Novel compound used as CBP / p300 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 method for preparing same; an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; and a pharmaceutical composition for preventing or treating cancer, inflammatory disorders, or autoimmune diseases, comprising at least one of these 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. 2024-0007499, 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] To solve the above problem, one aspect of the present invention relates to a compound represented by the following chemical formula I:

[0013] <Chemical Formula I>

[0014]

[0015] In the above formula,

[0016] X is C or N,

[0017] 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.

[0018] R is independently C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-5 Haloalkyl, C 6-10 Aryl, 5- to 9-membered heteroaryl, 3- to 14-membered heterocycloalkyl, 4- to 9-membered heterocycloalkenyl, halogen, cyano, carbonyl, formaldoxime, NRa R b , SO2NHR c , CONR d R e , CO2R f , NHCOR g OR h and R a Inland R h are each independently hydrogen, C 1-5 Alkyl, C 3-7 Cycloalkyl, C 1-4 Haloalkyl, C 6-10 Selected from the group consisting of aryl, halogen, carbonyl, or Boc groups,

[0019] Q is hydrogen, C 1-7 Alkyl or C 3-7 It is cycloalkyl,

[0020] A is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, C 6-10 Aryl, 3- to 16-membered heterocycloalkyl, 3- to 16-membered heterocycloalkenyl, 5- to 9-membered heteroaryl, halogen, carbonyl, NR i R j OR k and R i Inland R k are each independently hydrogen, C 1-8 Alkyl, C 3-10 Cycloalkyl, C 6-10 Selected from the group consisting of aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl or Boc group;

[0021] Z is C 1-8 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aryl, 5- to 13-membered heteroaryl or 3- to 8-membered heterocycloalkyl,

[0022] At this time, the above R, Ra Inland R k , Q, A and Z are each substituted or unsubstituted with substituent group I.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] The present invention can provide a compound represented by the following chemical formula I:

[0029] <Chemical Formula I>

[0030]

[0031] In the above formula, X can be C or N, 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 C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-5 Haloalkyl, C 6-10 Aryl, 5- to 9-membered heteroaryl, 3- to 14-membered heterocycloalkyl, 4- to 9-membered heterocycloalkenyl, halogen, cyano, carbonyl, formaldoxime, NR a R b , SO2NHR c , CONR d R e , CO2R f , NHCOR g OR h and R a Inland R h are each independently hydrogen, C 1-5 Alkyl, C 3-7 Cycloalkyl, C 1-4 Haloalkyl, C 6-10 may be selected from the group consisting of aryl, halogen, carbonyl, or Boc groups, and Q is hydrogen, C 1-7 Alkyl or C 3-7 It can be cycloalkyl, A is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, C 6-10 Aryl, 3- to 16-membered heterocycloalkyl, 3- to 16-membered heterocycloalkenyl, 5- to 9-membered heteroaryl, halogen, carbonyl, NR i R jOR k It can be, R i Inland R k are each independently hydrogen, C 1-8 Alkyl, C 3-10 Cycloalkyl, C 6-10 may be selected from the group consisting of aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl or Boc group, and Z is C 1-8 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aryl, 5- to 13-membered heteroaryl or 3- to 8-membered heterocycloalkyl, wherein R, R a Inland R k , Q, A and Z may each be substituted or unsubstituted by substituent group I.

[0032] Substituent group I: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 2-10 Alkenyl, substituted or unsubstituted C 2-10 alkynyl, 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 1-10Alkylthio, 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, substituted or unsubstituted carbonyl, carboxy, halogen, substituted or unsubstituted C 1-10 Consists of haloalkyl, hydroxy, substituted or unsubstituted amino, imine, cyano, nitro, amide, thiol, sulfone and phosphoric acid, wherein, C 1-10 Alkyl moieties are -O-, -S-, -SO-, -SO2-, -NR m -(R m is hydrogen or substituted or unsubstituted C 1-10 alkyl), -N=, =N-, -POR m - and -PO4R m - is 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] As used herein, the term "alkynyl" may be straight-chain or branched. Examples of alkynyl include, but are not limited to, acetylenyl, trimethylsilylacetylenyl, and the like.

[0041] As used herein, the term "cycloalkyl" refers to a monovalent aliphatic carbocycle in which one 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, cyclohexyl, cyclohexylene 3-methylcyclohexyl, 4-methylcyclohexyl, 2,3-dimethylcyclohexyl, 3,4,5-trimethylcyclohexyl, 4-tert-butylcyclohexyl, cycloheptyl, and cyclooctyl.

[0042] As used herein, the term "cycloalkenyl" refers to a cyclic hydrocarbon having a double bond. Examples of cycloalkenyl include, but are not limited to, cyclohexenyl. 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 "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, oxadiazolyl, or azaindoleyl, but the scope of the present invention is not limited thereto.

[0045] 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, fused cyclic or spirocyclic ring. Preferably, the number of heteroatoms may be 1, 1 to 2 or 1 to 3. Examples include, but are not limited to, piperazinyl, piperazinedioneyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinadioxadinyl, oxaazaspiroheptyl, hexahydrofuropyrrolyl, oxaazabicycloheptyl, imidazolidinyl, imidazolidinonyl, lactamyl, tetrahydropyranyl, tetrahydrofuranyl, diazabicyclooctanyl, oxaindolyl, benzoxazinionyl, oxacyclobutanyl, azetidinyl, or diazaspirooctanyl.

[0046] 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 thereof include, but are not limited to, tetrahydropyridinyl, dihydropyranyl, dihydroquinolinonyl, and the like.

[0047] As used herein, the term “halogen” includes, but is not limited to, fluoro, chloro, bromo, or iodo.

[0048] As used herein, the term "carbonyl" means "-C(=O)R car " as a substituent that can be represented as R car are, but are not limited to, hydrogen, substituted or unsubstituted, C 1-10 Alkyl, C 2-10 Alkenyl, substituted or unsubstituted C 3-10 Carbocycle, C 3-10 Cycloalkyl, C 6-30Aryl, 3- to 30-membered heterocycle, C 1-10 It can be haloalkyl, and the definitions of each of these are as explained above.

[0049] In this specification, the term “Boc group” means a tert-butyloxycarbonyl protecting group.

[0050] In this specification, 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 replaced by 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 replaced by another substituent may be a substituted amino. Meanwhile, for dialkylamino, the alkyl moieties may be the same or different.

[0051] 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, C 2-10 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.

[0052] 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.

[0053] 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.

[0054] In this specification, the term "oxy" means "-OR oxy " as a substituent that can be represented as R oxy is, but is not limited to, C, each substituted or unsubstituted 1-10 Alkyl, C 2-10 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, but is not limited to these.

[0055] In this specification, the term "thior" means "-SR thio " as a substituent that can be represented as Rthio is, but is not limited to, C, each substituted or unsubstituted 1-10 Alkyl, C 2-10 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, but is not limited to these.

[0056] 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, -CH2Cl, -CH2CF3, -C(Cl2)CF3, etc. are haloalkyl, but the scope of the present invention is not limited thereto.

[0057] 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.

[0058] As used herein, the term "sulfonyl" means "-S(=O)2R s1 " as a substituent that can be represented as R s1 Silver, but not limited to, each substituted or unsubstituted, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Carbocycle, C 3-10 Cycloalkyl, C 6-30 Aryl, 3- to 30-membered heterocycle, C 1-10It may be haloalkyl, but is not limited to these.

[0059] 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, C 2-10 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, but is not limited to these.

[0060] As used herein, the term "sulfinyl" means "-S(=O)R s2 " as a substituent that can be represented as R s2 is, but is not limited to, C, each substituted or unsubstituted 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Carbocycle, C 3-10 Cycloalkyl, C 6-30 Aryl, 3- to 30-membered heterocycle, 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.

[0061] 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, C, each substituted or unsubstituted 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Carbocycle, C 3-10 Cycloalkyl, C6-30 Aryl, 3- to 30-membered heterocycle, C 1-10 It may be haloalkyl, but is not limited to these.

[0062] In this specification, the term "ester" means "-OC(=O)R ester " as a substituent that can be represented as R ester is non-limitingly substituted or unsubstituted, C 1-10 Alkyl, C 3-10 Carbocycle, C 3-10 Cycloalkyl, C 6-30 Aryl, 3- to 30-membered heterocycle, C 1-10 It may be haloalkyl, but is not limited to these.

[0063] In one embodiment, the R, R a Inland R k , Q, A and Z may each be substituted or unsubstituted with substituent group I-1.

[0064] Substituent group I-1: substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-5 Alkenyl, substituted or unsubstituted C 2-7 alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 1-5 Haloalkyl, substituted or unsubstituted C 6-8 Aryl, substituted or unsubstituted carbonyl, substituted or unsubstituted 3- to 9-membered heterocycloalkyl, halogen, cyano, Boc group, OR p1 , NR p2 R p3 , CONR p4 R p5 , NHCOR p6 or CO2R p7 And, at this time, the above R p1 Inland R p7may each independently be hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted propenyl, substituted or unsubstituted mesylate, substituted or unsubstituted carbonyl or a Boc group.

[0065] In one embodiment, the compound of formula I may be represented by either formula I-1 or I-2:

[0066] <Chemical Formula I-1>

[0067]

[0068] <Chemical Formula I-2>

[0069]

[0070] In the above formula, n, R, Q, A and Z may each be as defined above.

[0071] In one embodiment, the compound of formula I-1 may be represented by either formula I-1-1 or I-1-2:

[0072] <Chemical Formula I-1-1>

[0073]

[0074] <Chemical Formula I-1-2>

[0075]

[0076] In the above formula, A 2 is C 1-8 Alkyl, C 2-8 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, C 6-10 Aryl, 3- to 16-membered heterocycloalkyl, 5- to 9-membered heteroaryl, halogen, carbonyl, NR i R j OR k , which may be substituted or unsubstituted with substituent group I, and R i Inland Rk , n, R, Q and Z may each be as defined above.

[0077] In one implementation example, A 2 is chloro, hydroxy, substituted or unsubstituted carbonyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted butyl, substituted or unsubstituted propenyl, substituted or unsubstituted butenyl, trimethylsilylacetylenyl, acetylenyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclohexenyl, substituted or unsubstituted cyclohexanonyl, substituted or unsubstituted phenyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperidinonyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydropyridinyl, substituted or Unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted thiomorpholine dioxide, substituted or unsubstituted oxaazaspiroheptyl, substituted or unsubstituted hexahydrofuropyrrolyl, substituted or unsubstituted oxaazabicycloheptyl, substituted or unsubstituted pyrazolyl, NR i R j OR k It can be, and at this time the above R i Inland R kmay be hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted butyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclohexylmethyl, substituted or unsubstituted oxacyclobutanyl, substituted or unsubstituted dimethyloxazolidinonyl, substituted or unsubstituted cyclohexanonylmethyl, substituted or unsubstituted phenyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrimidinyl or substituted or unsubstituted tetrahydropyranyl.

[0078] In one embodiment, the A 2 The atom connecting to the 2-oxo-benzimidazole of the parent nucleus can be C, but it can also be a heteroatom such as N or O. For example, A 2 When A is a substituted or unsubstituted azetidinyl, a substituted or unsubstituted aziridinyl, a substituted or unsubstituted pyrrolidinyl, a substituted or unsubstituted piperazinyl, a substituted or unsubstituted piperidinyl, a substituted or unsubstituted morpholinyl, a substituted or unsubstituted thiomorpholinyl, a substituted or unsubstituted thiomorpholine dioxide, a substituted or unsubstituted oxaazaspiroheptyl, a substituted or unsubstituted hexahydrofuropyrrolyl or a substituted or unsubstituted oxaazabicycloheptyl, 2 And the 2-oxo-benzimidazole of the parent nucleus can be linked to N.

[0079] In one embodiment, the compound of formula I-2 may be represented by either formula I-2-1 or I-2-2:

[0080] <Chemical Formula I-2-1>

[0081]

[0082] <Chemical Formula I-2-2>

[0083]

[0084] In the above formula, A 2 , n, R, Q and Z may each be as defined above.

[0085] In one embodiment, the compound of formula I-1-1 may be represented by any one of the following formulas I-1-1-1 or I-1-1-2:

[0086] <Chemical Formula I-1-1-1>

[0087]

[0088] <Chemical Formula I-1-1-2>

[0089]

[0090] In the above formula, R 111 , R 211 and R 311 are each independently C 1-5 Alkyl, C 1-3 Haloalkyl, C 6-8 Aryl, 5- to 7-membered heteroaryl, halogen, cyano, carbonyl, CONR d R e or CO2R f may be substituted or unsubstituted with substituent group I, and R d Inland R f , Q and Z may each be as defined above.

[0091] In one implementation, R 111 , R 211 and R 311 are each independently methyl, propyl, CF2H, phenyl, pyrazolyl, bromo, fluoro, cyano, aldehyde, CONR d R e or CO2R f It can be, and at this time the above R d Inland R f Each of R may independently be hydrogen or substituted or unsubstituted methyl, and 111 and R 211may be independently substituted or unsubstituted with substituent group I-1-1.

[0092] Substituent group I-1-1: substituted or unsubstituted C 1-3 Alkyl, Halogen, OR p1 , NR p2 R p3 , CONR p4 R p5 or NHCOR p6 It can be, and at this time the above R p1 Inland R p6 may each independently be hydrogen, substituted or unsubstituted methyl, or substituted or unsubstituted propyl.

[0093] In one embodiment, the compound of the above formula I-1-2 may be represented by any one of the following formulae I-1-2-1 to I-1-2-3.

[0094] <Chemical Formula I-1-2-1>

[0095]

[0096] <Chemical Formula I-1-2-2>

[0097]

[0098] <Chemical Formula I-1-2-3>

[0099]

[0100] In the above formula, A 2 may be as defined above, and R 112 and R 212 are each independently C 1-5 Alkyl, C 3-7 Cycloalkyl, C 1-5 Haloalkyl, C 6-10 Aryl, 5- to 9-membered heteroaryl, 3- to 14-membered heterocycloalkyl, 4- to 9-membered heterocycloalkenyl, halogen, cyano, carbonyl, formaldoxime, NR a R b , SO2NHR c , CONR d Re , CO2R f , NHCOR g OR h It can be, and the above R 112 and R 212 Each may be substituted or unsubstituted with substituent group I, and R a Inland R h , Q and Z may each be as defined above.

[0101] In one embodiment, the R 112 and R 212 are each independently methyl, cyclopropyl, CF3, CF2H, CFH2, phenyl, oxazolyl, pyrazolyl, thiazolyl, pyridinyl, oxadiazolyl, imidazolyl, triazolyl, lactamyl, oxindolyl, quinolinonyl, dihydroquinolinonyl, benzoxazinonyl, dihydropyranyl, fluoro, chloro, bromo, cyano, aldehyde, formaldoxime, NR a R b , SO2NHR c , CONR d R e , CO2R f , NHCOR g OR h It can be, and at this time the above R a Inland R h may each independently be hydrogen, substituted or unsubstituted methyl, CF2H, CF3, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted carbonyl or Boc group, and R 112 and R 212 Each may be independently substituted or unsubstituted with a substituent group I-1-2.

[0102] Substituent group I-1-2: substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-5 Alkenyl, substituted or unsubstituted C 1-4Haloalkyl, halogen, 4- to 8-membered heterocycloalkyl, OR p1 , NR p2 R p3 , CONR p4 R p5 or NHCOR p6 It can be, and at this time the above R p1 Inland R p6 may each independently be hydrogen, substituted or unsubstituted methyl, or substituted or unsubstituted carbonyl.

[0103] In one embodiment, the compound of formula I-2-1 may be represented by either formula I-2-1-1 or I-2-1-2:

[0104] <Chemical Formula I-2-1-1>

[0105]

[0106] <Chemical Formula I-2-1-2>

[0107]

[0108] In the above formula, R 221 and R 312 are each independently C 6-9 Aryl, 5- to 9-membered heteroaryl, halogen, or CONR d R e It can be, and the above R 221 and R 312 Each may be substituted or unsubstituted with substituent group I, and R d Inland R e , Q and Z may each be as defined above.

[0109] In one embodiment, the R 221 and R 312 are each independently phenyl, pyrazolyl, bromo or CONR d R e It can be, and at this time the above R d Inland R eEach of R may independently be hydrogen or substituted or unsubstituted methyl, and 221 and R 312 Each may be independently substituted or unsubstituted with substituent group I-1-3.

[0110] Substituent group I-1-3: substituted or unsubstituted C 1-3 Alkyl, halogen or CONR p4 R p5 It can be, and at this time the above R p4 Inland R p5 may each independently be hydrogen or substituted or unsubstituted methyl.

[0111] In one embodiment, the compound of formula I-2-2 may be represented by either formula I-2-2-1 or I-2-2-2:

[0112] <Chemical Formula I-2-2-1>

[0113]

[0114] <Chemical Formula I-2-2-2>

[0115]

[0116] In the above formula, A 2 may be as defined above, and R 222 and R 322 Each of R may independently be a 5- to 9-membered heteroaryl, and the R 222 and R 322 Each of which may be substituted or unsubstituted with a substituent group I, and each of Q and Z may be as defined above.

[0117] In one embodiment, the R 222 and R 322 Each of R can independently be pyrazolyl or thiazolyl, and the above R 222 and R 322 Each may be independently substituted or unsubstituted with substituent group I-1-4.

[0118] Substituent group I-1-4: substituted or unsubstituted C 1-3 Alkyl or substituted or unsubstituted C 1-3 It may be haloalkyl.

[0119] In one embodiment, Q can be hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl.

[0120] In one embodiment, Z can be substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted butyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted phenyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted oxetanyl.

[0121] In one embodiment, the compound may be any one selected from Table 2 below.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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, triethylamine 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.

[0132] As used herein, the term “hydrate” means a compound in which water (H2O) is bound to another compound.

[0133] 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.

[0134] 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.

[0135] In one embodiment, the cancer may be a cancer expressing AR, a tumor harboring a loss of function mutation of CBP or p300, or a cancer with activation of CBP and / or p300 function.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] Hereinafter, the present invention will be described in more detail through manufacturing examples, working examples, and experimental examples. However, the following working examples and experimental examples are intended to illustrate the present invention and are not intended to limit the scope of the present invention.

[0143] A compound having the structure of the above chemical formula I can be synthesized by the following method.

[0144] <Reaction Formula I>

[0145]

[0146] <Reaction Formula II>

[0147]

[0148] <Reaction Formula III>

[0149]

[0150] <Reaction Scheme IV>

[0151]

[0152] 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.)

[0153] 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)

[0154] Each starting material was a known compound, synthesized according to the literature, or purchased commercially.

[0155]

[0156] Intermediate synthesis method

[0157] Intermediate I-1: Preparation of 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0158] Step 1: Preparation of 5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0159] 4-Nitrobenzene-1,2-diamine (10 g, 65.3 mmol) was dissolved in tetrahydrofuran (365 mL), cooled to 0°C, and 1,1'-carbonyldiimidazole (21 g, 130.6 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was distilled under reduced pressure, and the resulting solid was washed with diethyl ether, 1 N hydrochloric acid, and water. The solid was dried under vacuum to obtain the title compound. (9.59 g, 53.5 mmol, 82% yield)

[0160] 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).

[0161] Step 2: Preparation of 1,3-dimethyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0162] 5-Nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (4.9 g, 27.5 mmol) obtained in Step 1 was dissolved in dimethylformamide (70 mL) and cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 4.4 g, 110 mmol) was added little by little, and iodomethane (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 oil 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)

[0163] 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).

[0164] Step 3: Preparation of 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0165] 1,3-Dimethyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (3.5 g, 16.9 mmol) obtained in Step 2 was dissolved in ethyl acetate (50 mL) and methanol (50 mL), and palladium / carbon (10 wt %, 0.7 g) was added. After the reaction system was replaced with hydrogen using a hydrogen balloon, the reaction solution was stirred under hydrogen conditions for 3 hours. After the reaction was completed, the reaction solution was filtered through a Celite pad to remove the catalyst. The filtrate was distilled 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)

[0166] 1 H-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).

[0167]

[0168] Intermediate I-2 (Synthetic Method IA): Preparation of 6-amino-4-chloro-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0169] Step 1: Preparation of 3-chloro-5-nitrobenzene-1,2-diamine

[0170] Sodium sulfide pentahydrate (3.95 g, 37.2 mmol) and sulfur (1.194 g, 37.2 mmol) were added to a solution of water (25 mL) and ethanol (6 mL) and stirred at 100°C for 15 minutes. A mixture of 2-chloro-4,6-dinitroaniline (5.4 g, 24.82 mmol) and ammonium chloride (1.991 g, 37.2 mmol) dissolved in ethanol (50 mL) and water (25 mL) was added dropwise to the reaction solution over 10 minutes. The reaction solution was stirred at 65°C for 1 hour. Then, 6 N sodium hydroxide (12.41 mL, 74.5 mmol) was added dropwise over 10 minutes and stirred at 65°C for 1 hour. The reaction mixture was cooled to 0°C, and 6 N hydrochloric acid (11.5 mL, 69 mmol) was added over 20 minutes, followed by water (25 mL). The reaction mixture was stirred at 0°C for 40 minutes, and the suspension was filtered. The filter cake was washed with water and ethanol, and dried under nitrogen to obtain a yellow solid (4 g, 21.32 mmol, 86% yield).

[0171] 1 H-NMR (500 MHz, Chloroform-d) δ 7.88 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 4.47 (s, 2H), 3.69-3.48 (m, 2H).

[0172] Step 2: Preparation of 4-chloro-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0173] 3-Chloro-5-nitrobenzene-1,2-diamine (4 g, 21.32 mmol) obtained in Step 1 was dissolved in dimethylformamide (80 mL), and 1,1'-carbonyldiimidazole (5.19 g, 32.0 mmol) was added at room temperature. The mixture was stirred at room temperature for 18 h. The reaction solution was cooled to 0°C, and water (80 mL) and 6 N hydrochloric acid (10.7 mL) were added, followed by stirring for 30 min. The suspension was filtered, and the filter cake was washed with methyl t-butyl ether and dried under nitrogen blowing conditions to obtain the title compound. (3.6 g, 16.86 mmol, 79% yield)

[0174] 1 H-NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 1.8 Hz, 1H), 7.70-7.66 (m, 1H).

[0175] Step 3: Preparation of 4-chloro-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0176] 4-Chloro-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (7.2 g, 33.7 mmol) obtained in Step 2 was dissolved in dimethylformamide (100 mL), and potassium carbonate (13.98 g, 101 mmol) and iodomethane (8.39 mL, 135 mmol) were added. The reaction solution was stirred for 3 hours. After the mixture was cooled to 0°C, water (100 mL) was added, and the mixture was stirred for 20 minutes. The solid formed during the reaction was filtered, and the filtered solid was washed with water, finally with methyl t-butyl ether, and dried under nitrogen to obtain the title compound. (5.9 g, 24.42 mmol, 72.4% yield)

[0177] 1 H-NMR (500 MHz, DMSO-d6) δ 8.07 (d, J = 1.8 Hz, 1H), 8.03-8.00 (1H), 3.66 (s, 3H), 3.43 (s, 3H).

[0178] Step 4: Preparation of 6-amino-4-chloro-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0179] Step 3: 4-Chloro-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (3 g, 12.42 mmol) and stannous chloride dihydrate (8.40 g, 37.2 mmol) were added to ethanol (30 mL) and stirred at 70°C for 5 h. The reaction solution was cooled to room temperature, water (40 mL) was added, and 6 N sodium hydroxide (40-60 mL) was added at 0°C to adjust the pH to about 10-12. After stirring for 20 min, the oil layer was extracted with ethyl acetate and washed with brine. The solid obtained by concentration under reduced pressure was used in the next reaction without further purification. (2.7 g, 12.76 mmol, 100% yield)

[0180] 1 H-NMR (500 MHz, Chloroform-d) δ 6.38 (s, 1H), 6.22 (s, 1H), 3.66 (s, 3H), 3.59 (s, 2H), 3.33 (s, 3H).

[0181]

[0182] Intermediate I-4 (Synthetic Method IB): Preparation of 6-amino-1,3-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0183] Step 1: Preparation of 4-(3,6-dihydro-2H-pyran-4-yl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0184] 4-Chloro-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound of step 3 of Synthesis IA, 1.2 g, 4.97 mmol) was added to 1,4-dioxane (20 mL), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.148 g, 5.46 mmol), potassium carbonate (1.373 g, 9.93 mmol), Xphos Pd G2 (0.195 g, 0.248 mmol), and Xphos (0.237 g, 0.497 mmol) were added, and the mixture was bubbled with nitrogen for 5 minutes. The reaction mixture was stirred at 90°C under nitrogen for 18 hours. After cooling to room temperature, water was added, extracted with ethyl acetate, and the oil layer was washed with brine. The oil layer was concentrated under reduced pressure and separated by MPLC to obtain the title compound.

[0185] 1 H-NMR (500 MHz, Chloroform-d) δ 7.85 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 5.86 (s, 1H), 4.35 (t, J = 2.6 Hz, 2H), 3.99 (t, J = 5.3 Hz, 2H), 3.56-3.52 (3H), 3.51 (s, 3H), 2.46 (d, J = 2.1 Hz, 2H).

[0186] Step 2: Preparation of 6-amino-1,3-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0187] 4-(3,6-dihydro-2H-pyran-4-yl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.45 g, 5.01 mmol) obtained in Step 1 was added to methanol (2 mL), and dihydroxypalladium (0.352 g, 2.506 mmol) was added. The solution was stirred at 60°C for 4 h under hydrogen conditions. The reaction solution was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The obtained material was used in the next reaction without further purification.

[0188] 1 H-NMR (500 MHz, DMSO-d6) δ 6.26 (s, 1H), 6.20 (s, 1H), 4.78 (s, 2H), 3.99-3.84 (m, 2H), 3.49 (d, J = 11.0 Hz, 4H), 3.19 (s, 3H), 1.74-1.59 (m, 4H).

[0189]

[0190] Intermediate I-8 (Synthetic method IC): Preparation of 6-amino-1,3-dimethyl-4-(propylamino)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0191] Step 1: Preparation of 1,3-dimethyl-6-nitro-4-(propylamino)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0192] 6-Amino-4-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (Intermediate I-3, 100 mg, 0.350 mmol) and propan-1-amine (0.057 mL, 0.699 mmol) were stirred with tris(dibenzylideneacetone)dipalladium(0) (28.5 mg, 0.035 mmol), Xantphos (60.7 mg, 0.105 mmol), and cesium carbonate (297 mg, 1.398 mmol) in the presence of toluene (3.5 mL) at 100°C for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (66 mg, 0.250 mmol, 71.4% yield)

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

[0194] 1,3-Dimethyl-6-nitro-4-(propylamino)-1,3-dihydro-2H-benzo[d]imidazol-2-one (66 mg, 0.250 mmol) obtained in Step 1 was added to stannous chloride dihydrate (169 mg, 0.749 mmol) in ethanol (1 mL) and stirred at 60°C for 18 hours. After quenching the reaction using 1 N sodium hydroxide, the oil layer was extracted using ethyl acetate, washed thoroughly with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the title compound. (50 mg, 0.213 mmol, 85% yield)

[0195] 1H-NMR (500 MHz, DMSO-d6) δ 5.74 (s, 2H), 4.76 (t, J = 5.6 Hz, 1H), 4.63 (s, 2H), 3.48 (s, 3H), 3.13 (s, 3H), 2.93 (dd, J = 13.0, 6.9 Hz, 2H), 1.60 (p, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0196]

[0197] Intermediate I-12: Preparation of 6-amino-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0198] Step 1: Preparation of N1-methyl-5-nitrobenzene-1,2-diamine

[0199] 4-Nitrobenzene-1,2-diamine (1.53 g, 9.99 mmol) and potassium carbonate (2.76 g, 19.98 mmol) were mixed in dimethylformamide (15 mL) with iodomethane (0.625 mL, 9.99 mmol), and stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed once with water, twice with brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (720 mg, 4.31 mmol, 43.1% yield)

[0200] 1 H-NMR (500 MHz, DMSO-d6) δ 7.50 (d, 1H), 7.11 (s, 1H), 6.56 (s, 1H), 6.12 (br s, 2H), 5.20 (s, 1H), 2.79 (d, 3H); LC / MS: 168 (M+H).

