Novel compound used as CBP / pa300 inhibitor, and pharmaceutical composition for preventing or treating cancer, inflammatory disorders, or autoimmune diseases comprising same as active ingredient

Abstract

The present invention provides: a novel compound used as a CBP / p300 inhibitor; a preparation method thereof; an isomer, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; and a pharmaceutical composition for preventing or treating cancer, inflammatory disorders, or autoimmune diseases, the pharmaceutical composition comprising at least one of the foregoing as an active ingredient.

Description

Novel compounds used as CBP / P300 inhibitors, and pharmaceutical compositions containing the same as active ingredients for preventing or treating cancer, inflammatory disorders, or autoimmune diseases

[0001] This application claims the benefit of priority to Republic of Korea Patent Application No. 2024-0007503, filed January 17, 2024, the entire disclosure of which is incorporated herein by reference. The present invention relates to a novel compound used as a CBP / p300 inhibitor, and a pharmaceutical composition comprising the same as an active ingredient for the prevention or treatment of cancer, inflammatory disorders, or autoimmune diseases.

[0002] CBP [CREB (cyclic-AMP response element binding protein) binding protein] and its paralog p300 are transcription coactivators composed of multiple functional domains, including a histone acetyl-transferase (HAT) domain and a bromodomain (BRD). They recognize and induce histone lysine acetylation at specific loci, such as enhancers and promoters, on chromatin, and are major epigenetic modulators that regulate the expression of various genes.

[0003] Given their high structural similarity and functional redundancy, overexpression or mutations of CBP and p300, often referred to as CBP / p300, have been associated with several diseases, particularly malignancies. For example, CBP and p300 bind to chromatin via BRD and HAT and acetylate histones at enhancer sites of oncogenes. This relaxes chromatin structure and allows transcriptional proteins, including RNA polymerase II, to recruit. Consequently, they increase the expression of oncogenes such as MYC and IRF4 in tumor cells, leading to tumor formation and growth. Inhibition of the HAT domain results in an overall decrease in acetylation, which is crucial for transcription, affecting not only tumor cells but also normal cells, particularly stem cells. It has been reported that this makes it difficult to secure a therapeutic window and may cause toxicity, so it is expected that these concerns can be overcome through a bromodomain inhibitor strategy.

[0004] Accordingly, various studies have been conducted to develop inhibitors that selectively inhibit the bromodomain of CBP / p300 and thereby reduce the transcription of activated oncogenes in tumor cells. For example, CCS1477, a CBP / p300 bromodomain inhibitor developed by CellCentric, is in phase 1b / 2a clinical trials for the treatment of hematological 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, developing effective and selective therapeutics targeting CBP / p300 remains a challenging task. Therefore, the development of more chemotypes of CBP / p300 inhibitors is necessary.

[0006] [Patent Document 1] WO2018073587

[0007] [Patent Document 2] WO2019191667

[0008] [Patent Document 3] WO2017205538

[0009] One object of the present invention is to provide a novel compound used as a CBP / p300 inhibitor.

[0010] Another object of the present invention is to provide an isomer of the compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0011] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, inflammatory disorders or autoimmune diseases, comprising at least one of the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient.

[0012] In order to solve the above problem, according to one aspect of the present invention, a compound represented by the following chemical formula I is provided:

[0013] <Chemical Formula I>

[0014]

[0015] In the above formula,

[0016] n is an integer from 0 to 3, and when n is an integer greater than or equal to 2, each R is equal to or different from each other, and each R is independently NR a R b , SO2NHR c , OR d , CONR e R f , halogen, cyano, amidinyl, imine, C 1-8 Alkyl, C 3-10 Cycloalkyl, C 6-10Aryl, 5- to 13-membered heteroaryl, 3- to 14-membered heterocycloalkyl or 4- to 9-membered heterocycloalkenyl, wherein R a Inland R f are each independently hydrogen, C 1-4 Alkyl, C 3-10 Cycloalkyl or C 6-10 is selected from the group consisting of aryl,

[0017] Z is C 1-8 Alkyl, C 3-10 Cycloalkyl, C 1-5 Haloalkyl, C 6-10 aryl, 5- to 13-membered heteroaryl or 3- to 14-membered heterocycloalkyl,

[0018] At this time, the above R, R a Inland R f and Z are each substituted or unsubstituted with substituent group I.

[0019] Another aspect of the present invention relates to an isomer of the compound, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

[0020] Another aspect of the present invention relates to a pharmaceutical composition for preventing or treating cancer, inflammatory disorders or autoimmune diseases, comprising at least one of the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient.

[0021] According to the present invention, it has been found that the compound represented by Chemical Formula I has excellent CBP / p300 inhibitory activity. Therefore, the compound represented by Chemical Formula I of the present invention; an isomer of the compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; and a pharmaceutical composition comprising at least one of these as an active ingredient can be usefully used for the prevention or treatment of cancer, inflammatory disorders, or autoimmune diseases, etc.

[0022] The effects of the present invention are not limited to the above-described effects, and should be understood to include all effects that can be inferred from the composition of the invention described in the description or claims of the present invention.

[0023] Below, the present invention will be described in more detail to facilitate understanding. The terms and words used in this specification and claims should not be interpreted based on their conventional or dictionary meanings. Based on the principle that the inventor can appropriately define the concepts of terms to best explain his or her invention, they should be interpreted in a way that aligns with the technical spirit of the present invention.

[0024] The present invention provides a compound represented by the following chemical formula I:

[0025] <Chemical Formula I>

[0026]

[0027] In the above formula,

[0028] n can be an integer from 0 to 3, and in this case, when n is an integer greater than or equal to 2, each R can be the same or different, and each R is independently NR a R b , SO2NHR c , OR d , CONR e R f , halogen, cyano, amidinyl, imine, C 1-8 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 5- to 13-membered heteroaryl, 3- to 14-membered heterocycloalkyl or 4- to 9-membered heterocycloalkenyl, wherein R a Inland R f are each independently hydrogen, C 1-4 Alkyl, C 3-10 Cycloalkyl or C 6-10may be selected from the group consisting of aryl, and Z is C 1-8 Alkyl, C 3-10 Cycloalkyl, C 1-5 Haloalkyl, C 6-10 Aryl, 5- to 13-membered heteroaryl or 3- to 14-membered heterocycloalkyl, wherein R, R a Inland R f and Z may be substituted or unsubstituted with substituent group I, respectively:

[0029] Substituent group I: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 3-20 Carbocycle, substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted 3- to 30-membered heterocycle, substituted or unsubstituted C 1-10 Alkoxy, substituted or unsubstituted C 2-10 Alkenyloxy, substituted or unsubstituted C 3-10 Cycloalkyloxy, substituted or unsubstituted C 6-30 Aryloxy, substituted or unsubstituted 3- to 30-membered heterocycloxy, substituted or unsubstituted C 1-10 Alkyl ketone, substituted or unsubstituted C 2-10 Alkenyl ketone, substituted or unsubstituted C 3-10 Cycloalkyl ketone, substituted or unsubstituted C 6-30 Aryl ketone, substituted or unsubstituted 3- to 30-membered heterocyclic ketone, substituted or unsubstituted C 1-10 Alkylthio, substituted or unsubstituted C 2-10 Alkenylthio, substituted or unsubstituted C 3-10 Cycloalkylthio, substituted or unsubstituted C 6-30 Arylthio, substituted or unsubstituted 3 to 30 membered heterocyclicthio, aldehyde, carboxy, halogen, substituted or unsubstituted C 1-10may be composed of haloalkyl, hydroxy, substituted or unsubstituted amino, imine, cyano, nitro, amide, thiol, sulfone and phosphoric acid,

[0030] Here, C 1-10 Alkyl moieties are -O-, -S-, -SO-, -SO2-, -NR g -(R g is hydrogen or substituted or unsubstituted C 1-10 alkyl), -N=, =N-, -POR g - and -PO4R g - may be interrupted by a heteroatom group selected from, and the heterocycle moiety may include at least one of S, N, P and O as a ring member atom.

[0031] In this specification, the matters regarding R are R1, , and The same can be applied to .

[0032] In defining the compound represented by Chemical Formula I throughout this specification, the following defined concepts are used. The following definitions apply to terms used individually or as part of a larger group throughout this specification, unless otherwise specified. Terms and abbreviations used herein have their original meanings unless otherwise defined.

[0033] As used herein, the term "substituted" may mean that a hydrogen atom bonded to a compound or each substituent listed in the substituent group is replaced and bonded with an arbitrary substituent. At this time, the position to be substituted is not limited to the position where the hydrogen atom bonded to each substituent listed in the compound or the substituent group exists, i.e., as long as the hydrogen atom is replaceable by the substituent. If two or more are substituted, the two or more substituents may be the same or different. Conversely, "unsubstituted" may mean that no hydrogen atom bonded to a carbon atom is replaced by an arbitrary substituent.

[0034] Any substituent applicable to the above “substitution” may be appropriately selected from the substituents listed in the substituent group described herein, but the category of substituents possible for substitution is not limited to this substituent group.

[0035] If a substituent is not separately described or mentioned in the chemical formula described herein, it may be considered that hydrogen is bonded, and in some cases, a substituent may be absent depending on the ring constituents forming the heterocycle.

[0036] As used herein, the term “halogen” includes, but is not limited to, fluoro, chloro, bromo, or iodo.

[0037] As used herein, the term "amino" is intended to encompass monovalent primary amines, monovalent secondary amines, and monovalent tertiary amines. That is, amino refers to both monovalent groups having two hydrogen atoms bonded to a nitrogen atom and monovalent groups having at least one hydrogen atom substituted with another substituent. In the above, a group having two hydrogen atoms bonded to a nitrogen atom may be an unsubstituted amino, and a group having at least one hydrogen atom substituted with another substituent may be a substituted amino. Meanwhile, for dialkylamino, the alkyl moieties may be the same or different.

[0038] As used herein, the term “imine or imino” refers to a primary ketimine (-C(=NH)R i-1 ), secondary ketamine (-C(N=R i-2 )R i-1 ), primary aldimine (-C(=NH)H), secondary aldimine (-C(=NR i-1 )H) is intended to encompass. At this time, R i-1 and R i-2 is, without limitation, Independently, C 1-10 Alkyl, C2-10 Alkenyl, C 3-10 Carbocycle, C 3-10 Cycloalkyl, C 6-30 Aryl, 3- to 30-membered heterocycle, C 1-10 It may be haloalkyl, each of which may be substituted or unsubstituted, but is not limited thereto.

[0039] As used herein, the term “alkyl” by itself or as part of another substituent, unless otherwise stated, refers to a group having the indicated number of carbon atoms (i.e., C 1-10 It means a straight or branched chain monovalent hydrocarbon having 1 to 10 carbons.

[0040] Examples of the above alkyl include, but are not limited to, 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, 5-methylhexyl, etc. The scope of the present invention is not limited.

[0041] As used herein, the term “cycloalkyl” refers to a monovalent aliphatic carbocycle in which a hydrogen atom is missing from any of the carbon atoms constituting the ring. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 3-methylcyclopentyl, 2,3-dimethylcyclopentyl, cyclohexylene, 3-methylcyclohexyl, 4-methylcyclohexyl, 2,3-dimethylcyclohexyl, 3,4,5-trimethylcyclohexyl, 4-tert-butylcyclohexyl, cycloheptyl, and cyclooctyl.

[0042] As used herein, the term “aryl” refers to a ring containing multiple unsaturated, typically aromatic hydrocarbon rings, wherein the aryl may be monocyclic or polycyclic. In the case of polycyclic rings, it includes a form in which only aromatic hydrocarbon rings are fused and a form in which an aliphatic hydrocarbon ring is fused with an aromatic hydrocarbon ring. Examples of such aryls include monocyclic aryls such as phenyl, biphenyl, terphenyl, and quaternyl, and polycyclic aryls such as naphthyl, anthracenyl, phenanthrenyl, pyrenyl, and benzopyrenyl.

[0043] As used herein, the term “heterocycle” means a ring comprising carbon atoms and 1 to 5 heteroatoms selected from non-carbon atoms, i.e., O, N, P and S, as ring constituent atoms. Here, the heterocycle may be aromatic, aliphatic, monocyclic or polycyclic and includes, but is not limited to, thiophenyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, pyridinyl, bipyridinyl, pyrimidinyl, triazinyl, triazolyl, pyridazinyl, pyrazinyl, pyridopyrimidyl, pyridopyrazinyl, pyrazinopyrazinyl, isoxazolyl, thiadiazolyl, etc., but the scope of the present invention is not limited thereto.

[0044] As used herein, the term "heterocycloalkyl" means a partially or fully saturated hydrocarbon group containing one or more heteroatoms selected from O, N, P and S as a reducing group and forming a single or fused ring. Preferably, the heteroatoms may be 1, 1 to 2 or 1 to 3. Examples thereof include, but are not limited to, piperazinyl, piperazinedioneyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolidinyl, imidazolidinonyl, lactamyl, tetrahydropyranyl, tetrahydrofuranyl, diazabicyclooctanyl or diazaspiroctanyl.

