1H), 6.76 (d, J = 1.68 Hz, 1H), 6.68 (t, 1H),4.00 (s, 3H), 3.83 (s, 3H), 3.42 (s, 3H), 3.03 (br. s., 4H), 1.89 (br. s.,2H), 1.72 (br. s., 2H), 1.40 (s, 9H), 1.35 (s, 3H); LC / MS: 578 (M+H).

[0560] Example 384: Preparation of 6-[5-(3,6-dihydro-2H-pyran-4-yl)-6-fluoro-2-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one]

[0561] Step 1: Preparation of 6-((2-amino-4-(3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)amino)-1,3-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0562] The title compound was obtained using 6-amino-1,3-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-4, 340 mg, 1.301 mmol) and 1-bromo-2,4-difluoro-5-nitrobenzene (310 mg, 1.301 mmol) in a manner similar to steps 1 and 2 of synthetic method C. (46.0% yield after two steps)

[0563] 1H-NMR (500 MHz, chloroform-d) δ 6.76 (d, J = 12.5 Hz, 1H), 6.69 (d, J =7.6 Hz, 1H), 6.59 (d, J = 1.8 Hz, 1H), 6.45 (d, J = 1.8 Hz, 1H), 5.99 (s,1H), 5.37 (s, 1H), 4.31 (q, J = 2.7 Hz, 2H), 4.18 (q, J = 2.8 Hz, 1H), 3.90(t, J = 5.3 Hz, 2H), 3.74 (t, J = 5.3 Hz, 1H), 3.65 (s, 3H), 3.57-3.53 (m,3H), 3.34 (s, 3H), 2.49-2.49 (m, 2H), 2.23-2.20 (m, 1H), 1.92-1.84 (m, 2H), 1.78-1.75 (m, 2H); LC / MS: 453 (M+H).

[0564] Step 2: Preparation of 6-[5-(3,6-dihydro-2H-pyran-4-yl)-6-fluoro-2-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one

[0565] The 6-((2-amino-4-(3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)amino)-1,3-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (87 mg, 0.192 mmol) obtained in step 1 was dissolved in trifluoroacetic acid (1 mL). The reaction solution was stirred at 100 °C for 3 hours. 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 (8 mg, 0.015 mmol, 7.84% yield).

[0566] 1H-NMR (500 MHz, chloroform-d) δ 7.80 (d, J = 6.7 Hz, 1H), 7.04 (d, J = 1.8Hz, 1H), 6.88 (d, J = 1.8 Hz, 1H), 6.83 (d, J = 10.4 Hz, 1H), 6.05 (s, 1H),4.36-4.34 (m, 2H), 4.13-4.11 (m, 2H), 3.97-3.95 (m, 2H), 3.77 (s, 3H), 3.60-3.52 (m, 3H), 3.44 (s, 3H), 2.55-2.55 (m, 2H), 1.93-1.82 (m, 4H); LC / MS: 531 (M+H).

[0567] Example 391: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(2,3-dihydroxy-2-methyl-propyl)amino]-1,3-dimethyl-benzimidazol-2-one

[0568] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one (Example 183, 25 mg, 0.045 mmol) was dissolved in 1,4-di... Add 0.7 mL of alkylene, then add hydrochloric acid (4 M, in 1,4-dialkylene oxide). In alkane, 0.017 mL (0.068 mmol). The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, 1 N sodium hydroxide (0.227 mL, 0.227 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction solution was dissolved in dimethylformamide (0.5 mL), and an additional 1 N sodium hydroxide (0.227 mL, 0.227 mmol) was added, followed by stirring at 100 °C for 7 hours. 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 PTLC to give the title compound (9 mg, 0.016 mmol, 34.9% yield).

[0569] 1H-NMR (500 MHz, chloroform-d) δ 7.77 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.22 (s, 1H), 6.67 (t, J = 55.7 Hz, 1H), 6.51 (s, 1H), 6.40 (s, 1H), 5.05-4.98 (m, 1H), 3.99 (s, 3H), 3.83 (s, 3H), 3.75-3.62 (m, 2H), 3.39 (s, 3H), 3.21-3.05 (m, 2H), 2.54 (d, J = 40.0 Hz, 1H), 2.10-2.07 (m, 1H), 1.41 (s,9H), 1.29 (d, J = 4.3 Hz, 3H); LC / MS: 568 (M+H).

[0570] Examples 2, 5, 11, 13-25, 27-46, 48, 50-53, 55-57, 61-96, 98, 100-106, 108-115, 117, 119-121, 124, 127, 129, 131-145, 147-177, 179-187, 190, 193-218, 220-242, 245-260, 263-271, 275-28 7, 289, 291, 293-298, 302-306, 308-310, 312-314, 316, 319, 320, 322-324, 327-330, 334-337, 340-341, 343-344, 349-356, 358, 360, 361, 363-365, 367-374, 376-383, 385-390 and 392-404

[0571] The synthesis was performed using the same synthesis method as in the representative embodiments described above.