[0201] Step 2: Preparation of 1-methyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0202] N1-Methyl-5-nitrobenzene-1,2-diamine (720 mg, 4.31 mmol) obtained in Step 1 was dissolved in tetrahydrofuran (30 mL), 1,1'-carbonyldiimidazole (838 mg, 5.17 mmol) was added, and the mixture was stirred at 80°C for 6 hours and at room temperature for 3 days. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was precipitated by trituration with ethyl acetate and dried to obtain the title compound. (614 mg, 3.18 mmol, 73.8% yield)

[0203] 1 H-NMR (500 MHz, DMSO-d6) δ 11.63 (br s, 1H), 8.01 (d, 1H), 7.99 (s, 1H), 7.15 (d, 1H), 3.78 (s, 3H); LC / MS: 192 (MH).

[0204] Step 3: Preparation of 6-amino-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0205] The title compound was obtained in a similar manner to step 3 of the synthesis of intermediate I-1 using 1-methyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (400 mg, 2.071 mmol) obtained in step 2 as a starting material. (331 mg, 2.028 mmol, 98% yield)

[0206] LC / MS: 164 (M+H).

[0207]

[0208] Intermediate I-13 (Synthetic Method ID): Preparation of 6-amino-1,3-dimethyl-4-(pyrrolidin-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0209] Step 1: Preparation of 1,3-dimethyl-6-nitro-4-(pyrrolidin-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0210] The title compound was obtained in a similar manner to step 1 of synthetic method IC using 6-amino-4-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-3, 300 mg, 1.049 mmol) and pyrrolidine (0.086 mL, 1.049 mmol). (160 mg, 0.579 mmol, 55.2% yield)

[0211] Step 2: Preparation of 6-amino-1,3-dimethyl-4-(pyrrolidin-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0212] 1,3-Dimethyl-6-nitro-4-(pyrrolidin-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (131 mg, 0.474 mmol) obtained in Step 1 was added to palladium / carbon (50.5 mg, 0.047 mmol) in a solvent of methanol (1.2 mL) and ethyl acetate (1.2 mL), and stirred under hydrogen gas for 18 hours. After completion of the reaction, the residue was filtered through Celite and concentrated under reduced pressure, and the title compound was obtained by purification using MPLC. (110 mg, 0.474 mmol, 94% yield)

[0213] 1 H-NMR (500 MHz, Chloroform-d) δ 6.26 (br s, 1H), 6.10 (br s, 1H), 3.61 (s, 3H), 3.54 (br s, 2H), 3.33 (s, 3H), 3.11 (br s, 2H), 3.02 (br s, 2H), 2.01 (br s, 2H), 1.93 (br s, 2H).

[0214]

[0215] Intermediate I-18 (Synthetic Method IE): Preparation of 6-amino-4-isopropoxy-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0216] Step 1: Preparation of 4-hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0217] To a solution of 4-bromo-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (15 g, 52.4 mmol) and potassium hydroxide (3.53 g, 62.9 mmol) in 1,4-dioxane (300 mL) were added tris(dibenzylideneacetone)dipalladium(0) (4.80 g, 5.24 mmol) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos) (4.45 g, 10.5 mmol), and nitrogen was blown in. The mixture was stirred at 100°C for 18 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtered solid was eluted by washing with 1,4-dioxane. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the title compound. (5 g, 21.7 mmol, 41.4% yield)

[0218] 1 H-NMR (400 MHz, Chloroform-d) δ 10.75 (s, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 3.53 (s, 3H), 3.35 (s, 3H); LC / MS: 224 (M+H).

[0219] Step 2: Preparation of 4-isopropoxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0220] 4-Hydroxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.116 g, 5.0 mmol) and potassium carbonate (0.829 g, 6.00 mmol) were dissolved in acetonitrile (25.00 mL). 2-Iodopropane (0.549 mL, 5.50 mmol) was added and stirred at 82°C for 10 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The obtained oil layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (1.065 g, 4.01 mmol, 80% yield)

[0221] 1 H-NMR (500 MHz, Chloroform-d) δ 7.64 (s, 1H), 7.59 (s, 1H), 4.79-4.74 (m, 1H), 3.71 (s, 3H), 3.48 (s, 3H), 1.46 (d, J = 5.8 Hz, 6H); LC / MS: 266 (M+H).

[0222] Step 3: Preparation of 6-amino-4-isopropoxy-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0223] The title compound was obtained in a similar manner to step 2 of Synthetic Method ID using 4-isopropoxy-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.06 g, 4.00 mmol) obtained in step 2 as a starting material. (812 mg, 3.45 mmol, 86% yield)

[0224] 1 H-NMR (500 MHz, Chloroform-d) δ 6.04 (s, 1H), 5.98 (s, 1H), 4.57-4.50 (m, 1H), 3.56 (d, J = 7.6 Hz, 5H), 3.31 (s, 3H), 1.36 (d, J = 6.1 Hz, 6H); LC / MS: 236 (M+H).

[0225]

[0226] Intermediate I-24: Preparation of 4-acetyl-6-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0227] Step 1: Preparation of 4-(1-ethoxyvinyl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0228] 4-Bromo-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (400 mg, 1.398 mmol) was dissolved in 1,4-dioxane (6 mL), and tributyl(1-ethoxyvinyl)stannane (0.566 mL, 1.678 mmol) and bis(triphenylphosphine)palladium(II) dichloride (49.1 mg, 0.070 mmol) were added. The solution was bubbled with nitrogen for 5 min. The reaction solution was stirred at 90°C under nitrogen for 18 h. Water and 1 N hydrochloric acid were added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The oil 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. (218.8 mg, 0.789 mmol, 56.4% yield)

[0229] 1 H-NMR (500 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.85 (s, 1H), 4.51 (s, 1H), 4.41 (s, 1H), 3.98 (q, J = 6.9 Hz, 2H), 3.53 (s, 3H), 3.51 (s, 3H), 1.42 (t, J = 6.9 Hz, 3H).

[0230] Step 2: Preparation of 4-acetyl-6-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0231] The title compound was obtained in a similar manner to step 2 of synthetic method IC using 4-(1-ethoxyvinyl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (125 mg, 0.451 mmol) obtained in step 1 as a starting material. (73.5 mg, 0.335 mmol, 74.4% yield)

[0232] 1 H-NMR (500 MHz, Chloroform-d) δ 6.68 (s, 1H), 6.49 (s, 1H), 3.67 (s, 2H), 3.42-3.35 (6H), 2.62 (s, 3H); LC / MS: 220(M+H).

[0233]

[0234] Intermediate I-43 (Synthetic method IF): Preparation of 6-amino-1,3-dimethyl-4-(pyridin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0235] Step 1: Preparation of 1,3-dimethyl-6-nitro-4-(pyridin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0236] 4-Bromo-1,3-dimethyl-6-nitro-1,3-benzodiazol-2-one (5 g, 17.48 mmol) and pyridin-4-yl boronic acid (4.30 g, 34.95 mmol) were added to 1,4-dioxane (150 mL) and water (25 mL), tetrakis(triphenylphosphine)palladium (2.02 g, 1.748 mmol) and sodium carbonate (7.41 g, 69.91 mmol) were added, and the mixture was stirred at 100°C for 24 h. The reaction mixture was cooled to room temperature, filtered, and washed with dichloromethane. The filtrate was washed with brine, and the oil layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound was obtained by separation by MPLC. (3 g, 9.97 mmol, 57.06% yield)

[0237] LC / MS: 285 (M+H).

[0238] Step 2: Preparation of 6-amino-1,3-dimethyl-4-(pyridin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0239] The title compound was obtained in a similar manner to step 2 of synthetic method ID using 1,3-dimethyl-6-nitro-4-(pyridin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2.5 g, 8.79 mmol) obtained in step 1 as a starting material. (1.5 g, 5.69 mmol, 64.73% yield)

[0240] 1 H-NMR (400 MHz, DMSO-d6) δ 8.69-8.53 (m, 2H), 7.50-7.29 (m, 2H), 6.44 (d, J = 2.1 Hz, 1H), 6.16 (d, J = 2.1 Hz, 1H), 4.99 (s, 2H), 3.26 (s, 3H), 2.82 (s, 3H).

[0241]

[0242] Intermediate I-50: Preparation of 1-bromo-2-(difluoromethyl)-4-fluoro-5-nitrobenzene

[0243] Step 1: Preparation of (2-bromo-5-fluorophenyl)methyl 2,2-dimethylpropionate

[0244] (2-Bromo-5-fluorophenyl)methanol (200 g, 0.976 mol) and triethylamine (370.7 mL, 2.93 mol) were dissolved in dichloromethane (3 L), and then trimethylacetyl chloride (141.15 g, 1.17 mol) was slowly added dropwise under nitrogen at 0°C. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, water was added, and the oil layer was extracted with dichloromethane. The oil 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. (144 g, 0.498 mol, 51.1% yield)

[0245] Step 2: Preparation of (2-bromo-5-fluoro-4-nitrophenyl)methanol

[0246] (2-Bromo-5-fluorophenyl)methyl 2,2-dimethylpropionate (160 g, 553.36 mmol) obtained in Step 1 was dissolved in sulfuric acid (1.6 L), and then potassium nitrate (67.13 g, 664.03 mmol) was slowly added dropwise at 0°C under nitrogen conditions. The reaction solution was stirred at 0°C for 3 hours. After the reaction was completed, ice water was poured into the reaction solution, and the oil layer was extracted with dichloromethane. The oil 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. (50 g, 199.98 mmol, 36.14% yield)

[0247] Step 3: Preparation of 2-bromo-5-fluoro-4-nitrobenzaldehyde

[0248] (2-Bromo-5-fluoro-4-nitrophenyl)methanol (40 g, 159.99 mmol) obtained in Step 2 was dissolved in dichloromethane (500 mL), and Dess-Martin (135.71 g, 319.97 mmol) was slowly added dropwise at 0°C under nitrogen conditions. The reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, a saturated aqueous sodium thiosulfate solution was added at room temperature, and the oil layer was extracted with dichloromethane. The oil 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. (30.8 g, 124.2 mmol, 77.63% yield)

[0249] 1 H-NMR (400 MHz, DMSO-d6) δ 10.16 (d, J = 2.6 Hz, 1H), 8.55 (d, J = 6.5 Hz, 1H), 7.93 (d, J = 10.8 Hz, 1H).

[0250] Step 4: Preparation of 1-bromo-2-(difluoromethyl)-4-fluoro-5-nitrobenzene

[0251] 2-Bromo-5-fluoro-4-nitrobenzaldehyde (31.5 g, 127 mmol) obtained in Step 3 was dissolved in dichloromethane (300 mL), and then diethylaminosulfur trifluoride (35.2 mL, 267 mmol) was added at 0°C. The reaction solution was stirred for 4 hours. After the reaction was completed, water was slowly added at 0°C to quench the reaction, and the oil layer was extracted with dichloromethane. The oil layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (32.4 g, 120 mmol, 94% yield)

[0252] 1 H-NMR (500 MHz, Chloroform-d) δ 8.33 (d, J = 6.7 Hz, 1H), 7.64 (d, J = 10.4 Hz, 1H), 6.87 (t, J = 54.0 Hz, 1H).

[0253]

[0254] Intermediate I-51: Preparation of 1-bromo-2-(difluoromethoxy)-4-fluoro-5-nitrobenzene

[0255] Step 1: Preparation of 1-bromo-2-(difluoromethoxy)-4-fluorobenzene

[0256] 2-Bromo-5-fluorophenol (25 g, 130.89 mmol) was dissolved in dimethylformamide, and sodium carbonate (27.75 g, 261.78 mmol) was slowly added at room temperature, followed by slow addition of 2-chloro-2,2-difluoroacetic acid (25.62 g, 196.34 mmol). The reaction solution was stirred at room temperature under nitrogen for 3 hours. After the reaction was completed, water was added, and the oil layer was extracted with ethyl acetate. The oil 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. (16.6 g, 68.85 mmol, 52.62% yield)

[0257] Step 2: Preparation of 1-bromo-2-(difluoromethoxy)-4-fluoro-5-nitrobenzene

[0258] 1-Bromo-2-(difluoromethoxy)-4-fluorobenzene (7.8 g, 32.36 mmol) obtained in Step 1 was dissolved in sulfuric acid, and potassium nitrate (4.58 g, 45.31 mmol) was added little by little at -10℃. The reaction solution was stirred at 0℃ under nitrogen for 3 hours. After the reaction was completed, ice was added to stop the reaction. Water was added, and the oil layer was extracted with ethyl acetate. The oil layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (5.1 g, 17.80 mmol, 55.10% yield)

[0259] 1 H-NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 11.0 Hz, 1H), 6.71 (t, 1H).

[0260]

[0261] Intermediate I-52: Preparation of 1-bromo-4-fluoro-5-nitro-2-(trifluoromethoxy)benzene

[0262] Step 1: Preparation of 2-fluoro-1-nitro-4-(trifluoromethoxy)benzene and 4-fluoro-1-nitro-2-(trifluoromethoxy)benzene

[0263] A mixture of the two title compounds was obtained in a similar manner to step 2 of the synthesis of intermediate I-51 using 1-fluoro-3-(trifluoromethoxy)benzene (15 g, 83.29 mmol) as a starting material. (12.1 g, 53.72 mmol, 64.54% yield)

[0264] LC / MS: 226 (M+H).

[0265] Step 2: Preparation of 1-bromo-4-fluoro-5-nitro-2-(trifluoromethoxy)benzene and 1-bromo-2-fluoro-5-nitro-4-(trifluoromethoxy)benzene

[0266] A mixture of 2-fluoro-1-nitro-4-(trifluoromethoxy)benzene and 4-fluoro-1-nitro-2-(trifluoromethoxy)benzene obtained in Step 1 (15 g, 66.64 mmol) and sulfuric acid (3 mL) was dissolved in trifluoroacetic acid (150 mL), and N-bromosuccinimide (35.58 g, 199.91 mmol) was slowly added little by little at room temperature. The reaction solution was stirred at 80°C for 18 hours. After the reaction was completed, water was added, and the oil layer was extracted with ethyl acetate. The oil layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to obtain a mixture of the two title compounds. (10.2 g, 33.72 mmol, 50.6% yield)

[0267] 1 H-NMR (400 MHz, Chloroform-d) δ 8.33 (d, J = 7.7 Hz, 1H), 8.23 ​​(d, J = 6.7 Hz, 1H), 7.30-7.16 (m, 2H); LC / MS: 304 (M+H)(isomer mixture).

[0268]

[0269] Intermediate I-53: Preparation of 2-bromo-5-fluoro-4-nitrophenol

[0270] 1-Bromo-4-fluoro-2-methoxy-5-nitrobenzene (5 g, 20 mmol) was dissolved in 1,2-dichloroethane (100 mL), and then boron tribromide (7.51 g, 30 mmol) was slowly added at 0°C. The reaction solution was stirred at 60°C under nitrogen for 18 h. After the reaction was completed, ice and water were added at 0°C, and the oil layer was extracted with ethyl acetate. The oil 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. (2.3 g, 9.82 mmol, 49.1% yield)

[0271] 1 H-NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 13.0 Hz, 1H).

[0272]

[0273] Intermediate I-54: Preparation of 1-(benzyloxy)-2-bromo-5-fluoro-4-nitrobenzene

[0274] Benzyl bromide (0.214 mL, 1.80 mmol) was added to a solution of 2-bromo-5-fluoro-4-nitrophenol (intermediate I-53, 354 mg, 1.50 mmol), potassium carbonate (415 mg, 3.00 mmol), and potassium iodide (24.9 mg, 0.15 mmol) in acetone (6.00 mL), and the mixture was stirred at 56°C for 18 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The obtained oil layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (456 mg, 1.40 mmol, 93% yield)

[0275] 1H-NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 7.9 Hz, 1H), 7.46-7.37 (m, 5H), 6.80 (d, J = 12.2 Hz, 1H), 5.24 (s, 2H); LC / MS: 326 (M+H).

[0276]

[0277] Intermediate I-55: Preparation of 4-(2,4-difluoro-5-nitrophenyl)-1-methyl-1H-pyrazole

[0278] Bromo-2,4-difluoro-5-nitrobenzene (3 g, 12.61 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.67 g, 17.65 mmol), and tetrakis(triphenylphosphine)palladium (0.728 g, 0.630 mmol) were stirred with sodium carbonate (2.67 g, 25.2 mmol) in the presence of 1,4-dioxane (40 mL) and water (10 mL) at 90°C for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (2.75 g, 11.5 mmol, 91% yield)

[0279] 1 H-NMR (500 MHz, Chloroform-d) δ 8.30 (t, J = 7.71 Hz, 1H), 7.87 (s, 1H), 7.81 (s, 1H), 7.10 (t, J = 10.22 Hz, 1H), 3.99 (s, 3H); LC / MS: 240 (M+H).

[0280]

[0281] Intermediate I-56: Preparation of ((2,4-difluoro-5-nitrophenyl)ethynyl)trimethylsilane

[0282] 1-Bromo-2,4-difluoro-5-nitrobenzene (213 mg, 0.895 mmol), bis(triphenylphosphine)palladium(II) dichloride (62.8 mg, 0.090 mmol), copper(I) iodide (25.6 mg, 0.134 mmol), and triethylamine (624 μL, 4.48 mmol) were dissolved in toluene (4.8 mL), and then ethynyltrimethylsilane (371 μL, 2.69 mmol) was added. The reaction solution was stirred at room temperature for 7 h. After the reaction was completed, water was added, and the oil layer was extracted with ethyl acetate. The oil 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. (197 mg, 0.772 mmol, 86% yield)

[0283] 1 H-NMR (500 MHz, Chloroform-d) δ 8.25 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 9.3 Hz, 1H), 0.28 (s, 9H).

[0284]

[0285] Intermediate I-57: Preparation of 5-(2,4-difluoro-5-nitrophenyl)-3-methyl-1,2,4-oxadiazole

[0286] Step 1: Preparation of 2,4-difluoro-5-nitrobenzoic acid

[0287] Methyl 2,4-difluoro-5-nitrobenzoate (1 g, 4.61 mmol) was dissolved in tetrahydrofuran (10 mL) and water (5 mL), and lithium hydroxide (0.221 g, 9.21 mmol) was slowly added. The reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure and diluted with ethyl acetate. The pH of the reaction solution was adjusted to 5-6 with 1 N aqueous hydrochloric acid solution, and the oil layer was extracted. The oil layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound. It was used directly in the next step without further purification. (955 mg, 4.70 mmol, 100% yield)

[0288] 1 H-NMR (500 MHz, DMSO-d6) δ 13.86 (s, 1H), 8.61 (t, J = 7.8 Hz, 1H), 7.87 (t, J = 10.8 Hz, 1H).

[0289] Step 2: Preparation of 5-(2,4-difluoro-5-nitrophenyl)-3-methyl-1,2,4-oxadiazole

[0290] 2,4-Difluoro-5-nitrobenzoic acid (200 mg, 0.99 mmol) and N-hydroxyacetimidamide (76 mg, 0.99 mmol) obtained in Step 1 were dissolved in ethyl acetate (2.5 mL), triethylamine (0.4 mL, 2.95 mmol) was added, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50 % wt in ethyl acetate, 5 mL, 2.46 mmol) was slowly added. The reaction solution was stirred at 80°C for 18 hours. After the reaction was completed, water was added, and the oil layer was extracted with ethyl acetate. The oil layer was washed with a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (68.8 mg, 0.285 mmol, 29.0% yield)

[0291] 1 H-NMR (500 MHz, Chloroform-d) δ 8.92 (t, J = 7.2 Hz, 1H), 7.28 (t, J = 9.6 Hz, 1H), 2.49 (s, 3H).

[0292]

[0293] Intermediate I-58: Preparation of 2,2-dimethyl-3-oxopropanenitrile

[0294] Step 1: Preparation of 3-hydroxy-2,2-dimethylpropanenitrile

[0295] Sodium borohydride (8.93 g, 235.96 mmol) was dissolved in methanol (100 mL) and stirred at 0°C for 5 minutes. Methyl 2-cyano-2,2-dimethylacetate (10 g, 78.65 mmol) was slowly added at 0°C over 5 minutes. The reaction solution was stirred at room temperature for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and water and dichloromethane were added to extract the oil layer. The oil layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (6.4 g, 64.6 mmol, 82.1% yield)

[0296] 1 H-NMR (400 MHz, DMSO-d6) δ 5.43 (t, J = 5.7 Hz, 1H), 3.36 (d, J = 5.4 Hz, 2H), 1.23 (s, 6H).

[0297] Step 2: Preparation of 2,2-dimethyl-3-oxopropanenitrile

[0298] Oxalyl chloride (8.25 mL, 96.84 mmol) was dissolved in dichloromethane (80 mL), and dimethyl sulfoxide (8.60 mL, 121.05 mmol) was added at -78°C under nitrogen conditions. 3-Hydroxy-2,2-dimethylpropanenitrile (8 g, 80.7 mmol) obtained in step 1 was slowly added at -78°C. The reaction solution was stirred at -78°C for 40 minutes under nitrogen conditions. Triethylamine (56.09 mL, 403.5 mmol) was slowly added at -78°C over 5 minutes. The reaction solution was further stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the oil layer was extracted by adding water and ethyl acetate. The oil layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound. It was used directly in the next step without further purification. (4 g, 41.16 mmol, 51.0% yield)

[0299] 1 H-NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 1.32-1.00 (m, 6H).

[0300] In addition, intermediates synthesized in a similar manner as above and their synthesis methods are shown in Table 1.