[0045] As used herein, the term "heterocycloalkenyl" refers to an unsaturated hydrocarbon group containing one or more heteroatoms selected from O, N, P, and S as a reducing group and forming a single or fused ring. Preferably, the number of heteroatoms may be 1, 1 to 2, or 1 to 3. Examples include, but are not limited to, tetrahydropyridinyl.

[0046] As used herein, the term “heteroaryl” refers to an aromatic heterocycle, which may be monocyclic or polycyclic. Polycyclic includes not only a form in which multiple aromatic rings are fused, but also a form in which an aromatic ring and an aliphatic ring are fused. Examples of heteroaryl include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isooxazolyl, thiazolyl, tetrazolyl, isothiazolyl, furyl, thienyl, pyridinyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, isoquinolinyl, thiophenyl, acridyl, indazolyl, carbazolyl, benzimidazolyl, benzocarbazolyl, benzofuranyl, benzothiophenyl, dibenzothiophenyl, pyrazolopyrimidinyl, or azaindoleyl, but the scope of the present invention is not limited thereto.

[0047] As used herein, the term “alkenyl” may be straight-chain or branched-chain. Alkenyl is, for example, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 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, 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-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,These include, but are not limited to, 2-nonenyl, 3-nonenyl, 4-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, and 5-decenyl.

[0048] As used herein, the terms "carbocycle" and "carbocyclic" refer to a ring whose ring members are composed of carbon. A carbocycle can be aliphatic or aromatic, saturated or unsaturated, and monocyclic or polycyclic. Polycyclic rings can be fused, bridged, or spiro polycyclic rings. A monocyclic carbocycle can have 3 to 17 carbon atoms, specifically 3 to 14 carbon atoms, more specifically 3 to 10 carbon atoms, and particularly specifically 3 to 7 carbon atoms.

[0049] As used herein, the term “alkoxy” refers to a substituent having oxygen bonded to alkyl, which may be straight-chain, branched-chain or cyclic. Specific examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, i-propyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, isopentyloxy, n-hexyloxy, 3,3-dimethylbutyloxy, 2-ethylbutyloxy, n-octyloxy, n-nonyloxy, n-decyloxy, benzyloxy, p-methylbenzyloxy or monohalogenated and polyhalogenated variants thereof.

[0050] In this specification, the term “oxy” means “-OR oxy As a substituent that can be represented as ", where R oxy is, but is not limited to, a substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 3-10 Carbocycle, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 6-30Aryl, substituted or unsubstituted 3- to 30-membered heterocycle or substituted or unsubstituted C 1-10 It may be haloalkyl, but is not limited to these.

[0051] As used herein, the term “carbonyl” means “-C(=O)R car As a substituent that can be represented as ", where R car are, but are not limited to, substituted or unsubstituted C respectively 1-10 Alkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 3-10 Carbocycle, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted 3- to 30-membered heterocycle or substituted or unsubstituted C 1-10 It can be haloalkyl, and the definitions of each of these are as explained above. “Carbonyl” can be referred to as “ketone”, and depending on its substituent and bonding site, it can be referred to as “alkylketone”.

[0052] In this specification, the term “thior” means “-SR thio As a substituent that can be represented as ", where R thio are, but are not limited to, substituted or unsubstituted C respectively 1-10 Alkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 3-10 Carbocycle, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted 3- to 30-membered heterocycle or substituted or unsubstituted C 1-10 It may be haloalkyl, but is not limited to these.

[0053] As used herein, the term “haloalkyl” is synonymous with “halogenated alkyl” and “halogen-substituted alkyl,” and may refer to alkyl in which any hydrogen atom in the alkyl is replaced with any halogen atom. For example, -CF3, -CF2H, -CH2Cl, -CH2CF3, -C(Cl2)CF3, etc. are haloalkyl, but the scope of the present invention is not limited thereto.

[0054] As used herein, the term "amide" refers to a substituent which may be represented, for example, by RC(=O)-NR'R'', wherein R, R' and R'' are each, but not limited to, hydrogen, substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 3-10 Carbocycle, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted 3- to 30-membered heterocycle or substituted or unsubstituted C 1-10 It may be haloalkyl, but is not limited to these.

[0055] As used herein, the term “sulfonyl” means “-S(=O)2R s1 As a substituent that can be represented as ", where R s1 Silver, but not limited to, each substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 3-10 Carbocycle, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted 3- to 30-membered heterocycle or substituted or unsubstituted C 1-10 It may be haloalkyl, but is not limited to these.

[0056] In this specification, the term “thioamide” means “-C(=S)NR ta 2”, “-C(=S)NHR ta” and “-C(=S)NH2” as substituents, R ta are independently and non-limitingly, each substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 3-10 Carbocycle, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted 3- to 30-membered heterocycle or substituted or unsubstituted C 1-10 It may be haloalkyl, but is not limited to these.

[0057] In this specification, the term “sulfinyl” means “-S(=O)R s2 As a substituent that can be represented as ", where R s2 is, but is not limited to, a substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 3-10 Carbocycle, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted 3- to 30-membered heterocycle or substituted or unsubstituted C 1-10 Haloalkyl may be used, each of which is defined as described above. Sulfinyl may also be used interchangeably with "thiocarbonyl", and in a narrower sense R s2 When it is alkyl, it may also be referred to as alkylthiocarbonyl.

[0058] In this specification, the term “phosphoric acid” means “-OP(=O)(OH)2” or “-OP(=O)(OH)(OR P ) as a substituent, wherein R P is, but is not limited to, a substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 3-10Carbocycle, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted 3- to 30-membered heterocycle or substituted or unsubstituted C 1-10 It may be haloalkyl, but is not limited to these.

[0059] In this specification, the term “ester” means “-OC(=O)R ester As a substituent that can be represented as ", where R ester is non-limitingly substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 3-10 Carbocycle, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted 3- to 30-membered heterocycle or substituted or unsubstituted C 1-10 It may be haloalkyl, but is not limited to these.

[0060] In one embodiment, the R, R a Inland R f and Z may be substituted or unsubstituted with substituent group I-1, respectively:

[0061] Substituent group I-1: substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, hydroxy, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-4 Haloalkyl, substituted or unsubstituted C 6-8 Aryl, substituted or unsubstituted 3- to 8-membered heteroaryl, substituted or unsubstituted cyano, substituted or unsubstituted amino, substituted or unsubstituted amide, aldehyde, halogen, CO2R p1 , NHCOR p2 , NHCO2R p3 or NHSO2R p4 It can be, and at this time the above Rp1 Inland R p4 are each independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted butyl, or substituted or unsubstituted phenyl.

[0062] In one embodiment, the compound of formula I may be represented by the following formula I-1:

[0063] <Chemical Formula I-1>

[0064]

[0065] In the above formula,

[0066] R 1 Silver NR a R b , SO2NHR c , OR d , CONR e R f , may be halogen, cyano or imine, each of which may be substituted or unsubstituted with substituent group I, and R a Inland R f and Z may be as defined above, respectively.

[0067] In this specification, unless otherwise specifically stated, matters relating to R are R 1 The same can be applied to .

[0068] In one implementation, R 1 Silver NR a R b , SO2NHR c , OR d , CONR e R f , bromo, cyano or amidinyl, wherein R a Inland R f may each independently be hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl or substituted or unsubstituted phenyl, wherein R 1may be substituted or unsubstituted with substituent group I-1-1:

[0069] Substituent group I-1-1: substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, hydroxy.

[0070] In one embodiment, the compound of formula I may be represented by the following formula I-2:

[0071] <Chemical Formula I-2>

[0072]

[0073] In the above formula,

[0074] may be C5 cycloalkyl, 5-membered heteroaryl or 5-membered heterocycloalkyl, m may be an integer from 0 to 3, and when m is an integer greater than or equal to 2, R A can be the same or different, and R A is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-4 It may be haloalkyl, substituted or unsubstituted cyano, substituted or unsubstituted amide, substituted or unsubstituted amino, or substituted or unsubstituted aldehyde.

[0075] In this specification, unless otherwise specifically stated, matters relating to R The same can be applied to .

[0076] In one implementation example, may be furanyl, isoxazolyl, oxadiazolyl, pyrazolyl, thiophenyl, triazolyl, thiazolyl or thiazolinyl.

[0077] In one embodiment, Z may be as described above.

[0078] In one embodiment, the compound of formula I may be represented by the following formula I-3:

[0079] <Chemical Formula I-3>

[0080]

[0081] In the above formula,

[0082] may be C6 cycloalkyl, C6 aryl, 6-membered heteroaryl, 6-membered heterocycloalkyl or 6-membered heterocycloalkenyl, p may be an integer from 0 to 3, and when p is an integer greater than or equal to 2, R B can be the same or different, and R B is substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted amide, substituted or unsubstituted amino, halogen, cyano, hydroxy, aldehyde, CO2R h , NHCOR i , NHCO2R j or NHSO2R k It may be, and at this time the above R h Inland R k may each independently be hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted butyl, or substituted or unsubstituted phenyl.

[0083] In this specification, unless otherwise specifically stated, matters relating to R The same can be applied to .

[0084] In one implementation example, may be phenyl, pyridonyl, pyridinyl, pyrimidinyl, piperidinyl or tetrahydropyridinyl.

[0085] In one embodiment, Z may be as described above.

[0086] In one embodiment, the compound of formula I may be represented by the following formula I-4:

[0087] <Chemical Formula I-4>

[0088]

[0089] In the above formula,

[0090] q can be an integer from 0 to 3, and if q is an integer greater than or equal to 2, R C may be the same or different, is C9 cycloalkyl, C 10 Cycloalkyl, C9 aryl, C 10 Aryl, 9-membered heteroaryl, 10-membered heteroaryl, 9-membered heterocycloalkyl or 10-membered heterocycloalkyl, R C is substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 3-7 It can be cycloalkyl, halogen or cyano.

[0091] In this specification, unless otherwise specifically stated, matters relating to R The same can be applied to .

[0092] In one implementation example, may be benzimidazolyl, benzodioxolyl, benzodioxanyl or dihydrobenzofuranyl.

[0093] In one embodiment, Z may be as described above.

[0094] In one implementation, q can be 0.

[0095] In one embodiment, Z can be methyl, ethyl, propyl, butyl, cyclopropyl, cyclohexyl, trifluoromethyl, phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, azaindolyl, indolyl, piperidinyl, tetrahydropyranyl, lactamyl or tetralinyl, wherein Z can be unsubstituted or substituted with substituent group I-1-2:

[0096] Substituent group I-1-2: substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 1-3Haloalkyl, halogen, hydroxy, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 6-8 Aryl, substituted or unsubstituted 3- to 8-membered heteroaryl, substituted or unsubstituted cyano, substituted or unsubstituted amino, substituted or unsubstituted amide, CO2R l , or NHCO2R m And, at this time, the above R l , R m are each independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted butyl, or substituted or unsubstituted phenyl.

[0097] In one embodiment, the compound represented by the above formula I may be any one selected from Table 1 below.

[0098] In one embodiment, the compound represented by the above formula I can be used as a CBP / p300 inhibitor. In the present specification, CBP / p300 can mean CBP and / or p300. The CBP refers to CREB (cyclic-AMP response element binding protein) binding protein, and the p300 refers to a paralog of CBP.

[0099] The above CBP / p300 induces histone H3 lysine 27 acetylation (H3K27ac) at target gene promoters, enhancers, and super enhancers, and simultaneously recognizes acetylated histones through BRD to activate gene transcription. As the above CBP / p300 is overexpressed in cancer cells and drug-resistant cancer cells, it activates oncogene transcription and induces cancer cell proliferation, survival, tumor formation, metastasis, immune evasion, or drug resistance. Therefore, there is a need to inhibit the overexpression of CBP / p300 in cancer cells, etc. The use of the compound represented by the chemical formula I herein as a CBP / p300 inhibitor may mean that it has the above-described activity of inhibiting the overexpression of CBP / p300. The compound represented by the formula (I) of the present invention can, for example, reduce the H3K27ac and downregulate oncogene transcription, thereby inhibiting cancer cell growth and inducing apoptosis, activating the immune response, overcoming drug resistance, and inhibiting tumor progression in vivo. The compound represented by the formula (I) of the present invention can also, for example, enhance the anticancer efficacy of chemotherapy, radiotherapy, and epigenetic anticancer agents by inhibiting BRD.

[0100] The present invention also provides an isomer of the compound represented by the above chemical formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0101] As used herein, the term “isomer” may include enantiomers, diastereomers thereof, tautomers thereof, and geometric isomers thereof. As used herein, enantiomers refer to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0102] As used herein, diastereomers refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral characteristics, and reactivities. Mixtures of diastereomers can be separated using high-resolution analytical procedures such as electrophoresis and chromatography.