[0572] Specifically, Example 2 was prepared in a similar manner according to A; Examples 5, 11, 13 to 15, 21, 23, 24, 27 to 46, 53, and 67 to 74 were prepared in a similar manner according to B; Examples 16, 18, and 20 were prepared in a similar manner according to C; Example 260 was prepared in a similar manner according to D; Example 285 was prepared in a similar manner according to E; Examples 17, 19, 22, 105, and 278 were prepared in a similar manner according to F; Example 25 was prepared in a similar manner according to G; Example 279 was prepared in a similar manner according to H; and Examples 48, 78 to 80, 83, 84, 86 to 89, 104, 124, 152, 161, 162, 179 to 182, 198, 205 to 208, 214, 215, and 216 were prepared in a similar manner according to B; Examples 16, 18, and 20 were prepared in a similar manner according to C; Example 260 was prepared in a similar manner according to D; Example 285 was prepared in a similar manner according to E; Examples 17, 19, 22, 105, and 278 were prepared in a similar manner according to F; Example 25 was prepared in a similar manner according to G; Example 279 was prepared in a similar manner according to H; Examples 48, 78 to 80, 83, 84, 86 to 89, 104, 124, 152, 161, 162, 179 to 182, 198, 205 to 208, 214, 215, and 216 were prepared in a similar manner according to B Examples 8, 230 to 234, 240, 241, 247 to 249, 251 to 254, 263 to 265, 280 to 282, 286, 294, 303 to 305, 312, 313, 316, 322 to 324, 337, 340, 361, 370, 376, 377, and 395 to 399 were prepared similarly according to I; Examples 50 to 52 were prepared similarly according to J; Examples 55 to 57, 64, 65, 76, 77, 103, 139, and 153 were prepared similarly according to K; Examples 63 and 154 were prepared similarly according to L; Examples 61, 62, 85, 92 to 95, 102, 106, 108 to 115, 127, and 134 to 1 Examples 38, 140 to 143, 150, 151, 156, 157, 163, 164, 169, 174, 175, 183, 194, 195, 197, 200, 201, 209 to 213, 216, 217, 238, 239, 250, 257 to 259, 266 to 271, 277, 283, 284, 287, 289, 295 to 298, 306, 308, 310, 327 to 330, 343, 350, 354 to 356, 358, 360, 363 to 365, and 400 to 404 were prepared similarly according to M, and Examples 66, 81, 82, 90, 91, 101, 155, and 173 were prepared similarly according to N. Examples 96, 98, 100, 120, 121, and 144 were prepared in a similar manner to O; Examples 117, 119, 148, 149, 160, 176, 177, 190, 204, 349, and 383 were prepared in a similar manner to P; Example 129 was prepared in a similar manner to Q; Examples 131 to 133, 158, 159, 167, 168, 202, 203, 224, 225, 227, 235 to 237, 255, and 256 were prepared in a similar manner to R; Examples 145, 147, 165, 166, 170, 171, 184, 185, 196, 199, 226, 228, 229, and 309 were prepared in a similar manner to S.Examples 75, 187, 352, and 367 were prepared in a similar manner according to T; Examples 353 and 368 were prepared in a similar manner according to U; Example 369 was prepared in a similar manner according to V; Example 193 was prepared in a similar manner according to W; Examples 172, 186, 220 to 223, 245, and 246 were prepared in a similar manner according to X; Example 242 was prepared in a similar manner according to Y; Examples 275 and 276 were prepared in a similar manner according to Z; Examples 291, 293, and 314 were prepared in a similar manner according to AA; Examples 301 and 302 were prepared in a similar manner according to AB; Example 31... Examples 7 and 344 were prepared in the same manner as AC; Examples 318 to 320 were prepared in the same manner as AD; Example 351 was prepared in the same manner as AE; Example 334 was prepared in the same manner as AF; Examples 338 and 341 were prepared in the same manner as AG; Examples 371, 385, and 386 were prepared in the same manner as AH; Examples 372, 378, 389, 390, and 392 to 394 were prepared in the same manner as AI; and Examples 335, 336, 373, 374, 379 to 382, ​​387, and 388 were prepared in the same manner as AJ.

[0573] The structures, names, NMR spectra, and synthetic methods of the compounds synthesized from each embodiment are listed in Table 2 below.

[0574] [Table 2]

[0575] (The difference between each of Examples 335 and 336 and Examples 373 and 374 is that the cyclohexyl group is either cis or trans.)

[0576] Experimental Example 1. CBP Inhibitory Activity

[0577] The activity of the CBP bromine domain was verified using time-resolved fluorescence resonance energy transfer (TR-FRET) experiments.

[0578] 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 (HEPES) (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 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 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. TR-FRET signals were measured using an EnVision multi-label plate reader (PerkinElmer; Mirror LNACE / DELFIA Dual / Bias). For data analysis, the TR-FRET ratio ((signal 665 nm / signal 615 nm) × 20000) was used to obtain the value for each well. Data analysis was performed using the TR-FRET ratio ((signal 665 nm / signal 615 nm) × 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)) × 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).

[0579] Experimental Example 2. BRD Inhibitory Activity

[0580] The BRD inhibitory activity was measured using time-resolved fluorescence resonance energy transfer (TR-FRET) experiments to verify the activity of the BRD4 bromine domain.