[0301] No. Compound name 1 H-NMR / MS Synthesis method I-36-Amino-4-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 6.59 (s, 1H), 6.29 (s, 1H), 3.90 (s, 3H), 3.60 (s, 2H), 3.35 (s, 3H); m / z NDI-AI-5-tert-Butyl 4-(6-amino-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate 1H-NMR (500 MHz, DMSO-d6) δ 6.90 (d, J = 2.1 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H), 5.96 (s, 1H), 4.78 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.55-3.42 (m, 2H), 3.33 (t, J = 5.5 Hz, 2H), 2.07 (s, 2H), 1.42 (s, 9H); m / z NDI-FI-66-amino-1,3-dimethyl-4-((2-morpholinoethyl)amino)-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Methanol-d4) δ 6.01 (t, J = 2.3 Hz, 2H), 3.75-3.68 (m, 4H), 3.65 (s, 3H), 3.28 (s, 3H), 3.22 (t, J = 6.2 Hz, 2H), 2.68 (t, J = 6.2 Hz, 2H), 2.53 (s, 4H); m / z NDI-CI-76-amino-4-(cyclopentylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 6.15-6.13 (m, 1H), 6.12 (s, 1H), 3.81-3.75 (m, 1H), 3.65 (s, J = 5.7 Hz, 3H), 3.30 (s, 3H), 2.07-2.00 (m, 2H), 1.73 (dt, J = 12.3, 3.7 Hz, 2H), 1.68-1.59 (m, 2H), 1.55-1.48 (m, 2H); m / z NDI-CI-96-amino-4-(cyclopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1H-NMR (500 MHz, Methanol-d4) δ 6.43 (d, J = 1.9 Hz, 1H), 6.05 (d, J = 1.9 Hz, 1H), 3.56 (s, 3H), 3.28 (s, 3H), 2.45-2.39 (m, 1H), 0.78-0.72 (m, 2H), 0.53-0.48 (m, 2H); m / z NDI-CI-106-amino-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, DMSO-d6) δ 6.16 (d, J = 1.9 Hz, 1H), 6.11 (d, J = 1.9 Hz, 1H), 4.81 (s, 2H), 3.73 (s, 4H), 3.49 (s, 3H), 3.17 (s, 3H), 2.83 (s, 4H); m / z NDI-CI-116-amino-1,3-dimethyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, DMSO-d6) δ 6.25 (d, J = 2.1 Hz, 1H), 6.03 (d, J = 2.1 Hz, 1H), 5.58-5.55 (m, 1H), 4.79 (s, 2H), 3.22 (s, 3H), 3.20 (s, 3H), 2.97 (dd, J = 5.8, 2.8 Hz, 2H), 2.55 (t, J = 5.6 Hz, 2H), 2.32 (d, J = 1.8 Hz, 2H), 2.27 (s, 3H); m / z NDI-FI-146-amino-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 5.85 (s, 2H), 3.64 (s, 3H), 3.60-3.55 (m, 2H), 3.29 (s, 3H), 1.24 (d, J = 5.8 Hz, 6H); m / z NDI-DI-156-amino-4-(cyclopentylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one1 H-NMR (500 MHz, Chloroform-d) δ 5.86 (d, J = 9.61 Hz, 2H), 3.78 (br. s., 1H), 3.64 (s, 4H), 3.30 (s, 3H), 2.04 (d, J = 7.02 Hz, 2H), 1.75 (br. s., 2H), 1.66 (br. s., 2H); m / z NDI-DI-166-amino-4-(cyclobutylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 5.85 (s, 1H), 5.73 (s, 1H), 4.00-3.82 (m, 2H), 3.66 (s, 3H), 3.52 (br. s., 1H), 3.30 (s, 3H), 2.46 (br. s., 2H), 1.98-1.74 (m, 4H); m / z NDI-DI-176-amino-4-(tert-butylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Methanol-d4) δ 6.32 (s, 1H), 6.22 (s, 1H), 3.65 (s, 3H), 1.28 (s, 9H); m / z NDI-DI-196-amino-1,3-dimethyl-4-(phenylamino)-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 7.20 (t, J = 7.55 Hz, 2H), 6.83 (t, J = 7.32 Hz, 1H), 6.70 (d, J = 7.93 Hz, 2H), 6.23 (s, 1H), 6.25 (s, 1H), 5.29 (s, 1H), 3.57 (br. s., 2H), 3.41 (s, 3H), 3.36 (s, 3H); m / z NDI-DI-206-amino-4-((4-fluorophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1H-NMR (500 MHz, Chloroform-d) δ 6.91 (t, J = 8.16 Hz, 2H), 6.66 (br. s., 2H), 6.21 (d, J = 9.77 Hz, 2H), 3.58 (br. s., 2H), 3.41 (s, 3H), 3.36 (s, 3H); m / z NDI-DI-216-amino-4-((4-(dimethylamino)phenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 6.85–6.74 (m, J = 8.54 Hz, 2H), 6.74–6.67 (m, J = 8.54 Hz, 2H), 6.10 (s, 1H), 6.12 (s, 1H), 3.49 (s, 5H), 3.35 (s, 3H), 2.89 (s, 6H); m / z NDI-DI-226-amino-4-((4-methoxyphenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 6.85–6.78 (m, J = 7.48 Hz, 2H), 6.78–6.68 (m, J = 7.48 Hz, 2H), 6.16 (s, 2H), 3.77 (s, 3H), 3.55 (br. s., 2H), 3.45(s, 3H), 3.36 (s, 3H); m / z NDI-DI-236-amino-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 6.39 (s, 1H), 6.22 (s, 1H), 3.61 (s, 3H), 3.57-3.51 (m, 1H), 3.33 (s, 3H), 1.28 (d, J = 6.7 Hz, 6H); m / z 220.I-BI-256-amino-4-(cyclohexylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1H-NMR (500 MHz, Chloroform-d) δ 5.85 (d, J = 11.90 Hz, 2H), 3.65 (s, 4H), 3.52 (br. s., 2H), 3.30 (s, 3H), 3.24 (br. s., 1H), 2.07 (d, J = 13.58 Hz, 2H), 1.77 (d, J = 13.43 Hz, 2H), 1.66 (d, J = 13.58 Hz, 1H), 1.44-1.33 (m, 2H), 1.30-1.18 (m, 3H); m / z NDI-DI-266-amino-4-(sec-butylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 5.84 (s, 2H), 3.69-3.58 (m, 4H), 3.52 (br. s., 2H), 3.38 (d, J = 6.10 Hz, 1H), 3.30 (s, 3H), 1.63 (dd, J = 6.79, 13.96 Hz, 1H), 1.53 (dd, J = 7.17, 14.19 Hz, 1H), 1.21 (d, J = 6.26 Hz, 3H), 0.98 (t, J = 7.48 Hz, 3H); m / z NDI-DI-276-amino-4-(3,3-difluoroazetidin-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (300 MHz, DMSO-d6) δ 6.09–5.99 (m, 2H), 4.24 (s, 1H), 4.18 (d, J = 12.5 Hz, 3H), 3.43 (s, 3H), 3.32 (s, 2H), 3.17 (s, 3H); m / z NDI-DI-286-amino-4-(azetidin-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1H-NMR (300 MHz, Methanol-d4) δ 6.16 (dd, J = 11.7, 2.0 Hz, 2H), 3.82 (t, J = 7.1 Hz, 4H), 3.59 (s, 3H), 3.28 (s, 3H), 2.25 (p, J = 7.1 Hz, 2H); m / z NDI-DI-296-amino-4-(3-hydroxy-3-methylazetidin-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 6.03 (s, 1H), 5.99 (s, 1H), 3.78-3.68 (m, 4H), 3.61 (s, 3H), 3.57 (br. s., 2H), 3.31 (s, 3H), 1.94 (s, 1H), 1.65 (s, 3H); m / z NDI-DI-306-amino-4-(3-hydroxyazetidin-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one ND; m / z 249.I-DI-31 tert-butyl 4-(6-amino-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate 1 H-NMR (400 MHz, DMSO-d6) δ 6.23 (s, 2H), 4.75 (s, 2H), 4.06 (d, J = 13.1 Hz, 2H), 3.48 (s, 3H), 3.27 (d, J = 3.2 Hz, 1H), 3.19 (s, 3H), 2.86 (s, 2H), 1.75 (d, J = 12.9 Hz, 2H), 1.42 (s, 11H); m / z 361.I-BI-32(R)-6-amino-1,3-dimethyl-4-(3-methylmorpholino)-1,3-dihydro-2H-benzo[d]imidazol-2-one 1H-NMR (500 MHz, Chloroform-d) δ 6.24 (s, 1H), 6.15 (s, 1H), 3.96 (d, 1H), 3.86-3.80 (m, 2H), 3.65 (s, 3H), 3.60 (br s, 2H), 3.32 (s, 3H), 2.97 (d, 1H), 2.93-2.86 (m, 2H), 2.58-2.53 (m, 1H), 1.20 (d, 3H); m / z 277.I-DI-33(S)-6-amino-1,3-dimethyl-4-(3-methylmorpholino)-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 6.26 (s, 1H), 6.17 (s, 1H), 3.98 (d, 1H), 3.88-3.82 (m, 2H), 3.66 (s, 3H), 3.62 (br s, 2H), 3.34 (s, 3H), 2.99 (d, 1H), 2.95-2.88 (m, 2H), 2.60-2.55 (m, 1H), 1.22 (d, 3H); m / z 277.I-DI-346-amino-1,3-dimethyl-4-[(2R)-2-methylazetidin-1-yl]-1,3-benzodiazol-2-one 1 H-NMR (300 MHz, DMSO-d6) δ 5.97 (s, 2H), 4.12 (p, J = 6.7 Hz, 1H), 3.84 (ddd, J = 8.5, 6.4, 3.3 Hz, 1H), 3.45 (s, 3H), 3.34-3.26 (m, 1H), 3.15 (s, 3H), 2.21 (dtd, J = 10.6, 7.7, 3.2 Hz, 1H), 2.02-1.80 (m, 1H), 1.18 (d, J = 6.1 Hz, 3H); m / z NDI-DI-35 tert-Butyl 4-(6-amino-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazine-1-carboxylate 1H-NMR (500 MHz, Chloroform-d) δ 6.24 (s, 1H), 6.17 (s, 1H), 4.23-4.00 (m, 2H), 3.67 (s, 3H), 3.59 (br. s., 2H), 3.43-3.29 (m, 3H), 3.04 (br. s., 4H), 2.79 (br. s., 2H), 1.51 (s, 9H); m / z NDI-DI-366-amino-1,3-dimethyl-4-(2-morpholinoethoxy)-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 6.03 (s, 1H), 6.01 (s, 1H), 4.14 (t, J = 5.0 Hz, 2H), 3.73 (s, 4H), 3.58 (s, 3H), 3.31 (s, 3H), 2.83-2.82 (m, 2H), 2.57 (s, 4H); m / z 307.I-EI-376-amino-1,3-dimethyl-4-(oxetan-3-yloxy)-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 6.02 (s, 1H), 5.54 (s, 1H), 5.22 (dd, J = 16.3, 5.3 Hz, 1H), 4.99 (t, J = 6.6 Hz, 2H), 4.80-4.77 (m, 2H), 3.61 (s, 3H), 3.56 (s, 2H), 3.32 (s, 3H); m / z 250.I-EI-386-amino-4-((4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1H-NMR (500 MHz, Chloroform-d) δ 6.31 (s, 1H), 6.10 (s, 1H), 4.62 (br. s., 1H), 4.04 (d, J = 7.63 Hz, 1H), 3.87 (s, 1H), 3.67 (d, J = 7.78 Hz, 1H), 3.65 (s, 3H), 3.57 (br. s., 2H), 3.50 (d, J = 10.22 Hz, 1H), 3.32 (s, 3H), 3.17 (d, J = 10.07 Hz, 1H), 2.08 (d, J = 9.77 Hz, 1H), 1.94 (d, J = 9.61 Hz, 1H); m / z NDI-DI-396-Amino-4-(benzyloxy)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (400 MHz, DMSO-d6) δ 7.50–7.44 (m, 2H), 7.44–7.38 (m, 2H), 7.37–7.30 (m, 1H), 6.15 (d, J = 1.7 Hz, 1H), 5.99 (d, J = 1.7 Hz, 1H), 5.09 (s, 2H), 4.86 (s, 2H), 3.39 (s, 3H), 3.17 (s, 3H); m / z 284.I-EI-406-amino-1,3-dimethyl-4-thiomorpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 6.26 (s, 1H), 6.16 (s, 1H), 3.68-3.62 (m, 3H), 3.58 (br. s., 2H), 3.44-3.27 (m, 5H), 3.18 (br. s., 1H), 3.05 (br. s., 4H), 2.57 (br. s., 2H); m / z NDI-DI-41(R)-6-amino-1,3-dimethyl-4-(2-methylazetidin-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 1H-NMR (300 MHz, DMSO-d6) δ 5.97 (s, 2H), 4.12 (p, J = 6.7 Hz, 1H), 3.84 (ddd, J = 8.5, 6.4, 3.3 Hz, 1H), 3.45 (s, 3H), 3.34-3.26 (m, 1H), 3.15 (s, 3H), 2.21 (dtd, J = 10.6, 7.7, 3.2 Hz, 1H), 2.02-1.80 (m, 1H), 1.18 (d, J = 6.1 Hz, 3H); m / z NDI-DI-426-amino-4-(3-hydroxypyrrolidin-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 6.27 (d, J = 1.98 Hz, 1H), 6.13 (d, J = 1.98 Hz, 1H), 4.55 (br. s., 1H), 3.64 (s, 3H), 3.57 (br. s., 2H), 3.33 (s, 3H), 3.30 (dd, J = 7.93, 15.26 Hz, 1H), 3.22 (dd, J = 5.04, 10.22 Hz, 1H), 3.07 (dd, J = 1.83, 10.22 Hz, 1H), 2.93 (dt, J = 5.87, 8.81 Hz, 1H), 2.36-2.29 (m, 1H), 1.95-1.88 (m, 1H), 1.79 (d, J = 5.49 Hz, 1H); m / z NDI-DI-446-amino-4-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1H-NMR (400 MHz, DMSO-d6) δ 7.20 (s, 1H), 6.12-5.91 (m, 2H), 4.84 (s, 2H), 4.10-3.97 (m, 2H), 3.81 (d, J = 8.6 Hz, 2H), 3.42 (s, 3H), 3.17 (d, J = 5.3 Hz, 3H); m / z NDI-DI-456-amino-4-(4-hydroxy-4-methylpiperidin-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 6.31 (br. s., 1H), 6.13 (d, J = 1.98 Hz, 1H), 3.72-3.64 (m, 3H), 3.60 (br. s., 2H), 3.33 (s, 3H), 3.04 (br. s., 2H), 2.94 (br. s., 2H), 1.84 (br. s., 2H), 1.70 (br. s., 2H), 1.34 (s, 3H); m / z NDI-DI-466-Amino-1,3-dimethyl-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (400 MHz, DMSO-d6) δ 6.18 (d, J = 1.9 Hz, 1H), 6.09 (d, J = 1.9 Hz, 1H), 4.77 (s, 2H), 3.91 (s, 4H), 3.49 (s, 3H), 3.17 (s, 3H), 3.05-2.71 (m, 4H), 1.77 (s, 4H); m / z 319.I-DI-47 tert-butyl (1-(6-amino-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-methylazetidin-3-yl)carbamate 1H-NMR (400 MHz, DMSO-d6) δ 7.35 (s, 1H), 5.95 (d, J = 1.9 Hz, 1H), 5.88 (d, J = 1.9 Hz, 1H), 4.79 (s, 2H), 3.73 (d, J = 6.3 Hz, 2H), 3.60-3.56 (m, 2H), 3.41 (s, 3H), 3.15 (s, 3H), 1.55 (s, 3H), 1.39 (s, 9H); m / z 362.I-DI-486-amino-1,3-dimethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (300 MHz, DMSO-d6) δ 6.26 (d, J = 2.1 Hz, 1H), 6.17 (d, J = 2.0 Hz, 1H), 4.76 (s, 2H), 3.89 (d, J = 1.6 Hz, 4H), 3.47 (s, 3H), 3.18 (s, 4H), 1.71 (qd, J = 9.6, 3.8 Hz, 8H); m / z 318.I-BI-496-amino-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 1 H-NMR (500 MHz, Chloroform-d) δ 6.27 (d, J = 1.98 Hz, 1H), 6.13 (d, J = 1.98 Hz, 1H), 3.64 (s, 3H), 3.56 (br. s., 2H), 3.38-3.30 (m, 4H), 3.11-3.07 (m, 1H), 3.03-2.95 (m, 2H), 2.05 (t, J = 7.10 Hz, 2H), 2.01 (s, 1H), 1.49 (s, 3H); m / z NDI-D

[0302] The synthesis method commonly used in each example is as follows.

[0303] Example 1 (Synthetic Method A): Preparation of 3-(7-chloro-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-methyl-1H-indol-3-yl)benzimidazole-5-sulfonamide

[0304] Step 1: Preparation of 3-fluoro-N-methyl-4-nitrobenzenesulfonamide

[0305]

[0306] A solution of 3-fluoro-4-nitrobenzenesulfonyl chloride (10 g, 41.7 mmol) in dichloromethane (100 mL) was cooled to 0°C, and then a methanamine solution (2 M in tetrahydrofuran, 52.2 mL, 104 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the methylamine salt was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure and used in the next reaction without further purification. (11.4 g, 48.6 mmol, 100% yield)

[0307] 1 H-NMR (400 MHz, Chloroform-d) δ 8.26-8.14 (m, 2H), 7.80 (t, J = 9.3 Hz, 2H), 4.56 (s, 1H), 2.83-2.74 (m, 3H).

[0308] Step 2: Preparation of 3-((7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methyl-4-nitrobenzenesulfonamide

[0309]

[0310] 6-Amino-4-chloro-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (Intermediate I-2, 0.43 g, 2.05 mmol) and 3-fluoro-N-methyl-4-nitrobenzenesulfonamide (0.4 g, 1.71 mmol) obtained in step 1 were added to 1,4-dioxane (10 mL), diisopropylethylamine (0.6 mL, 3.42 mmol) was added, and the mixture was stirred at 80°C for 18 h. The reaction mixture was concentrated under reduced pressure, and the resulting solid was washed with dichloromethane and methanol and filtered. The filter cake was washed with methanol, dried under nitrogen, and used in the next reaction without further purification. (430 mg, 0.73 mmol, 59% yield)

[0311] Step 3: Preparation of 4-amino-3-((7-chloro-1,3-dimethyl-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methylbenzenesulfonamide

[0312]

[0313] 3-((7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methyl-4-nitrobenzenesulfonamide (430 mg, 1.01 mmol) and iron (169 mg, 3.03 mmol) obtained in Step 2 were added to methanol (6 mL) and water (3 mL), ammonium chloride (270 mg, 5.05 mmol) was added, and the reaction solution was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, ethyl acetate (30 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through a pad of Celite, the filtrate was washed with brine, and the water was removed with anhydrous magnesium sulfate. The oil layer was concentrated under reduced pressure and purified by MPLC to obtain the title compound. (220 mg, 0.56 mmol, 55% yield)

[0314] 1H-NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.02 (m, 2H), 6.96 (m, 1H), 6.90 (m, 1H), 6.73 (s, 1H), 6.14 (m, 1H), 4.41 (d, J = 6.5 Hz, 2H), 3.57 (s, 3H), 3.27(s, 3H), 2.37 (d, J = 5 Hz, 3H).

[0315] Step 4: Preparation of 3-(7-chloro-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-methyl-1H-indol-3-yl)benzimidazole-5-sulfonamide

[0316]

[0317] Copper(II) acetate (92 mg, 0.51 mmol) was added to a solution of 4-amino-3-((7-chloro-1,3-dimethyl-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-N-methylbenzenesulfonamide (200 mg, 0.51 mmol) and 6-methyl-1H-indole-3-carbaldehyde (80 mg, 0.51 mmol) obtained in Step 3 in acetic acid (7 mL). The solution was stirred at 80°C for 3 h. The reaction solution was cooled to room temperature, water and 1 N sodium hydroxide were added, and the oil layer was extracted with ethyl acetate and washed with brine. The oil layer was concentrated under reduced pressure and separated by MPLC to obtain the title compound. (16 mg, 0.03 mmol, 5.92% yield)

[0318] 1 H-NMR (500 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.49 (d, 1H), 8.12 (s, 1H), 7.62 (m, 2H), 7.43 (s, 1H), 7.37 (m, 1H), 7.25 (m, 2H), 7.08 (d, 1H), 6.68 (d, 1H), 3.73 (s, 3H), 3.35 (s, 3H), 2.43 (s, 6H).

[0319]

[0320] Examples 3 and 4 (Synthetic Method B): Preparation of methyl 6-bromo-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazole-5-carboxylate and methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazole-5-carboxylate

[0321] Step 1: Preparation of methyl 2-bromo-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-4-nitrobenzoate

[0322]

[0323] 5-Amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (Intermediate I-1, 0.637 g, 3.60 mmol) was dissolved in 1,4-dioxane (9 mL), and methyl 2-bromo-5-fluoro-4-nitrobenzoate (1 g, 3.60 mmol) and diisopropylethylamine (0.942 mL, 5.40 mmol) were added. The reaction solution was stirred at 100°C for 18 h. After the reaction was completed, water was added, and the oil layer was extracted with dichloromethane. The oil 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. (1.5 g, 3.45 mmol, 96% yield)

[0324] 1 H-NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.33 (s, 1H), 7.24 (s, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1H), 7.05 (dd, J = 8.2, 1.8 Hz, 1H), 3.76 (s, 3H), 3.31 (s, 3H).

[0325] Step 2: Preparation of methyl 4-amino-2-bromo-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)benzoate

[0326]

[0327] Methyl 2-bromo-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-4-nitrobenzoate (1.5 g, 3.45 mmol) obtained in Step 1 was dissolved in ethanol (11.50 mL) and water (5.70 mL), and then iron (1.155 g, 20.68 mmol) and ammonium chloride (0.221 g, 4.14 mmol) were added. The reaction solution was stirred at 100°C for 2 hours. After the reaction was completed, the filtrate was passed through a Celite filter, and the filtrate was concentrated and purified by MPLC to obtain the title compound. (1.3 g, 3.21 mmol, 93% yield)

[0328] 1 H-NMR (500 MHz, DMSO-d6) δ 7.51 (s, 1H), 7.03-6.98 (m, 3H), 6.66-6.60 (m, 2H), 3.67 (s, 3H), 3.28 (s, 3H), 3.24 (s, 3H).

[0329] Step 3: Preparation of methyl 6-bromo-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazole-5-carboxylate (Example 3)

[0330]

[0331] 1-Methyl-1H-imidazole-5-carbaldehyde (54.3 mg, 0.494 mmol) and methyl 4-amino-2-bromo-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)benzoate (200 mg, 0.494 mmol) obtained in step 2 were dissolved in acetic acid (8.2 mL), and copper(II) acetate (90 mg, 0.494 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 oil layer was extracted with dichloromethane. The oil 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. (102 mg, 0.206 mmol, 41.7% yield)

[0332] 1 H-NMR (500 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.56 (brs, 1H), 7.51 (s, 1H), 7.16-7.08 (m, 2H), 6.92 (s, 1H), 6.47 (br s, 1H), 4.17 (s, 3H), 3.88 (s, 3H), 3.53 (s, 3H), 3.41 (s, 3H).

[0333] Step 4: Preparation of methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazole-5-carboxylate (Example 4)

[0334]

[0335] Methyl 6-bromo-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazole-5-carboxylate (102 mg, 0.206 mmol) obtained in Step 3, (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (48.7 mg, 0.247 mmol) and tripotassium phosphate (87 mg, 0.412 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 (16.82 mg, 0.021 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 oil layer was extracted with dichloromethane. The oil 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. (111 mg, 0.196 mmol, 95% yield)

[0336] 1 H-NMR (500 MHz, Chloroform-d) δ 8.12 (t, J = 8.1 Hz, 1H), 7.73 (s, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.17-7.12 (m, 3H), 6.96 (s, 1H), 6.83-6.80 (m, 1H), 6.47 (s, 1H), 4.17 (s, 3H), 3.59 (s, 3H), 3.52 (s, 3H), 3.41 (s, 3H), 3.05 (d, J = 4.3 Hz, 3H); LC / MS: 568 (M+H).

[0337]

[0338] Example 6 (Synthetic Method C): Preparation of 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile

[0339] Step 1: Preparation of 4-amino-2-bromo-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)benzonitrile

[0340]

[0341] The title compound was obtained in a similar manner to step 1 and step 2 of Synthetic Method B using 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-1, 56 mg, 0.316 mmol) and 5-fluoro-4-nitrobenzonitrile (77 mg, 0.316 mmol) as starting materials. (70.5% yield over 2 steps)

[0342] Step 2: Preparation of 4-amino-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)benzonitrile

[0343]

[0344] 4-Amino-2-bromo-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)benzonitrile (78 mg, 0.210 mmol) obtained in Step 1, potassium carbonate (57.9 mg, 0.419 mmol), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (52.3 mg, 0.251 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 (17.11 mg, 0.021 mmol) was added. The reaction mixture was stirred at 100°C under nitrogen for 18 hours. After the reaction was completed, water was added, and the oil layer was extracted with dichloromethane. The oil 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. (54 mg, 0.145 mmol, 69.0% yield)

[0345] 1 H-NMR (500 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.84 (s, 1H), 7.25 (s, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J = 7.0 Hz, 1H), 6.69 (dd, J = 8.5, 1.8 Hz, 1H), 6.64 (d, J = 1.8 Hz, 1H), 6.58 (s, 2H), 3.95 (s, 3H), 3.39 (s, 3H), 3.35 (s, 3H).

[0346] Step 3: Preparation of 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile

[0347]

[0348] The title compound was obtained in a similar manner to step 3 of Synthetic Method B using 4-amino-5-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)benzonitrile (27 mg, 0.072 mmol) and 1-methyl-1H-imidazole-5-carbaldehyde (7.96 mg, 0.072 mmol) obtained in step 2 as starting materials. (19 mg, 0.041 mmol, 56.7% yield)

[0349] 1 H-NMR (400 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.90 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 7.49 (s, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 1.8 Hz, 1H), 7.20 (dd, J = 8.2, 1.8 Hz, 1H), 6.51 (s, 1H), 4.11 (s, 3H), 3.96 (s, 3H), 3.49 (s, 3H), 3.40 (s, 3H).

[0350]

[0351] Example 7 (Synthetic Method D): Preparation of 5-[6-(hydroxymethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0352]

[0353] Methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylate (Example 5, 300 mg, 0.550 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0°C, and diisobutylaluminum hydride (DIBAL-H) ​​(1 M in tetrahydrofuran, 2.2 mL, 2.2 mmol) was slowly added. The reaction solution was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate and washed with water and brine. Anhydrous sodium sulfate was added to the oil layer to remove water, filtered, and the filtrate was concentrated under reduced pressure and purified by MPLC to obtain the title compound. (125 mg, 0.242 mmol, 43.9% yield)

[0354] 1 H-NMR (400 MHz, DMSO-d6) δ 11.11(s, 1H), 8.52 (d, 1H), 7.96 (d, 1H), 7.72 (d, 2H), 7.46 (m, 2H), 7.22 (m, 2H), 7.12 (s, 1H), 7.04 (d, 1H), 6.50 (s, 1H), 5.12 (t, 1H), 4.55 (d, 2H), 3.92 (s, 3H), 3.47 (s, 3H), 3.38 (s, 3H), 2.50 (s, 3H); LC / MS: 518 (M+H).

[0355]

[0356] Example 8 (Synthetic Method E): Preparation of 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbaldehyde

[0357]

[0358] 5-[6-(hydroxymethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 7, 100 mg, 0.193 mmol) was dissolved in dichloromethane (1 mL), and manganese dioxide (33.6 mg, 0.386 mmol) was added. The reaction solution was stirred at 45°C for 4 hours. The reaction solution was filtered to remove the catalyst, and the filter filtrate was concentrated under reduced pressure. The title compound was obtained by purification by MPLC. (90 mg, 0.193 mmol, 90.0% yield)

[0359] 1 H-NMR (400 MHz, Chloroform-d) δ 10.22 (s, 1H), 8.59 (d, 1H), 8.21 (m, 1H), 7.88 (d, 1H), 7.74 (d, 1H), 7.68 (s, 1H), 7.55 (d, 1H), 7.24 (m, 3H), 7.03 (s, 1H), 6.64 (d, 1H), 4.05 (s, 3H), 3.57 (s, 3H), 3.42 (s, 3H), 2.51 (s, 3H); LC / MS: 516 (M+H).

[0360]

[0361] Example 9: Preparation of 5-[6-(difluoromethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0362]

[0363] 3-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbaldehyde (Example 8, 90 mg, 0.175 mmol) was dissolved in dichloromethane (2 mL), cooled to 0°C, and diethylaminosulfur trifluoride (98 mg, 0.61 mmol) was slowly added. The reaction solution was stirred at room temperature for 12 h. Saturated sodium bicarbonate solution was added to the reaction solution, and it was extracted with dichloromethane. Anhydrous sodium sulfate was added to the combined oil layer to remove water, and then filtered. The filtrate was concentrated under reduced pressure and purified by MPLC to obtain the title compound. (15 mg, 0.028 mmol, 16.0% yield)

[0364] 1 H-NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.53 (d, 1H), 7.92 (d, 1H), 7.79 (s, 1H), 7.67 (d, 1H), 7.50 (m, 2H), 7.28 (d, 1H), 7.22 (d, 2H), 7.07 (m, 2H), 6.54 (d, 1H), 3.94 (s, 3H), 3.47 (s, 3H), 3.36 (s, 3H), 2.43 (s, 3H); LC / MS: 538 (M+H).

[0365]

[0366] Example 10 (Synthetic Method F): Preparation of 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylic acid

[0367]

[0368] Methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylate (Example 5, 20 mg, 0.037 mmol) was dissolved in methanol (1 mL), and 1 N sodium hydroxide (0.11 mL, 0.11 mmol) was slowly added. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was neutralized with 1 N hydrochloric acid. The reaction solution was diluted with water and extracted with ethyl acetate. Anhydrous sodium sulfate was added to the oil layer to remove water, and the filtrate was concentrated under reduced pressure and purified by MPLC to obtain the title compound. (11 mg, 21 μmol, 56.5% yield)

[0369] 1 H-NMR (400 MHz, Methanol-d4) δ 8.00 (d, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.65 (s, 1H), 7.60 (m, 1H), 7.45 (m, 2H), 7.38 (d, 1H), 7.29 (m, 1H), 7.12 (d, 1H), 7.06 (s, 1H), 3.98 (s, 3H), 3.55 (s, 3H), 3.35 (s, 3H), 2.47 (s, 3H); LC / MS: 532 (M+H).

[0370]

[0371] Example 12 (Synthetic Method G): Preparation of 5-[6-(1-hydroxy-1-methyl-ethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0372]

[0373] Methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylate (Example 5, 30 mg, 0.055 mmol) was dissolved in tetrahydrofuran (1 mL), and methylmagnesium bromide (3 M in diethyl ether, 0.055 mL, 0.165 mmol) was slowly added. The reaction solution was stirred at room temperature for 24 hours. Ice was added to the reaction solution, diluted with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. Anhydrous sodium sulfate was added to the oil layer to remove water, filtered, and the filtrate was concentrated under reduced pressure and purified by MPLC to obtain the title compound. (4.3 mg, 0.0079 mmol, 14.3% yield)

[0374] 1 H-NMR (400 MHz, Chloroform-d) δ 8.39 (m, 2H), 7.66 (d, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.21 (m, 1H), 7.15 (m, 2H), 7.08 (d, 1H), 6.98 (s, 1H), 6.54 (s, 1H), 4.01 (s, 3H), 3.78 (s, 1H), 3.54 (s, 3H), 3.38 (s, 3H), 2.47 (s, 3H), 1.53 (s, 6H); LC / MS: 546 (M+H).