[0103] In this specification, geometric isomers refer to cis type, in which the same type of atoms or atomic groups are on the same side of a double bond, and trans type, in which the same type of atoms or atomic groups are on the opposite side of a double bond.

[0104] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are compatible with each other through a low energy barrier. For example, proton tautomers (also known as protic tautomers) interconvert via the transfer of a proton, such as keto-enol and imine-enamine isomerization. Valence tautomers interconvert via the retransfer of some bonding electrons.

[0105] In the present specification, any atom present in the compounds of the present invention may exist in the form of its available naturally occurring isotopes. For example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, 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 There may be an I.

[0106] As used herein, the term "acceptable salt" refers to a salt of an active compound prepared with an acid or base, which depends on the specific substituents in the compound described herein. When a compound according to the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a neutral compound with a sufficient amount of the desired base in the absence of solvent or in a suitable inert solvent.

[0107] Acceptable salts include, for example, alkali metal salts, for example, sodium or potassium salts; alkaline earth metal salts, for example, calcium or magnesium salts; ammonium salts; aliphatic amine salts, for example, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine or procaine salts; aralkyl amine salts, for example, N,N-dibenzylethylenediamine salts; heterocyclic aromatic amine salts, for example, pyridine salts, picolino salts, quinoline salts or isoquinoline salts; quaternary ammonium salts, for example, tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts, for example, arginine salts or lysine salts. The acid salts may be, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate or perchlorate; organic acid salts such as acetate, propionate, lactate, malate, fumarate, tartrate, malate, fumarate, citrate, ascorbate, formic acid; sulfonates such as methanesulfonate, isothionate, benzenesulfonate or p-toluenesulfonate; and acidic amino acid salts such as aspartate or glutamate.

[0108] As used herein, the term “hydrate” means a compound in which water (H2O) is bound to another compound.

[0109] As used herein, the term "solvate" refers to an aggregate or complex of a compound of the present invention with one or more solvent molecules. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0110] The present invention also provides a pharmaceutical composition for preventing or treating cancer, inflammatory disorders or autoimmune diseases, comprising at least one of a compound represented by the above chemical formula I, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient.

[0111] In one embodiment, the cancer may be a cancer dependent on the oncogene MYC, a tumor harboring a loss of function mutation of CBP or p300, or a cancer with activation of CBP and / or p300 function.

[0112] In one embodiment, the cancer disease may be at least one selected from the group consisting of blood cancer, prostate cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer, and melanoma.

[0113] In one embodiment, the cancer disease is 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 carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelioid carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, glioma, heavy chain disease head and neck cancer, hemangioblastoma, Hepatoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphoendothelioma, lymphangiosarcoma, lymphocytic leukemia, lymphoma, lymphoid malignancy of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell It may be at least one selected from the group consisting of carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Waldenstrom macroglobulinemia, testicular tumor, uterine cancer, and Wilms tumor.

[0114] In one embodiment, the inflammatory disorder or autoimmune disease is Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin disease, 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, Takayasu's arteritis, toxic shock, thyroiditis, type 1 diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's It may be one or more selected from the group consisting of granulomatous diseases.

[0115] In one embodiment, the pharmaceutical composition may further comprise a pharmaceutically acceptable diluent or carrier. Specifically, the pharmaceutical composition of the present invention 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, each according to a conventional method. The pharmaceutically acceptable carrier may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, the pharmaceutically acceptable carrier may include diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, and surfactants. Oral solid preparations may include tablets, pills, powders, granules, capsules, etc., and these solid preparations may include at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc., and lubricants, such as magnesium stearate, talc, etc. Oral liquid preparations may include suspensions, oral solutions, emulsions, syrups, etc., and may include diluents, such as water or liquid paraffin, wetting agents, sweeteners, flavoring agents, preservatives, etc. Parenteral preparations may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and non-aqueous solvents and suspending agents may include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable esters, such as ethyl oleate.Suppository bases that can be used include witepsol, macrogol, tween 61, cocoa butter, laurin butter, and glycerogelatin.

[0116] In one embodiment, the dosage of the compound represented by formula I, its isomer, its pharmaceutically acceptable salt, its hydrate or its solvate contained in the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, the degree of the disease, the drug form, the route and period of administration, and may be appropriately selected by a person skilled in the art. For example, the compound represented by formula I, or its pharmaceutically acceptable salt, may be administered at a dosage of 0.0001 to 1000 mg / kg per day, preferably 0.01 to 1000 mg / kg, and the administration may be administered once a day or in several divided doses. In addition, the pharmaceutical composition of the present invention may contain the compound represented by formula I, or its pharmaceutically acceptable salt, in a weight percentage of 0.001 to 90% based on the total weight of the composition.

[0117] In one embodiment, the pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans by various routes, for example, orally, intraperitoneally, rectally, or by intravenous, intramuscular, subcutaneous, intrauterine, or intracerebroventricular injection.

[0118] Hereinafter, the present invention will be described in more detail through manufacturing examples, examples, and experimental examples. However, the following manufacturing examples, examples, and experimental examples are intended to illustrate the present invention and are not intended to limit the scope of the present invention.

[0119] A compound having the structure of the above chemical formula I can be synthesized by the following method.

[0120]

[0121] The analyses of the compounds prepared in the following manufacturing examples and examples were performed as follows: Nuclear magnetic resonance (NMR) spectral analysis was performed on a Bruker 500 MHz or Jeol 400 MHz spectrometer. Mass spectrometry was performed using LC / MS (Agilent 1260 infinity 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, 80Å, Mobile phase: water / acetonitrile / formic acid (30 / 70 / 0.1%), isocratic elution for 3 min.)

[0122] In addition, MPLC (Medium pressure liquid chromatography, CombiFlash Nextgen 300+) or prepHPLC (Thermo Ultimate 3000 equipped with a diode array detector, UV detection: 215 nm, 254 nm, 280 nm) was used for the purification of the compound. The prepHPLC conditions were as follows. (Column: Phenomenex Luna, 10 μm, C18(2), 100Å, 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)

[0123] Each starting material was a known compound, synthesized according to the literature, or purchased commercially.

[0124] The analyses of the compounds prepared in the following manufacturing examples and examples were performed as follows: Nuclear magnetic resonance (NMR) spectral analysis was performed on a Bruker 500 MHz or Jeol 400 MHz spectrometer. Mass spectrometry was performed using LC / MS (Agilent 1260 infinity 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, 80Å, Mobile phase: water / acetonitrile / formic acid (30 / 70 / 0.1%), isocratic elution for 3 min.)

[0125] In addition, MPLC (Medium pressure liquid chromatography, CombiFlash Nextgen 300+) or prepHPLC (Thermo Ultimate 3000 equipped with a diode array detector, UV detection: 215 nm, 254 nm, 280 nm) was used for the purification of the compound. The prepHPLC conditions were as follows. (Column: Phenomenex Luna, 10 μm, C18(2), 100Å, 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)

[0126] Each starting material was a known compound, synthesized according to the literature, or purchased commercially.

[0127] Intermediate synthesis method

[0128] Intermediate I-1: Preparation of 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0129] Step 1) Preparation of 5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0130] 4-Nitrobenzene-1,2-diamine (10 g, 65.3 mmol) was dissolved in tetrahydrofuran (365 mL), cooled to 0°C, and 1,1-carboimidazole (21 g, 130.6 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting solid was washed with diethyl ether, 1 N hydrochloric acid, and water. The solid was dried under vacuum to obtain the title compound. (9.59 g, 53.5 mmol, 82% yield)

[0131] 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)

[0132] Step 2) Preparation of 1,3-dimethyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0133] 5-Nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (4.9 g, 27.5 mmol) was dissolved in dimethylformamide (70 mL) and cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 4.4 g, 110 mmol) was added little by little, and methyl iodide (11.7 g, 5.13 mL, 83.0 mmol) was added. The reaction solution was stirred at 60°C for 2 hours and then quenched by adding water. 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 obtained solid was washed with hexane and dried under vacuum to obtain the title compound. (4.95 g, 23.4 mmol, 87% yield)

[0134] 1 H 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)

[0135] Step 3) Preparation of 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0136] 1,3-Dimethyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (3.5 g, 16.9 mmol) was dissolved in ethyl acetate / methanol (50 mL / 50 mL), and palladium / carbon (10 wt%, 0.7 g) was added. The reaction system was replaced with hydrogen using a hydrogen balloon, and the reaction solution was stirred under hydrogen conditions for 3 hours. Upon completion of the reaction, the reaction solution was filtered through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without further purification. (2.79 g, 15.7 mmol, 93% yield)

[0137] 1H NMR (500 MHz, DMSO-d6) δ 6.78 (d, J = 8.2 Hz, 1H), 6.35 (d, J = 2.0 Hz, 1H), 6.31 (dd, J = 8.2, 2.1 Hz, 1H), 4.77 (s, 2H), 3.22 (s, 3H), 3.21 (s, 3H)

[0138]

[0139] Intermediate I-2: Preparation of 4-fluoro-N-methyl-3-nitrobenzenesulfonamide

[0140] 4-Fluoro-3-nitrobenzenesulfonyl chloride (1.076 g, 4.49 mmol) was dissolved in dichloromethane (8.98 mL), and methylamine (2 M in tetrahydrofuran, 5.6 mL, 11.23 mmol) was slowly added dropwise at 0°C. The reaction solution was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (533 mg, 2.276 mmol, 50.7% yield)

[0141] 1 H-NMR (400 MHz, CHLOROFORM-d) δ 8.55 (dd, J = 6.9, 2.3 Hz, 1H), 8.16-8.13 (m, 1H), 7.51-7.47 (m, 1H), 5.10-5.07 (m, 1H), 2.71 (d, J = 5.0 Hz, 3H)

[0142]

[0143] Intermediate I-3: Preparation of 4-fluoro-N-methyl-3-nitrobenzamide

[0144] 4-Fluoro-3-nitrobenzoic acid (2 g, 10.8 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.69 g, 14.1 mmol) were dissolved in dichloromethane (30 mL), and methylamine (2 M in tetrahydrofuran, 5.4 mL, 10.8 mmol) was slowly added dropwise at 0 °C. The reaction solution was stirred at room temperature for 2 h. After the reaction was completed, the solution was cooled to 0 °C, water was added, and the organic layer was extracted with dichloromethane. The organic layer was washed with 1 N aqueous sodium hydroxide solution and brine, and concentrated under reduced pressure. The product was used in the subsequent reaction without further purification. (1.8 g, 9.08 mmol, 84% yield)

[0145] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 8.47 (dd, J = 6.9, 2.3 Hz, 1H), 8.14 (qd, J = 4.3, 2.4 Hz, 1H), 7.41 (dd, J = 10.1, 8.8 Hz, 1H), 6.21 (s, 1H), 3.08 (d, J = 4.9 Hz, 3H)

[0146]

[0147] Intermediate I-4 (Synthetic Method IA): Preparation of 3-amino-4-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-methylbenzenesulfonamide

[0148] Step 1) Preparation of 4-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methyl-3-nitrobenzenesulfonamide

[0149] 4-Fluoro-N-methyl-3-nitrobenzenesulfonamide (Intermediate I-2, 533 mg, 2.276 mmol) was dissolved in 1,4-dioxane (5.5 mL), and 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (Intermediate I-1, 403 mg, 2.276 mmol) and N,N-diisopropylethylamine (994 μl, 5.69 mmol) were added. The reaction solution was stirred at 110 °C for 18 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the resulting solid was washed with dichloromethane and methanol to obtain the title compound without further purification. (846 mg, 2.161 mmol, 95% yield)

[0150] 1 H-NMR (400 MHz, CHLOROFORM-d) δ 9.80 (s, 1H), 8.74 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.07-7.03 (m, 3H), 6.90 (s, 1H), 4.40-4.39 (m, 1H), 3.47 (s, 3H), 3.43 (s, 3H), 2.70 (d, J = 5.0 Hz, 3H)

[0151] Step 2) Preparation of 3-amino-4-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methylbenzenesulfonamide

[0152] The compound 4-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methyl-3-nitrobenzenesulfonamide (846 mg, 2.161 mmol) obtained above was dissolved in ethanol (10 mL), and tin(II) chloride dihydrate (1.463 g, 6.48 mmol) was added. The reaction solution was stirred at 90°C for 18 hours. After the reaction was completed, 1 N aqueous sodium hydroxide solution was added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (610 mg, 1.688 mmol, 78% yield)

[0153] 1 H-NMR (400 MHz, DMSO-d6) δ 7.34 (brs, 1H), 7.15 (s, 1H), 7.09-7.04 (m, 2H), 7.00-6.94 (m, 2H), 6.88 (d, J = 1.8 Hz, 1H), 6.80 (dd, J = 8.2, 1.8 Hz, 1H), 3.31 (s, 3H), 3.28 (s, 3H), 2.38 (d, J = 3.7 Hz, 3H)