[0581] 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 containing 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES) (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 15 nM) was transferred to the high control and test wells. Ten concentration points for each compound were prepared by sequential 3-fold dilutions from the highest concentration in dimethyl sulfoxide (DMSO) solvent. Each compound was then diluted in assay buffer to prepare a solution of the compound at a concentration 4 times higher than the final concentration. 2 μL of each compound or dimethyl sulfoxide prepared in this manner was allocated to the assay plate to achieve a final test concentration ranging from a minimum of 0.5 μM to a maximum of 10 μM (final DMSO concentration 1%). 6 μL of 1X assay buffer was added to the low control wells, and 2 μL to the high control and test wells. Then, 2 μL of 4X BRD4 (BD1) protein (final concentration 7.5 nM, BPS bioscience, catalog number 31040) was added to initiate the PPI reaction. The plate was incubated at room temperature for 2 hours, and then the signal was measured. The TR-FRET signal was measured using an EnVision multi-label plate reader (PerkinElmer; Mirror LNACE / DELFIA Dual / Bias). For data analysis, the TR-FRET ratio ((signal 665 nm / signal 615 nm) × 20000) was used to obtain the value for each well. Data analysis was performed using the TR-FRET ratio ((signal 665 nm / signal 615 nm) × 20000). Data were reported as the percentage of inhibition compared to the control well according to the following equation: % activity = ((FRET compound – FRET low av) / (FRET high av – FRET low av)) × 100. IC50 analysis was performed using a standard 4-parameter curve fitting algorithm with GraphPad Prism 7.0 (GraphPad Software Inc., La Jolla, CA, USA). All data are expressed as mean ± standard error of mean (SEM).

[0582] The results from Experiments 1 and 2 are shown in Tables 3 and 4 below.

[0583] In Tables 3 and 4 below, activity values ​​of 0 to 500 nM are indicated as “+++”, 500 nM to 5 μM are indicated as “++”, and greater than 5 μM are indicated as “+”.

[0584] [Table 3]

[0585] [Table 4]

Claims

1. A compound represented by formula I: <Formula I> in X is C or N. 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. R is C independently. 1-7 Alkyl, C 3-7 cycloalkyl, C 1-5 Haloalkyl, C 6-10 Aryl, 5- to 9-membered heteroaryl, 3- to 14-membered heterocyclic alkyl, 4- to 9-membered heterocyclic alkenyl, halogen, cyano, carbonyl, formaldehyde oxime, NR a R b SO2NHR c CONR d R e CO2R f , NHCOR g OR h And R a To R f Each is independently selected from hydrogen and C. 1-5 Alkyl, C 3-7 cycloalkyl, C 1-4 Haloalkyl, C 6-10 Aryl, halogen, carbonyl, and Boc groups, Q represents hydrogen, and C represents... 1-7 Alkyl or C 3-7 cycloalkyl, A is hydrogen, C 1-8 Alkyl, C 2-8 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, C 6-10 Aryl, 3- to 16-membered heterocyclic alkyl, 3- to 16-membered heterocyclic alkenyl, 5- to 9-membered heteroaryl, halogen, carbonyl, NR i R j OR k And R i To R k Each is independently selected from hydrogen and C. 1-8 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl, and Boc groups, and Z is C 1-8 Alkyl, C 3-7 cycloalkyl, C 6-10 Aryl, 5- to 13-membered heteroaryl, or 3- to 8-membered heterocyclic alkyl, Among them, R, R a To R k Q, A, and Z are either substituted by or unsubstituted by the substituent group I: Substituent group I: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2-10 Alkyne, 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, substituted or unsubstituted carbonyl groups, 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. m -(R) m It is hydrogen or substituted or unsubstituted C 1-10 Alkyl groups, -N=, =N-, -POR m -and-PO4R m - 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 k Q, A, and Z are either substituted by or unsubstituted by the substituent group I-1: Substituent group I-1: substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-5 alkenyl, substituted or unsubstituted C 2-7 Alkyne, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-5 Halogenated alkyl, substituted or unsubstituted C 6-8 Aryl, substituted or unsubstituted carbonyl, substituted or unsubstituted 3- to 9-membered heterocyclic alkyl, halogen, cyano, Boc group, OR p1 NR p2 R p3 CONR p4 R p5 , NHCOR p6 or CO2R p7 , where R p1 To R p7 Each of these groups is independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted propenyl, substituted or unsubstituted methanesulfonate, carbonyl, and Boc groups.

3. The compound according to claim 1, wherein the compound of formula I is represented by any one of formula I-1 or I-2: <Formula I-1> <Formula I-2> in n, R, Q, A, and Z are the same as those defined in claim 1.

4. The compound according to claim 3, wherein the compound of formula I-1 is represented by any one of formula I-1-1 or I-1-2: <Formula I-1-1> <Formula I-1-2> in A 2 It is C 1-8 Alkyl, C 2-8 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, C 6-10 Aryl, 3- to 16-membered heterocyclic alkyl, 3- to 16-membered heterocyclic alkenyl, 5- to 9-membered heteroaryl, halogen, carbonyl, NR i R j OR k It is either substituted by or unsubstituted by the substituent group I, and R i To R k , n, R, Q and Z are the same as those defined in claim 1.