[0375]

[0376] Example 26 (Synthetic Method H): Preparation of 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-N-methyl-2-(3-methylimidazol-4-yl)benzimidazole-5-carboxamide

[0377]

[0378] 3-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazole-5-carboxylic acid (Example 22, 78 mg, 0.141 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (40.5 mg, 0.211 mmol), and hydroxybenzotriazole (32.4 mg, 0.211 mmol) were dissolved in dimethylformamide (1.4 mL), and then methanamine (2 M in tetrahydrofuran (176 μL, 0.352 mmol) was added. The reaction solution was stirred at room temperature for 6 hours. After the reaction was completed, water was added, and the oil layer was extracted with dichloromethane. The oil layer was washed with water and brine and dried. After drying over magnesium sulfate, the residue was concentrated under reduced pressure and purified by MPLC to obtain the title compound. (54 mg, 0.095 mmol, 67.6% yield)

[0379] 1 H-NMR (500 MHz, Chloroform-d) δ 8.15 (t, J = 8.1 Hz, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.27-7.24 (m, 1H), 7.14-7.09 (m, 2H), 6.95 (s, 1H), 6.82-6.78 (m, 1H), 6.47 (s, 1H), 5.36 (d, J = 4.9 Hz, 1H), 4.17 (s, 3H), 3.52 (s, 3H), 3.41 (s, 3H), 3.06 (d, J = 4.9 Hz, 3H), 2.69 (d, J = 4.9 Hz, 3H).

[0380]

[0381] Example 47 (Synthetic method I): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0382] Step 1: Preparation of 6-((4-bromo-5-fluoro-2-nitrophenyl)amino)-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0383]

[0384] 6-Amino-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one (Intermediate I-10, 47 mg, 0.179 mmol) and 1-bromo-2,4-difluoro-5-nitrobenzene (42.6 mg, 0.179 mmol) were dissolved in 1,4-dioxane (2.00 mL), diisopropylethylamine (0.064 mL, 0.358 mmol) was added dropwise, and the mixture was stirred at 100°C for 18 hours. The reaction solution was diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (77.6 mg, 0.162 mmol, 90% yield)

[0385] 1 H-NMR (500 MHz, Chloroform-d) δ 9.54 (s, 1 H), 8.51 (s, 1 H), 6.79 (dd, 3 H), 3.92 (br. s., 4 H), 3.79 (s, 3 H), 3.42 (s, 3H), 3.01 (s, 4H).

[0386] Step 2: Preparation of 5-bromo-6-fluoro-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-7'-morpholino-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one

[0387]

[0388] Step 1: 6-((4-bromo-5-fluoro-2-nitrophenyl)amino)-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one] (77.6 mg, 0.162 mmol) and sodium dithionite (99 mg, 0.485 mmol) were stirred with 1-methyl-1H-imidazole-5-carbaldehyde (175 mg, 0.162 mmol) in the presence of dimethyl sulfoxide (2.3 mL) and water (0.23 mL) at 90 °C for 1 h. The mixture was diluted with water and ethyl acetate, and 25% ammonia water was added to quench the reaction. The oil layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (48 mg, 0.162 mmol, 55% yield)

[0389] 1 H-NMR (500 MHz, Chloroform-d) δ 8.01 (d, 1H), 7.53 (s, 1H), 6.88 (d, 1H), 6.84 (s, 1H), 6.74 (s, 1H), 6.45 (s, 1H), 4.16 (s, 3 H), 3.89 (br, s, 4H), 3.83 (s, 3H), 3.40 (s, 3H), 2.97 (s, 4H).

[0390] Step 3: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0391]

[0392] The title compound was obtained in a similar manner to step 4 of Synthetic Method B using 5-bromo-6-fluoro-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-7'-morpholino-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (7.5 mg, 0.014 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.04 mg, 0.019 mmol) obtained in step 2 as starting materials. (0.8 mg, 0.014 mmol, 10.6% yield)

[0393] 1 H-NMR (500 MHz, Chloroform-d) δ 7.92 (s, 1H), 7.79 (br. s., 1H), 7.53 (s, 1H), 6.87 (s, 2H), 6.77 (s, 1H), 6.46 (s, 1H), 4.18 (s, 3H), 3.99 (s, 3H), 3.83 (s, 3H), 3.40 (s, 3H), 2.98 (br. s., 4H); LC / MS: 542 (M+H).

[0394]

[0395] Example 49 (Synthetic Method J): Preparation of 1-ethyl-5-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-3-methyl-benzimidazol-2-one

[0396]

[0397] 5-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-3-methyl-1H-benzimidazol-2-one (Example 48, 25 mg, 0.057 mmol) was dissolved in dimethylformamide (2 mL). Potassium carbonate (23.43 mg, 0.170 mmol) and bromoethane (6.33 μL, 0.085 mmol) were added to the solution, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and water, and the separated aqueous layer was extracted with ethyl acetate. The oil layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by PTLC to obtain the title compound. (17.6 mg, 0.037 mmol, 66.2% yield)

[0398] 1 H-NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.10 (d, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.45-7.42 (m, 2H), 7.18 (d, 1H), 6.98 (d, 1H), 6.37 (s, 1H), 4.05 (s, 3H), 3.99-3.97 (m, 2H), 3.91 (s, 3H), 3.35 (s, 3H), 1.29 (t, 3H); LC / MS: 471 (M+H).

[0399]

[0400] Example 54 (Synthetic Method K): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropenyl-1,3-dimethyl-benzimidazol-2-one

[0401]

[0402] 4-Chloro-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 53, 30 mg, 0.061 mmol) and 4,4,5,5-tetramethyl-2-(pro-1-en-2-yl)-1,3,2-dioxaborolane (20.54 mg, 0.122 mmol) and 2 M aqueous sodium carbonate solution (0.122 mL, 0.244 mmol) were added to 1,4-dioxane (1 mL) and stirred for 5 minutes while bubbling with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (7.06 mg, 6.11 μmol) was added to the reaction mixture and stirred at 90°C under nitrogen for 18 h. After the reaction was completed, water was added, the mixture was extracted with ethyl acetate, and the oil layer was washed with brine and concentrated under reduced pressure. The title compound was obtained by purification using MPLC and PTLC. (26 mg, 0.052 mmol, 86% yield)

[0403] 1 H-NMR (500 MHz, Chloroform-d) δ 8.12-7.98 (m, 2H), 7.83 (s, 1H), 7.08-6.75 (m, 4H), 6.72 (s, 1H), 5.44 (s, 1H), 5.10 (s, 1H), 4.40 (s, 3H), 4.04 (s, 3H), 3.60 (s, 3H), 3.45 (s, 3H), 2.16 (s, 3H); LC / MS: 497(M+H).

[0404]

[0405] Example 58 (Synthetic Method L): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one

[0406]

[0407] 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropenyl-1,3-dimethyl-benzimidazol-2-one (Example 54, 30 mg, 0.060 mmol) and palladium hydroxide on carbon (21.21 mg, 0.030 mmol) were added to ethanol (1 mL) / methanol (1 mL) and stirred at 50°C under hydrogen balloon pressure for 18 hours. The reaction solution was filtered through a pad of Celite to remove the catalyst, concentrated under reduced pressure, and separated by MPLC and PTLC to obtain the title compound. (18 mg, 0.036 mmol, 59.8% yield)

[0408] 1 H-NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 7.02 (s, 1H), 6.84 (d, J = 10.4 Hz, 1H), 6.77 (s, 1H), 6.45 (s, 1H), 4.23-4.12 (3H), 3.98 (s, 3H), 3.77 (s, 3H), 3.75-3.65 (m, 1H), 3.39 (s, 3H), 1.33 (d, J = 6.7 Hz, 6H); LC / MS: 499(M+H).

[0409]

[0410] Example 59 (Synthetic Method M): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one

[0411] Step 1: Preparation of 6-((4-bromo-5-fluoro-2-nitrophenyl)amino)-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0412]

[0413] The title compound was obtained in a similar manner to step 1 of synthetic method B using 6-amino-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-14, 235 mg, 1.003 mmol) and 1-bromo-2,4-difluoro-5-nitrobenzene (239 mg, 1.003 mmol) as starting materials. (378 mg, 0.836 mmol, 83% yield)

[0414] 1 H-NMR (500 MHz, Chloroform-d) δ 9.52 (s, 1H), 8.49 (d, J = 8.9 Hz, 1H), 6.83 (d, J = 13.4 Hz, 1H), 6.37 (s, 1H), 6.33 (s, 1H), 3.83 (s, 1H), 3.77 (s, 3H), 3.63-3.59 (m, 1H), 3.39 (s, 3H), 1.29 (d, J = 7.9 Hz, 6H); LC / MS: 452, 454 (M+H).

[0415] Step 2: Preparation of 6-((5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)amino)-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0416]

[0417] The title compound was obtained in a similar manner to step 4 of synthetic method B using 6-((4-bromo-5-fluoro-2-nitrophenyl)amino)-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (701 mg, 1.550 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (387 mg, 1.860 mmol) obtained in step 1 as starting materials. (487 mg, 1.074 mmol, 69.3% yield)

[0418] 1H-NMR (500 MHz, Chloroform-d) δ 9.49 (s, 1H), 8.42 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 6.82 (d, J = 13.1 Hz, 1H), 6.38 (s, 1H), 6.34 (s, 1H), 3.95 (s, 3H), 3.75 (s, 3H), 3.61-3.59 (m, 1H), 3.37 (s, 3H), 1.27 (d, J = 6.1 Hz, 6H); LC / MS: 454 (M+H).

[0419] Step 3: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one]

[0420]

[0421] Step 2: 6-((5-Fluoro-4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)amino)-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (358 mg, 0.789 mmol) and sodium dithionite (412 mg, 2.368 mmol) obtained in Step 2 were stirred with 1-methyl-1H-imidazole-5-carbaldehyde (87 mg, 0.789 mmol) in the presence of ethanol (11.8 mL) and water (3.93 mL) at 90°C for 1 h. The reaction was quenched with 25% ammonia water. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (263 mg, 0.512 mmol, 64.9% yield)

[0422] 1H-NMR (500 MHz, Chloroform-d) δ 7.94 (d, J = 6.1 Hz, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.51 (s, 1H), 6.88 (d, J = 10.4 Hz, 1H), 6.62 (s, 1H), 6.39 (d, J = 7.6 Hz, 2H), 4.17 (s, 3H), 3.98 (s, 3H), 3.90 (d, J = 7.0 Hz, 1H), 3.81 (s, 3H), 3.54-3.52 (m, 1H), 3.35 (s, 3H), 1.22 (d, J = 6.1 Hz, 6H); LC / MS: 514 (M+H).

[0423]

[0424] Example 60 (Synthetic Method N): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(propylamino)benzimidazol-2-one

[0425]

[0426] 4-Chloro-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 53, 38 mg, 0.077 mmol) and sodium tert-butoxide (22.32 mg, 0.232 mmol) were added to 1,4-dioxane (1 mL), and propane-1-amine (0.025 mL, 0.310 mmol) and PEPPSI-iPr catalyst (5.26 mg, 7.74 μmol) were added. The mixture was stirred using a microwave at 120°C for 40 min. Water was added to the reaction mixture, extracted with ethyl acetate, and the oil layer was concentrated under reduced pressure. The title compound was obtained by separation by MPLC and PTLC. (14 mg, 0.027 mmol, 35.2% yield)

[0427] 1H-NMR (500 MHz, Chloroform-d) δ 7.94 (d, J = 6.1 Hz, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 6.88 (d, J = 10.4 Hz, 1H), 6.62 (s, 1H), 6.41 (s, 1H), 6.37 (s, 1H), 4.16 (s, 3H), 3.98 (s, 3H), 3.82 (s, 3H), 3.35 (s, 3H), 3.03 (t, J = 7.0 Hz, 2H), 1.74-1.59 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H); LC / MS: 514(M+H).

[0428]

[0429] Example 97: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-hydroxy-1,3-dimethyl-benzimidazol-2-one

[0430]

[0431] 4-Chloro-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 53, 25 mg, 0.050 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.289 mg, 2.500 μmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (5.89 mg, 10.00 μmol), potassium hydroxide (8.42 mg, 0.150 mmol) were added to a reaction vessel, 1,4-dioxane (0.10 mL) and water (0.10 mL) were added, and nitrogen was blown in, and the mixture was stirred at 100°C for 18 The mixture was stirred for 1 h. The reaction mixture was cooled to room temperature, acidified with 1 N hydrochloric acid, and extracted with ethyl acetate. The obtained oil layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (2.3 mg, 4.87 μmol, 9.7% yield)

[0432] 1 H-NMR (500 MHz, Chloroform-d) δ 7.88 (d, J = 7.0 Hz, 2H), 7.75 (s, 1H), 7.61 (s, 1H), 6.77 (d, J = 11.6 Hz, 2H), 6.49 (s, 1H), 6.35 (s, 1H), 4.13 (s, 3H), 3.97 (s, 3H), 3.79 (s, 3H), 3.34 (s, 3H); LC / MS: 473 (M+H).

[0433]

[0434] Example 99 (Synthetic Method O): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-propoxy-benzimidazol-2-one

[0435]

[0436] 4-Chloro-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 53, 49 mg, 0.100 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.57 mg, 4.99 μmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (11.75 mg, 0.020 mmol), potassium hydroxide (16.80 mg, 0.299 mmol) were added to a reaction vessel, 1,4-dioxane (0.10 mL) and water (0.10 mL) were added, and nitrogen was blown in, and the mixture was stirred at 100°C for 18 hours. The mixture was stirred. The reaction mixture was cooled to room temperature, and cetyltrimethylammonium bromide (3.6 mg, 9.98 μmol) and 1-bromopropane (0.018 mL, 0.200 mmol) were added, and the mixture was stirred at 100°C for an additional 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The obtained oil layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (16.1 mg, 0.031 mmol, 31.3% yield)

[0437] 1 H-NMR (500 MHz, Chloroform-d) δ 7.94 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 6.85 (d, J = 10.4 Hz, 1H), 6.61 (d, J = 7.0 Hz, 2H), 6.54 (s, 1H), 4.17 (s, 3H), 3.98 (s, 3H), 3.95 (t, J = 6.1 Hz, 2H), 3.75 (s, 3H), 3.38 (s, 3H), 1.85 (td, J = 13.6, 6.5 Hz, 2H), 1.07 (t, J = 7.3 Hz, 3H); LC / MS: 515 (M+H).

[0438]

[0439] Example 107: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[isopropyl(methyl)amino]-1,3-dimethyl-benzimidazol-2-one

[0440]

[0441] To a solution of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one (Example 59, 29 mg, 0.056 mmol) in 1,2-dichloroethane (0.565 mL) were added formaldehyde (37 wt % in water, 0.021 mL, 0.282 mmol), acetic acid (0.016 mL, 0.282 mmol), and sodium triacetoxyborohydride (35.9 mg, 0.169 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane. The obtained oil layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (7 mg, 0.013 mmol, 23.5% yield)

[0442] 1 H-NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 6.86 (s, 1H), 6.83 (d, J = 10.7 Hz, 1H), 6.69 (s, 1H), 6.50 (s, 1H), 4.16 (s, 3H), 3.98 (s, 3H), 3.79 (s, 3H), 3.38 (s, 3H), 3.34-3.29 (m, 1H), 2.64 (s, 3H), 1.11 (d, J = 4.6 Hz, 6H); LC / MS: 528 (M+H).

[0443]

[0444] Example 116 (Synthetic Method P): Preparation of 6-[6-fluoro-2-(1-methylcyclopropyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one

[0445] Step 1: Preparation of 6-((2-amino-5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0446]

[0447] The title compound was synthesized in a similar manner to step 1 and step 2 of Synthetic Method C using 6-amino-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-23, 540 mg, 2.463 mmol) and 1-bromo-2,4-difluoro-5-nitrobenzene (310 μL, 2.463 mmol) as starting materials. (50.9% yield over 2 steps)

[0448] 1 H-NMR (500 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.69 (s, 1H), 6.95 (d, J = 7.3 Hz, 1H), 6.85 (d, J = 12.2 Hz, 1H), 6.63 (s, 1H), 6.42 (s, 1H), 3.94 (s, 3H), 3.65 (s, 3H), 3.62-3.57 (m, 1H), 3.34 (s, 3H), 1.31 (d, J = 6.7 Hz, 6H); LC / MS: 409 (M+H).

[0449] Step 2: Preparation of 6-[6-fluoro-2-(1-methylcyclopropyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one

[0450]

[0451] 6-((2-amino-5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (39 mg, 0.095 mmol) obtained in Step 1, 1-methylcyclopropane-1-carboxylic acid (10.51 mg, 0.105 mmol), and diisopropylethylamine (0.033 mL, 0.191 mmol) were dissolved in ethyl acetate (1 mL), and then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50 % wt in ethyl acetate, 0.284 mL, 0.477 mmol) was added. The reaction solution was stirred at 110°C for 3 hours using a microwave. After the reaction was completed, the mixture was diluted with water, 1 N aqueous sodium hydroxide solution was added, and the oil layer was extracted with ethyl acetate. The oil 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. (8.3 mg, 0.018 mmol, 18.40% yield)

[0452] 1 H-NMR (500 MHz, Chloroform-d) δ 7.85-7.84 (m, 2H), 7.72 (s, 1H), 7.11 (s, 1H), 6.89 (s, 1H), 6.83 (d, J = 10.4 Hz, 1H), 3.96 (s, 3H), 3.76 (s, 3H), 3.75-3.71 (m, 1H), 3.45 (s, 3H), 1.37 (d, J = 6.7 Hz, 7H), 1.30 (s, 2H), 1.14 (s, 3H), 0.72 (s, 2H); LC / MS: 473 (M+H).

[0453]

[0454] Example 118: Preparation of 6-[6-fluoro-2-(3-methyloxetan-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one

[0455]

[0456] (3-Methyloxetan-3-yl)methanol (15.00 mg, 0.147 mmol) was dissolved in ethyl acetate (0.5 mL) and dimethyl sulfoxide (0.25 mL), and then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50 % wt in ethyl acetate, 0.131 mL, 0.220 mmol) was added at 0°C. The reaction solution was stirred at room temperature for 2 hours. After the oxidation reaction of alcohol was completed, 6-((2-amino-5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound of step 1 of Synthetic method P, 30 mg, 0.073 mmol) was added and stirred for an additional hour. After the reaction was completed, water was added and the oil layer was extracted with dichloromethane. The oil 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. (11.3 mg, 0.023 mmol, 31.5% yield)

[0457] 1 H-NMR (400 MHz, Chloroform-d) δ 7.90 (d, J = 6.4 Hz, 1H), 7.87 (s, 1H), 7.74 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.79-6.76 (m, 2H), 5.22 (d, J = 5.9 Hz, 2H), 4.27-4.26 (m, 2H), 3.97 (s, 3H), 3.76 (s, 3H), 3.73-3.68 (m, 1H), 3.43 (s, 3H), 1.76 (s, 3H), 1.34 (d, J = 6.9 Hz, 6H); LC / MS: 489 (M+H).

[0458]

[0459] Example 122: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-trimethylsilylethynyl)benzimidazol-2-one

[0460] Step 1: Preparation of 4-bromo-6-((5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0461]

[0462] 6-Amino-4-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (Intermediate I-3, 100 mg, 0.390 mmol) and 4-(2,4-difluoro-5-nitrophenyl)-1-methyl-1H-pyrazole (Intermediate I-55, 112 mg, 0.469 mmol) were reacted with anhydrous potassium fluoride (85 mg, 0.586 mmol) in a microwave in the presence of dimethylformamide (1.5 mL) at 160°C for 4 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (75.4 mg, 0.159 mmol, 40.6% yield).

[0463] 1 H-NMR (500 MHz, Chloroform-d) δ 9.46 (br, s, 1 H), 8.43 (d, J=7.78 Hz, 1 H), 7.82(s, 1 H), 7.71 (s, 1 H), 7.17 (s, 1 H), 6.85 (s, 1 H), 6.75 (d, J=12.97 Hz, 1 H), 3.97 (s, 3 H), 3.79 (s, 3 H), 3.43 (s, 3 H).

[0464] Step 2: Preparation of 7'-bromo-6-fluoro-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one

[0465]

[0466] 4-Bromo-6-((5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (75.4 mg, 0.159 mmol) obtained in Step 1, 1-methyl-1H-imidazole-5-carbaldehyde (17.5 mg, 0.159 mmol), and sodium sulfate (83 mg, 0.476 mmol) were reacted in the presence of dimethyl sulfoxide (1 mL, 0.786 mmol) at 90°C for 3 h. The reaction was quenched with 25% ammonium hydroxide, diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (35.4 mg, 0.066 mmol, 41.7% yield)

[0467] 1 H-NMR (500 MHz, Chloroform-d) δ 7.96(d, 2H) 7.79(s, 1H) 7.54(s, 1H) 6.89(s, 1H) 6.86(d, 1H) 6.55(s, 1H) 4.17(s, 1H) 3.99(s, 1H) 3.86(s, 3H) 3.41(s, 3H); LC / MS: 535, 537 (M+H).

[0468] Step 3: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-trimethylsilylethynyl)benzimidazol-2-one

[0469]

[0470] 7'-Bromo-6-fluoro-1',3'-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (50 mg, 0.093 mmol) obtained in Step 2 was dissolved in dimethylformamide (1 mL), and ethynyltrimethylsilane (0.026 mL, 0.187 mmol), copper(I) iodide (1.779 mg, 9.34 μmol), triethylamine (0.130 mL, 0.934 mmol), and bis(triphenylphosphine)palladium(II) dichloride (6.56 mg, 9.34 μmol) were added. The reaction mixture was stirred at 100°C for 18 hours. The mixture was cooled to room temperature, and the oil layer was extracted with water and ethyl acetate, which were then washed with brine. The oil layer was concentrated under reduced pressure and purified by MPLC and PTLC to obtain the title compound (17 mg, 0.031 mmol, 32.9% yield).

[0471] 1 H-NMR (500 MHz, Chloroform-d) δ 7.94 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.18 (s, 1H), 6.85 (s, 1H), 6.82 (d, J = 10.4 Hz, 1H), 6.53 (s, 1H), 4.20-4.13 (3H), 4.02-3.94 (3H), 3.86 (s, 3H), 3.41-3.35 (3H), 0.30-0.22 (9H); LC / MS: 553 (M+H).

[0472]

[0473] Example 123: Preparation of 4-ethynyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0474]

[0475] 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-trimethylsilylethynyl)benzimidazol-2-one (Example 122, 14 mg, 0.025 mmol) was added to tetrahydrofuran (0.5 mL), and tetra-n-butylammonium fluoride (1 M in tetrahydrofuran, 0.076 mL, 0.076 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. Water was added to the reaction solution, the oil layer was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solution was filtered, concentrated under reduced pressure, and purified by PTLC to obtain the title compound. (9.7 mg, 0.020 mmol, 80% yield)

[0476] 1 H-NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.21 (s, 1H), 6.90 (s, 1H), 6.83 (d, J = 10.4 Hz, 1H), 6.56-6.49 (1H), 4.16 (s, 3H), 3.98 (s, 3H), 3.90-3.81 (3H), 3.40 (s, 3H), 3.36 (s, 1H); LC / MS: 481 (M+H).

[0477]

[0478] Example 125: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-hydroxyethyl)-1,3-dimethyl-benzimidazol-2-one

[0479]

[0480] 4-Acetyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 124, 20 mg, 0.040 mmol) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.2 mL), and sodium borohydride (3.04 mg, 0.080 mmol) was added at 0°C. The reaction solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, the oil layer was extracted with ethyl acetate, and the mixture was concentrated under reduced pressure. The title compound was obtained by purification by PTLC. (20 mg, 0.040 mmol, 100% yield)

[0481] 1 H-NMR (500 MHz, Chloroform-d) δ 7.94 (d, J = 6.4 Hz, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.49 (s, 1H), 7.28 (s, 1H), 6.87 (s, 1H), 6.83 (d, J = 10.4 Hz, 1H), 6.43 (s, 1H), 5.55 (q, J = 6.1 Hz, 1H), 4.14 (s, 3H), 3.97 (s, 3H), 3.77 (s, 3H), 3.44-3.36 (3H), 1.59 (d, J = 6.4 Hz, 3H); LC / MS: 501 (M+H).

[0482]

[0483] Example 126: Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-hydroxy-1-methyl-ethyl)-1,3-dimethyl-benzimidazol-2-one

[0484]

[0485] 4-Acetyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 124, 25 mg, 0.050 mmol) was added to tetrahydrofuran (0.5 mL), cooled to 0°C, and methylmagnesium bromide (3.4 M in methyltetrahydrofuran, 0.074 mL, 0.251 mmol) was added. The reaction solution was stirred at room temperature for 18 h. Water was added to the reaction solution, the oil layer was extracted with ethyl acetate, and then concentrated under reduced pressure. The title compound was obtained by purification by PTLC. (11.5 mg, 0.022 mmol, 44.6% yield)

[0486] 1 H-NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 6.4 Hz, 1H), 7.90 (s, 1H), 7.77 (s, 1H), 7.51 (s, 1H), 7.04 (s, 1H), 6.90 (s, 1H), 6.83 (d, J = 10.4 Hz, 1H), 6.43 (s, 1H), 4.16 (s, 3H), 3.98 (s, 3H), 3.96 (s, 3H), 3.41 (s, 3H), 2.85 (br, 1H), 1.71 (s, 6H); LC / MS: 515 (M+H).

[0487]

[0488] Example 128 (Synthetic Method Q): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-methoxyethyl)-1,3-dimethyl-benzimidazol-2-one

[0489]

[0490] 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-hydroxyethyl)-1,3-dimethyl-benzimidazol-2-one (Example 125, 22 mg, 0.044 mmol) was dissolved in tetrahydrofuran (0.5 mL), cooled to 0°C, and sodium hydride (60% dispersion in mineral oil, 2.64 mg, 0.066 mmol) was added. The solution was stirred for 10 minutes, iodomethane (0.027 mL, 0.440 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, the oil layer was extracted with ethyl acetate, and then washed with brine. The oil layer was concentrated under reduced pressure and purified by PTLC to obtain the title compound. (6 mg, 0.012 mmol, 26.5% yield)

[0491] 1 H-NMR (500 MHz, Chloroform-d) δ 7.96 (d, J = 6.7 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.17 (s, 1H), 6.88 (s, 1H), 6.85 (d, J = 10.4 Hz, 1H), 6.44 (s, 1H), 5.10-4.93 (m, 1H), 4.16 (s, 3H), 3.98 (s, 3H), 3.82-3.69 (3H), 3.42 (s, 3H), 3.26 (s, 3H), 1.54 (d, J = 6.1 Hz, 3H); LC / MS: 515 (M+H).