[0154]

[0155] Intermediate I-5 (Synthetic Method IB): Preparation of 5-bromo-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one

[0156] Step 1) Preparation of 5-((4-bromo-2-nitrophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0157] The title compound was obtained in a similar manner to step 1 of Synthetic Method IA using 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-1, 2.85 g, 16.07 mmol) and 4-bromo-1-fluoro-2-nitrobenzene (2 mL, 16.07 mmol). (3 g, 7.95 mmol, 49.5% yield)

[0158] 1 H-NMR (500 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.59-7.56 (m, 1H), 7.22-7.19 (m, 2H), 7.04-7.02 (m, 1H), 6.94 (d, J) = 9.2 Hz, 1H), 3.35 (s, 3H), 3.31 (s, 3H)

[0159] Step 2) Preparation of 5-((2-amino-4-bromophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0160] The title compound was obtained in a similar manner to step 2 of Synthetic Method IA using the compound 5-((4-bromo-2-nitrophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (3 g, 7.95 mmol) obtained previously. (2.4 g, 6.91 mmol, 87% yield)

[0161] 1 H-NMR (400 MHz, DMSO-d6) δ 6.96 (d, J = 8.2 Hz, 1H), 6.92 (s, 1H), 6.87-6.85 (m, 2H), 6.62-6.59 (m, 2H), 6.56 (dd, J = 8.2, 1.8 Hz, 1H), 5.04 (s, 2H), 3.27 (s, 3H), 3.23 (s, 3H), LC / MS: 347 349 (M+H)

[0162] Step 3) Preparation of 5-bromo-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one

[0163] The compound 5-((2-amino-4-bromophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (450 mg, 1.296 mmol) obtained above and 1-methyl-1H-imidazole-5-carbaldehyde (143 mg, 1.296 mmol) were dissolved in acetic acid (1 mL), and then copper acetate (118 mg, 0.648 mmol) was added. The reaction solution was stirred at 80 °C for 30 minutes. After the reaction was completed, water and 1 N aqueous sodium hydroxide solution were added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (337 mg, 0.771 mmol, 59.5% yield)

[0164] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 7.95 (s, 1H), 7.61 (s, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.12-7.06 (m, 2H), 6.94-6.91 (m, 2H), 6.57 (s, 1H), 4.14 (s, 3H), 3.51 (s, 3H), 3.39 (s, 3H)

[0165]

[0166] Intermediate I-6 (Synthetic method IC): Preparation of 3'-amino-4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide

[0167] Step 1) Preparation of 4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-3'-nitro-[1,1'-biphenyl]-4-carboxamide

[0168] 5-((4-Bromo-2-nitrophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound of step 1 of Synthetic Method IB, 353 mg, 0.936 mmol), (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (203 mg, 1.029 mmol), and tripotassium phosphate (397 mg, 1.872 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), and then 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (76 mg, 0.094 mmol) was added. The reaction solution was stirred at 100 °C for 3 h under nitrogen conditions. After the reaction was completed, water was added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was washed with ethanol and used in the next reaction without further purification. (438 mg, 0.565 mmol, 60.4% yield)

[0169] 1 H-NMR (500 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.46 (s, 1H), 8.22 (m, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.72-7.59 (m, 3H), 7.24-7.22 (m, 2H), 7.09 (s, 1H), 7.07 (s, 1H), 3.36 (s, 3H), 3.32 (s, 3H), 2.79 (d, J = 4.3 Hz, 3H)

[0170] Step 2) Preparation of 3'-amino-4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide

[0171] The title compound was obtained in a similar manner to step 2 of Synthetic Method IA using the compound 4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-3'-nitro-[1,1'-biphenyl]-4-carboxamide (254 mg, 0.565 mmol) obtained above. (228 mg, 0.446 mmol, 79% yield)

[0172] 1 H-NMR (500 MHz, DMSO-d6) δ 8.17-8.16 (m, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.47-7.41 (m, 2H), 7.10 (s, 1H), 7.06 (s, 1H), 7.04-6.99 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.74 (s, 1H), 6.68 (d, J = 8.2 Hz, 1H), 4.90 (s, 2H), 3.29 (s, 3H), 3.26 (s, 3H), 2.79 (d, J = 4.6 Hz, 3H), LC / MS: 420 (M+H)

[0173]

[0174] Intermediate I-7: Preparation of ((4-fluoro-3-nitrophenyl)ethynyl)trimethylsilane

[0175] 4-Bromo-1-fluoro-2-nitrobenzene (4.4 g, 20 mmol), bis(triphenylphosphine)palladium(II) dichloride (1.4 g, 2 mmol), and copper iodide (0.570 g, 3 mmol) were dissolved in toluene (66 mL) and water (33 mL), and then trimethylsilylacetylene (4.2 mL, 30 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the organic layer was extracted by adding water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (4.13 g, 17.4 mmol, 87% yield)

[0176] 1 H NMR (500 MHz, CHLOROFORM-d) δ 8.14 (dd, J = 7.1, 2.1 Hz, 1H), 7.68 (ddd, J = 8.6, 4.2, 2.2 Hz, 1H), 7.23 (dd, J = 10.5, 8.6 Hz, 1H), 0.26 (s, 9H)

[0177]

[0178] Example Synthesis Method

[0179] Example 1 (Synthetic Method A): Preparation of 1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(3-methylimidazol-4-yl)benzimidazole-5-sulfonamide

[0180]

[0181] 3-Amino-4-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methylbenzenesulfonamide (intermediate I-4, 42.3 mg, 0.117 mmol) and 1-methyl-1H-imidazole-5-carbaldehyde (12.9 mg, 0.117 mmol) were dissolved in acetic acid (5.3 mL), and then copper acetate (21.28 mg, 0.117 mmol) was added. The reaction solution was stirred at 85°C for 1 h. After the reaction was complete, water and 1 N aqueous sodium hydroxide solution were added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC and PTLC to obtain the title compound. (21 mg, 0.047 mmol, 39.7% yield)

[0182] 1 H-NMR (400 MHz, Methanol-d4) δ 8.25 (d, J = 1.4 Hz, 1H), 7.82 (brs, 1H), 7.74 (dd, J = 8.5, 1.6 Hz, 1H), 7.38-7.35 (m, 2H), 7.31 (d, J = 8.2 Hz, 1H), 7.22 (dd, J = 8.2, 1.8 Hz, 1H), 6.56 (brs, 1H), 4.10 (s, 3H), 3.50 (s, 3H), 3.40 (s, 3H), 2.53 (s, 3H)

[0183]

[0184] Example 3 (Synthetic Method B): Preparation of 1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(3-phenylimidazol-4-yl)benzimidazole-5-sulfonamide

[0185]

[0186] 3-Amino-4-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methylbenzenesulfonamide (intermediate I-4, 50 mg, 0.138 mmol), 1-phenyl-1H-imidazole-5-carboxylic acid (26.0 mg, 0.138 mmol), N,N-diisopropylethylamine (0.031 mL, 0.180 mmol) were dissolved in ethyl acetate (3.2 mL), and then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% wt in ethyl acetate, 0.107 mL, 0.180 mmol) and acetic acid (78 μl, 1.38 mmol) were added. The mixture was stirred at 90°C for 48 hours. After the reaction was completed, 1 N aqueous sodium hydroxide solution was added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to obtain the title compound. (10 mg, 0.019 mmol, 14.07% yield)

[0187] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 7.85 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.2, 1.5 Hz, 1H), 7.68 (s, 1H), 7.63 (s, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.15-7.12 (m, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.89-6.83 (m, 3H), 6.79 (dd, J = 8.2, 1.8 Hz, 1H), 6.62 (d, J = 1.8 Hz, 1H), 3.51 (s, 3H), 3.37 (s, 3H), 2.62 (d, J = 5.2 Hz, 3H)

[0188]

[0189] Example 7 (Synthetic Method C): Preparation of 1,3-dimethyl-5-[2-(3-methylimidazol-4-yl)-5-phenyl-benzimidazol-1-yl]benzimidazol-2-one

[0190]

[0191] 5-Bromo-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (Intermediate I-5, 37.9 mg, 0.087 mmol), phenylboronic acid (12.68 mg, 0.104 mmol), and tripotassium phosphate (36.8 mg, 0.173 mmol) were dissolved in 1,4-dioxane (0.8 mL) and water (0.2 mL), and then 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (7.08 mg, 8.67 μmol) was added. The reaction solution was stirred at 100 °C under nitrogen for 4 h. After the reaction was completed, water was added and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to obtain the title compound. (30 mg, 0.069 mmol, 80% yield)

[0192] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 8.05 (s, 1H), 7.68-7.66 (m, 2H), 7.51-7.44 (m, 4H), 7.34 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.12 (s, 2H), 6.96 (s, 1H), 6.47 (s, 1H), 4.17 (s, 3H), 3.51 (s, 3H), 3.40 (s, 3H), LC / MS: 434 (M+H)

[0193]

[0194] Example 8, Example 13 (Synthetic Method D): Preparation of 5-[5-bromo-2-(6-methyl-1H-indol-3-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one and tert-butyl 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-yl]piperidine-1-carboxylate

[0195] Step 1) Preparation of 5-[5-bromo-2-(6-methyl-1H-indol-3-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 8)

[0196]

[0197] The title compound was obtained in a similar manner to step 3 of Synthesis IB using 5-((2-amino-4-bromophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound of step 2 of Synthesis IB, 250 mg, 0.720 mmol) and 6-methyl-1H-indole-3-carbaldehyde (114.6 mg, 0.720 mmol). (280 mg, 0.576 mmol, 80.0% yield)

[0198] 1 H-NMR (400MHz, DMSO-d6) δ 11.19 (s, 1H), 8.47 (d, 1H), 7.93 (s, 1H), 7.47 (m, 2H), 7.42 (d, 1H), 7.22 (m, 2H), 7.05 (d, 1H), 6.96 (m, 1H), 6.51 (d, 1H), 3.46 (s, 3H), 3.34 (s, 3H), 2.42 (s, 3H), LC / MS: 486, 488 (M+H)

[0199] Step 2) Preparation of tert-butyl 4-(1',3'-dimethyl-2-(6-methyl-1H-indol-3-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazol]-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0200] The title compound was obtained in the same manner as in Synthetic Method C using the compound 5-[5-bromo-2-(6-methyl-1H-indol-3-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 8, 300 mg, 0.617 mmol) obtained above and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (191 mg, 0.617 mmol). (267 mg, 0.454 mmol, 73.5% yield)

[0201] Step 3) Preparation of tert-butyl 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-yl]piperidine-1-carboxylate (Example 13)

[0202]

[0203] The compound obtained above, tert-butyl 4-(1',3'-dimethyl-2-(6-methyl-1H-indol-3-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazol]-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.340 mmol), was dissolved in methanol / tetrahydrofuran (2:1), and palladium / carbon (36 mg, 0.340 mmol) was added. The reaction solution was stirred at room temperature for 2 hours under hydrogen conditions. After the reaction was completed, the residue was passed through a Celite filter, and the filtrate was concentrated and purified by MPLC to obtain the title compound. (175 mg, 0.296 mmol, 87.0% yield)

[0204] 1H-NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.48 (d, 1H), 7.58 (s, 1H), 7.46 (m, 2H), 7.19 (m, 2H), 7.03 (m, 2H), 6.92 (d, 1H), 6.49 (s, 1H), 4.12 (brs, 2H), 3.45 (s, 3H), 3.32 (s, 3H), 2.84 (m, 3H), 2.42 (s, 3H), 1.85 (m, 2H), 1.61 (m, 2H), 1.44 (s, 9H), LC / MS: 591 (M+H)

[0205]

[0206] Example 14 (Synthetic Method E): Preparation of 1,3-dimethyl-5-[2-(6-methyl-1H-indol-3-yl)-5-(4-piperidyl)benzimidazol-1-yl]benzimidazol-2-one

[0207]

[0208] Tert-Butyl 4-[1-(1,3-dimethyl-2-oxo-benzidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-yl]piperidine-1-carboxylate (Example 13, 170 mg, 0.288 mmol) was dissolved in dichloromethane, and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure and neutralized with saturated sodium bicarbonate solution. The organic layer was extracted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (105 mg, 0.214 mmol, 74.4% yield)

[0209] 1H-NMR (400MHz, DMSO-d6) δ 11.11 (d, 1H), 8.48 (d, 1H), 7.57 (s, 1H), 7.42 (m, 2H), 7.20 (m, 2H), 7.05 (m, 2H), 6.93 (d, 1H), 6.50 (d, 1H), 3.45 (s, 3H), 3.34 (s, 3H), 3.19 (m, 3H), 2.80 (m, 3H), 2.42 (s, 3H), 1.86 (m, 2H), 1.72 (m, 2H), 1.44 (s, 9H), LC / MS 491 (M+H)

[0210]

[0211] Example 15: Preparation of 5-(1-ethylpiperidin-4-yl)-1',3'-dimethyl-2-(6-methyl-1H-indol-3-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one formate