5. The compound according to claim 3, wherein the compound of formula I-2 is represented by any one of formula I-2-1 or I-2-2: <Formula I-2-1> <Formula I-2-2> in A 2 Same as defined in claim 4, and n, R, Q, and Z are the same as those defined in claim 1.

6. The compound according to claim 4, wherein the compound of formula I-1-1 is represented by any one of formula I-1-1-1 or I-1-1-2: <Formula I-1-1-1> <Formula I-1-1-2> in R 111 R 211 and R 311 Each is C independently 1-5 Alkyl, C 1-3 Haloalkyl, C 6-8 Aryl, 5- to 7-membered heteroaryl, halogen, cyano, carbonyl, CONR d R e or CO2R f It is either substituted by or unsubstituted by the substituent group I, and R d To R f Q and Z are the same as those defined in claim 1.

7. The compound according to claim 6, wherein... R 111 R 211 and R 311 Each of these groups independently represents a methyl, propyl, CF2H, phenyl, pyrazolyl, bromine, fluorine, cyano, aldehyde, or CONR group. d R e or CO2R f , where R d To R f Each is independently hydrogen or a substituted or unsubstituted methyl group, and R 111 and R 211 Each is independently substituted by or unsubstituted by the substituent group I-1-1: Substituent group I-1-1: substituted or unsubstituted C 1-3 Alkyl, halogen, OR p1 NR p2 R p3 CONR p4 R p5 or NHCOR p6 , where R p1 To R p6 Each is independently hydrogen, substituted or unsubstituted methyl, or substituted or unsubstituted propyl.

8. The compound according to claim 4, wherein the compound of formula I-1-2 is represented by any one of the following formulas I-1-2-1 to I-1-2-3: <Formula I-1-2-1> <Formula I-1-2-2> <Formula I-1-2-3> in A 2 Same as defined in claim 4, R 112 and R 212 Each is C independently 1-5 Alkyl, C 3-7 cycloalkyl, C 1-5 Haloalkyl, C 6-10 Aryl, 5- to 9-membered heteroaryl, 3- to 14-membered heterocyclic alkyl, 4- to 9-membered heterocyclic alkenyl, halogen, cyano, carbonyl, formaldehyde oxime, NR a R b SO2NHR c CONR d R e CO2R f , NHCOR g OR h , where R 112 and R 212 Each is either substituted by or unsubstituted by the base set I, and R a To R h Q and Z are the same as those defined in claim 1.

9. The compound according to claim 8, wherein... R 112 and R 212 Each of these components independently is methyl, cyclopropyl, CF3, CF2H, CFH2, phenyl, azole, pyrazol, thiazolyl, pyridinyl diazole, imidazole, triazole, lactam, hydroxyindole, quinolinone, dihydroquinolinone, benzo[] Phosphone group, dihydropyranyl group, fluorine, chlorine, bromine, cyano group, aldehyde, formaldehyde oxime, NR a R b SO2NHR c CONR d R e CO2R f , NHCOR g OR h , where R a To R h Each of these elements is independently hydrogen, substituted or unsubstituted methyl, CF2H, CF3, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted carbonyl, or a Boc group. R 112 and R 212 Each is independently substituted by or unsubstituted with the substituent group I-1-2: Substituent group I-1-2: substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 3-5 cycloalkyl, substituted or unsubstituted C 1-5 alkenyl, substituted or unsubstituted C 1-4 Halogenated alkyl groups, halogens, 4- to 8-membered heterocyclic alkyl groups, OR p1 NR p2 R p3 CONR p4 R p5 or NHCOR p6 , where R p1 To R p6 Each is independently hydrogen or a substituted or unsubstituted methyl group.

10. The compound according to claim 5, wherein the compound of formula I-2-1 is represented by any one of formula I-2-1-1 or I-2-1-2: <Formula I-2-1-1> <Formula I-2-1-2> in R 221 and R 312 Each is C independently 6-9 Aryl, 5- to 9-membered heteroaryl, halogen or CONR d R e , where R 221 and R 312 Each is either substituted by or unsubstituted by the base set I, and R d To R e Q and Z are the same as those defined in claim 1.

11. The compound according to claim 10, wherein... R 221 and R 312 Each is independently phenyl, pyrazolyl, bromine, or CONR d R e , where R d To R e Each is independently hydrogen or a substituted or unsubstituted methyl group, and R 221 and R 312 Each is independently substituted by or unsubstituted with the substituent group I-1-3: Substituent group I-1-3: substituted or unsubstituted C 1-3 Alkyl, halogen or CONR p4 R p5 , where R p4 To R p5 Each is independently hydrogen or a substituted or unsubstituted methyl group.