[0492]

[0493] Example 130 (Synthetic Method R): Preparation of 4-isopropyl-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one

[0494] Step 1: Preparation of 6-((4-bromo-2-nitro-5-(trifluoromethyl)phenyl)amino)-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0495]

[0496] A solution of 6-amino-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (121 mg, 0.550 mmol), 1-bromo-4-iodo-5-nitro-2-(trifluoromethyl)benzene (198 mg, 0.500 mmol), tris(dibenzylideneacetone)dipalladium(0) (11.45 mg, 0.013 mmol), xantphos (28.9 mg, 0.050 mmol), and potassium tert-butoxide (67.3 mg, 0.600 mmol) in toluene (1.000 mL) was stirred at 80°C for 18 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The obtained oil layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (192 mg, 0.394 mmol, 79% yield)

[0497] 1 H-NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.52 (s, 1H), 7.48 (s, 1H), 6.92 (s, 1H), 6.71 (s, 1H), 3.71 (s, 3H), 3.69-3.64 (m, 1H), 3.41 (s, 3H), 1.32 (d, J = 6.7 Hz, 6H); LC / MS: 487, 489 (M+H).

[0498] Step 2: Preparation of 4-isopropyl-1,3-dimethyl-6-((4-(1-methyl-1H-pyrazol-4-yl)-2-nitro-5-(trifluoromethyl)phenyl)amino)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0499]

[0500] The title compound was obtained in a similar manner to step 4 of synthetic method B using 6-((4-bromo-2-nitro-5-(trifluoromethyl)phenyl)amino)-4-isopropyl-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (146 mg, 0.300 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (94 mg, 0.450 mmol) obtained in step 1 as starting materials. (125.3 mg, 0.257 mmol, 86% yield)

[0501] 1 H-NMR (500 MHz, Chloroform-d) δ 9.50 (s, 1H), 8.23 ​​(s, 1H), 7.57 (s, 1H), 7.54 (s, 1H), 7.47 (s, 1H), 6.96 (s, 1H), 6.75 (s, 1H), 3.97 (s, 3H), 3.72 (s, 3H), 3.70-3.64 (m, 1H), 3.41 (s, 3H), 1.33 (d, J = 6.7 Hz, 6H); LC / MS: 489 (M+H).

[0502] Step 3: Preparation of 4-isopropyl-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one

[0503]

[0504] A mixture of 4-isopropyl-1,3-dimethyl-6-((4-(1-methyl-1H-pyrazol-4-yl)-2-nitro-5-(trifluoromethyl)phenyl)amino)-1,3-dihydro-2H-benzo[d]imidazol-2-one (19.3 mg, 0.040 mmol) and sodium dithionite (20.64 mg, 0.119 mmol) obtained in Step 2 was dissolved in ethanol (0.3 mL) and water (0.1 mL) and stirred at 90°C. After confirming the exhaustion of the starting material on TLC (approximately 30 min), 1-methyl-1H-imidazole-5-carbaldehyde (4.35 mg, 0.040 mmol) was added and stirred at 90°C for 18 h. The reaction mixture was cooled to room temperature, quenched with 25% ammonia water, diluted with water, and extracted with ethyl acetate. The obtained oil layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (15.5 mg, 0.028 mmol, 71.5% yield)

[0505] 1 H-NMR (500 MHz, Chloroform-d) δ 7.81 (s, 1H), 7.63 (s, 1H), 7.54 (s, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.03 (s, 1H), 6.78 (s, 1H), 6.48 (s, 1H), 4.19 (s, 3H), 3.99 (s, 3H), 3.79 (s, 3H), 3.76-3.71 (m, 1H), 3.40 (s, 3H), 1.33 (d, J = 6.4 Hz, 6H); LC / MS: 549 (M+H).

[0506]

[0507] Example 146 (Synthetic Method S): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1-piperidyl)benzimidazol-2-one

[0508]

[0509] 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-trimethylsilylethynyl)benzimidazol-2-one (Compound of Example 122 Synthesis step 2, 0.03 g, 0.056 mmol), piperidine (0.022 mL, 0.224 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.58 mg, 0.006 mmol), xantphos (9.73 mg, 0.017 mmol), and cesium carbonate (0.055 g, 0.168 mmol) were stirred in toluene (3 mL) at 100°C for 18 hours. The reaction product was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (8.4 mg, 0.016 mmol, 27.8% yield)

[0510] 1 H-NMR (500 MHz, Chloroform-d) δ 7.96 (d, J = 5.80 Hz, 1H), 7.92 (s., 1H), 7.79 (s., 2H), 7.52 (s., 2H), 6.85 (s, 1H), 6.87 (s, 1H), 6.69 (s., 1H), 6.50 (s., 1H), 4.17 (s., 4H), 3.99 (br. s., 3H), 3.83 (br. s., 3H), 3.38 (br. s., 3H), 1.76 (br. s., 4H), 1.26 (br. s., 6H); LC / MS: 540 (M+H).

[0511]

[0512] Example 178 (Synthetic Method T): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-piperidyl)benzimidazol-2-one

[0513]

[0514] Tert-Butyl 4-[6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylate (Example 174, 190 mg, 0.297 mmol) was added to tetrahydrofuran (3 mL) and methanol (1 mL), and hydrochloric acid (4 M in 1,4-dioxane, 0.742 mL, 2.97 mmol) was added. The reaction solution was stirred at room temperature for 18 h. The reaction solution was concentrated under reduced pressure and purified by prepHPLC to obtain the title compound. (150 mg, 0.278 mmol, 94% yield)

[0515] 1 H-NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 7.00 (s, 1H), 6.83 (d, J = 13.7 Hz, 2H), 6.41 (s, 1H), 4.16 (s, 3H), 3.99 (s, 3H), 3.76 (s, 3H), 3.40 (s, 4H), 3.24 (d, J = 11.9 Hz, 2H), 2.79 (d, J = 12.2 Hz, 2H), 1.90 (d, J = 16.5 Hz, 2H), 1.70 (br, 2H); LC / MS: 540 (M+H).

[0516]

[0517] Example 188 (Synthetic Method U): Preparation of 4-(1-acetyl-4-piperidyl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0518]

[0519] Tert-Butyl 4-[6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylate (Example 174, 30 mg, 0.056 mmol) was dissolved in dichloromethane (1 mL), and acetyl chloride (4.35 μL, 0.061 mmol) and pyridine (5.40 μL, 0.067 mmol) were added at 0°C. The reaction solution was stirred at room temperature for 18 h. Water was added to the reaction solution, the oil layer was extracted with dichloromethane, and then concentrated under reduced pressure. The title compound was obtained by separation by MPLC and PTLC. (17 mg, 0.029 mmol, 52.6% yield)

[0520] 1 H-NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 6.9 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J = 2.7 Hz, 1H), 7.51 (s, 1H), 6.93-6.90 (m, 1H), 6.86 (dd, J = 6.4, 1.8 Hz, 1H), 6.81 (d, J = 10.5 Hz, 1H), 6.36 (d, J = 3.7 Hz, 1H), 4.82 (d, J = 13.3 Hz, 1H), 4.17 (s, 3H), 3.98 (s, 4H), 3.78 (s, 3H), 3.50 (d, J = 11.9 Hz, 1H), 3.41 (s, 3H), 3.24-3.18 (m, 1H), 2.67-2.62 (m, 1H), 2.09 (s, 3H), 1.96 (t, J = 14.2 Hz, 2H), 1.67 (d, J = 12.8 Hz, 2H); LC / MS: 582 (M+H).

[0521]

[0522] Example 189 (Synthetic Method V): Preparation of 6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1-methyl-4-piperidyl)benzimidazol-2-one

[0523]

[0524] Tert-Butyl 4-[6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylate (Example 174, 50 mg, 0.093 mmol) was added to acetonitrile (1 mL), and formaldehyde (37 wt % in water, 15.90 mg, 0.185 mmol), sodium triacetoxyborohydride (29.5 mg, 0.139 mmol), and acetic acid (5.56 mg, 0.093 mmol) were added. The reaction solution was stirred at room temperature for 5 hours. The pH was adjusted to 9-11 with 1 N sodium hydroxide, and the oil layer was extracted with dichloromethane. The collected oil layer was concentrated under reduced pressure and purified by PTLC to obtain the title compound. (18 mg, 0.033 mmol, 35.1% yield)

[0525] 1 H-NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 6.9 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.51 (s, 1H), 6.99 (d, J = 2.1 Hz, 1H), 6.86-6.83 (m, 2H), 6.40 (s, 1H), 4.15 (s, 3H), 3.98 (s, 3H), 3.75 (s, 3H), 3.41 (s, 3H), 3.28-3.24 (m, 1H), 3.10-3.04 (m,2H), 2.36 (s, 3H), 2.18 (s, 2H), 1.90 (s, 4H); LC / MS: 554 (M+H).

[0526]

[0527] Example 191: Preparation of 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one

[0528] Step 1: Preparation of 5-bromo-2-(tert-butyl)-6-fluoro-7'-(isopropylamino)-1',3'-dimethyl-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one

[0529]

[0530] The title compound was obtained in a similar manner to step 1 and step 2 of Synthesis I using 6-amino-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-14, 474 mg, 2.023 mmol) and 1-bromo-2,4-difluoro-nitrobenzene (481 mg, 2.023 mmol) as starting materials. (33.5% yield over 2 steps)

[0531] 1 H-NMR (500 MHz, Chloroform-d) δ 7.93 (d, J = 5.8 Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H), 6.42 (s, 1H), 6.40-6.34 (m, 1H), 3.80 (s, 3H), 3.59-3.50 (m, 1H), 3.37 (s, 3H), 1.39 (s, 9H), 1.28-1.16 (m, 6H); LC / MS: 488, 490 (M+H).

[0532] Step 2: Preparation of 2-(tert-butyl)-6-fluoro-7'-(isopropylamino)-1',3'-dimethyl-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-carbonitrile

[0533]

[0534] 5-Bromo-2-(tert-butyl)-6-fluoro-7'-(isopropylamino)-1',3'-dimethyl-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (50 mg, 0.102 mmol) obtained in Step 1 was dissolved in anhydrous dimethylformamide (1 mL), and then dicyanozinc (36.1 mg, 0.307 mmol) and tetrakis(triphenylphosphine)palladium (11.83 mg, 10.24 μmol) were added. The reaction solution was stirred under a nitrogen balloon at 100 °C for 18 h. After the reaction was completed, water was added, and the oil layer was extracted with ethyl acetate. The oil 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. (44 mg, 0.101 mmol, 99% yield)

[0535] 1 H-NMR (500 MHz, Chloroform-d) δ 7.92 (d, 1H), 6.60 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.93 (s, 1H), 3.78 (s, 3H), 3.53 (s, 1H), 3.34 (s, 3H), 1.38 (s, 9H), 1.23 (t, 6H); LC / MS: 435 (M+H).

[0536] Step 3: Preparation of 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one

[0537]

[0538] 2-(tert-butyl)-6-fluoro-7'-(isopropylamino)-1',3'-dimethyl-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-carbonitrile (44 mg, 0.101 mmol) and potassium carbonate (28.0 mg, 0.203 mmol) obtained in Step 2 were dissolved in ethanol (1 mL), and then hydroxylamine aqueous solution (0.012 mL, 0.203 mmol) was added. The reaction solution was stirred at 80 °C for 18 h. After confirming that the starting material had disappeared, the solvent was removed by concentration under reduced pressure, and the mixture was dissolved in pyridine (1.0 mL), followed by addition of acetic anhydride (10.73 μL, 0.111 mmol). The reaction solution was stirred at 80 °C for 3 h. After the reaction was completed, water was added, and the oil layer was extracted with ethyl acetate. The oil 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. (8.5 mg, 0.017 mmol, 17.08% yield)

[0539] 1 H-NMR (500 MHz, Chloroform-d) δ 8.45-8.42 (m, 1H), 6.69-6.66 (m, 1H), 6.46 (s, 1H), 6.39 (s, 1H), 3.80 (s, 3H), 3.57-3.52 (m, 1H), 3.38 (s, 3H), 2.67 (s, 3H), 1.42 (s, 9H), 1.25 (d, J = 5.8 Hz, 6H); LC / MS: 492 (M+H).

[0540]

[0541] Example 192 (Synthetic Method W): Preparation of 6-[2-tert-butyl-6-fluoro-5-(3-methyl-1,2,4-oxadiazol-5-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one

[0542]

[0543] The title compound was obtained in a similar manner to step 1 and step 2 of Synthetic Method I using 6-amino-4-(isopropylamino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-14, 42.8 mg, 0.182 mmol) and 5-(2,4-difluoro-5-nitrophenyl)-3-methyl-1,2,4-oxadiazole (intermediate I-57, 40 mg, 0.166 mmol) as starting materials. (23.5% yield over 2 steps)

[0544] 1 H-NMR (500 MHz, Chloroform-d) δ 8.45 (s, 1H), 6.68 (d, J = 16.5 Hz, 1H), 6.45 (s, 1H), 6.38 (s, 1H), 3.80 (s, 3H), 3.55-3.53 (m, 1H), 3.37 (s, 3H), 2.49 (s, 3H), 1.41 (s, 9H), 1.24 (s, 6H); LC / MS: 492 (M+H).

[0545]

[0546] Example 219 (Synthetic Method X): Preparation of 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-methoxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0547]

[0548] 6-[6-(Difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one (Example 218, 25 mg, 0.044 mmol) was added to tetrahydrofuran (0.5 mL), and sodium hydride (2.61 mg, 0.065 mmol) was added at 0°C. After stirring for 30 minutes, iodomethane (0.027 mL, 0.436 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the oil layer was extracted with ethyl acetate and washed with brine. The oil layer was concentrated under reduced pressure and separated by PTLC to obtain the title compound. (7 mg, 0.012 mmol, 27.3% yield)

[0549] 1 H-NMR (500 MHz, Chloroform-d) δ 7.81 (s, 1H), 7.66 (s, 1H), 7.54 (s, 2H), 7.48 (s, 1H), 6.88-6.58 (m, 3H), 6.56 (s, 1H), 4.19 (s, 3H), 4.01 (s, 3H), 3.86-3.80 (2H), 3.78 (s, 3H), 3.69 (d, J = 7.0 Hz, 2H), 3.37 (s, 3H), 3.24 (s, 3H), 1.60 (s, 3H); LC / MS: 588 (M+H).

[0550]

[0551] Example 243 (Synthetic Method Y): Preparation of 6-[2-tert-butyl-5-(2-methylthiazol-5-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0552] Step 1: Preparation of 6-((4-bromo-2-nitro-5-(trifluoromethyl)phenyl)amino)-4-(3-hydroxy-3-methylazetidin-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0553]

[0554] The title compound was obtained in a similar manner to step 1 of Synthesis R using 6-amino-4-(3-hydroxy-3-methylazetidin-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-29, 13.12 g, 50 mmol) and 1-bromo-4-iodo-5-nitro-2-(trifluoromethyl)benzene (21.77 g, 55.0 mmol) as starting materials. (15.64 g, 29.5 mmol, 59.0% yield)

[0555] 1 H-NMR (500 MHz, Chloroform-d) δ 9.46 (s, 1H), 8.51 (s, 1H), 7.45 (s, 1H), 6.54 (s, 1H), 6.48 (s, 1H), 3.78 (dd, J = 12.4, 7.5 Hz, 4H), 3.71 (s, 3H), 3.37 (s, 3H), 2.01 (s, 1H), 1.67 (s, 3H); LC / MS: 530, 532 (M+H).

[0556] Step 2: Preparation of 5-bromo-2-(tert-butyl)-7'-(3-hydroxy-3-methylazetidin-1-yl)-1',3'-dimethyl-6-(trifluoromethyl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one

[0557]

[0558] The title compound was obtained in a similar manner to step 3 of Synthetic Method R using 6-((4-bromo-2-nitro-5-(trifluoromethyl)phenyl)amino)-4-(3-hydroxy-3-methylazetidin-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (135 mg, 0.255 mmol) and pivaldehyde (55.3 μL, 0.509 mmol) obtained in step 1 as starting materials. (28 mg, 0.049 mmol, 19.4% yield).

[0559] 1H-NMR (500 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.15 (s, 1H), 6.62 (s, 1H), 6.54 (s, 1H), 3.83-3.77 (m, 4H), 3.77 (s, 3H), 3.40 (s, 3H), 1.68 (s, 3H), 1.38 (s, 9H); LC / MS: 566, 568 (M+H).

[0560] Step 3: Preparation of 6-[2-tert-butyl-5-(2-methylthiazol-5-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0561]

[0562] The title compound was obtained in a similar manner to step 4 of Synthetic Method B using 5-bromo-2-(tert-butyl)-7'-(3-hydroxy-3-methylazetidin-1-yl)-1',3'-dimethyl-6-(trifluoromethyl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (15 mg, 0.026 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (8.94 mg, 0.040 mmol) obtained in step 2 as starting materials. (4.6 mg, 7.87 μmol, 29.7% yield)

[0563] 1 H-NMR (500 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.55 (s, 1H), 7.21 (s, 1H), 6.64 (s, 1H), 6.57 (s, 1H), 3.83-3.78 (m, 4H), 3.78 (s, 3H), 3.40 (s, 3H), 2.75 (s, 3H), 2.11 (s, 1H), 1.68 (s, 3H), 1.39 (s, 9H); LC / MS: 585 (M+H).

[0564]

[0565] Example 244: Preparation of 6-[5-(1-cyclopropylpyrazol-4-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0566]

[0567] 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1H-pyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one (Example 230, 6.8 mg, 0.013 mmol), cyclopropylboronic acid (4.43 mg, 0.052 mmol), pyridine (10.4 μL, 0.129 mmol), and triethylamine (9.0 μL, 0.064 mmol) were dissolved in tetrahydrofuran (0. 8 mL), and then copper(II) acetate (7.02 mg, 0.039 mmol) was added. The reaction solution was stirred at 100°C under a nitrogen balloon for 1 h. After the reaction was completed, the solution was diluted with ethyl acetate, passed through a Celite filter, and the filtrate was concentrated. The residue was purified by PTLC to obtain the title compound (1.5 mg, 2.64 μmol, 20.50% yield).

[0568] 1 H-NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 6.7 Hz, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 6.85 (m, 2H), 6.76 (s, 1H), 6.45 (s, 1H), 4.17 (s, 3H), 3.88 (s, 4H), 3.82 (s, 3H), 3.65-3.68 (m, 1H), 3.39 (s, 3H), 2.97 (s, 4H), 2.36-2.33 (m, 2H), 2.30-2.28 (m, 2H); LC / MS: 568 (M+H).

[0569]

[0570] Example 261: Preparation of 6-[2-tert-butyl-6-(methoxymethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0571]

[0572] 6-[2-tert-butyl-6-(hydroxymethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one (Example 260, 15 mg, 0.028 mmol) was added to tetrahydrofuran (0.3 mL), cooled to 0°C, and sodium hydride (60% dispersion in mineral oil, 1.699 mg, 0.042 mmol) was added. After stirring for 30 minutes, iodomethane (0.018 mL, 0.283 mmol) was added to the reaction solution. The reaction solution was stirred at room temperature for 18 hours. After the reaction was complete, water was added, the oil layer was extracted with ethyl acetate, and then washed with brine. The oil layer was concentrated under reduced pressure and purified by MPLC and PTLC to obtain the title compound. (11.5 mg, 0.021 mmol, 74.7% yield)

[0573] 1 H-NMR (400 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.65 (d, J = 0.9 Hz, 1H), 7.55 (s, 1H), 6.90 (t, J = 1.6 Hz, 2H), 6.80 (d, J = 2.3 Hz, 1H), 4.37 (s, 2H), 3.98 (s, 3H), 3.90 (s, 4H), 3.83 (s, 3H), 3.41 (s, 3H), 3.34 (s, 3H), 3.00-2.96 (m, 4H), 1.38 (s, 9H); LC / MS: 544 (M+H).

[0574]

[0575] Example 262: Preparation of 6-[2-tert-butyl-6-(fluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0576]

[0577] 6-[2-tert-butyl-6-(hydroxymethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one (Example 260, 15 mg, 0.028 mmol) was added to dichloromethane (0.5 mL), and diethylaminosulfur trifluoride (0.011 mL, 0.085 mmol) was added dropwise at 0°C. The reaction solution was stirred at 0°C for 2 hours. Water and a saturated sodium bicarbonate solution were added to the reaction solution, and the oil layer was extracted with dichloromethane and washed with brine. The oil layer was concentrated under reduced pressure and separated by MPLC to obtain the title compound. (7.5 mg, 0.014 mmol, 49.8% yield)

[0578] 1 H-NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 6.94 (d, J = 2.7 Hz, 1H), 6.91 (d, J = 1.8 Hz, 1H), 6.80 (d, J = 1.8 Hz, 1H), 5.39 (s, 1H), 5.27 (s, 1H), 3.99 (s, 3H), 3.90 (s, 4H), 3.84 (s, 3H), 3.42 (s, 3H), 2.99 (s, 4H), 1.39 (s, 9H); LC / MS: 532(M+H).

[0579]

[0580] Example 272: Preparation of methyl 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazole-5-carboxylate

[0581]

[0582] The title compound was obtained in a similar manner to step 1 and step 2 of Synthesis I using 6-amino-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-10, 133 mg, 0.507 mmol) and methyl 2,4-difluoro-5-nitrobenzoate (100 mg, 0.461 mmol) as starting materials. (68.9% yield over 2 steps)

[0583] 1 H-NMR (500 MHz, Chloroform-d) δ 8.36 (d, J = 5.5 Hz, 1H), 6.85 (s, 1H), 6.76 (s, 1H), 6.50 (d, J = 12.8 Hz, 1H), 3.91 (s, 4H), 3.87 (s, 3H), 3.79 (s, 3H), 3.40 (s, 3H), 2.96 (s, 4H), 1.35 (s, 9H); LC / MS: 496 (M+H).

[0584]

[0585] Example 273: Preparation of 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazole-5-carboxylic acid

[0586]

[0587] Methyl 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazole-5-carboxylate (Example 272,160 mg, 0.323 mmol) was dissolved in methanol (2 mL) and water (1 mL), and lithium hydroxide hydrate (135 mg, 3.23 mmol) was added. The reaction solution was stirred at 50°C for 1 h. After completion of the reaction, the reaction was quenched with 1 N aqueous hydrochloric acid solution, and the pH of the reaction solution was adjusted to 5-6. The oil layer was extracted using dichloromethane. The oil 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.

[0588] 1 H-NMR (500 MHz, Chloroform-d) δ 8.51 (d, J = 6.1 Hz, 1H), 6.88 (s, 1H), 6.79 (s, 1H), 6.54 (d, J = 10.4 Hz, 1H), 3.90 (s, 4H), 3.83 (s, 3H), 3.42 (s, 3H), 2.99 (s, 4H), 1.38 (s, 9H); LC / MS: 482 (M+H).

[0589]

[0590] Example 274 (Synthetic Method Z): Preparation of 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-N-methyl-benzimidazole-5-carboxamide

[0591]

[0592] 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazole-5-carboxylic acid (Example 273, 35 mg, 0.073 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (20.90 mg, 0.109 mmol), and hydroxybenzotriazole (16.70 mg, 0.109 mmol) were dissolved in dichloromethane (0.8 mL), and then methanamine (2 M in tetrahydrofuran (0.109 mL, 0.218 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. After the reaction was completed, water was added, and the oil layer was extracted with dichloromethane. The oil layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue The title compound was obtained by purification using MPLC and PTLC. (35.6 mg, 0.072 mmol, 99% yield)

[0593] 1H-NMR (500 MHz, Chloroform-d) δ 8.55 (d, J = 6.7 Hz, 1H), 6.87 (s, 1H), 6.77 (s, 1H), 6.73 (d, J = 11.6 Hz, 1H), 6.50 (d, J = 12.2 Hz, 1H), 3.90 (s, 4H), 3.82 (s, 3H), 3.41 (s, 3H), 3.04 (d, J = 4.3 Hz, 3H), 2.99 (s, 4H), 1.37 (s, 9H); LC / MS: 495 (M+H).

[0594]

[0595] Example 288: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-hydroxy-1,3-dimethyl-benzimidazol-2-one

[0596]

[0597] To a solution of 4-benzyloxy-6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one (Example 286, 221 mg, 0.387 mmol) in ethyl acetate (0.968 mL) and methanol (0.968 mL) was added palladium / carbon (10 wt %, 41.2 mg, 0.039 mmol). The reaction mixture was subjected to hydrogen / vacuum exchange three times to sufficiently fill the inside of the reaction vessel with hydrogen, and the mixture was stirred at room temperature for 4 hours in the presence of a hydrogen balloon. The reaction mixture was passed through Celite and filtered while eluting with dichloromethane. The filtrate was concentrated under reduced pressure, and the resulting residue was used in the next reaction without further purification. (156 mg, 0.325 mmol, 84% yield)

[0598] 1H-NMR (500 MHz, Chloroform-d) δ 7.62 (s, 1H), 7.47 (s, 1H), 7.34 (s, 1H), 7.17 (s, 1H), 6.67-6.45 (m, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.41 (s, 3H), 1.31 (s, 9H); LC / MS: 481 (M+H).

[0599]

[0600] Example 290 (Synthetic Method AA): Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(3-methylpyrazol-1-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0601] Step 1: Preparation of 5-bromo-2-(tert-butyl)-6-(difluoromethyl)-7'-(3-hydroxy-3-methylazetidin-1-yl)-1',3'-dimethyl-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one

[0602]

[0603] The title compound was obtained in a similar manner to step 1 and step 2 of Synthesis I using 6-amino-4-(3-hydroxy-3-methylazetidin-1-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-29, 180 mg, 0.686 mmol) and 1-bromo-2-(difluoromethyl)-4-fluoro-5-nitrobenzene (intermediate I-50, 185 mg, 0.686 mmol) as starting materials. (24.4% yield over 2 steps)

[0604] 1H-NMR (400 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.13 (s, 1H), 6.97 (t, J = 55.3 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), 6.58 (d, J = 1.8 Hz, 1H), 3.82 (dd, J = 11.2, 7.1 Hz, 4H), 3.76 (s, 3H), 3.38 (s, 3H), 1.69 (s, 3H), 1.37 (s, 9H); LC / MS: 548, 550 (M+H).

[0605] Step 2: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(3-methylpyrazol-1-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0606]

[0607] 5-Bromo-2-(tert-butyl)-6-(difluoromethyl)-7'-(3-hydroxy-3-methylazetidin-1-yl)-1',3'-dimethyl-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (32 mg, 0.058 mmol) obtained in Step 1 was dissolved in toluene (0.8 mL), and then (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.84 μL, 0.012 mmol), 3-methyl-1H-pyrazole (9.58 mg, 0.117 mmol), potassium carbonate (16.13 mg, 0.117 mmol), and copper(I) iodide (0.556 mg, 2.92 μmol) were added. The mixture was stirred at 150°C for 8 hours using a microwave. After the reaction was completed, water was added, and the oil layer was extracted with ethyl acetate. The oil 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. (1.5 mg, 2.73 μmol, 4.68% yield)

[0608] 1H-NMR (500 MHz, Chloroform-d) δ 7.75 (s, 1H), 7.57 (s, 1H), 7.21 (s, 1H), 6.92 (t, J = 55.5 Hz, 1H), 6.66 (s, 1H), 6.58 (s, 1H), 6.25 (s, 1H), 3.83-3.80 (m, 4H), 3.78 (s, 3H), 3.41 (s, 3H), 2.37 (s, 3H), 2.04 (s, 3H), 1.68 (s, 3H), 1.39 (s, 9H); LC / MS: 550 (M+H).