[0212]

[0213] 1,3-Dimethyl-5-[2-(6-methyl-1H-indol-3-yl)-5-(4-piperidyl)benzimidazol-1-yl]benzimidazol-2-one (Example 14, 30 mg, 0.061 mmol) was dissolved in acetonitrile, and then bromoethane (8 mg, 0.073 mmol) and potassium carbonate (17 mg, 0.122 mmol) were added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by prepHPLC to obtain the title compound. (16 mg, 0.031 mmol, 50.4% yield)

[0214] 1H-NMR (400 MHz, DMSO-d6) δ 11.11 (d, 1H), 8.48 (d, 1H), 8.20 (s, 1H), 7.59 (s, 1H), 7.42 (m, 2H), 7.20 (m, 2H), 7.07 (m, 2H), 6.92 (d, 1H), 6.49 (d, 1H), 3.45 (s, 3H), 3.36 (s, 3H), 3.14 (m, 4H), 2.68 (m, 1H), 2.42 (s, 3H), 2.24 (m 2H), 1.88 (m, 4H), 1.11 (t, 3H) ; LC / MS: 519 (M+H)

[0215]

[0216] Example 20 (Synthetic Method F): Preparation of 1,3-dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(1-piperidyl)benzimidazol-1-yl]benzimidazol-2-one

[0217]

[0218] 5-Bromo-1'3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (Intermediate I-5, 58.2 mg, 0.133 mmol), piperidine (131 μl, 1.331 mmol), potassium tert-butoxide (59.7 mg, 0.532 mmol) were dissolved in toluene (0.9 mL), and then di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (5.65 mg, 0.013 mmol) and tris(dibenzylideneacetone)dipalladium(0) (6.09 mg, 6.65 μmol) were added. The reaction mixture was stirred at 110°C under nitrogen for 18 hours. After the reaction was completed, the mixture was passed through a Celite filter, and the filtrate was concentrated and purified by PTLC to obtain the title compound. (1.3 mg, 0.003 mmol, 2.2% yield)

[0219] 1H-NMR (500 MHz, Methanol-d4) δ 7.76 (s, 1H), 7.35 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.27 (s, 1H), 7.17-7.09 (m, 3H), 6.61 (s, 1H), 3.97 (s, 3H), 3.50 (s, 3H), 3.40 (s, 3H), 3.17-3.15 (m, 4H), 1.82-1.77 (m, 4H), 1.64-1.59 (m, 3H)

[0220]

[0221] Example 30 (Synthetic Method G): Preparation of 5-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-N-methyl-pyridine-2-carboxamide

[0222]

[0223] Compound 5-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazol]-5-yl)picolinic acid (45 mg, 0.094 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (27.0 mg, 0.141 mmol), and 1-hydroxybenzotriazole hydrate (21.56 mg, 0.141 mmol) obtained by method H were dissolved in dimethylformamide (1 mL), and then methylamine (2 M in tetrahydrofuran, 117 μl, 0.235 mmol) was slowly added. The reaction solution was stirred at room temperature for 18 h. After the reaction was completed, water was added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by PTLC to obtain the title compound. (5 mg, 10.15 μmol, 10.82% yield)

[0224] 1H-NMR (500 MHz, CHLOROFORM-d) δ 8.84 (d, J = 1.8 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H), 8.10-8.07 (m, 2H), 8.04-8.01 (m, 1H), 7.54 (s, 1H), 7.50 (dd, J = 8.5, 1.5 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.16-7.09 (m, 2H), 6.97 (s, 1H), 6.47 (s, 1H), 4.19 (s, 3H), 3.53 (s, 3H), 3.42 (s, 3H), 3.07 (d, J = 5.2 Hz, 3H)

[0225]

[0226] Example 44 (Synthetic Method H): Preparation of 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]benzoic acid

[0227]

[0228] Methyl 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]benzoate (Example 43, 22 mg, 0.045 mmol) was dissolved in methanol (0.2 mL) and water (0.1 mL), and then lithium hydroxide hydrate (18.74 mg, 0.447 mmol) was added. The reaction solution was stirred at 50°C for 5 h. After the reaction was completed, the reaction solution was neutralized with 1 N aqueous hydrochloric acid solution. Ethyl acetate was added, and the organic layer was extracted. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by PTLC to obtain the title compound. (5.6 mg, 0.012 mmol, 26.2% yield)

[0229] LC / MS: 479 (M+H)

[0230]

[0231] Example 58: Preparation of 5-[5-[4-(hydroxymethyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0232]

[0233] Methyl 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]benzoate (Example 43, 22 mg, 0.045 mmol) was dissolved in tetrahydrofuran (0.4 mL), and lithium aluminum hydride (1 M in tetrahydrofuran, 0.089 mL, 0.089 mmol) was slowly added at 0 °C. The reaction solution was stirred at room temperature for 4 hours. Water was slowly added at 0 °C to stop the reaction, and the reaction solution was filtered. Water and ethyl acetate were added to the filtrate, and the organic layer was extracted. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (10.5 mg, 0.023 mmol, 50.6% yield)

[0234] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 8.03 (s, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.53 (s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.12-7.10 (m, 3H), 6.95 (s, 1H), 6.46 (s, 1H), 4.75 (s, 2H), 4.17 (s, 3H), 3.52 (s, 3H), 3.40 (s, 3H)

[0235]

[0236] Example 71: Preparation of 1,3-dimethyl-5-[2-(3-methylimidazol-4-yl)-5-phenoxy-benzimidazol-1-yl]benzimidazol-2-one

[0237]

[0238] 5-Bromo-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (Intermediate I-5, 19.8 mg, 0.045 mmol) was dissolved in 1,4-dioxane (1.4 mL), and phenol (12.78 mg, 0.136 mmol), cesium carbonate (88.6 mg, 0.272 mmol), dimethylglycine (8.74 μl, 0.09 mmol), and copper iodide (7.77 mg, 0.042 mmol) were added. The reaction mixture was stirred at 110 ℃ for 18 h. After the reaction was completed, the mixture was passed through a Celite filter, and the filtrate was concentrated and purified by PTLC to obtain the title compound. (5.3 mg, 0.012 mmol, 26.0% yield)

[0239] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 7.51 (s, 1H), 7.46 (s, 1H), 7.34-7.31 (m, 2H), 7.12 (s, 2H), 7.08 (t, J = 7.5 Hz, 1H), 7.04-7.02 (m, 4H), 6.96 (s, 1H), 6.45 (s, 1H), 4.14 (s, 3H), 3.52 (s, 3H), 3. 41 (s, 3H), LC / MS: 451 (M+H)

[0240]

[0241] Example 84 (Synthetic Method I): Preparation of 4-[2-cyclopropyl-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide

[0242]

[0243] 3'-Amino-4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide (Intermediate I-6, 30 mg, 0.072 mmol) and cyclopropanecarbaldehyde (5.01 mg, 0.072 mmol) were dissolved in ethanol (1 mL) and acetic acid (0.1 mL), and then copper acetate (6.50 mg, 0.036 mmol) was added. The reaction solution was stirred at 80 °C for 30 min. After the reaction was complete, water and 1 N aqueous sodium hydroxide solution were added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC and PTLC to obtain the title compound. (22.7 mg, 0.048 mmol, 67.6% yield)

[0244] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 8.15 (t, J = 8.2 Hz, 1H), 7.92 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 13.7 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.15-7.13 (m, 2H), 7.08 (s, 1H), 6.81-6.77 (m, 1H), 3.51 (s, 3H), 3.46 (s, 3H), 3.04 (d, J = 4.9 Hz, 3H), 1.86-1.81 (m, 1H), 1.36-1.33 (m, 2H), 1.06-1.02 (m, 2H), LC / MS: 470 (M+H)

[0245]

[0246] Example 87 (Synthetic Method J): Preparation of 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-isoxazol-5-yl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide

[0247]

[0248] 3'-Amino-4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide (intermediate I-6, 27.8 mg, 0.066 mmol), isoxazole-5-carboxylic acid (8.24 mg, 0.073 mmol), N,N-diisopropylethylamine (0.013 mL, 0.073 mmol) were dissolved in ethyl acetate (0.8 mL), and then 2,4,6-tripropyl-1,3,5,2,4,6-triphosphinane 2,4,6-trioxide (50% wt in ethyl acetate, 0.197 mL, 0.331 mmol) was added. The reaction solution was stirred at 110°C for 30 minutes using a microwave. After the reaction was completed, the mixture was diluted with water, 1 N aqueous sodium hydroxide solution was added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to obtain the title compound. (18.9 mg, 0.038 mmol, 57.4% yield)

[0249] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 8.24 (s, 1H), 8.18 (t, J = 8.2 Hz, 1H), 8.09 (s, 1H), 7.57-7.52 (m, 2H), 7.39-7.36 (m, 1H), 7.23-7.21 (m, 1H), 7.18-7.14 (m, 2H), 7.04 (s, 1H), 6.82-6.79 (m, 1H), 6.46 (s, 1H), 3.53 (s, 3H), 3.43 (s, 3H), 3.05 (d, J = 4.9 Hz, 3H), LC / MS 497 (M+H)

[0250]

[0251] Example 100 (Synthetic Method K): Preparation of 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-thienyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide

[0252]

[0253] 4'-((1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-3'-nitro-[1,1'-biphenyl]-4-carboxamide (step 1 compound of synthetic method IC, 20.3 mg, 0.045 mmol) was dissolved in dimethyl sulfoxide (0.5 mL), and then thiophene-2-carbaldehyde (5.07 mg, 0.045 mmol) and sodium hyposulfite (23.59 mg, 0.136 mmol) were added. The reaction solution was stirred at 90 ℃ for 18 h. After the reaction was completed, water and aqueous ammonium hydroxide solution were added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC and PTLC to obtain the title compound. (13.6 mg, 0.027 mmol, 58.9% yield)

[0254] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 8.18 (t, J = 8.2 Hz, 1H), 8.06 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.39-7.36 (m, 2H), 7.20-7.16 (m, 2H), 7.10 (d, J = 8.5 Hz, 1H), 7.03 (s, 1H), 6.98 (d, J = 3.7 Hz, 1H), 6.94-6.93 (m, 1H), 6.81-6.78 (m, 1H), 3.54 (s, 3H), 3.43 (s, 3H), 3.06 (d, J = 4.6 Hz, 3H), LC / MS 512 (M+H)

[0255]

[0256] Example 124: Preparation of 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-isopropyl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide

[0257]

[0258] Methyl 2-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-5-[3-fluoro-4-(methylcarbamoyl)phenyl]benzimidazol-2-yl]-2-methyl-propanoate (Example 123, 33 mg, 0.062 mmol) was dissolved in methanol (0.24 mL) and water (0.8 mL), and then lithium hydroxide hydrate (13.07 mg, 0.312 mmol) was added. The reaction solution was stirred at 45 °C for 6 hours. After the reaction was completed, the reaction solution was neutralized with 1 N aqueous hydrochloric acid solution. Dichloromethane was added, and the organic layer was extracted. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by PTLC to obtain the title compound. (3.1 mg, 6.01 μmol, 9.65% yield)

[0259] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 8.18 (t, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 14.0 Hz, 1H), 7.16-7.09 (m, 3H), 6.97 (s, 1H), 6.80-6.76 (m, 1H), 3.53 (s, 3H), 3.46 (s, 3H), 3.12-3.08 (m, 1H), 3.06 (d, J = 4.6 Hz, 3H), 1.38 (d, J = 6.7 Hz, 6H), LC / MS: 472 (M+H)

[0260]

[0261] Example 128 (Synthetic Method L): Preparation of 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-[2-methyl-3-(1-methylpyrazol-4-yl)phenyl]benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide

[0262]

[0263] 4-[2-(3-Bromo-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide (Example 127, 30 mg, 0.050 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12.52 mg, 0.060 mmol), tripotassium phosphate (21.28 mg, 0.100 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.250 mL) to give 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (4.09 mg, 5.01 μmol) was added. The reaction solution was stirred at 100°C for 18 hours under nitrogen conditions. After the reaction was completed, water was added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to obtain the title compound. (24 mg, 0.040 mmol, 80% yield)

[0264] 1H-NMR (500 MHz, CHLOROFORM-d) δ 8.17 (t, J = 8.2 Hz, 1H), 8.09 (s, 1H), 7.57-7.53 (m, 2H), 7.50 (s, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 7.38 (s, 1H), 7.33 (d, J = 7.3 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.17-7.14 (m, 1H), 7.00-6.95 (m, 2H), 6.88-6.84 (m, 1H), 6.83 (s, 1H), 3.93 (s, 3H), 3.42 (s, 3H), 3.31 (s, 3H), 3.04 (d, J = 4.3 Hz, 3H), 2.22 (s, 3H), LC / MS: 600 (M+H)

[0265]