12. The compound according to claim 5, wherein the compound of formula I-2-2 is represented by any one of formula I-2-2-1 or I-2-2-2: <Formula I-2-2-1> <Formula I-2-2-2> in A 2 Same as defined in claim 3, R 222 and R 322 Each is an independent 5- to 9-membered heteroaryl group, of which R 222 and R 322 Each is either substituted by or unsubstituted by the base set I, and Q and Z are the same as those defined in claim 1.

13. The compound according to claim 12, wherein... R 222 and R 322 Each is independently either a pyrazolyl group or a thiazolyl group, wherein R 222 and R 322 Each is independently substituted by or unsubstituted with the substituent group I-1-4: Substituent group I-1-4: substituted or unsubstituted C 1-3 Alkyl or substituted or unsubstituted C 1-3 Halogenated alkyl groups.

14. The compound of claim 1, wherein Q is hydrogen, a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, or a substituted or unsubstituted propyl group.

15. The compound of claim 1, wherein Z is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted propyl, a substituted or unsubstituted butyl, a substituted or unsubstituted cyclopropyl, a substituted or unsubstituted cyclobutyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted imidazolyl, a substituted or unsubstituted indolyl, a substituted or unsubstituted thiophene, a substituted or unsubstituted pyridinyl, a substituted or unsubstituted pyrimidinyl, a substituted or unsubstituted thiazolyl, or a substituted or unsubstituted oxacyclobutane.