[0609]

[0610] Example 292: Preparation of 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,3,4-oxadiazol-2-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0611] Step 1: Preparation of N'-acetyl-2-(tert-butyl)-6-fluoro-1',3'-dimethyl-7'-morpholino-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-carbohydrazide

[0612]

[0613] 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazole-5-carboxylic acid (Example 273, 42.3 mg, 0.088 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (25.3 mg, 0.132 mmol), and hydroxybenzotriazole (20.18 mg, 0.132 mmol) were dissolved in dimethylformamide (1 mL), and then acetohydrazide (19.52 mg, 0.264 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. After the reaction was complete, water was added, and the oil layer was extracted with dichloromethane. The oil 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. (44 mg, 0.082 mmol, 9% yield)

[0614] 1 H-NMR (500 MHz, Chloroform-d) δ 9.47 (q, J = 6.4 Hz, 1H), 9.33 (s, 1H), 8.52 (d, J = 6.7 Hz, 1H), 6.86 (s, 1H), 6.77 (s, 1H), 6.56 (d, J = 11.6 Hz, 1H), 3.90 (s, 4H), 3.82 (s, 3H), 3.42 (s, 3H), 2.99 (s, 4H), 2.14 (s, 3H), 1.37 (s, 9H); LC / MS: 538 (M+H).

[0615] Step 2: Preparation of 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,3,4-oxadiazol-2-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0616]

[0617] N'-Acetyl-2-(tert-butyl)-6-fluoro-1',3'-dimethyl-7'-morpholino-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-5-carbohydrazide (41 mg, 0.076 mmol) obtained in Step 1 was dissolved in tetrahydrofuran (0.8 mL), and Burgess reagent (72.6 mg, 0.306 mmol) was added. The reaction solution was stirred at 100°C for 2 h. After the reaction was completed, water was added, and the oil layer was extracted with ethyl acetate. The oil 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. (30 mg, 0.058 mmol, 76% yield)

[0618] 1 H-NMR (500 MHz, Chloroform-d) δ 8.32 (d, J = 5.8 Hz, 1H), 6.88 (s, 1H), 6.79 (s, 1H), 6.62 (d, J = 10.1 Hz, 1H), 3.88 (s, 4H), 3.81 (s, 3H), 3.41 (s, 3H), 2.98 (s, 4H), 2.61 (s, 3H), 1.36 (s, 9H); LC / MS: 520 (M+H).

[0619]

[0620] Example 299: Preparation of (5E)-2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbaldehyde oxime

[0621]

[0622] 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbaldehyde (Example 285, 12 mg, 0.023 mmol) was added to methanol (0.5 mL), and hydroxylamine hydrochloride (1.738 mg, 0.025 mmol) and potassium carbonate (3.46 mg, 0.025 mmol) were added. The mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the oil layer was extracted with ethyl acetate. The combined oil layers were concentrated under reduced pressure and purified by MPLC to obtain the title compound. (11.1 mg, 0.020 mmol, 90% yield)

[0623] 1 H-NMR (500 MHz, Chloroform-d) δ 8.34 (s, 1H), 7.77 (s, 1H), 7.57-7.53 (1H), 7.39 (s, 1H), 7.32-7.28 (1H), 6.91-6.84 (1H), 6.78 (s, 1H), 4.00-3.96 (3H), 3.89 (s, 4H), 3.82 (s, 3H), 3.40 (s, 3H), 2.98 (s, 4H), 1.38 (s, 9H); LC / MS: 543 (M+H).

[0624]

[0625] Example 300: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(6-chloropyrimidin-4-yl)oxy-1,3-dimethyl-benzimidazol-2-one

[0626]

[0627] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-hydroxy-1,3-dimethyl-benzimidazol-2-one (Example 288, 15 mg, 0.031 mmol), 4,6-dichloropyrimidine (5.12 mg, 0.034 mmol), potassium carbonate (12.94 mg, 0.094 mmol) were dissolved in dimethylformamide (0.312 mL). The reaction solution was stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The obtained oil layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (8.9 mg, 0.015 mmol, 48.1% yield)

[0628] 1 H-NMR (500 MHz, Chloroform-d) δ 8.57 (s, 1H), 7.77 (s, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 7.26 (s, 1H), 7.12 (s, 1H), 6.94 (s, 1H), 6.90 (s, 1H), 6.68 (t, J = 55.5 Hz, 1H), 3.99 (s, 3H), 3.52 (s, 3H), 3.47 (s, 3H), 1.43 (s, 9H); LC / MS: 593 (M+H).

[0629]

[0630] Example 301 (Synthetic Method AB): Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-methoxyphenoxy)-1,3-dimethyl-benzimidazol-2-one

[0631]

[0632] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-hydroxy-1,3-dimethyl-benzimidazol-2-one (Example 288, 15 mg, 0.031 mmol), (4-methoxyphenyl)boronic acid (14.2 mg, 0.094 mmol), and copper(II) acetate (5.67 mg, 0.031 mmol) were dissolved in dichloromethane (1.56 mL). 4Å molecular sieves were added and the mixture was stirred at room temperature for 10 min. Triethylamine (26.1 μL, 0.187 mmol) was added to the reaction mixture, and the reaction vessel was ventilated and stirred at room temperature for 18 h. The reaction mixture was diluted with dichloromethane and filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (15.2 mg, 0.026 mmol, 83% yield)

[0633] 1 H-NMR (400 MHz, Chloroform-d) δ 7.73 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 7.17 (s, 1H), 7.00 (d, J = 9.1 Hz, 2H), 6.86 (d, J = 9.1 Hz, 2H), 6.80-6.52 (m, 2H), 6.51 (d, J = 1.8 Hz, 1H), 3.98 (s, 3H), 3.76 (s, 3H), 3.74 (s, 3H), 3.45 (s, 3H), 1.35 (s, 9H); LC / MS: 587 (M+H).

[0634]

[0635] Example 307: Preparation of 6-[2-tert-butyl-6-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0636]

[0637] 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,3,4-oxadiazol-2-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one (Example 292, 17 mg, 0.033 mmol) was dissolved in acetic acid (0.6 mL), and ammonium acetate (50.4 mg, 0.654 mmol) was added. The reaction solution was stirred using a microwave at 150°C for 12 h. After the reaction was completed, a 1 N aqueous sodium hydroxide solution was added, and the oil layer was extracted with ethyl acetate. The oil 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. (8 mg, 0.015 mmol, 47.1% yield)

[0638] 1 H-NMR (500 MHz, Chloroform-d) δ 8.64 (s, 1H), 6.89 (s, 1H), 6.80 (s, 1H), 6.60 (d, J = 11.3 Hz, 1H), 3.91 (s, 4H), 3.83 (s, 3H), 3.42 (s, 3H), 3.00 (s, 4H), 2.52 (s, 3H), 1.39 (s, 9H); LC / MS: 519 (M+H).

[0639]

[0640] Example 311: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1,1-dioxo-1,4-thiazinan-4-yl)-1,3-dimethyl-benzimidazol-2-one

[0641]

[0642] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-thiomorpholino-benzimidazol-2-one (Example 298, 8.6 mg, 0.015 mmol) and 3-chlorobenzoperoxoic acid (15.33 mg, 0.068 mmol) were stirred in chloroform (1 mL) for 3 hours at 10-15°C. The reaction was quenched with saturated aqueous sodium bicarbonate. The reaction mass was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the title compound. (6 mg, 0.010 mmol, 66.0% yield)

[0643] 1 H-NMR (500 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.62 (s, 1H), 7.50 (s, 1H), 7.14 (s, 1H), 6.99 (d, J = 1.68 Hz, 1H), 6.88 (d, J = 1.53 Hz, 1H), 6.68 (t, 1H), 4.01 (s, 3H), 3.84 (s, 3H), 3.55 (br. s., 4H), 3.50-3.36 (m, 5H), 3.16 (br. s., 2H); LC / MS: 598 (M+H).

[0644]

[0645] Example 315: Preparation of 6-[2-tert-butyl-6-fluoro-5-(1-methyltriazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0646] Step 1: Preparation of 6-((4-ethynyl-5-fluoro-2-nitrophenyl)amino)-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0647]

[0648] A mixture of the two title compounds was obtained in the same manner as in step 1 of Synthesis I using 6-amino-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one (Intermediate I-10, 362 mg, 1.379 mmol) and ((2,4-difluoro-5-nitrophenyl)ethynyl)trimethylsilane (Intermediate I-56, 320 mg, 1.253 mmol) as starting materials. (202 mg, 0.475 mmol, 37.9% yield)

[0649] Example 315-1A: 1 H-NMR (500 MHz, Chloroform-d) δ 9.65 (s, 1H), 8.43 (d, J = 7.0 Hz, 1H), 6.77 (s, 1H), 6.69 (s, 1H), 6.65 (d, J = 11.0 Hz, 1H), 3.90 (s, 4H), 3.76 (s, 3H), 3.40 (s, 3H), 3.22 (s, 1H), 2.98 (s, 4H); LC / MS: 426 (M+H).

[0650] Example 315-1B: 1 H-NMR (500 MHz, Chloroform-d) δ 9.63 (s, 1H), 8.40 (d, J = 7.0 Hz, 1H), 6.79 (s, 1H), 6.70 (s, 1H), 6.63 (d, 1H), 3.90 (s, 4H), 3.76 (s, 3H), 3.40 (s, 3H), 2.98 (s, 4H), 0.25 (s, 9H).

[0651] Step 2: Preparation of 2-(tert-butyl)-5-ethynyl-6-fluoro-1',3'-dimethyl-7'-morpholino-1',3'-dihydro-2'H-[1,5'-benzo[d]imidazol]-2'-one and 2-(tert-butyl)-6-fluoro-1',3'-dimethyl-7'-morpholino-5-((trimethylsily)ethynyl)-1',3'-dihydro-2'H-[1,5'-benzo[d]imidazol]-2'-one

[0652]

[0653] A mixture of 6-((4-ethynyl-5-fluoro-2-nitrophenyl)amino)-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one, 6-((5-fluoro-2-nitro-4-((trimethylsilyl)ethynyl)phenyl)amino)-1,3-dimethyl-4-morpholino-1,3-dihydro-2H-benzo[d]imidazol-2-one (202 mg, 0.475 mmol) obtained in Step 1 and pivaldehyde (155 μL, 1.424 mmol) was used as a starting material in the same manner as in Step 2 of Synthetic Method I to obtain a mixture of the two title compounds. (83 mg, 0.180 mmol, 37% yield)

[0654] Example 315-2A: 1 H-NMR (500 MHz, Chloroform-d) δ 7.87 (d, J = 5.8 Hz, 1H), 6.86 (s, 1H), 6.76 (s, 1H), 6.49 (d, J = 8.9 Hz, 1H), 3.89 (s, 4H), 3.81 (s, 3H), 3.41 (s, 3H), 3.25 (s, 1H), 2.98 (s, 4H), 1.36 (s, 9H); LC / MS: 462 (M+H).

[0655] Example 315-2B: 1 H-NMR (500 MHz, Chloroform-d) δ 7.80 (d, J = 5.8 Hz, 1H), 6.85 (s, 1H), 6.75 (s, 1H), 6.44 (d, J = 8.9 Hz, 1H), 3.89 (s, 4H), 3.80 (s, 3H), 3.40 (s, 3H), 2.97 (s, 4H), 1.34 (s, 9H), 0.25 (s, 9H); LC / MS: 534 (M+H).

[0656] Step 3: Preparation of 2-(tert-butyl)-5-ethynyl-6-fluoro-1',3'-dimethyl-7'-morpholino-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one

[0657]

[0658] A mixture of 2-(tert-butyl)-5-ethynyl-6-fluoro-1',3'-dimethyl-7'-morpholino-1',3'-dihydro-2'H-[1,5'-benzo[d]imidazol]-2'-one and 2-(tert-butyl)-6-fluoro-1',3'-dimethyl-7'-morpholino-5-((trimethylsilyl)ethynyl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one obtained in Step 2 (83 mg, 0.156 mmol) was dissolved in tetrahydrofuran (0.8 mL), and then tetra-n-butylammonium fluoride (1 M in tetrahydrofuran, 0.311 mL, 0.311 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and ethyl acetate was added to dilute the mixture. Water was added, and the oil layer was extracted with ethyl acetate. The oil layer was washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (61 mg, 0.132 mmol, 85% yield)

[0659] 1 H-NMR (500 MHz, Chloroform-d) δ 7.85 (d, J = 5.2 Hz, 1H), 6.85 (s, 1H), 6.76 (s, 1H), 6.48 (d, J = 8.9 Hz, 1H), 3.88 (s, 4H), 3.80 (s, 3H), 3.39 (s, 3H), 3.24 (s, 1H), 2.97 (s, 4H), 1.34 (s, 9H); LC / MS: 462 (M+H).

[0660] Step 4: Preparation of 2-(tert-butyl)-6-fluoro-1',3'-dimethyl-7'-morpholino-5-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one

[0661]

[0662] 2-(tert-butyl)-5-ethynyl-6-fluoro-1',3'-dimethyl-7'-morpholino-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (32 mg, 0.069 mmol) obtained in Step 3 was dissolved in dimethylformamide (0.8 mL), and copper(I) iodide (2.64 mg, 0.014 mmol) and diisopropylethylamine (0.012 mL, 0.069 mmol) were added. After 5 minutes, (azidomethyl)trimethylsilane (0.051 mL, 0.347 mmol) was added, and the reaction solution was stirred at room temperature for 8 hours. After the reaction was complete, water was added, and the oil layer was extracted with ethyl acetate. The oil 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. (29 mg, 0.049 mmol, 70.8% yield)

[0663] 1 H-NMR (500 MHz, Chloroform-d) δ 8.62 (d, J = 6.1 Hz, 1H), 7.72 (s, 1H), 6.89 (s, 1H), 6.79 (s, 1H), 6.53 (d, J = 10.1 Hz, 1H), 3.93 (s, 2H), 3.89 (s, 4H), 3.81 (s, 3H), 3.41 (s, 3H), 2.99 (s, 4H), 1.37 (s, 9H), 0.17 (s, 9H); LC / MS: 591 (M+H).

[0664] Step 5: Preparation of 6-[2-tert-butyl-6-fluoro-5-(1-methyltriazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0665]

[0666] The title compound was obtained in a similar manner to step 3 above using 2-(tert-butyl)-6-fluoro-1',3'-dimethyl-7'-morpholino-5-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (29 mg, 0.049 mmol) obtained in step 4 as a starting material. (23 mg, 0.044 mmol, 90% yield)

[0667] 1 H-NMR (500 MHz, Chloroform-d) δ 8.62 (s, 1H), 7.83 (s, 1H), 6.89 (s, 1H), 6.79 (s, 1H), 6.54 (d, J = 10.1 Hz, 1H), 4.13 (s, 3H), 3.89 (s, 4H), 3.81 (s, 3H), 3.41 (s, 3H), 2.98 (s, 4H), 1.36 (s, 9H); LC / MS: 519 (M+H).

[0668]

[0669] Example 317 (Synthetic Method AC): Preparation of 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0670]

[0671] Tert-Butyl N-[2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl]carbamate (Example 316, 160 mg, 0.260 mmol) was dissolved in dichloromethane (2 mL) and hydrochloric acid (4 M in 1,4-dioxane, 0.651 mL, 2.60 mmol) was added. The reaction solution was stirred at room temperature for 1 h. The reaction solution was adjusted to pH 10 with 1 N sodium hydroxide and extracted with dichloromethane. The oil layer was concentrated under reduced pressure and used in the next reaction without further purification. (120 mg, 0.233 mmol, 90% yield)

[0672] 1 H-NMR (400 MHz, Chloroform-d) δ 7.67 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 6.91 (d, J = 1.8 Hz, 1H), 6.80 (d, J = 1.8 Hz, 1H), 6.15 (s, 1H), 3.97 (s, 3H), 3.91 (s, 4H), 3.82 (s, 3H), 3.65 (s, 2H), 3.41 (s, 3H), 2.99 (s, 4H), 1.36 (s, 9H); LC / MS: 515 (M+H).

[0673]

[0674] Example 318 (Synthetic Method AD): Preparation of 6-[2-tert-butyl-6-(methylaminomethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0675]

[0676] 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbaldehyde (Example 285, 20 mg, 0.038 mmol) was dissolved in dichloroethane (0.5 mL), and methanamine (2 M in tetrahydrofuran, 0.038 mL, 0.076 mmol), acetic acid (2.170 μL, 0.038 mmol), and sodium triacetoxyborohydride (10.44 mg, 0.049 mmol) were added. The reaction solution was stirred at room temperature for 4 hours. After the reaction, the pH was adjusted to 9-11 by adding water and 1 N sodium hydroxide, and the oil layer was extracted with dichloromethane. The collected oil layer was concentrated under reduced pressure and separated by PTLC to obtain the title compound. (7 mg, 0.013 mmol, 34.0% yield)

[0677] 1H-NMR (400 MHz, Chloroform-d) δ 7.75 (s, 1H), 7.63 (s, 1H), 7.56 (s, 1H), 6.90 (d, J = 1.8 Hz, 1H), 6.85 (s, 1H), 6.80 (d, J = 1.4 Hz, 1H), 3.98 (s, 3H), 3.91 (s, 4H), 3.83 (s, 3H), 3.80-3.73 (m, 2H), 3.42 (s, 3H), 2.99 (s, 4H), 2.36 (s, 3H), 2.23 (s, 1H), 1.37 (s, 9H); LC / MS: 543 (M+H).

[0678]

[0679] Example 321: Preparation of N-[2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl]acetamide

[0680]

[0681] 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one (Example 317, 30 mg, 0.058 mmol) was added to dichloromethane (1 mL), and acetyl chloride (4.16 μL, 0.058 mmol) and diisopropylethylamine (0.020 mL, 0.117 mmol) were added. The mixture was stirred at room temperature for 18 h. Water was added to the reaction mixture, the oil layer was extracted with dichloromethane, and the mixture was concentrated under reduced pressure. The title compound was obtained by purification by MPLC. (22.3 mg, 0.040 mmol, 68.7% yield)

[0682] 1H-NMR (400 MHz, Chloroform-d) δ 7.70 (s, 1H), 7.66 (s, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 6.90 (d, J = 1.8 Hz, 1H), 6.80 (d, J = 1.8 Hz, 1H), 4.01 (s, 3H), 3.89 (s, 4H), 3.82 (s, 3H), 3.40 (s, 3H), 2.99 (d, J = 4.6 Hz, 4H), 2.05 (s, 3H), 1.37 (s, 9H); LC / MS: 557 (M+H).

[0683]

[0684] Example 325 (Synthetic Method AE): Preparation of 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxetan-3-ylmethoxy)benzimidazol-2-one

[0685] Step 1: Preparation of 7'-(benzyloxy)-2-(tert-butyl)-6-fluoro-1',3'-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one

[0686]

[0687] The title compound was obtained in a similar manner to Synthesis M using 6-amino-4-(benzyloxy)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4.53 g, 16 mmol), 1-bromo-2,4-difluoro-5-nitrobenzene (3.81 g, 16.00 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.70 g, 13.00 mmol), and pivaldehyde (2.12 mL, 19.50 mmol) as starting materials. (2.71 g, 5.03 mmol, 52% yield over 3 steps)

[0688] 1H-NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 6.4 Hz, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.38-7.34 (m, 5H), 6.65 (s, 2H), 6.50 (d, J = 10.5 Hz, 1H), 5.19 (d, J = 12.3 Hz, 1H), 5.11 (d, J = 11.9 Hz, 1H), 3.96 (s, 3H), 3.75 (s, 3H), 3.41 (s, 3H), 1.31 (s, 9H); LC / MS: 539 (M+H).

[0689] Step 2: Preparation of 2-(tert-butyl)-6-fluoro-7'-hydroxy-1',3'-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one

[0690]

[0691] The title compound was obtained in a similar manner to the synthesis of Example 288 using 7'-(benzyloxy)-2-(tert-butyl)-6-fluoro-1',3'-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (2.478 g, 4.6 mmol) obtained in Step 1 as a starting material. (2.04 g, 4.55 mmol, 99% yield)

[0692] 1 H-NMR (400 MHz, Chloroform-d) δ 7.75 (s, 1H), 7.74 (d, J = 6.4 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 6.52 (d, J = 1.4 Hz, 1H), 6.46 (d, J = 10.1 Hz, 1H), 6.13 (s, 1H), 3.94 (s, 3H), 3.84 (s, 3H), 3.40 (s, 3H), 1.26 (s, 9H); LC / MS: 449 (M+H).

[0693] Step 3: Preparation of 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxetan-3-ylmethoxy)benzimidazol-2-one

[0694]

[0695] 2-(tert-butyl)-6-fluoro-7'-hydroxy-1',3'-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (27.0 mg, 0.060 mmol) and cesium carbonate (23.5 mg, 0.072 mmol) obtained in Step 2 were dissolved in dimethylformamide (0.300 mL). 3-(bromomethyl)oxetane (9.06 mg, 0.060 mmol) was added and the mixture was stirred at 100°C for 18 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The obtained oil layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (26.7 mg, 0.051 mmol, 86% yield)

[0696] 1 H-NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 6.7 Hz, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 6.70 (s, 1H), 6.65 (s, 1H), 6.56 (d, J = 10.4 Hz, 1H), 4.94-4.91 (m, 2H), 4.64 (t, J = 6.1 Hz, 2H), 4.26-4.20 (m, 2H), 3.96 (s, 3H), 3.74 (s, 3H), 3.52-3.46 (m, 1H), 3.42 (s, 3H), 1.39-1.42 (9H); LC / MS: 519 (M+H).

[0697]

[0698] Example 326 (Synthetic Method AF): Preparation of 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(1-methyl-4-piperidyl)oxy]benzimidazol-2-one

[0699]

[0700] To a solution of 2-(tert-butyl)-6-fluoro-7'-hydroxy-1',3'-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (compound of step 2 of synthetic method AE, 22.0 mg, 0.050 mmol) in anhydrous tetrahydrofuran (0.500 mL) were added 1-methylpiperidin-4-ol (6.91 mg, 0.060 mmol) and triphenylphosphine (19.7 mg, 0.075 mmol). The temperature of the reaction mixture was lowered to 0°C, diisopropyl azodicarboxylate (14.6 μL, 0.075 mmol) was added, and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained oil layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (15.9 mg, 0.029 mmol, 58.3% yield)

[0701] 1H-NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 6.7 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J = 2.1 Hz, 1H), 6.64 (d, J = 1.5 Hz, 1H), 6.61 (d, J = 1.5 Hz, 1H), 6.56 (d, J = 10.4 Hz, 1H), 4.37 (s, 1H), 3.96 (s, 3H), 3.75 (s, 3H), 3.41 (s, 3H), 2.68 (s, 2H), 2.34-2.29 (m, 5H), 2.05 (t, J = 6.9 Hz, 3H), 1.95-1.87 (m, 3H), 1.41-1.39 (9H); LC / MS: 546 (M+H).

[0702]

[0703] Examples 331 and 332: Synthesis of 6-[2-tert-butyl-6-(methylamino)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one and 6-[2-tert-butyl-6-(dimethylamino)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0704]

[0705] 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one (Example 317, 30 mg, 0.058 mmol) was added to 1,2-dichloroethane (0.5 mL), and formaldehyde (37 wt % in water, 4.34 μL, 0.058 mmol), acetic acid (3.34 μL, 0.058 mmol), and sodium triacetoxyborohydride (16.06 mg, 0.076 mmol) were added. The mixture was stirred at room temperature for 3 hours. After the reaction, the pH was adjusted to 9-11 with water and 1 N sodium hydroxide, and the oil layer was extracted with dichloromethane. The collected oil layers were concentrated under reduced pressure and separated by PTLC to obtain two title compounds, Example 331 (7 mg, 0.013 mmol, 22.71% yield) and Example 332 (5 mg, 0.009 mmol, 15.9% yield).

[0706] Example 331: 1 H-NMR (400 MHz, Chloroform-d) δ 7.63 (s, 1H), 7.56 (s, 1H), 7.48 (s, 1H), 6.92 (d, J = 1.4 Hz, 1H), 6.82 (d, J = 1.4 Hz, 1H), 5.92 (s, 1H), 3.98 (s, 3H), 3.90 (s, 4H), 3.84 (s, 3H), 3.42 (s, 3H), 2.99 (s, 4H), 2.66 (s, 3H), 1.35 (s, 9H); LC / MS: 529 (M+H).

[0707] Example 332: 1H-NMR (400 MHz, Chloroform-d) δ 7.90 (s, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 6.46 (s, 1H), 3.96 (s, 3H), 3.92 (s, 4H), 3.84 (s, 3H), 3.43 (s, 3H), 3.00 (s, 4H), 2.53 (s, 6H), 1.35 (s, 9H); LC / MS: 543 (M+H).

[0708]

[0709] Example 333: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(3-chloro-2-hydroxy-2-methyl-propyl)amino]-1,3-dimethyl-benzimidazol-2-one

[0710]

[0711] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one (Example 183, 100 mg, 0.18 mmol) was added to dichloromethane (2 mL), hydrochloric acid (4 M in 1,4-dioxane, 0.045 mL, 0.18 mmol) was added, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and separated by MPLC to obtain the title compound.

[0712] 1H-NMR (500 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.22 (s, 1H), 6.67 (t, J = 55.7 Hz, 1H), 6.53 (s, 1H), 6.42 (s, 1H), 4.70 (s, 1H), 3.99 (s, 3H), 3.84 (s, 3H), 3.76-3.56 (m, 2H), 3.40 (s, 3H), 3.23 (d, J = 5.8 Hz, 1H), 3.13 (t, J = 5.6 Hz, 1H), 2.70 (s, 1H), 1.42 (s, 9H); LC / MS: 586 (M+H).

[0713]

[0714] Example 338 (Synthetic Method AG): Preparation of 6-[2-tert-butyl-6-hydroxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0715]

[0716] To a solution of 6-[6-benzyloxy-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one (Example 337, 43 mg, 0.071 mmol) in methanol (0.355 mL) was added palladium / carbon (10 wt %, 7.6 mg, 7.10 μmol). The reaction mixture was subjected to hydrogen / vacuum exchange three times to sufficiently fill the inside of the reaction vessel with hydrogen, and the mixture was stirred at room temperature for 4 hours in the presence of a hydrogen balloon. The reaction mixture was passed through Celite and filtered while eluting with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was purified by PTLC to obtain the title compound. (31 mg, 0.060 mmol, 85% yield)

[0717] 1H-NMR (500 MHz, Chloroform-d) δ 7.74 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 6.64 (d, J = 1.8 Hz, 1H), 6.59 (d, J = 1.8 Hz, 1H), 6.36 (s, 1H), 3.98 (s, 3H), 3.81-3.73 (m, 7H), 3.37 (s, 3H), 1.67 (s, 3H), 1.36 (s, 9H); LC / MS: 516 (M+H).