[0266] Example 132: Preparation of 4-[2-[3-[2-(dimethylamino)ethylamino]-2-methyl-phenyl]-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide

[0267]

[0268] 4-[2-(3-Bromo-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide (Example 127, 52.3 mg, 0.044 mmol), N1,N1-dimethylethane-1,2-diamine (5.17 μl, 0.048 mmol), rac-[1,1'-binaphthalene]-2,2'-diylbis(diphenylphosphine) (27.2 mg, 0.044 mmol), potassium tert-butoxide (9.81 mg, 0.087 mmol) were dissolved in toluene (0.8 mL) and tris(dibenzylideneacetone)dipalladium(0) (4.00 mg, 4.37 μmol) was added. The reaction solution was stirred at 100°C for 48 hours under nitrogen conditions. After the reaction was completed, water was added and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to obtain the title compound. (9.2 mg, 0.015 mmol, 34.8% yield)

[0269] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 8.19 (t, J = 8.2 Hz, 1H), 8.09 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.43-7.38 (m, 2H), 7.09-7.06 (m, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.84-6.80 (m, 2H), 6.73 (d, J = 7.6 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 3.47 (s, 3H), 3.42 (s, 3H), 3.31 (s, 3H), 3.15 (t, J = 5.6 Hz, 2H), 3.06 (d, J = 4.3 Hz, 3H), 2.57 (t, J = 5.5 Hz, 2H), 2.22 (s, 6H), LC / MS: 606 (M+H)

[0270]

[0271] Example 142: Preparation of 4-[2-(3,5-dimethylimidazol-4-yl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide

[0272]

[0273] 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(4-fluorophenyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide (Example 141, 10 mg, 0.020 mmol) was dissolved in tetrahydrofuran (0.5 mL), and then 1,4-diazabicyclo[5,4,0]undec-7-ene (5.92 μl, 0.040 mmol) and methyl iodide (2.454 μl, 0.040 mmol) were added. The reaction solution was stirred at 50 °C for 4 hours. After the reaction was completed, 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, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by PTLC to obtain the title compound. (1.4 mg, 2.67 μmol, 13.62% yield)

[0274] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 8.22 (t, J = 7.9 Hz, 1H), 8.12 (s, 1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.48-7.42 (m, 3H), 7.05-7.02 (m, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 6.79-6.77 (m, 1H), 3.65 (s, 3H), 3.49 (s, 3H), 3.47 (s, 3H), 3.38 (s, 3H), 3.07 (s, 3H), LC / MS: 524 (M+H)

[0275]

[0276] Example 145 (Synthetic Method M): Preparation of 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(trifluoromethyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide

[0277]

[0278] 3'-Amino-4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide (Intermediate I-6, 60 mg, 0.054 mmol) was dissolved in trifluoroacetic acid (1 mL), and the reaction solution was stirred at 90 °C for 18 h. The reaction solution was stirred at 100 °C for 3 h. After the reaction was completed, the mixture was diluted with water, and 1 N aqueous sodium hydroxide solution was added at 0 °C, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (19.2 mg, 0.039 mmol, 71.0% yield)

[0279] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 8.23-8.20 (m, 1H), 8.15 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 13.4 Hz, 1H), 7.20-7.13 (m, 3H), 7.04 (s, 1H), 6.80-6.77 (m, 1H), 3.53 (s, 3H), 3.46 (s, 3H), 3.07 (d, J = 3.0Hz, 3H), LC / MS: 498 (M+H)

[0280]

[0281] Example 152: Preparation of 4-[2-(3-cyano-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide

[0282]

[0283] 4-[2-(3-Bromo-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide (Example 127, 12 mg, 0.020 mmol) was dissolved in anhydrous dimethylformamide (0.8 mL), and dicyanozinc (23.54 mg, 0.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (11.59 mg, 0.01 mmol) were added. The reaction solution was stirred using a microwave at 130 °C for 10 h. After the reaction was complete, the organic layer was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC and PTLC to obtain the title compound. (4.8 mg, 8.81 μmol, 44.0% yield)

[0284] 1 H-NMR (500 MHz, CHLOROFORM-d) δ 8.22 (t, J = 8.0 Hz, 1H), 8.12 (s, 1H), 7.67 (d, J = 17.7 Hz, 1H), 7.60-7.57 (m, 3H), 7.45-7.40 (m, 2H), 7.30 (d, J = 8.5 Hz, 1H), 6.98-6.97 (m, 1H), 6.92-6.90 (m, 1H), 6.81-6.78 (m, 2H), 3.46 (s, 3H), 3.36 (s, 3H), 3.07 (d, J = 5.5 Hz, 3H), 2.46 (s, 3H), LC / MS : 545 (M+H)

[0285]

[0286] Example 156: Preparation of 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(1-methoxy-1-methyl-ethyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide

[0287]

[0288] 2-Methoxy-2-methylpropan-1-ol (26.6 mg, 0.256 mmol) was dissolved in ethyl acetate (1 mL) and dimethyl sulfoxide (0.5 mL), and then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% wt in ethyl acetate, 0.277 mL, 0.465 mmol) was added at 0 °C. The reaction solution was stirred at room temperature for 2 hours. After the oxidation of alcohol was completed, 3'-amino-4'-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide (Intermediate I-6, 195 mg, 0.232 mmol) was added and stirred for an additional 3 hours. After the reaction was completed, water and a saturated aqueous sodium bicarbonate solution were added, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC and PTLC to obtain the title compound. (4.8 mg, 9.57 μmol, 4.12% yield)

[0289] 1H-NMR (500 MHz, CHLOROFORM-d) δ 8.18 (t, J = 8.0 Hz, 1H), 8.07 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 13.7 Hz, 1H), 7.16-7.14 (m, 1H), 7.11-7.09 (m, 1H), 7.01 (m, 2H), 6.80-6.77 (m, 1H), 3.51 (s, 3H), 3.44 (s, 3H), 3.16 (s, 3H), 3.06 (d, J = 3.0 Hz, 3H), 1.65 (d, J = 21.1 Hz, 6H), LC / MS : 502 (M+H)

[0290]

[0291] Example 158: Preparation of N'-hydroxy-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-carboxymidamide

[0292]

[0293] 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-carbonitrile (Example 157, 100.0 mg, 0.2608 mmol) was dissolved in dimethylformamide (1 mL), and then 3 N hydroxylamine solution (1 mL) was added. The reaction solution was stirred at 50°C for 18 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the title compound was obtained without further purification. (97.0 mg, 0.2329 mmol, 89% yield)

[0294] 1 H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.89 (s, 2H), 8.10 (s, 1H), 7.82 (s, 1H), 7.80 (s, 2H), 7.64 (dd, J = 8.7, 1.3 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.18 (dd, J = 8.2, 2.0 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.36 (s, 1H), 4.05 (d, J = 3.6 Hz, 3H), 3.43 (s, 3H), 3.33 (s, 3H)

[0295]

[0296] Example 159: Preparation of 3-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazol]-5-yl)-1,2,4-oxadiazol-5(2H)-one

[0297]

[0298] N'-Hydroxy-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-carboxymidamide (Example 158, 20.0 mg, 0.048 mmol) and 1,8-diamazaicyclo[5.4.0]undec-7-ene (0.022 mL, 0.1441 mmol) were dissolved in dimethylformamide (0.5 mL), and then 1,1'-carbonyldiimidazole (16.0 mg, 0.096 mmol) was added. The reaction solution was stirred at 80 °C for 18 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by prepHPLC to obtain the title compound. (2.5 mg, 5.651 μmol, 12% yield)

[0299] 1 H NMR (500 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.25 (d, J = 1.0 Hz, 1H), 8.14 (s, 1H), 7.76 (dd, J = 8.5, 1.4 Hz, 1H), 7.48 (d, J = 1.7 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.23 (dd, J = 8.2, 1.7 Hz, 1H), 6.55 (s, 1H), 4.10 (s, 3H), 3.43 (s, 3H), 3.33 (s, 3H)

[0300]

[0301] Example 163: Preparation of 5-(4,5-dihydrothiazol-2-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one

[0302]

[0303] 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-carbonitrile (Example 157, 38.0 mg, 0.09911 mmol) was dissolved in methanol (1 mL), and 2-aminoethane-1-thiol (38.0 mg, 0.4956 mmol) was added. The reaction solution was stirred at 80 ℃ for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by MPLC to obtain the title compound. (0.0135 g, 0.03044 mmol, 31% yield)

[0304] 1 H NMR (500 MHz, CHLOROFORM-d) δ 8.26 (d, J = 0.8 Hz, 1H), 7.86 (dd, J = 8.5, 1.4 Hz, 1H), 7.52 (s, 1H), 7.15 - 7.10 (m, 2H), 7.07 (d, J = 8.5 Hz, 1H), 6.95 (s, 1H), 6.44 (s, 1H), 4.49 (t, J = 8.2 Hz, 2H), 4.18 (s, 3H), 3.52 (s, 3H), 3.45 (t, J = 8.2 Hz, 2H), 3.41 (s, 3H)

[0305]

[0306] Example 164 (Synthetic Method O): Preparation of ethyl 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-yl)-1H-1,2,3-triazol-1-yl)acetate

[0307]

[0308] Step 1) Preparation of 5-ethynyl-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one

[0309] The title compound was obtained in a similar manner to Synthetic Method IB using ((4-fluoro-3-nitrophenyl)ethynyl)trimethylsilane (intermediate I-7, 4.1 g, 17.4 mmol) and 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-1, 3.08 g, 17.4 mmol). (13.5% yield over 3 steps)

[0310] 1 H NMR (500 MHz, CHLOROFORM-d) δ 7.97 (s, 1H), 7.60 (s, 1H), 7.37 (dd, J = 8.3, 1.3 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.08 (dd, J = 8.1, 1.1 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.93 (s, 1H), 6.48 (s, 1H), 4.15 (s, 3H), 3.52 (s, 3H), 3.40 (s, 3H), 3.07 (s, 1H)

[0311] Step 2) Preparation of ethyl 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-yl)-1H-1,2,3-triazol-1-yl)acetate (Example 164)

[0312] The compound 5-ethynyl-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (1 g, 2.6 mmol), sodium ascorbate (0.051 g, 0.26 mmol), and copper iodide (0.098 g, 0.52 mmol) obtained above were dissolved in methanol (18 mL) and water (9 mL), and then ethyl azidoacetate (0.670 g, 5.2 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (0.5140 g, 1.005 mmol, 39% yield)

[0313] 1 H NMR (500 MHz, CHLOROFORM-d) δ 8.23 ​​(d, J = 0.9 Hz, 1H), 7.96 (s, 1H), 7.86 (dd, J = 8.4, 1.5 Hz, 1H), 7.57 (s, 1H), 7.14 (s, 1H), 7.13 (s, 3H), 6.97 (s, 1H), 6.49 (s, 1H), 5.24 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.18 (s, 3H), 3.53 (s, 3H), 3.42 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H)

[0314]

[0315] Example 165: Preparation of 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-yl)-1H-1,2,3-triazol-1-yl)acetic acid

[0316]

[0317] Ethyl 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazol]-5-yl)-1H-1,2,3-triazol-1-yl)acetate (Example 164, 0.510 g, 0.9970 mmol) was dissolved in methanol / tetrahydrofuran (2:3), and 1 M aqueous lithium hydroxide solution (2.991 mL, 2.991 mmol) was added. The reaction solution was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, water was added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the title compound was obtained without further purification. (0.4387 g, 0.9073 mmol, 91% yield)

[0318] 1 H NMR (500 MHz, Methanol-d4) δ 8.33 (s, 1H), 8.26 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.27 - 7.19 (m, 2H), 6.61 (s, 1H), 5.04 (s, 2H), 4.06 (s, 3H), 3.52 (s, 3H), 3.42 (s, 3H)

[0319]

[0320] Example 167 (Synthetic Method P): Preparation of 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazol]-5-yl)-1H-1,2,3-triazol-1-yl)-N-methylacetamide

[0321]

[0322] 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-yl)-1H-1,2,3-triazol-1-yl)acetic acid (Example 165, 43.5 mg, 0.09 mmol) and methylamine (2 M in tetrahydrofuran, 0.0585 mL, 0.117 mmol) were dissolved in dimethylformamide (0.45 mL), and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.0419 g, 0.27 mmol), 1-hydroxybenzotriazole hydrate (0.0365 g, 0.27 mmol), N,N-Diisopropylethylamine (0.047 mL, 0.27 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, water was added, and the organic layer was extracted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (5.8 mg, 0.0117 mmol, 13% yield)

[0323] 1 H NMR (500 MHz, CHLOROFORM-d) δ 8.23 ​​(d, J = 1.0 Hz, 1H), 7.94 (s, 1H), 7.82 (dd, J = 8.4, 1.5 Hz, 2H), 7.57 (s, 1H), 7.13 (dd, J = 12.6, 5.3 Hz, 2H), 6.95 (d, J = 1.7 Hz, 1H), 6.46 (d, J = 0.8 Hz, 1H), 6.14 (s, 1H), 5.12 (s, 2H), 4.18 (s, 3H), 3.54 (s, 3H), 3.41 (s, 3H), 2.85 (d, J = 4.9 Hz, 3H)

[0324]

[0325] Examples 2, 4-6, 9-12, 16-19, 21-29, 31-43, 45-57, 59-70, 72-83, 85, 86, 88-99, 101-123, 125-127, 129-131, 133-141, 143, 144, 146-151, 153-155, 157, 160-162, 166, and 168-176

[0326] It was manufactured similarly using the same synthetic method as the representative examples above.