16. The compound according to claim 1, wherein it is selected from any one of the following groups: 3-(7-chloro-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-sulfonamide; 3-(1,3-dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-N-methyl-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-sulfonamide; 6-Bromo-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-carboxylic acid methyl ester; 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-5-carboxylic acid methyl ester; 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylic acid methyl ester; 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 5-[6-(hydroxymethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxaldehyde; 5-[6-(difluoromethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylic acid; 1,3-Dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-tetrahydropyran-4-yl-benzimidazol-2-one; 5-[6-(1-hydroxy-1-methyl-ethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 5-[6-bromo-2-(6-methyl-1H-indol-3-yl)imidazo[4,5-c]pyridin-3-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-5-[2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)imidazo[4,5-c]pyridin-3-yl]benzimidazol-2-one; 6-Bromo-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-carboxynitrile; 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-methyl-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylic acid; 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-methyl-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylic acid methyl ester; 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylic acid; 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylic acid methyl ester; 4-[6-cyano-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 3-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-5-carboxylic acid; 4-[1-(1,3-dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 5-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-hydroxy-1-methyl-ethyl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 3-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-N-methyl-2-(3-methylimidazol-4-yl)benzimidazol-5-carboxamide; 4-[3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)imidazo[4,5-c]pyridin-6-yl]-2-fluoro-N-methylbenzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; N-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; 5-[6-fluoro-5-(3-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)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]-2-methylpropionamide; 5-[5-(4-aminophenyl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; N-[4-[1-(1,3-dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; 6-[5-(4-aminophenyl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[5-[4-(dimethylamino)phenyl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 4-[1-(1,3-dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[6-fluoro-5-[4-(methylamino)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 4-[6-[5-(4-acetamidophenyl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester; N-[4-[1-[1,3-dimethyl-7-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-2-oxo-benzimidazol-5-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; N-[4-[1-[1,3-dimethyl-7-(2-morpholinylethylamino)-2-oxo-benzimidazol-5-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; N-[4-[1-[7-(cyclopentylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; N-[4-[1-[1,3-dimethyl-2-oxo-7-(propylamino)benzimidazol-5-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; N-[4-[6-fluoro-1-[7-(isopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; N-[4-[1-[7-(cyclopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; N-[4-[1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 5-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-3-methyl-1H-benzimidazol-2-one; 1-Ethyl-5-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-3-methylbenzimidazol-2-one; 5-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1-isopropyl-3-methyl-benzimidazol-2-one; 1-(cyclopropylmethyl)-5-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-3-methyl-benzimidazol-2-one; 5-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1-(2-hydroxyethyl)-3-methyl-benzimidazol-2-one; 4-Chloro-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropenyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1-methylpyrazol-4-yl)benzimidazol-2-one; 4-Cyclopropyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-fluorophenyl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(propylamino)benzimidazol-2-one; N-[4-[1-(1,3-dimethyl-2-oxo-7-pyrrolidone-1-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-pyrrolidine-1-yl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isobutyl-1,3-dimethylbenzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-methylpropyl-1-enyl)benzimidazol-2-one; 4-[6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester; 4-(cyclopropylmethylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[1-(1,3-dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-3,4-dihydro-1H-quinolin-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(2-oxoindoline-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 7-[1-(1,3-dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-4H-1,4-benzo[] Azine-3-one; 6-[5-(4-chloro-3-methoxy-phenyl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[5-(3-chloro-4-methoxy-phenyl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[1-(1,3-dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-4H-1,4-benzo[] Azine-3-one; 6-[1-(1,3-dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-1H-quinoline-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-methoxyphenyl)-1,3-dimethyl-benzimidazol-2-one; 5-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 2-[6-fluoro-1-[7-(isopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-5-(1-methylpyrazol-4-yl)benzimidazol-2-yl]-2-methylpropionitrile; 2-[6-fluoro-1-[7-(isopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-5-(3-oxo-4H-1,4-benzo[] [Azine-7-yl)benzimidazol-2-yl]-2-methylpropionitrile; 4-(cyclohexylmethylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(3,3,3-trifluoropropylamino)benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethylbenzimidazol-2-one; 7-[2-tert-butyl-6-fluoro-1-[7-(isopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]benzimidazol-5-yl]-4H-1,4-benzo[ Azine-3-one; 4-(cyclopentylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-3-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethylbenzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(2-methylthiazo-5-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethylbenzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(2-methoxyethylamino)-1,3-dimethyl-benzimidazol-2-one; 4-[2-(dimethylamino)ethylamino]-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-(cyclobutylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-(tert-butylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropoxy-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(cyclobutylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isobutoxy-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-hydroxy-1,3-dimethylbenzimidazol-2-one; 4-(cyclopentoxy)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-propoxy-benzimidazol-2-one; 4-(cyclopropylmethoxy)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-(cyclobutylmethylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(2-methoxyphenyl)-1,3-dimethyl-benzimidazol-2-one; 2-tert-butyl-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylic acid methyl ester; 2-tert-butyl-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylic acid; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(cyclopentylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[isopropyl(methyl)amino]-1,3-dimethylbenzimidazol-2-one; 2-tert-butyl-3-(7-isopropyl-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 2-tert-butyl-3-[7-(isopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 4-Aniline-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-(4-fluoroanilino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-[4-(dimethylamino)anilino]-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 3-(7-isopropyl-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 3-[7-(isopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-methoxyanilino)-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(1-methylcyclopropyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(1-methylcyclobutyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methyloxetane-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethylbenzimidazol-2-one; 6-[6-fluoro-5-(1-methylpyrazol-4-yl)-2-[1-(trifluoromethyl)cyclopropyl]benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(tetrahydropyran-4-ylmethoxy)benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropoxy-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-trimethylsilylethynyl)benzimidazol-2-one; 4-Ethynyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-Acetyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-hydroxyethyl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-hydroxy-1-methyl-ethyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-methoxyethyl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-methoxy-1-methyl-ethyl)-1,3-dimethyl-benzimidazol-2-one; 4-Isopropyl-1,3-Dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethylbenzimidazol-2-one; 4-(isopropylamino)-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethylbenzimidazol-2-one; 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 4-(cyclohexylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(cyclohexylamino)-1,3-dimethylbenzimidazol-2-one; 3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 4-(cyclohexen-1-yl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(sec-butylamino)benzimidazol-2-one; 