[0718]

[0719] Example 339: Preparation of [2-tert-butyl-3-[7-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl] acetate

[0720]

[0721] To a solution of 6-[2-tert-butyl-6-hydroxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one (Example 338, 16 mg, 0.031 mmol) in dichloromethane (0.155 mL) was added pyridine (5.02 μL, 0.062 mmol). The temperature of the reaction mixture was lowered to 0°C, acetyl chloride (3.31 μL, 0.047 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate. The obtained oil layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound. (7.7 mg, 0.014 mmol, 44.5% yield)

[0722] 1H-NMR (500 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.70 (s, 1H), 7.53 (s, 1H), 6.68 (d, J = 1.8 Hz, 1H), 6.61 (d, J = 1.8 Hz, 1H), 6.58 (s, 1H), 3.95 (s, 3H), 3.82-3.73 (m, 7H), 3.39 (s, 3H), 2.20 (s, 3H), 2.06 (s, 1H), 1.68 (s, 3H), 1.38 (s, 9H); LC / MS: 558 (M+H).

[0723]

[0724] Example 342: Preparation of 6-[2-tert-butyl-6-fluoro-5-(2-methyloxazol-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one

[0725]

[0726] 2-(tert-butyl)-5-ethynyl-6-fluoro-1',3'-dimethyl-7'-morpholino-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazol]-2'-one (step 3 compound of Example 315 synthesis, 33 mg, 0.071 mmol) was dissolved in acetonitrile (0.8 mL), and then triphenylphosphingold(I) bis(trifluoromethanesulfonyl)imidate (14.80 mg, 0.093 mmol) was added. The reaction solution was stirred at 60°C for 18 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained residue was purified by PTLC to obtain the title compound. (18.2 mg, 0.035 mmol, 49.1% yield)

[0727] 1H-NMR (500 MHz, Chloroform-d) δ 8.11 (d, J = 6.4 Hz, 1H), 7.27 (s, 1H), 6.88 (d, J = 1.8 Hz, 1H), 6.78 (d, J = 1.8 Hz, 1H), 6.56 (d, J = 10.4 Hz, 1H), 3.90 (s, 4H), 3.82 (s, 3H), 3.42 (s, 3H), 3.00-2.98 (m, 4H), 2.55 (s, 3H), 1.38 (s, 9H); LC / MS: 519 (M+H).

[0728]

[0729] Examples 345 and 346: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-vinylpyrazol-4-yl)benzimidazol-1-yl]-4-[3-(dimethylamino)-3-methyl-azetidin-1-yl]-1,3-dimethyl-benzimidazol-2-one and 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]benzimidazol-1-yl]-4-[3-(dimethylamino)-3-methyl-azetidin-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0730] Step 1: Preparation of 1-(2-(tert-butyl)-6-(difluoromethyl)-1',3'-dimethyl-5-(1-(2-((methylsulfonyl)oxy)ethyl)-1H-pyrazol-4-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazole]-7'-yl)-3-methylazetidin-3-yl methanesulfonate

[0731]

[0732] 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-hydroxyethyl)pyrazol-4-yl]benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one (Example 313, 42.4 mg, 0.073 mmol) was dissolved in dichloromethane (0.8 mL), and then methanesulfonyl chloride (0.0165 mL, 0.219 mmol) and triethylamine (0.051 mL, 0.366 mmol) were added at 0°C. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, water and dichloromethane were added, and the oil layer was extracted. The oil 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. (54.2 mg, 0.074 mmol, 100% yield)

[0733] 1 H-NMR (400 MHz, Chloroform-d) δ 7.75 (s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.19 (s, 1H), 6.79-6.51 (m, 3H), 4.63 (t, J = 4.8 Hz, 2H), 4.50 (t, J = 4.8 Hz, 2H), 4.16-4.11 (m, 2H), 3.93-3.87 (m, 2H), 3.75 (s, 3H), 3.39 (s, 3H), 3.04 (s, 3H), 2.87 (s, 3H), 1.99 (s, 3H), 1.37 (s, 9H); LC / MS: 735 (M+H).

[0734] Step 2: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-vinylpyrazol-4-yl)benzimidazol-1-yl]-4-[3-(dimethylamino)-3-methyl-azetidin-1-yl]-1,3-dimethyl-benzimidazol-2-one and 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]benzimidazol-1-yl]-4-[3-(dimethylamino)-3-methyl-azetidin-1-yl]-1,3-dimethyl-benzimidazol-2-one

[0735]

[0736] 1-(2-(tert-butyl)-6-(difluoromethyl)-1',3'-dimethyl-5-(1-(2-((methylsulfonyl)oxy)ethyl)-1H-pyrazol-4-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazol]-7'-yl)-3-methylazetidin-3-yl methanesulfonate (27 mg, 0.037 mmol) obtained in Step 1 was dissolved in acetonitrile (0.8 mL), and then dimethylamine (0.022 mL, 0.044 mmol) and cesium carbonate (17.93 mg, 0.055 mmol) were added. The reaction solution was stirred at 80°C for 18 h. After the reaction was completed, water was added, and the oil layer was extracted with ethyl acetate. The oil 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 compounds, respectively.

[0737] Example 345: 1 H-NMR (500 MHz, Chloroform-d) δ 7.81 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.22 (s, 1H), 7.10 (dd, J = 15.9, 8.9 Hz, 1H), 6.78-6.56 (m, 3H), 5.60 (d, J = 15.9 Hz, 1H), 4.92 (d, J = 8.9 Hz, 1H), 3.78 (s, 3H), 3.74-3.69 (m, 2H), 3.63-3.57 (m, 2H), 3.40 (s, 3H), 2.15 (s, 6H), 1.43 (s, 3H), 1.39 (s, 9H); LC / MS: 589 (M+H).

[0738] Example 346: 1H-NMR (500 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.63 (s, 1H), 7.61 (s, 1H), 7.20 (s, 1H), 6.79-6.57 (m, 3H), 4.30 (t, J = 6.7 Hz, 2H), 3.77 (s, 3H), 3.75-3.70 (m, 2H), 3.62-3.57 (m, 2H), 3.39 (s, 3H), 2.85 (t, J = 6.6 Hz, 2H), 2.32 (s, 6H), 2.15 (s, 6H), 1.43 (s, 3H), 1.39 (s, 9H); LC / MS: 634 (M+H).

[0739]

[0740] Example 347: Preparation of [1-[6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-morpholinoethyl)pyrazol-4-yl]benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3-methyl-azetidin-3-yl] methanesulfonate

[0741]

[0742] 1-(2-(tert-butyl)-6-(difluoromethyl)-1',3'-dimethyl-5-(1-(2-((methylsulfonyl)oxy)ethyl)-1H-pyrazol-4-yl)-2'-oxo-2',3'-dihydro-1'H-[1,5'-bibenzo[d]imidazol]-7'-yl)-3-methylazetidin-3-yl methanesulfonate (compound of step 1 of Examples 345 and 346, 27 mg, 0.037 mmol) was dissolved in morpholine (0.5 mL, 5.80 mmol) and stirred at room temperature for 18 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and water and ethyl acetate were added to extract the oil layer. The oil 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. (16.5 mg, 0.023 mmol, 61.9% yield)

[0743] 1H-NMR (500 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.64 (s, 1H), 7.61 (s, 1H), 7.20 (s, 1H), 6.79-6.57 (m, 3H), 4.32 (s, 2H), 4.18-4.13 (m, 2H), 3.91 (dd, J = 22.4, 8.4 Hz, 2H), 3.76 (s, 3H), 3.71 (s, 4H), 3.40 (s, 3H), 3.05 (s, 3H), 2.88 (s, 2H), 2.52 (s, 4H), 2.01 (s, 3H), 1.39 (s, 9H); LC / MS: 727 (M+H).

[0744]

[0745] Example 348: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-morpholinoethyl)pyrazol-4-yl]benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one

[0746]

[0747] [1-[6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-morpholinoethyl)pyrazol-4-yl]benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3-methyl-azetidin-3-yl] methanesulfonate (Example 347, 7.4 mg, 10.18 μmol) was dissolved in dimethyl sulfoxide (0.3 mL), 1 M aqueous triethylammonium acetate solution (0.015 mL, 0.015 mmol) was added, and the mixture was stirred at 60 ℃ for 18 hours. After the reaction was completed, water was added, and the oil layer was extracted with ethyl acetate. The oil 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. (3.5 mg, 5.39 μmol, 53.0% yield)

[0748] 1H-NMR (500 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.63 (s, 1H), 7.62 (s, 1H), 7.21 (s, 1H), 6.79-6.57 (m, 3H), 4.31 (t, J = 6.3 Hz, 2H), 3.83-3.76 (m, 7H), 3.70 (t, J = 4.4 Hz, 4H), 3.40 (s, 3H), 2.86 (t, J = 6.3 Hz, 2H), 2.51 (s, 4H), 1.68 (s, 3H), 1.39 (s, 9H); LC / MS: 649 (M+H).

[0749]

[0750] Example 357: Preparation of 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(2,3-dihydroxy-2-methyl-propyl)amino]-1,3-dimethyl-benzimidazol-2-one

[0751]

[0752] Tert-Butyl N-[2-tert-butyl-3-[7-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl]carbamate (Example 343, 36 mg, 0.059 mmol) and trifluoroacetic acid (0.031 mL, 0.468 mmol) were stirred in the presence of dichloromethane (0.3 mL) for 1 hour. The reaction solution was diluted with dichloromethane (3 mL), and saturated aqueous sodium bicarbonate solution was added dropwise at 0°C. The reaction solution was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (1 mg, 0.002 mmol, 3.3% yield)

[0753] 1H-NMR (500 MHz, Chloroform-d) δ 7.67 (s, 1H), 7.59 (br. s., 1H), 7.54 (s, 1H), 6.50 (s, 1H), 6.40 (s, 1H), 6.17 (d, J = 2.59 Hz, 1H), 5.03 (br. s., 1H), 4.03-3.92 (m, 4H), 3.86-3.79 (m, 3H), 3.77-3.72 (m, 2H), 3.70-3.62 (m, 2H), 3.44-3.34 (m, 4H), 3.21-3.14 (m, 1H), 3.12-3.05 (m, 1H), 1.46-1.35 (m, 9H), 1.30 (d, J = 1.83 Hz, 3H); LC / MS: 533 (M+H).

[0754]

[0755] Example 359 (Synthetic Method AH): Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidyl)benzimidazol-2-one

[0756]

[0757] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1,3-dimethyl-benzimidazol-2-one (Example 361, 220 mg, 0.363 mmol) was dissolved in tetrahydrofuran (1.8 mL) and 1 M hydrochloric acid (2.54 mL, 2.54 mmol) was added. The mixture was reacted at room temperature for 18 hours. After neutralizing with aqueous sodium hydroxide solution, the mixture was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound. (141 mg, 0.251 mmol, 69.1% yield)

[0758] 1H-NMR (500 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.61 (s, 1H), 7.49 (s, 1H), 7.18 (s, 1H), 6.92 (d, J = 1.68 Hz, 1H), 6.84 (d, J = 1.68 Hz, 1H), 6.68 (t, 1H), 4.00 (s, 3H), 3.96-3.88 (m, 3H), 3.54 (br. s., 1H), 3.50 (br. s., 1H), 3.48-3.40 (m, 3H), 3.14 (br. s., 2H), 2.84 (br. s., 2H), 2.53 (br. s.) s., 2H), 1.48-1.32 (m, 9H); LC / MS: 562 (M+H).

[0759]

[0760] Example 362 (Synthetic Method AI): Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one

[0761]

[0762] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidyl)benzimidazol-2-one (Example 359, 22 mg, 0.039 mmol) was stirred in an ethanol (0.2 mL) solvent, and sodium borohydride (2.67 mg, 0.071 mmol) was added at 0°C, followed by stirring for 2 hours. The reaction was quenched using a saturated ammonium chloride aqueous solution, diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the title compound. (9.7 mg, 0.017 mmol, 43.9% yield)

[0763] 1H-NMR (500 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.61 (s, 1H), 7.49 (s, 1H), 7.19 (s, 1H), 6.77 (d, J = 1.68 Hz, 1H), 6.68 (t, 1H), 4.00 (s, 3H), 3.84 (s, 3H), 3.75 (br. s., 1H), 3.42 (s, 3H), 3.19 (br. s., 2H), 2.75 (br. s., 2H), 2.12-2.06 (m, 2H), 1.87-1.76 (m, 3H), 1.72-1.64 (m, 1H); LC / MS: 564 (M+H).

[0764]

[0765] Example 366: Preparation of 4-[[[6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]amino]methyl]-4-methyl-oxazolidin-2-one

[0766]

[0767] Tert-Butyl N-[1-[6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3-methyl-azetidin-3-yl]carbamate (Example 364, 28 mg, 0.043 mmol) was dissolved in dichloromethane (0.3 mL), and trifluoroacetic acid (33 μL, 0.432 mmol) was added. The reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, 1 N aqueous sodium hydroxide solution and ethyl acetate were added to extract the oil layer. The oil 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. (16.3 mg, 0.028 mmol, 63.7% yield)

[0768] 1H-NMR (500 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.68-6.56 (m, 2H), 6.41 (s, 1H), 5.35 (d, J = 11.9 Hz, 1H), 4.52-4.45 (m, 1H), 4.33-4.32 (m, 1H), 4.17 (d, J = 8.9 Hz, 1H), 3.99 (s, 3H), 3.81 (s, 3H), 3.40 (s, 3H), 3.19-3.08 (m, 2H), 1.47 (s, 3H), 1.41 (s, 9H); LC / MS: 593 (M+H).

[0769]

[0770] Example 375 (Synthetic Method AJ): Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one

[0771]

[0772] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidyl)benzimidazol-2-one (Example 359, 30 mg, 0.053 mmol) was stirred at 0°C in the presence of tetrahydrofuran (0.4 mL) solvent, and methylmagnesium bromide (3 M in diethyl ether, 0.036 mL, 0.107 mmol) was added dropwise at the same temperature, followed by stirring at room temperature for 1 hour. The reaction was quenched with water, extracted with dichloromethane as an oil layer, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by MPLC to obtain the title compound. (11.7 mg, 0.020 mmol, 37.9% yield)

[0773] 1H-NMR (500 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.62 (s, 1H), 7.49 (s, 1H), 7.20 (s, 1H), 6.93 (br. s., 1H), 6.76 (d, J = 1.68 Hz, 1H), 6.68 (t, 1H), 4.00 (s, 3H), 3.83 (s, 3H), 3.42 (s, 3H), 3.03 (br. s., 4H), 1.89 (br. s., 2H), 1.72 (br. s., 2H), 1.40 (s, 9H), 1.35 (s, 3H); LC / MS: 578 (M+H).

[0774]

[0775] Example 384: Preparation of 6-[5-(3,6-dihydro-2H-pyran-4-yl)-6-fluoro-2-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one

[0776] Step 1: Preparation of 6-((2-amino-4-(3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)amino)-1,3-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0777]

[0778] The title compound was obtained in a similar manner to step 1 and step 2 of Synthetic Method C using 6-amino-1,3-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (intermediate I-4, 340 mg, 1.301 mmol) and 1-bromo-2,4-difluoro-5-nitrobenzene (310 mg, 1.301 mmol). (46.0% yield over 2 steps)

[0779] 1H-NMR (500 MHz, Chloroform-d) δ 6.76 (d, J = 12.5 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.59 (d, J = 1.8 Hz, 1H), 6.45 (d, J = 1.8 Hz, 1H), 5.99 (s, 1H), 5.37 (s, 1H), 4.31 (q, J = 2.7 Hz, 2H), 4.18 (q, J = 2.8 Hz, 1H), 3.90 (t, J = 5.3 Hz, 2H), 3.74 (t, J = 5.3 Hz, 1H), 3.65 (s, 3H), 3.57-3.53 (m, 3H), 3.34 (s, 3H), 2.49-2.49 (m, 2H), 2.23-2.20 (m, 1H), 1.92-1.84 (m, 2H), 1.78-1.75 (m, 2H); LC / MS: 453 (M+H).

[0780] Step 2: Preparation of 6-[5-(3,6-dihydro-2H-pyran-4-yl)-6-fluoro-2-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one

[0781]

[0782] 6-((2-amino-4-(3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)amino)-1,3-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (87 mg, 0.192 mmol) obtained in Step 1 was dissolved in trifluoroacetic acid (1 mL). The reaction solution was stirred at 100°C for 3 h. After the reaction was completed, the solution was diluted with water, 1 N aqueous sodium hydroxide solution was added, and the oil layer was extracted with ethyl acetate. The oil 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. (8 mg, 0.015 mmol, 7.84% yield)

[0783] 1H-NMR (500 MHz, Chloroform-d) δ 7.80 (d, J = 6.7 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.88 (d, J = 1.8 Hz, 1H), 6.83 (d, J = 10.4 Hz, 1H), 6.05 (s, 1H), 4.36-4.34 (m, 2H), 4.13-4.11 (m, 2H), 3.97-3.95 (m, 2H), 3.77 (s, 3H), 3.60-3.52 (m, 3H), 3.44 (s, 3H), 2.55-2.55 (m, 2H), 1.93-1.82 (m, 4H); LC / MS: 531 (M+H).

[0784]

[0785] Example 391: Preparation of 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(2,3-dihydroxy-2-methyl-propyl)amino]-1,3-dimethyl-benzimidazol-2-one

[0786]

[0787] 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one (Example 183, 25 mg, 0.045 mmol) was dissolved in 1,4-dioxane (0.7 mL), and then hydrochloric acid (4 M in 1,4-dioxane, 0.017 mL, 0.068 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, 1 N sodium hydroxide (0.227 mL, 0.227 mmol) was added and stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was dissolved in dimethylformamide (0.5 mL), 1 N sodium hydroxide (0.227 mL, 0.227 mmol) was additionally added, and the mixture was stirred at 100°C for 7 hours. The reaction solution was diluted with water, and the oil layer was extracted with ethyl acetate. The oil 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. (9 mg, 0.016 mmol, 34.9% yield)

[0788] 1 H-NMR (500 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.22 (s, 1H), 6.67 (t, J = 55.7 Hz, 1H), 6.51 (s, 1H), 6.40 (s, 1H), 5.05-4.98 (m, 1H), 3.99 (s, 3H), 3.83 (s, 3H), 3.75-3.62 (m, 2H), 3.39 (s, 3H), 3.21-3.05 (m, 2H), 2.54 (d, J = 40.0 Hz, 1H), 2.10-2.07 (m, 1H), 1.41 (s, 9H), 1.29 (d, J = 4.3 Hz, 3H); LC / MS: 568 (M+H).

[0789]

[0790] Examples 2, 5, 11, 13-25. 27-46, 48, 50-53, 55-57, 61-96, 98, 100-106, 108-115, 117, 119-121, 124, 127, 129, 131-145, 147-177, 179-187, 190, 193-218, 220-242, 245-260, 263-271, 275-287. 289, 291, 293-298, 302-306, 308-310, 312-314, 316, 319, 320, 322-324, 327-330, 334-337, 340-341, 343-344, 349-356, 358, 360, 361, 363-365, 367-374, 376-383, 385-390, and 392-404

[0791] It was manufactured similarly using the same synthetic method as the representative examples above.

[0792] Specifically, Example 2 was similarly prepared with A, Examples 5, 11, 13 to 15, 21, 23, 24, 27 to 46, 53 and 67 to 74 were similarly prepared with B, Examples 16, 18 and 20 were similarly prepared with C, Example 260 was similarly prepared with D, Example 285 was similarly prepared with E, Examples 17, 19, 22, 105 and 278 were similarly prepared with F, Example 25 was similarly prepared with G, Example 279 was similarly prepared with H, Examples 48, 78 to 80, 83, 84, 86 to 89, 104, 124. 152, 161, 162, 179 to 182, 198, 205 to 208, 214, 215, 218, 230 to 234, 240, 241, 247 to 249, 251 to 254, 263 to 265, 280 to 282, 286, 294, 303 to 305, 312, 313, 316, 322 to 324, 337, 340, 361, 370, 376, 377 and 395 to 399 were similarly prepared with I, Examples 50 to 52 were similarly prepared with J, Examples 55 to 57, 64, 65, 76, 77, 103, 139 and 153 were similarly prepared with K, Examples 63 and 154 were similarly prepared with L, and Examples 61, 62, 85, 92 to 95, 102, 106, 108 to 115, 127, 134 to 138, 140 to 143. 150, 151, 156, 157, 163, 164, 169, 174, 175, 183, 194, 195, 197, 200, 201, 209 to 213, 216, 217, 238, 239, 250, 257 to 259, 266 to 271, 277, 283, 284, 287, 289, 295 to 298, 306, 308, 310, 327 to 330, 343, 350, 354 to 356, 358, 360,363 to 365 and 400 to 404 were similarly prepared with M, examples 66, 81, 82, 90, 91, 101, 155 and 173 were similarly prepared with N, examples 96, 98, 100, 120, 121 and 144 were similarly prepared with O, examples 117, 119, 148, 149, 160, 176, 177, 190, 204, 349 and 383 were similarly prepared with P, example 129 was similarly prepared with Q, examples 131 to 133, 158, 159, 167, 168, 202, 203, 224, 225, 227, 235 to 237, 255 and 256 were similarly prepared with R, examples 145, 147, 165, 166, 170, 171, 184, 185, 196, 199, 226, 228, 229 and 309 were similarly prepared with S, examples 75, 187, 352 and 367 were similarly prepared with T, examples 353 and 368 were similarly prepared with U, example 369 was similarly prepared with V, example 193 was similarly prepared with W, examples 172, 186, 220 to 223, 245 and 246 were similarly prepared with X, example 242 was similarly prepared with Y, examples 275 and 276 were similarly prepared with Z, and examples 291, 293 and 314 were similarly prepared with AA. Examples 301 and 302 were similarly prepared with AB, Examples 317 and 344 were similarly prepared with AC, Examples 318 to 320 were similarly prepared with AD, Example 351 was similarly prepared with AE, Example 334 was similarly prepared with AF, Examples 338 and 341 were similarly prepared with AG, Examples 371, 385 and 386 were similarly prepared with AH, Examples 372, 378, 389, 390 and 392 to 394 were similarly prepared with AI, and Examples 335, 336, 373, 374,379 to 382, ​​387 and 388 were similarly manufactured with AJ.

[0793] The structure, name, NMR and synthetic method of the compounds synthesized from each of the above examples are described in Table 2 below.

[0794] [Correction pursuant to Rule 91, March 14, 2025] [Table 2]

[0795] (Examples 335 and 336 and Examples 373 and 374 differ in that the cyclohexyl group is cis or trans, respectively.)

[0796] Experimental Example 1. CBP Inhibitory Activity

[0797] The CBP bromodomain activity was measured using a time-resolved fluorescence resonance energy transfer (TR-FRET) experiment.

[0798] 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. The TR-FRET fluorescence acceptor and Tb donor were 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid; Dilute the solution in assay buffer containing [HEPES] (hereafter, assay buffer, BPS Bioscience, cat. 33012), and transfer 3 μL of each solution to all wells of a white 384-low-volume well plate (Corning, cat. 4513). Transfer 2 μL of 4X Ac-H4 peptide (final concentration 85 nM) to the high control wells and test wells. Prepare 10 concentration points by serially diluting the compounds 3-fold from the highest concentration in dimethyl sulfoxide solvent. Then, dilute each concentration of the compound in assay buffer to prepare a diluted compound solution 4-fold more concentrated than the final concentration. Dispense 2 μL of each compound or dimethyl sulfoxide prepared in this way into the assay plate so that the final test concentration is from 0.5 μM to 10 μM (final dimethyl sulfoxide concentration 1%). Add 6 μL of 1X assay buffer to the low control wells and 2 μL to the high control and test wells. Then, 2 μL of 4X CBP BRD protein (final concentration 7.5 nM, BPS bioscience, cat. 31128) was added to initiate the PPI reaction. The plate was allowed to incubate for 2 hours at room temperature before measuring the signal.TR-FRET signals were measured using an EnVision Multilabel plate reader (PerkinElmer; Mirror LNACE / DELFIA Dual / Bias). Data analysis was performed using the TR-FRET ratio ((Signal665nm / Signal615nm) 20000) to obtain the values ​​for each well. Data analysis was 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. IC. 50 Analysis was performed using a standard four-parameter curve fitting 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).

[0799]

[0800] Experimental Example 2. BRD Inhibitory Activity

[0801] BRD inhibitory activity was measured using time-resolved fluorescence resonance energy transfer (TR-FRET) assay to verify BRD4 bromodomain activity.

[0802] 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. The TR-FRET fluorescence acceptor and Tb donor were 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid; Dilute the solution in assay buffer containing [HEPES] (hereafter, assay buffer, BPS Bioscience, cat. 33012), and transfer 3 μL of each solution to all wells of a white 384-low-volume well plate (Corning, cat. 4513). Transfer 2 μL 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 (DMSO) to prepare 10 concentration points. Then, dilute each concentration of the compound in assay buffer to prepare a diluted compound solution 4-fold more concentrated than the final concentration. Dispense 2 μL of each compound or dimethyl sulfoxide prepared in this way into the assay plate so that the final test concentrations range from 0.5 μM to 10 μM (final DMSO concentration 1%). Add 6 μL of 1X assay buffer to the low control wells and 2 μL to the high control and test wells. Then, 2 μL of 4X BRD4 (BD1) protein (final concentration 7.5 nM, BPS bioscience, cat. 31040) was added to initiate the PPI reaction. The plate was allowed to incubate for 2 hours at room temperature before measuring the signal.TR-FRET signals were measured using an EnVision Multilabel plate reader (PerkinElmer; Mirror LNACE / DELFIA Dual / Bias). Data analysis was performed using the TR-FRET ratio ((Signal665nm / Signal615nm) 20000) to obtain the value for each well. Data analysis was 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. IC. 50 Analysis was performed using a standard four-parameter curve fitting 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).

[0803] The results according to Experimental Examples 1 and 2 are shown in Tables 3 and 4 below.

[0804] In Tables 3 and 4 below, if the activity value is 0 or more and 500 nM or less, it is marked as '+++', if it is more than 500 nM and 5 μM or less, it is marked as '++', and if it is more than 5 μM, it is marked as '+'.