[0327] Specifically, Examples 2, 4, 6, 10 and 11 were similarly prepared by Synthesis Method A, Examples 5, 12 and 16 were similarly prepared by Synthesis Method B, Examples 9, 17 to 19, 21 to 29, 31 to 43, 45, 47 to 57, 59 to 69, 73 to 83, 86, 160 to 162 and 172 to 176 were similarly prepared by Synthesis Method C, Example 157 was similarly prepared by Synthesis Method D, Examples 16, 93 and 154 were similarly prepared by Synthesis Method E, Example 70 was similarly prepared by Synthesis Method F, Example 72 was similarly prepared by Synthesis Method G, Example 46 was similarly prepared by Synthesis Method H, and Examples 85, 89 to 91, 94, 96, 97, 99, 101 to 103, 106 to 109, 112 and 113 were similarly prepared by Synthesis Method I, Examples 88, 92, 95, 98, 110, 111 and 129 were similarly prepared by Synthesis Method J, Examples 104, 105, 114 to 123, 125 to 127, 130, 133 to 141, 143, 144, 147 to 151, 153 and 155 were similarly prepared by Synthesis Method K, Example 131 was similarly prepared by Synthesis Method L, Example 146 was similarly prepared by Synthesis Method M, Example 166 was similarly prepared by Synthesis Method O, and Examples 168 to 171 were similarly prepared by Synthesis Method P.

[0328]

[0329] The structure and name, NMR, LC / MS, and synthetic method of the compounds synthesized from each of the above examples are described in Table 1 below.

[0330] [Correction pursuant to Rule 91, March 18, 2025] [Table 1]

[0331]

[0332] Experimental Example 1. CBP Inhibitory Activity

[0333] CBP inhibitory activity was measured using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay to verify CBP bromodomain activity.

[0334] The assay was performed in a final volume of 14 μl and optimized based on the CREBBP Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) assay kit (BPS Bioscience, cat. 32619) to maximize the assay window and was performed in a total final volume of 14 μl. The TR-FRET fluorescence acceptor and Tb donor were diluted in assay buffer containing 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (assay buffer, BPS Bioscience, cat. 33012), and 3 μl of each solution was transferred to all wells of a white 384-low-volume well plate (Corning, cat. 4513). Transfer 2 ul of 4X Ac-H4 peptide (final concentration 85 nM) to the high control wells and test wells. The compounds are serially diluted 3-fold from the highest concentration in dimethyl sulfoxide solvent to prepare 10 concentration points. Then, dilute each concentration of compound in assay buffer to prepare a diluted compound solution 4-fold more concentrated than the final concentration. Dispense 2 ul of each compound or dimethyl sulfoxide prepared in this way into the assay plate so that the final test concentration is from 0.5 uM to 10 uM (final dimethyl sulfoxide concentration 1%). Add 6 μL of 1X assay buffer to the low control wells and 2 ul to the high control and test wells. The PPI reaction was then initiated by adding 2 ul of 4X CBP BRD protein (final concentration 7.5 nM, BPS bioscience, cat 31128). The plate was allowed to react at room temperature for 2 hours before measuring the signal. The TR-FRET signal was measured using an EnVision Multilabel plate reader (PerkinElmer; Mirror LNACE / DELFIA Dual / Bias).

[0335] Data analysis is performed using the TR-FRET ratio ((Signal665nm / Signal615nm) 20000) to obtain the values ​​for each well. Data analysis is performed using the TR-FRET ratio ((Signal665nm / Signal615nm) 20000). Data are reported as percent inhibition compared to control wells based on the following equation: % Activity = ((FRETcompound - FRETLow av) / (FRETHigh av - FRETLow av)) 100. IC50 analysis was determined by standard four-parameter curve fitting according to the algorithm using GraphPad Prism 7.0 (GraphPad Software Inc., La Jolla, CA, USA). All data are expressed as mean ± standard error of the mean (SEM).

[0336]

[0337] Experimental Example 2. BRD4 Inhibitory Activity

[0338] BRD4 inhibitory activity was measured using time-resolved fluorescence resonance energy transfer (TR-FRET) assay to verify BRD4 bromodomain activity.

[0339] The assay was performed in a final volume of 14 μl and optimized based on the CREBBP Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) assay kit (BPS Bioscience, cat. 32613) to maximize the assay window and was performed in a total final volume of 14 μl. The TR-FRET fluorescence acceptor and Tb donor were diluted in assay buffer containing 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (assay buffer, BPS Bioscience, cat. 33012), and 3 μl of each solution was transferred to all wells of a white 384-low-volume well plate (Corning, cat. 4513). Transfer 2 ul of 4X Ac-H4 peptide (final concentration 15 nM) to the high control wells and test wells. The compounds are serially diluted 3-fold from the highest concentration in dimethyl sulfoxide to prepare 10 concentration points. Then, dilute each concentration of compound in assay buffer to prepare a diluted compound solution 4-fold more concentrated than the final concentration. Dispense 2 ul of each compound or dimethyl sulfoxide prepared in this way into the assay plate so that the final test concentration is from 0.5 uM to 10 uM (final dimethyl sulfoxide concentration 1%). Add 6 μL of 1X assay buffer to the low control wells and 2 ul to the high control and test wells. The PPI reaction was then initiated by adding 2 ul of 4X BRD4 (BD1) protein (final concentration 7.5 nM, BPS bioscience, cat 31040). The plate was allowed to react at room temperature for 2 hours before measuring the signal. The TR-FRET signal was measured using an EnVision Multilabel plate reader (PerkinElmer; Mirror LNACE / DELFIA Dual / Bias).Data analysis is performed using the TR-FRET ratio ((Signal665nm / Signal615nm) 20000) to obtain the values ​​for each well. Data analysis is performed using the TR-FRET ratio ((Signal665nm / Signal615nm) 20000). Data are reported as percent inhibition compared to control wells based on the following equation: % Activity = ((FRETcompound - FRETLow av) / (FRETHigh av - FRETLow av)) 100. IC50 analysis was determined by standard four-parameter curve fitting according to the algorithm using GraphPad Prism 7.0 (GraphPad Software Inc., La Jolla, CA, USA). All data are expressed as mean ± standard error of the mean (SEM).

[0340] The results according to Experimental Examples 1 and 2 are shown in Tables 2 and 3 below.

[0341] In Tables 2 and 3 below, if the activity value is 0 or more and 500 nM or less, it is marked as '+++', if it is more than 500 and 5 uM or less, it is marked as '++', and if it is more than 5 uM, it is marked as '+'.

[0342] Example CBP BRD IC 50 Example CBP BRD IC 501+89+2+90++3+91+4+92+5+93+6+94+7++95+8+96+9++97++10++98+11++99+++12+100+13+101++14++102+++15++103+16++104+17++105++18++106+19+107+20++108++21+++109++22++110+++23++111++24++112++25+++113+++26++114++27 ++115++28+++116++29++117++30++118++31++119++32++120++33++121+++34++122++35+++123++36++124++37++125+38+++126++39+++127+++40+++128++41+++129+42+++130+++43+++131+++44+++132++45++133++46+++134++47+++135+ +48+++136++49++137+++50++138+++51++139++52++140+53+++141++54+++142++55+++143++56+++144+++57++145++58+++146++59+++147+++60+++148+61+++149++62+++150++63+++151+64+++152++65+++153+++66+++154+++67+++155++ 68+++156++69+++157+70++158+71++159+++72++160+++73+++161++74+++162++75+++163+++76+++164++77++165++78+++166++79++167++80+++168++81+++169++82++170++83+++171++84++172++85++173++86++174+++87+175++88+176++

[0343]

[0344] Example BRD4 (BD1) IC 50 Example BRD4 (BD1) IC 50<h2 style=";text-align:left;direction:ltr">1+89+2+90+3N.D91+4N.D92+5N.D93+6N.D94+7+95+8N.D96+9+97+10+98+11+99+12N.D100+13N.D101+14+102+15+103+16+104+17++105+18+106+19+107+20+108+21+109+22+110+23+111+2 4+112+25++113+26+114+27+115+28+116+29+117+30+118+31+119+32+120+33+121+34+122+35+123+36+124+37++125++38++126+39++127+40+128+41++129+42++130++43+131+44+132+45+1 33+46+134+47+135+48+136+49+137+50+138+51+139+52+140+53+141++54++142+55+143+56+144+57+145+58+146+59+147+60+148+61++149+62++150+63+151+64+152+65++153+66+154+67+ +155+68++156+69+157+70+158+71+159+72++160+73+161+74++162+75++163+76+164+77+165+78++166+79++167+80+168+81+169+82+170+83+171+84+172+85+173+86+174+87+175+88+176+

Claims

1. A compound represented by the following chemical formula I: <Chemical Formula I> In the above formula, n is an integer from 0 to 3, and when n is an integer greater than or equal to 2, each R is equal to or different from each other, and each R is independently NR. a R b , SO2NHR c , OR d , CONR e R f , halogen, cyano, amidinyl, imine, C 1-8 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 5- to 13-membered heteroaryl, 3- to 14-membered heterocycloalkyl or 4- to 9-membered heterocycloalkenyl, wherein R a Inland R f are each independently hydrogen, C 1-4 Alkyl, C 3-10 Cycloalkyl or C 6-10 is selected from the group consisting of aryl, Z is C 1-8 Alkyl, C 3-10 Cycloalkyl, C 1-5 Haloalkyl, C 6-10 aryl, 5- to 13-membered heteroaryl or 3- to 14-membered heterocycloalkyl, At this time, the above R, R a Inland R f and Z are each substituted or unsubstituted with substituent group I: Substituent group I: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 3-20 Carbocycle, substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted 3- to 30-membered heterocycle, substituted or unsubstituted C 1-10 Alkoxy, substituted or unsubstituted C 2-10 Alkenyloxy, substituted or unsubstituted C 3-10 Cycloalkyloxy, substituted or unsubstituted C 6-30 Aryloxy, substituted or unsubstituted 3- to 30-membered heterocycleoxy, substituted or unsubstituted C 1-10 Alkyl ketone, substituted or unsubstituted C 2-10 Alkenyl ketone, substituted or unsubstituted C 3-10 Cycloalkyl ketone, substituted or unsubstituted C 6-30 Aryl ketone, substituted or unsubstituted 3- to 30-membered heterocyclic ketone, substituted or unsubstituted C 1-10 Alkylthio, substituted or unsubstituted C 2-10 Alkenylthio, substituted or unsubstituted C 3-10 Cycloalkylthio, substituted or unsubstituted C 6-30 Arylthio, substituted or unsubstituted 3 to 30 membered heterocyclicthio, aldehyde, carboxy, halogen, substituted or unsubstituted C 1-10 Consisting of haloalkyl, hydroxy, substituted or unsubstituted amino, imine, cyano, nitro, amide, thiol, sulfone and phosphoric acid, Here, C 1-10 Alkyl moieties are -O-, -S-, -SO-, -SO2-, -NR g -(R g is hydrogen or substituted or unsubstituted C 1-10 alkyl), -N=, =N-, -POR g - and -PO4R g - is interrupted by a heteroatom group selected from, wherein the heterocycle moiety contains at least one of S, N, P and O as a ring member atom.

2. In the first paragraph, R, R a Inland R f and Z are each substituted or unsubstituted with substituent group I-1, a compound: Substituent group I-1: substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, hydroxy, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-4 Haloalkyl, substituted or unsubstituted C 6-8 Aryl, substituted or unsubstituted 3- to 8-membered heteroaryl, substituted or unsubstituted cyano, substituted or unsubstituted amino, substituted or unsubstituted amide, aldehyde, halogen, CO2R p1 , NHCOR p2 , NHCO2R p3 or NHSO2R p4 And, at this time, the above R p1 Inland R p4 are each independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted butyl or substituted or unsubstituted phenyl.

3. In paragraph 1, the compound of formula I is a compound represented by the following formula I-1: <Chemical Formula I-1> In the above formula, R 1 Silver NR a R b , SO2NHR c , OR d , CONR e R f , halogen, cyano or imine, each of which is substituted or unsubstituted with substituent group I, R a Inland R f and Z are as defined in Article 1, respectively.