4-(3,3-difluoroazacyclobutane-1-yl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-(azacyclobutan-1-yl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yloxy-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-methylpiperazin-1-yl)benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1-piperidinyl)benzimidazol-2-one; 4-(4,4-difluoro-1-piperidinyl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(1-fluoro-1-methyl-ethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethylbenzimidazol-2-one; 6-[2-(1,1-difluoroethyl)-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[2-(2,3-dimethylphenyl)-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(1-methyl-1-phenyl-ethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[5-(1-ethylpyrazol-4-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-methoxyphenyl)-1,3-dimethyl-benzimidazol-2-one; 4-Cyclohexyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isobutylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3,3-difluoroazacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-(azacyclobutane-1-yl)-6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-(1,1-dimethylprop-2-ynyl)-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(2-methoxy-4-pyridyl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethylbenzimidazol-2-one; 6-[5-(2-amino-4-pyridinyl)-2-tert-butyl-6-fluoro-benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 3-(7-isopropoxy-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 2-tert-butyl-3-(7-isopropoxy-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(2S)-2-methylmorpholin-4-yl]benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-oxa-6-azaspiro[3.3]hept-6-yl)benzimidazol-2-one; 4-Isopropoxy-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-isopropoxy-1,3-dimethylbenzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxyazacyclobutane-1-yl)-1,3-dimethylbenzimidazol-2-one; 4-(3,3-difluoropyrrolidone-1-yl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrrol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-methoxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(tetrahydropyran-4-ylmethylamino)benzimidazol-2-one; 4-[6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylic acid tert-butyl ester; 4-[6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylic acid tert-butyl ester; 2-(1,1-Dimethylprop-2-ynyl)-3-(7-isopropyl-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 2-(1,1-Dimethylprop-2-ynyl)-3-(7-isopropoxy-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-piperidinyl)benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[racemic-(3R)-3-methylmorpholin-4-yl]benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[racemic-(3S)-3-methylmorpholin-4-yl]benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[racemic-(3R)-3-methylmorpholin-4-yl]benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[racemic-(3S)-3-methylmorpholin-4-yl]benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-(1,3,3a,4,6,6a-hexahydrofurano[3,4-c]pyrrolo-5-yl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxetane-3-ylamino)benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-methoxyazacyclobutane-1-yl)-1,3-dimethylbenzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-piperidinyl)benzimidazol-2-one; 4-(1-acetyl-4-piperidinyl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1-methyl-4-piperidinyl)benzimidazol-2-one; 6-[2-(1,1-dimethylprop-2-ynyl)-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,2,4-] [diazol-3-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethylbenzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(3-methyl-1,2,4-] [diazol-5-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethylbenzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(3-methyl-1,2,4-] [diazol-5-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethylbenzimidazol-2-one; 2-tert-butyl-3-[7-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 3-[7-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)benzimidazol-2-one; 4-[6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperazine-1-carboxylic acid tert-butyl ester; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-(3,3-Dimethylazacyclobutan-1-yl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropoxy-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropoxy-1,3-dimethyl-benzimidazol-2-one; 4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-(1,1-dimethylprop-2-ynyl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[5-(1-ethylpyrazol-4-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-fluoro-5-(1-isopropylpyrazol-4-yl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[5-[1-(difluoromethyl)pyrazol-4-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 3-[7-(3-methoxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 2-tert-butyl-3-[7-(3-methoxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 3-[7-(azacyclobutan-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-2-tert-butyl-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 3-[7-(3,3-difluoroazacyclobutane-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 2-tert-butyl-3-[7-(3,3-difluoroazacyclobutane-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 3-(1,3-Dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 2-tert-butyl-3-(1,3-dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxynitrile; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-methoxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-methoxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-ethoxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-(3-methoxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3-methoxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-(azacyclobutan-1-yl)-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 4-(3,3-Difluoroazacyclobutane-1-yl)-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(2S,3R)-3-hydroxy-2-methyl-azacyclobutane-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3,3-difluoroazacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(2S)-2-methylazacyclobutane-1-yl]benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1H-pyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 4-[1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methylbenzamide; 6-[5-[1-(cyclopropylmethyl)pyrazol-4-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(2-methylthiazo-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 5-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 4-(azacyclobutane-1-yl)-6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 1,3-Dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 4-(azacyclobutan-1-yl)-6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-(azacyclobutane-1-yl)-6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-isopropylpyrazole-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-5-(2-methylthiazolyl-5-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[5-(1-Cyclopropylpyrazol-4-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-isopropoxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-(3-allyloxy-3-methyl-azacyclobutane-1-yl)-6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-isopropylpyrazole-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 2-tert-butyl-3-[7-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(2-methylthiazolyl-5-yl)benzimidazol-5-carboxynitrile; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[2-tert-butyl-6-(1-methylpyrazol-4-yl)imidazo[4,5-c]pyridin-3-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylic acid methyl ester; 6-[2-tert-butyl-6-(2-methylthiazolyl-5-yl)imidazo[4,5-c]pyridin-3-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-5-(2-methylthiazolyl-5-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-5-(2-methylthiazolyl-5-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 4-(3,3-Difluoroazacyclobutane-1-yl)-6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3,3-difluoroazacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-[6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperazine-1-carboxylic acid tert-butyl ester; 6-[2-tert-butyl-6-(hydroxymethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(methoxymethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(fluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 1,3-Dimethyl-6-[2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)imidazo[4,5-c]pyridin-3-yl]-4-morpholinyl-benzimidazol-2-one; 1,3-Dimethyl-6-[2-(3-methylimidazol-4-yl)-6-(2-methylthiazo-5-yl)imidazo[4,5-c]pyridin-3-yl]-4-morpholinyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-morpholinylethoxy)benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(2-methylthiazo-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-morpholinylethoxy)benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-morpholinylethoxy)benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxetane-3-yloxy)benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxetane-3-yloxy)benzimidazol-2-one; 6-[2-tert-butyl-6-methoxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-methoxy-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazol-5-carboxylic acid methyl ester; 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazol-5-carboxylic acid; 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-N-methyl-benzimidazol-5-carboxamide; 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-N,N-dimethyl-benzimidazol-5-carboxamide; 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-N-phenyl-benzimidazol-5-carboxamide; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]benzimidazol-2-one; 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxylic acid; 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-N-methyl-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxamide; 