[0805] Example CBP BRD IC 50 Example CBP BRD IC 50

[0806] Example BRD4 (BD1) IC 50 Example BRD4 (BD1) IC 50

Claims

1. A compound represented by the following chemical formula I: <Chemical Formula I> In the above formula, X is C or N, 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. R is each independently C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-5 Haloalkyl, C 6-10 Aryl, 5- to 9-membered heteroaryl, 3- to 14-membered heterocycloalkyl, 4- to 9-membered heterocycloalkenyl, halogen, cyano, carbonyl, formaldoxime, NR a R b , SO2NHR c , CONR d R e , CO2R f , NHCOR g OR OR h And, R a Inland R h are each independently hydrogen, C 1-5 Alkyl, C 3-7 Cycloalkyl, C 1-4 Haloalkyl, C 6-10 is selected from the group consisting of aryl, halogen, carbonyl, or Boc groups, Q is hydrogen, C 1-7 Alkyl or C 3-7 It is cycloalkyl, A is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, C 6-10 Aryl, 3- to 16-membered heterocycloalkyl, 3- to 16-membered heterocycloalkenyl, 5- to 9-membered heteroaryl, halogen, carbonyl, NR i R j OR OR k and R i Inland R k are each independently hydrogen, C 1-8 Alkyl, C 3-10 Cycloalkyl, C 6-10 Selected from the group consisting of aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl or Boc group; Z is C 1-8 Alkyl, C 3-7 Cycloalkyl, C 6-10 aryl, 5- to 13-membered heteroaryl or 3- to 8-membered heterocycloalkyl, At this time, the above R, R a Inland R k , Q, A 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 2-10 Alkynyl, 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, substituted or unsubstituted carbonyl, 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 m -(R m is hydrogen or substituted or unsubstituted C 1-10 alkyl), -N=, =N-, -POR m - and -PO4R m - is interrupted by a heteroatom group selected from, and 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 k , Q, A and Z are each substituted or unsubstituted with substituent group I-1, a compound: Substituent group I-1: substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-5 Alkenyl, substituted or unsubstituted C 2-7 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 1-5 Haloalkyl, substituted or unsubstituted C 6-8 Aryl, substituted or unsubstituted carbonyl, substituted or unsubstituted 3- to 9-membered heterocycloalkyl, halogen, cyano, Boc group, OR p1 , NR p2 R p3 , CONR p4 R p5 , NHCOR p6 or CO2R p7 And, at this time, the above R p1 Inland R p7 are each independently hydrogen, a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted propyl, a substituted or unsubstituted propenyl, a substituted or unsubstituted mesylate, a carbonyl or a Boc group.

3. In paragraph 1, the compound of formula I is a compound represented by either the following formula I-1 or I-2: <Chemical Formula I-1> <Chemical Formula I-2> In the above formula, n, R, Q, A and Z are as defined in Article 1, respectively.

4. In the third paragraph, the compound of chemical formula I-1 is a compound represented by either chemical formula I-1-1 or I-1-2 below: <Chemical Formula I-1-1> <Chemical Formula I-1-2> In the above formula, A 2 is C 1-8 Alkyl, C 2-8 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, C 6-10 Aryl, 3- to 16-membered heterocycloalkyl, 3- to 16-membered heterocycloalkenyl, 5- to 9-membered heteroaryl, halogen, carbonyl, NR i R j OR OR k , and is substituted or unsubstituted with substituent group I, R i Inland R k , n, R, Q and Z are as defined in Article 1, respectively.

5. In the third paragraph, the compound of chemical formula I-2 is a compound represented by either chemical formula I-2-1 or I-2-2 below: <Chemical Formula I-2-1> <Chemical Formula I-2-2> In the above formula, A 2 is as defined in Article 4, n, R, Q and Z are as defined in Article 1, respectively.

6. In paragraph 4, the compound of chemical formula I-1-1 is a compound represented by either chemical formula I-1-1-1 or I-1-1-2: <Chemical Formula I-1-1-1> <Chemical Formula I-1-1-2> In the above formula, R 111 , R 211 and R 311 are each independently C 1-5 Alkyl, C 1-3 Haloalkyl, C 6-8 Aryl, 5- to 7-membered heteroaryl, halogen, cyano, carbonyl, CONR d R e or CO2R f , and is substituted or unsubstituted with substituent group I, R d Inland R f , Q and Z are as defined in Article 1, respectively.

7. In paragraph 6, R 111 , R 211 and R 311 are each independently methyl, propyl, CF2H, phenyl, pyrazolyl, bromo, fluoro, cyano, aldehyde, CONR d R e or CO2R f And, at this time, the above R d Inland R f are each independently hydrogen or substituted or unsubstituted methyl, Above R 111 and R 211 A compound, wherein each is independently substituted or unsubstituted with a substituent group I-1-1: Substituent group I-1-1: substituted or unsubstituted C 1-3 Alkyl, Halogen, OR p1 , NR p2 R p3 , CONR p4 R p5 or NHCOR p6 And, at this time, the above R p1 Inland R p6 are each independently hydrogen, substituted or unsubstituted methyl, or substituted or unsubstituted propyl.

8. In paragraph 4, the compound of chemical formula I-1-2 is a compound represented by any one of the following chemical formulas I-1-2-1 to I-1-2-3: <Chemical Formula I-1-2-1> <Chemical Formula I-1-2-2> <Chemical Formula I-1-2-3> In the above formula, A 2 is as defined in Article 4, R 112 and R 212 are each independently C 1-5 Alkyl, C 3-7 Cycloalkyl, C 1-5 Haloalkyl, C 6-10 Aryl, 5- to 9-membered heteroaryl, 3- to 14-membered heterocycloalkyl, 4- to 9-membered heterocycloalkenyl, halogen, cyano, carbonyl, formaldoxime, NR a R b , SO2NHR c , CONR d R e , CO2R f , NHCOR g OR OR h And, the above R 112 and R 212 are each substituted or unsubstituted with substituent group I, R a Inland R h , Q and Z are as defined in Article 1, respectively.

9. In paragraph 8, R 112 and R 212 are each independently selected from the group consisting of methyl, cyclopropyl, CF3, CF2H, CFH2, phenyl, oxazolyl, pyrazolyl, thiazolyl, pyridinyl, oxadiazolyl, imidazolyl, triazolyl, lactamyl, oxindolyl, quinolinonyl, dihydroquinolinonyl, benzoxazinonyl, dihydropyranyl, fluoro, chloro, bromo, cyano, aldehyde, formaldoxime, NR a R b , SO2NHR c , CONR d R e , CO2R f , NHCOR g OR OR h And, at this time, the above R a Inland R h are each independently hydrogen, substituted or unsubstituted methyl, CF2H, CF3, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted carbonyl or a Boc group, Above R 112 and R 212 A compound, wherein each is independently substituted or unsubstituted with a substituent group I-1-2: Substituent group I-1-2: substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-5 Alkenyl, substituted or unsubstituted C 1-4 Haloalkyl, halogen, 4- to 8-membered heterocycloalkyl, OR p1 , NR p2 R p3 , CONR p4 R p5 or NHCOR p6 And, at this time, the above R p1 Inland R p6 are each independently hydrogen or substituted or unsubstituted methyl.

10. In paragraph 5, the compound of chemical formula I-2-1 is a compound represented by either chemical formula I-2-1-1 or I-2-1-2 below: <Chemical Formula I-2-1-1> <Chemical Formula I-2-1-2> In the above formula, R 221 and R 312 are each independently C 6-9 Aryl, 5- to 9-membered heteroaryl, halogen or CONR d R e And, the above R 221 and R 312 are each substituted or unsubstituted with substituent group I, R d Inland R e , Q and Z are as defined in Article 1, respectively.

11. In clause 10, R 221 and R 312 are each independently phenyl, pyrazolyl, bromo or CONR d R e And, at this time, the above R d Inland R e are each independently hydrogen or substituted or unsubstituted methyl, Above R 221 and R 312 A compound, wherein each is independently substituted or unsubstituted with a substituent group I-1-3: Substituent group I-1-3: substituted or unsubstituted C 1-3 Alkyl, halogen or CONR p4 R p5 And, at this time, the above R p4 Inland R p5 are each independently hydrogen or substituted or unsubstituted methyl.

12. In paragraph 5, the compound of chemical formula I-2-2 is a compound represented by either chemical formula I-2-2-1 or I-2-2-2 below: <Chemical Formula I-2-2-1> <Chemical Formula I-2-2-2> In the above formula, A 2 is as defined in Article 3, R 222 and R 322 are each independently a 5- to 9-membered heteroaryl, and R 222 and R 322 are each substituted or unsubstituted with substituent group I, Q and Z are as defined in Article 1, respectively.

13. In paragraph 12, R 222 and R 322 are each independently pyrazolyl or thiazolyl, and R 222 and R 322 A compound, wherein each is independently substituted or unsubstituted with a substituent group I-1-4: Substituent group I-1-4: substituted or unsubstituted C 1-3 Alkyl or substituted or unsubstituted C 1-3 It is haloalkyl.

14. In paragraph 1, A compound wherein Q is hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, or substituted or unsubstituted propyl.

15. In paragraph 1, A compound wherein Z is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted butyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted phenyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted oxetanyl.

16. In paragraph 1, a compound selected from the following group: 3-(7-chloro-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-N-methyl-2-(6-methyl-1H-indol-3-yl)benzimidazole-5-sulfonamide; 3-(1,3-Dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-N-methyl-2-(6-methyl-1H-indol-3-yl)benzimidazole-5-sulfonamide; Methyl 6-bromo-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazole-5-carboxylate; Methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazole-5-carboxylate; Methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylate; 3-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 5-[6-(Hydroxymethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 3-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbaldehyde; 5-[6-(difluoromethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 3-(1,3-Dimethyl-2-oxo-benzimidazole-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylic acid; 1,3-Dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-tetrahydropyran-4-yl-benzimidazol-2-one; 5-[6-(1-Hydroxy-1-methyl-ethyl)-2-(6-methyl-1H-indol-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 5-[6-Bromo-2-(6-methyl-1H-indol-3-yl)imidazo[4,5-c]pyridin-3-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-5-[2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)imidazo[4,5-c]pyridin-3-yl]benzimidazol-2-one; 6-Bromo-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)benzimidazole-5-carbonitrile; 3-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(6-methyl-1H-indol-3-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 3-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-methyl-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylic acid; Methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-methyl-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylate; 3-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylic acid; Methyl 3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylate; 4-[6-Cyano-1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 3-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-(3-methylimidazol-4-yl)benzimidazole-5-carboxylic acid; 4-[1-(1,3-Dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 5-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-hydroxy-1-methyl-ethyl)-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 3-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-6-[3-fluoro-4-(methylcarbamoyl)phenyl]-N-methyl-2-(3-methylimidazol-4-yl)benzimidazole-5-carboxamide; 4-[3-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)imidazo[4,5-c]pyridin-6-yl]-2-fluoro-N-methyl-benzamide; 4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; N-[4-[1-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; 5-[6-Fluoro-5-(3-methoxyphenyl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; N-[4-[1-(1,3-Dimethyl-2-oxo-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]-2-methyl-propanamide; 5-[5-(4-Aminophenyl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; N-[4-[1-(1,3-dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; 6-[5-(4-Aminophenyl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[5-[4-(dimethylamino)phenyl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 4-[1-(1,3-Dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[6-Fluoro-5-[4-(methylamino)phenyl]-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; tert-Butyl 4-[6-[5-(4-acetamidophenyl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate; N-[4-[1-[1,3-dimethyl-7-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-2-oxo-benzimidazol-5-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; N-[4-[1-[1,3-dimethyl-7-(2-morpholinoethylamino)-2-oxo-benzimidazol-5-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; N-[4-[1-[7-(cyclopentylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; N-[4-[1-[1,3-dimethyl-2-oxo-7-(propylamino)benzimidazol-5-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; N-[4-[6-fluoro-1-[7-(isopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; N-[4-[1-[7-(cyclopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; N-[4-[1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 5-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-3-methyl-1H-benzimidazol-2-one; 1-Ethyl-5-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-3-methyl-benzimidazol-2-one; 5-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1-isopropyl-3-methyl-benzimidazol-2-one; 1-(Cyclopropylmethyl)-5-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-3-methyl-benzimidazol-2-one; 5-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1-(2-hydroxyethyl)-3-methyl-benzimidazol-2-one; 4-Chloro-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropenyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1-methylpyrazol-4-yl)benzimidazol-2-one; 4-Cyclopropyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-fluorophenyl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(propylamino)benzimidazol-2-one; N-[4-[1-(1,3-dimethyl-2-oxo-7-pyrrolidin-1-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]phenyl]acetamide; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-pyrrolidin-1-yl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isobutyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-methylprop-1-enyl)benzimidazol-2-one; tert-Butyl 4-[6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate; 4-(Cyclopropylmethylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[1-(1,3-dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-3,4-dihydro-1H-quinolin-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(2-oxoindolin-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 7-[1-(1,3-Dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-4H-1,4-benzoxazin-3-one; 6-[5-(4-chloro-3-methoxy-phenyl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[5-(3-chloro-4-methoxy-phenyl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[1-(1,3-Dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-4H-1,4-benzoxazin-3-one; 6-[1-(1,3-Dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-1H-quinolin-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-methoxyphenyl)-1,3-dimethyl-benzimidazol-2-one; 5-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 2-[6-Fluoro-1-[7-(isopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-5-(1-methylpyrazol-4-yl)benzimidazol-2-yl]-2-methyl-propanenitrile; 2-[6-Fluoro-1-[7-(isopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-5-(3-oxo-4H-1,4-benzoxazin-7-yl)benzimidazol-2-yl]-2-methyl-propanenitrile; 4-(Cyclohexylmethylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(3,3,3-trifluoropropylamino)benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 7-[2-tert-butyl-6-fluoro-1-[7-(isopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]benzimidazol-5-yl]-4H-1,4-benzoxazin-3-one; 4-(Cyclopentylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-3-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(2-methoxyethylamino)-1,3-dimethyl-benzimidazol-2-one; 4-[2-(dimethylamino)ethylamino]-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-(Cyclobutylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-(tert-butylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropoxy-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(cyclobutylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isobutoxy-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-hydroxy-1,3-dimethyl-benzimidazol-2-one; 4-(Cyclopentoxy)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-propoxy-benzimidazol-2-one; 4-(Cyclopropylmethoxy)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-(Cyclobutylmethylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(2-methoxyphenyl)-1,3-dimethyl-benzimidazol-2-one; Methyl 2-tert-butyl-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylate; 2-tert-butyl-3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylic acid; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(cyclopentylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[isopropyl(methyl)amino]-1,3-dimethyl-benzimidazol-2-one; 2-tert-butyl-3-(7-isopropyl-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 2-tert-butyl-3-[7-(isopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 4-Anilino-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-(4-Fluoroanilino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-[4-(Dimethylamino)anilino]-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 3-(7-Isopropyl-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 3-[7-(Isopropylamino)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-methoxyanilino)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(1-methylcyclopropyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(1-methylcyclobutyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methyloxetan-3-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-5-(1-methylpyrazol-4-yl)-2-[1-(trifluoromethyl)cyclopropyl]benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(tetrahydropyran-4-ylmethoxy)benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropoxy-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-trimethylsilylethynyl)benzimidazol-2-one; 4-Ethynyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-Acetyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-hydroxyethyl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-hydroxy-1-methyl-ethyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-methoxyethyl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1-methoxy-1-methyl-ethyl)-1,3-dimethyl-benzimidazol-2-one; 4-Isopropyl-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 4-(Isopropylamino)-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 4-(Cyclohexylamino)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(cyclohexylamino)-1,3-dimethyl-benzimidazol-2-one; 3-(1,3-Dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 4-(Cyclohexen-1-yl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(sec-butylamino)benzimidazol-2-one; 4-(3,3-difluoroazetidin-1-yl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-(azetidin-1-yl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yloxy-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-methylpiperazin-1-yl)benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1-piperidyl)benzimidazol-2-one; 4-(4,4-difluoro-1-piperidyl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(1-fluoro-1-methyl-ethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[2-(1,1-difluoroethyl)-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[2-(2,3-dimethylphenyl)-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(1-methyl-1-phenyl-ethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[5-(1-ethylpyrazol-4-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-methoxyphenyl)-1,3-dimethyl-benzimidazol-2-one; 4-Cyclohexyl-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(isobutylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3,3-difluoroazetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-(azetidin-1-yl)-6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-(1,1-dimethylprop-2-ynyl)-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(2-methoxy-4-pyridyl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[5-(2-Amino-4-pyridyl)-2-tert-butyl-6-fluoro-benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 3-(7-Isopropoxy-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 2-tert-butyl-3-(7-isopropoxy-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(2S)-2-methylmorpholin-4-yl]benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzimidazol-2-one; 4-Isopropoxy-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-isopropoxy-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxyazetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-(3,3-difluoropyrrolidin-1-yl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-methoxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(tetrahydropyran-4-ylmethylamino)benzimidazol-2-one; tert-Butyl 4-[6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylate; tert-Butyl 4-[6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylate; 2-(1,1-Dimethylprop-2-ynyl)-3-(7-isopropyl-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 2-(1,1-Dimethylprop-2-ynyl)-3-(7-isopropoxy-1,3-dimethyl-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-piperidyl)benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(3R)-3-methylmorpholin-4-yl]benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(3S)-3-methylmorpholin-4-yl]benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(3R)-3-methylmorpholin-4-yl]benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(3S)-3-methylmorpholin-4-yl]benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-(1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxetan-3-ylamino)benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-methoxyazetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-piperidyl)benzimidazol-2-one; 4-(1-Acetyl-4-piperidyl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(1-methyl-4-piperidyl)benzimidazol-2-one; 6-[2-(1,1-dimethylprop-2-ynyl)-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(3-methyl-1,2,4-oxadiazol-5-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 2-tert-butyl-3-[7-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 3-[7-(3-Hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)benzimidazol-2-one; tert-Butyl 4-[6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperazine-1-carboxylate; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-(3,3-dimethylazetidin-1-yl)-6-[6-fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropoxy-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-isopropoxy-1,3-dimethyl-benzimidazol-2-one; 4-(3-Hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-(1,1-dimethylprop-2-ynyl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[5-(1-ethylpyrazol-4-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-Fluoro-5-(1-isopropylpyrazol-4-yl)-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[5-[1-(difluoromethyl)pyrazol-4-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 3-[7-(3-Methoxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 2-tert-butyl-3-[7-(3-methoxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 3-[7-(azetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-2-tert-butyl-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 3-[7-(3,3-difluoroazetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 2-tert-butyl-3-[7-(3,3-difluoroazetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 3-(1,3-Dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 2-tert-butyl-3-(1,3-dimethyl-2-oxo-7-tetrahydropyran-4-yl-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbonitrile; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-methoxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-methoxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-ethoxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-(3-methoxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3-methoxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-(azetidin-1-yl)-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 4-(3,3-difluoroazetidin-1-yl)-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3,3-difluoroazetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(2S)-2-methylazetidin-1-yl]benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1H-pyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 4-[1-(1,3-Dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 6-[5-[1-(cyclopropylmethyl)pyrazol-4-yl]-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 5-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-(azetidin-1-yl)-6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 1,3-Dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 4-(azetidin-1-yl)-6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-(azetidin-1-yl)-6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-isopropylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-5-(2-methylthiazol-5-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[5-(1-Cyclopropylpyrazol-4-yl)-6-fluoro-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-isopropoxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 4-(3-Allyloxy-3-methyl-azetidin-1-yl)-6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-isopropylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 2-tert-butyl-3-[7-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(2-methylthiazol-5-yl)benzimidazole-5-carbonitrile; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[2-tert-butyl-6-(1-methylpyrazol-4-yl)imidazo[4,5-c]pyridin-3-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; Methyl 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylate; 6-[2-tert-butyl-6-(2-methylthiazol-5-yl)imidazo[4,5-c]pyridin-3-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-5-(2-methylthiazol-5-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-5-(2-methylthiazol-5-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 4-(3,3-difluoroazetidin-1-yl)-6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3,3-difluoroazetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; tert-Butyl 4-[6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperazine-1-carboxylate; 6-[2-tert-butyl-6-(hydroxymethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(methoxymethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(fluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 1,3-Dimethyl-6-[2-(3-methylimidazol-4-yl)-6-(1-methylpyrazol-4-yl)imidazo[4,5-c]pyridin-3-yl]-4-morpholino-benzimidazol-2-one; 1,3-Dimethyl-6-[2-(3-methylimidazol-4-yl)-6-(2-methylthiazol-5-yl)imidazo[4,5-c]pyridin-3-yl]-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-morpholinoethoxy)benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-morpholinoethoxy)benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(2-morpholinoethoxy)benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxetan-3-yloxy)benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxetan-3-yloxy)benzimidazol-2-one; 6-[2-tert-butyl-6-methoxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-methoxy-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; Methyl 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazole-5-carboxylate; 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-benzimidazole-5-carboxylic acid; 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-N-methyl-benzimidazole-5-carboxamide; 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-N,N-dimethyl-benzimidazole-5-carboxamide; 2-tert-butyl-1-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-fluoro-N-phenyl-benzimidazole-5-carboxamide; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]benzimidazol-2-one; 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxylic acid; 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-N-methyl-6-(1-methylpyrazol-4-yl)benzimidazole-5-carboxamide; 6-[2-tert-butyl-6-(difluoromethoxy)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethoxy)-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-(difluoromethoxy)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[6-chloro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbaldehyde; 4-Benzyloxy-6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 4-Benzyloxy-6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-hydroxy-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxetan-3-yloxy)benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(3-methylpyrazol-1-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(4-methylpyrazol-1-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(5-methyl-1,3,4-oxadiazol-2-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(4-methylimidazol-1-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-5-cyclopropyl-6-(difluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-methoxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]benzimidazol-2-one; 5-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-thiomorpholino-benzimidazol-2-one; (5E)-2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazole-5-carbaldehyde oxime; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(6-chloropyrimidin-4-yl)oxy-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-methoxyphenoxy)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-fluorophenoxy)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethoxy)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-methoxy-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 4-(3-Hydroxy-3-methyl-azetidin-1-yl)-6-[6-methoxy-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; Methyl 1-[6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]aziridine-2-carboxylate; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-thiomorpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1,1-dioxo-1,4-thiazinan-4-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-thiomorpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-hydroxyethyl)pyrazol-4-yl]benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-oxopyrrolidin-1-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methyltriazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; tert-Butyl N-[2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl]carbamate; 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(methylaminomethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-[(dimethylamino)methyl]-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(morpholinomethyl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; N-[2-tert-butyl-3-(1,3-dimethyl-7-morpholino-2-oxo-benzimidazol-5-yl)-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl]acetamide; 4-(3-Hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-6-[2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)-6-(trifluoromethoxy)benzimidazol-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethoxy)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-5-(2-methylthiazol-5-yl)-6-(trifluoromethoxy)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(oxetan-3-ylmethoxy)benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(1-methyl-4-piperidyl)oxy]benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(2R)-2-methylazetidin-1-yl]benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(2R)-2-methylazetidin-1-yl]benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxypyrrolidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxypyrrolidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(methylamino)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(dimethylamino)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(3-chloro-2-hydroxy-2-methyl-propyl)amino]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-[(4-oxocyclohexyl)methoxy]benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(4-hydroxy-4-methyl-cyclohexyl)methoxy]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(4-hydroxy-4-methyl-cyclohexyl)methoxy]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Benzyloxy-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-hydroxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; [2-tert-butyl-3-[7-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl] acetate; 6-[6-Benzyloxy-2-tert-butyl-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-hydroxy-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(2-methyloxazol-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-morpholino-benzimidazol-2-one; tert-Butyl N-[2-tert-butyl-3-[7-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]-6-(1-methylpyrazol-4-yl)benzimidazol-5-yl]carbamate; 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-vinylpyrazol-4-yl)benzimidazol-1-yl]-4-[3-(dimethylamino)-3-methyl-azetidin-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]benzimidazol-1-yl]-4-[3-(dimethylamino)-3-methyl-azetidin-1-yl]-1,3-dimethyl-benzimidazol-2-one; [1-[6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-morpholinoethyl)pyrazol-4-yl]benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3-methyl-azetidin-3-yl] methanesulfonate; 6-[2-tert-butyl-6-(difluoromethyl)-5-[1-(2-morpholinoethyl)pyrazol-4-yl]benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-5-(1-methylpyrazol-4-yl)-2-(2-methyl-3-thienyl)benzimidazol-1-yl]-4-isopropyl-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-5-(1-methylpyrazol-4-yl)-2-(3-pyridyl)benzimidazol-1-yl]-4-isopropoxy-1,3-dimethyl-benzimidazol-2-one; tert-Butyl 4-[6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]oxypiperidine-1-carboxylate; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-piperidyloxy)benzimidazol-2-one; 4-[(1-acetyl-4-piperidyl)oxy]-6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-pyridyl)benzimidazol-2-one; 6-[6-Fluoro-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-pyridyl)benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[6-amino-2-tert-butyl-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(2,3-dihydroxy-2-methyl-propyl)amino]-1,3-dimethyl-benzimidazol-2-one; 6-[6-Fluoro-5-methyl-2-(3-methylimidazol-4-yl)benzimidazol-1-yl]-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidyl)benzimidazol-2-one; 6-[2-tert-butyl-6-fluoro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; tert-Butyl 4-[6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]piperazine-1-carboxylate; tert-Butyl N-[1-[6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3-methyl-azetidin-3-yl]carbamate; tert-Butyl N-[1-[6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]-3-methyl-azetidin-3-yl]carbamate; 4-[[[6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-2-oxo-benzimidazol-4-yl]amino]methyl]-4-methyl-oxazolidin-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-piperazin-1-yl-benzimidazol-2-one; 4-(4-acetylpiperazin-1-yl)-6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-methylpiperazin-1-yl)benzimidazol-2-one; 6-(2-tert-butyl-6-fluoro-benzimidazol-1-yl)-4-(isopropylamino)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxocyclohexyl)benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxycyclohexyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-cyclohexyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-cyclohexyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-pyrrolidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidyl)benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-methoxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-methoxy-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; 6-[5-(3,6-dihydro-2H-pyran-4-yl)-6-fluoro-2-(2-methyl-3-thienyl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[5-(3,6-dihydro-2H-pyran-4-yl)-6-fluoro-2-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-tetrahydropyran-4-yl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidyl)benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-1,3-dimethyl-4-(4-oxo-1-piperidyl)benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(4-hydroxy-4-methyl-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(3-methylimidazol-4-yl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-5-(1-methylpyrazol-4-yl)-6-(trifluoromethyl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-[(2,3-dihydroxy-2-methyl-propyl)amino]-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-chloro-5-(2-methylthiazol-5-yl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-methoxy-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(4-hydroxy-1-piperidyl)-1,3-dimethyl-benzimidazol-2-one; 4-[2-tert-butyl-6-(difluoromethyl)-1-[7-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]benzimidazol-5-yl]-2-fluoro-N-methyl-benzamide; 6-[2-tert-butyl-6-(difluoromethyl)-5-(2-methoxy-4-pyridyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[2-tert-butyl-6-(difluoromethyl)-5-(3,5-dimethoxyphenyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[5-(4-Aminophenyl)-2-tert-butyl-6-(difluoromethyl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; N-[4-[2-tert-butyl-6-(difluoromethyl)-1-[7-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-2-oxo-benzimidazol-5-yl]benzimidazol-5-yl]phenyl]acetamide; 6-[6-(difluoromethyl)-2-(2-methoxyphenyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(2,3-dimethylphenyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)-2-pyrimidin-5-yl-benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-(difluoromethyl)-2-(2-methoxy-3-pyridyl)-5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one; 6-[6-(Difluoromethyl)-5-(1-methylpyrazol-4-yl)-2-thiazol-5-yl-benzimidazol-1-yl]-4-(3-hydroxy-3-methyl-azetidin-1-yl)-1,3-dimethyl-benzimidazol-2-one.

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

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

19. 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.

20. A pharmaceutical composition according to claim 19, 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.

21. A pharmaceutical composition according to claim 19, 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.

22. In the 19th 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.

23. In paragraph 19, 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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