4. In paragraph 3, R 1 Silver NR a R b , SO2NHR c , OR d , CONR e R f , bromo, cyano or amidinyl, and At this time, the above R a Inland R f are each independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl or substituted or unsubstituted phenyl, Above R 1 is substituted or unsubstituted with a substituent group I-1-1, compound: Substituent group I-1-1: substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, hydroxy.

5. In paragraph 1, the compound of formula I is a compound represented by the following formula I-2: <Chemical Formula I-2> In the above formula, is C5 cycloalkyl, 5-membered heteroaryl or 5-membered heterocycloalkyl, m is an integer from 0 to 3, and R if m is an integer greater than or equal to 2. A are equal or different, and R A is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-4 haloalkyl, substituted or unsubstituted cyano, substituted or unsubstituted amide, substituted or unsubstituted amino, or aldehyde, Z is as defined in paragraph 1.

6. In paragraph 5, A compound which is furanyl, isoxazolyl, oxadiazolyl, pyrazolyl, thiophenyl, triazolyl, thiazolyl or thiazolinyl.

7. In paragraph 1, the compound of formula I is a compound represented by the following formula I-3: <Chemical Formula I-3> In the above formula, is C6cycloalkyl, C6aryl, 6-membered heteroaryl, 6-membered heterocycloalkyl or 6-membered heterocycloalkenyl, p is an integer from 0 to 3, and R if p is an integer greater than or equal to 2. B are equal or different, and R B is substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted amide, substituted or unsubstituted amino, halogen, cyano, hydroxy, aldehyde, CO2R h , NHCOR i , NHCO2R j or NHSO2R k , and at this time the above R h Inland R k are each independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted butyl, or substituted or unsubstituted phenyl, Z is as defined in paragraph 1.

8. In paragraph 7, is phenyl, pyridonyl, pyridinyl, pyrimidinyl, piperidinyl or tetrahydropyridinyl, compound.

9. In paragraph 1, the compound of formula I is a compound represented by the following formula I-4: <Chemical Formula I-4> In the above formula, q is an integer from 0 to 3, and R if q is an integer greater than or equal to 2. C are equal or different from each other, is C9 cycloalkyl, C 10 Cycloalkyl, C9aryl, C 10 aryl, 9-membered heteroaryl, 10-membered heteroaryl, 9-membered heterocycloalkyl or 10-membered heterocycloalkyl, R C is substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, halogen or cyano, Z is as defined in paragraph 1.

10. In paragraph 9, A compound wherein benzimidazolyl, benzodioxolyl, benzodioxanyl or dihydrobenzofuranyl, and q is 0.

11. In paragraph 1, Z is methyl, ethyl, propyl, butyl, cyclopropyl, cyclohexyl, trifluoromethyl, phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, azaindolyl, indolyl, piperidinyl, tetrahydropyranyl, lactamyl or tetralinyl, A compound wherein the above Z is substituted or unsubstituted with a substituent group I-1-2: Substituent group I-1-2: substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 1-3 Haloalkyl, halogen, hydroxy, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 6-8 Aryl, substituted or unsubstituted 3- to 8-membered heteroaryl, substituted or unsubstituted cyano, substituted or unsubstituted amino, substituted or unsubstituted amide, CO2R l , or NHCO2R m And, at this time, the above R l , R m are each independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted butyl or substituted or unsubstituted phenyl.

12. In paragraph 1, a compound selected from the following group: 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(3-methylimidazol-4-yl)benzimidazole-5-sulfonamide; 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-methyl-1H-indol-3-yl)benzimidazole-5-sulfonamide; 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(3-phenylimidazol-4-yl)benzimidazole-5-sulfonamide; 2-[3-(3,4-difluorophenyl)imidazol-4-yl]-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-benzimidazole-5-sulfonamide; 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-oxo-2-piperidyl)benzimidazole-5-sulfonamide; 2-(6-Bromo-1H-indol-3-yl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-benzimidazole-5-sulfonamide; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-phenyl-benzimidazol-1-yl]benzimidazol-2-one; 5-[5-Bromo-2-(6-methyl-1H-indol-3-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-5-[2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzimidazol-2-one; 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-methyl-1H-indol-3-yl)benzimidazole-5-carboxamide; 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(3-methylimidazol-4-yl)benzimidazole-5-carboxamide; 1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-oxo-2-piperidyl)benzimidazole-5-carboxamide; tert-Butyl 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)benzimidazol-5-yl]piperidine-1-carboxylate; 1,3-Dimethyl-5-[2-(6-methyl-1H-indol-3-yl)-5-(4-piperidyl)benzimidazol-1-yl]benzimidazol-2-one; 5-(1-Ethylpiperidin-4-yl)-1',3'-dimethyl-2-(6-methyl-1H-indol-3-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one formate; 1',3'-Dimethyl-2-(6-methyl-1H-indol-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one formate; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]benzimidazol-1-yl]benzimidazol-2-one; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-methyl-pyrazole-3-carbonitrile; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(1-piperidyl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(4-pyridyl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(4-methyl-2-thienyl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(3-pyridyl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-pyrimidin-5-yl-benzimidazol-1-yl]benzimidazol-2-one; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 5-[5-(2-methoxyphenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 2-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]benzonitrile; Methyl 5-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]pyridine-2-carboxylate; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(2-pyridyl)benzimidazol-1-yl]benzimidazol-2-one; 5-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-N-methyl-pyridine-2-carboxamide; 5-[5-(2-fluorophenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(3-fluorophenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(4-fluorophenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(2-fluoro-4-pyridyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(3-methoxyphenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(1-methyl-2-oxo-4-pyridyl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(1-methyl-6-oxo-3-pyridyl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(2-methyl-4-pyridyl)benzimidazol-1-yl]benzimidazol-2-one; 5-[5-(2-methoxy-4-pyridyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(2-oxo-1H-pyridin-4-yl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(6-oxo-1H-pyridin-3-yl)benzimidazol-1-yl]benzimidazol-2-one; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-N-methyl-benzamide; Methyl 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]benzoate; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]benzoic acid; Methyl 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-benzoate; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-benzoic acid; 5-[5-(4-methoxyphenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; N-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; 2-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]pyrazol-1-yl]acetamide; 5-[5-[1-(2-Hydroxy-2-methyl-propyl)pyrazol-4-yl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]benzimidazol-1-yl]benzimidazol-2-one; 5-[5-[1-(2,2-difluoroethyl)pyrazol-4-yl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]benzamide; 5-[5-(2-amino-4-pyridyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-3-yl)benzimidazol-1-yl]benzimidazol-2-one; 5-[5-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-[4-(hydroxymethyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(3-hydroxyphenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(4-hydroxyphenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(3-Fluoro-4-hydroxy-phenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(4-aminophenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(6-amino-3-pyridyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(2-Aminopyrimidin-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 2-Chloro-4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-N,N-dimethyl-benzamide; 5-[5-(3-Aminophenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 3-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-N-methyl-benzamide; N-[3-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; 5-[5-anilino-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-5-[2-(3-methylimidazol-4-yl)-5-phenoxy-benzimidazol-1-yl]benzimidazol-2-one; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2,6-difluoro-N-methyl-benzamide; 5-[5-[3-(dimethylamino)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; N-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-phenyl]acetamide; N-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]methanesulfonamide; 5-[5-(3,5-dimethoxyphenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; tert-Butyl N-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]carbamate; N-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]benzamide; 5-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 3-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-4-fluoro-N-methyl-benzamide; 5-[5-[4-(dimethylamino)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(2-Aminothiazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[5-(1H-Benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-[2-Cyclopropyl-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-phenyl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 1,3-Dimethyl-5-[5-[4-(methylamino)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]benzimidazol-2-one; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-isoxazol-5-yl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-Cyclohexyl-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(4-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; tert-Butyl 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-5-[3-fluoro-4-(methylcarbamoyl)phenyl]benzimidazol-2-yl]piperidine-1-carboxylate; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(4-piperidyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-tetrahydropyran-4-yl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(cyclohexylmethyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-Benzyl-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-thiazol-5-yl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-furyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(1-methylpyrrol-2-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-thienyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(o-tolyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(2,3-dimethylphenyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-oxazol-4-yl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(1H-imidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(1-methylpyrazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-thiazol-4-yl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-oxazol-5-yl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-thienyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-furyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-methyl-3-thienyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-methyl-3-furyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-[3-(trifluoromethyl)phenyl]benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-tetrazol-5-yl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(4-methyl-3-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-methyl-3-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(5-methyl-3-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(4-amino-3-pyridyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(m-tolyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(3-chlorophenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(2,3-Dichlorophenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-fluoro-2-methyl-phenyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-pyrimidin-5-yl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; Methyl 2-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-5-[3-fluoro-4-(methylcarbamoyl)phenyl]benzimidazol-2-yl]-2-methyl-propanoate; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-isopropyl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-hydroxy-3-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-hydroxy-4-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(3-Bromo-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-[2-methyl-3-(1-methylpyrazol-4-yl)phenyl]benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-[2-(dimethylamino)ethyl]-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(3-Cyclopropyl-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-[3-[2-(dimethylamino)ethylamino]-2-methyl-phenyl]-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-[2-methyl-3-(trifluoromethyl)phenyl]benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-fluorophenyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(2-chlorophenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-[2-(trifluoromethyl)phenyl]benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methoxy-2-methyl-phenyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-methoxyphenyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methoxyphenyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(4-fluorophenyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(4-methyl-1H-imidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(3,5-dimethylimidazol-4-yl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(2,3-dimethylimidazol-4-yl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-tert-butyl-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(trifluoromethyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-methyl-benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-methoxy-3-pyridyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(2-Anilino-1,1-dimethyl-2-oxo-ethyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(2-methylpyrazol-3-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(2-amino-3-pyridyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; Tert-Butyl N-[1-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-5-[3-fluoro-4-(methylcarbamoyl)phenyl]benzimidazol-2-yl]-1-methyl-ethyl]carbamate; 4-[2-(3-cyano-2-methyl-phenyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(1-cyano-1-methyl-ethyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(1-Amino-1-methyl-ethyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[2-(2-chloro-3-pyridyl)-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(1-methoxy-1-methyl-ethyl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-carbonitrile; N'-Hydroxy-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-carboximidamide; 3-(1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-yl)-1,2,4-oxadiazol-5(2H)-one; 5-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one; 5-(2,3-dihydrobenzofuran-5-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one; 5-(1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazol]-5-yl)furan-2-carbaldehyde; 5-(4,5-Dihydrothiazol-2-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one; Ethyl 2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-yl)-1H-1,2,3-triazol-1-yl)acetate; 2-(4-(1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-yl)-1H-1,2,3-triazol-1-yl)acetic acid; 5-(1-(2-Hydroxyethyl)-1H-1,2,3-triazol-4-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one; 2-(4-(1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-yl)-1H-1,2,3-triazol-1-yl)-N-methylacetamide; 2-(4-(1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-yl)-1H-1,2,3-triazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide; 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-5-(1-(2-oxo-2-(piperidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one; 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-5-(1-(2-morpholino-2-oxoethyl)-1H-1,2,3-triazol-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one; N-Benzyl-2-(4-(1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-yl)-1H-1,2,3-triazol-1-yl)acetamide; 5-(3,5-Dimethylisoxazol-4-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one; 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-5-(5-methylfuran-2-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one; 5-(Benzo[d][1,3]dioxol-5-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one; 5-(Furan-3-yl)-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one; 1',3'-Dimethyl-2-(1-methyl-1H-imidazol-5-yl)-5-(1-methyl-1H-pyrazol-5-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one.

13. A compound used as a CBP / p300 inhibitor in claim 1.

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

15. A pharmaceutical composition for preventing or treating cancer, inflammatory disorders or autoimmune diseases, comprising as an active ingredient at least one of the compound according to paragraph 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof.

16. A pharmaceutical composition according to claim 15, wherein the cancer is a cancer dependent on the oncogene MYC, a tumor harboring a loss of function mutation of CBP or p300, or a cancer with activation of CBP and / or p300 function.

17. A pharmaceutical composition according to claim 15, wherein the cancer disease is at least one selected from the group consisting of blood cancer, prostate cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer, and melanoma.

18. In the 15th paragraph, the cancer disease is 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 carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colon cancer, colon cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferative changes, embryonal carcinoma, endometrial cancer, endothelioma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, pedunculation, heavy chain disease head and neck cancer, Hemangioblastoma, hepatoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphoendothelioma, lymphangiosarcoma, lymphocytic leukemia, lymphoma, lymphoid malignancy of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, A pharmaceutical composition comprising at least one selected from the group consisting of gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Waldenstrom macroglobulinemia, testicular tumor, uterine cancer, and Wilms tumor.

19. In paragraph 15, the inflammatory disorder or autoimmune disease is Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin disease, 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, Takayasu's arteritis, toxic shock, thyroiditis, type 1 diabetes, ulcerative colitis, uveitis, vitiligo, A pharmaceutical composition comprising at least one selected from the group consisting of vasculitis and Wegener's granulomatosis.

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