6-[2-tert-butyl-6-(difluoromethoxy)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethoxy)-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-(difluoromethoxy)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-chloro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxaldehyde; 4-Benzoxy-6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-Benzoxy-6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-hydroxy-1,3-dimethylbenzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxetane-3-yloxy)benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(3-methylpyrazol-1-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(4-methylpyrazol-1-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,3,4-] [diazol-2-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(4-methylimidazol-1-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-5-cyclopropyl-6-(difluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-methoxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]benzimidazol-2-one; 5-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethylbenzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-thiomorpholino-benzimidazol-2-one; (5E)-2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-carboxoxime; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(6-chloropyrimidin-4-yl)oxy-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-methoxyphenoxy)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-fluorophenoxy)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethoxy)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-methoxy-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-6-[6-methoxy-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1-[6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]azacyclopropane-2-carboxylate; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-thiomorpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1,1-dioxo-1,4-thiazin-4-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(2-methylthiazo-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-thiomorpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-hydroxyethyl)pyrazol-4-yl]benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-oxopyrrolidone-1-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methyltriazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; N-[2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl]carbamate; 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(methylaminomethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-[(dimethylamino)methyl]-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(morpholinylmethyl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholinyl-benzimidazol-2-one; N-[2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl]acetamide; 4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethoxy)benzimidazol-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethoxy)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-5-(2-methylthiazolyl-5-yl)-6-(trifluoromethoxy)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxetane-3-ylmethoxy)benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(1-methyl-4-piperidinyl)oxy]benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(2R)-2-methylazacyclobutane-1-yl]benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(2R)-2-methylazacyclobutane-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxypyrrolidone-1-yl)-1,3-dimethylbenzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxypyrrolidone-1-yl)-1,3-dimethylbenzimidazol-2-one; 6-[2-tert-butyl-6-(methylamino)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(dimethylamino)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(3-chloro-2-hydroxy-2-methyl-propyl)amino]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(4-oxocyclohexyl)methoxy]benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(4-hydroxy-4-methyl-cyclohexyl)methoxy]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(4-hydroxy-4-methyl-cyclohexyl)methoxy]-1,3-dimethyl-benzimidazol-2-one; 6-[6-benzoxy-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-hydroxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; [2-tert-butyl-3-[7-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl]acetate; 6-[6-benzoxy-2-tert-butyl-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-hydroxy-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(2-methyl)] [[5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; N-[2-tert-butyl-3-[7-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl] tert-butyl carbamate; 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-vinylpyrazole-4-yl)benzimidazol-1-yl]-4-[3-(dimethylamino)-3-methyl-azacyclobutane-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]benzimidazol-1-yl]-4-[3-(dimethylamino)-3-methyl-azacyclobutane-1-yl]-1,3-dimethyl-benzimidazol-2-one; [1-[6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-morpholinylethyl)pyrazol-4-yl]benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3-methyl-azacyclobutane-3-yl]methanesulfonate; 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-morpholinylethyl)pyrazol-4-yl]benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-5-(1-methylpyrazol-4-yl)-2-(2-methyl-3-thienyl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-5-(1-methylpyrazol-4-yl)-2-(3-pyridyl)benzimidazol-1-yl]-4-isopropoxy-1,3-dimethylbenzimidazol-2-one; 4-[6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]oxypiperidine-1-carboxylic acid tert-butyl ester; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-piperidinyloxy)benzimidazol-2-one; 4-[(1-acetyl-4-piperidinyl)oxy]-6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-pyridyl)benzimidazol-2-one; 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-pyridyl)benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[3-hydroxy-3-(trifluoromethyl)azacyclobutane-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(2,3-dihydroxy-2-methyl-propyl)amino]-1,3-dimethyl-benzimidazol-2-one; 6-[6-fluoro-5-methyl-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidinyl)benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 4-[6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperazine-1-carboxylic acid tert-butyl ester; N-[1-[6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3-methyl-azacyclobutane-3-yl] tert-butyl carbamate; N-[1-[6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3-methyl-azacyclobutane-3-yl] tert-butyl carbamate; 4-[[[6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]amino]methyl]-4-methyl- 2-oxazolidinone; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-piperazin-1-yl-benzimidazol-2-one; 4-(4-acetylpiperazin-1-yl)-6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-methylpiperazin-1-yl)benzimidazol-2-one; 6-(2-tert-butyl-6-fluoro-benzimidazol-1-yl)-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxocyclohexyl)benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxycyclohexyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-cyclohexyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-cyclohexyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-pyrrolidone-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[3-hydroxy-3-(trifluoromethyl)azacyclobutane-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidinyl)benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-methoxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-methoxy-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 6-[5-(3,6-dihydro-2H-pyran-4-yl)-6-fluoro-2-(2-methyl-3-thienyl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[5-(3,6-dihydro-2H-pyran-4-yl)-6-fluoro-2-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidinyl)benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidinyl)benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(2,3-dihydroxy-2-methyl-propyl)amino]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(2-methylthiazolyl-5-yl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-methoxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidinyl)-1,3-dimethyl-benzimidazol-2-one; 4-[2-tert-butyl-6-(difluoromethyl)-1-[7-(3-hydroxy-3-methyl-azacyclobutan-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-methoxy-4-pyridyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(3,5-dimethoxyphenyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[5-(4-aminophenyl)-2-tert-butyl-6-(difluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; N-[4-[2-tert-butyl-6-(difluoromethyl)-1-[7-(3-hydroxy-3-methyl-azacyclobutan-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]benzimidazol-5-yl]phenyl]acetamide; 6-[6-(difluoromethyl)-2-(2-methoxyphenyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(2,3-dimethylphenyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; [6-[6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)-2-pyrimidin-5-yl-benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(2-methoxy-3-pyridyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)-2-thiazolyl-5-yl-benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azacyclobutane-1-yl)-1,3-dimethyl-benzimidazol-2-one.

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

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

19. 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.

20. The pharmaceutical composition of claim 19, 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.

21. The pharmaceutical composition according to claim 19, wherein the cancer is selected from one or more of hematologic malignancies, prostate cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer, and melanoma.

22. The pharmaceutical composition according to claim 19, 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.

23. The pharmaceutical composition of claim 19, 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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