Novel benzimidazolone derivative compounds as autochemokine inhibitors

Abstract

The present invention relates to a novel benzimidazolone derivative compound as an autochemokine inhibitor.

Description

Technical Field

[0001] Cross-reference with related applications

[0002] This application claims the benefit of Korean Patent Application No. 10-2023-0043118, filed on March 31, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0003] This invention relates to a novel compound as an autotaxin inhibitor. Specifically, this invention relates to a novel benzimidazolone derivative compound as an autotaxin inhibitor. Background Technology

[0004] Autochemin (ATX), also known as exonucleonucleotide pyrophosphatase / phosphodiesterase 2 or lysophospholipase D, is an enzyme that increases lysophosphatidic acid (LPA) and is a secreted enzyme that plays a crucial role in the conversion of lysophosphatidylcholine (LPC) to LPA, a biologically active signal transduction molecule. Lysophosphatidic acid (LPA) is a biologically active lipid that exhibits biological activity through signal transduction via specific G protein-coupled receptors (LPA1-6) and influences the migration, proliferation, and survival of various cell types. Since plasma lysophosphatidic acid (LPA) levels are correlated with ATX activity, autochemin is an important source of extracellular lysophosphatidic acid (LPA).

[0005] Specifically, recent studies have found that lysophosphatidylcholine (LPA) is involved in various physiological activities, and in cancer patients, excessive LPA production due to the action of autochemin promotes the growth, migration, metastasis, invasion, and colony formation of cancer cells. Specifically, it has been reported that autochemin is excessively produced and secreted in cancer cells from patients with cancers such as renal cell carcinoma, ovarian and breast cancer with severe metastasis, thyroid cancer, Hodgkin's lymphoma, neuroblastoma, aggressive glioblastoma multiforme, prostate cancer, and skin cancer (melanoma). The secreted autochemin converts LPC to LPA, producing approximately 40 times more LPA than normal, thereby promoting the growth, metastasis, and invasion of various cancer cells.

[0006] Furthermore, LPA produced by autochemin binds to receptors present on cells, inducing angiogenesis and sclerosis. Increased concentrations of LPA and LPA receptors are known in various diseases such as fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, skin diseases, and diseases associated with abnormal angiogenesis.

[0007] Therefore, inhibitors targeting autochemin (an enzyme involved in the production of lysophosphatidylcholine (LPA)) are expected to have the potential to treat a variety of diseases, including cancer and fibrosis. However, limitations exist in existing autochemin inhibitors, such as low in vivo exposure, which hinders their efficacy, or competition with lysophosphatidylcholine (LPC), a substrate of this enzyme, resulting in reduced autochemin inhibitory activity. Therefore, there is a need to develop novel autochemin inhibitors exhibiting superior inhibitory activity and high in vivo exposure. Summary of the Invention

[0008] [Technical Issues]

[0009] One aspect of the present invention provides a novel compound having autochemin inhibitory activity.

[0010] Another aspect of the invention provides a compound that can be used to prevent or treat autochemoattractant-mediated diseases.

[0011] [Technical Solution]

[0012] According to one aspect of the invention, a compound having the chemical structure of Formula 1 below or a pharmaceutically acceptable salt thereof is provided.

[0013] [Formula 1]

[0014]

[0015] According to another aspect of the invention, a pharmaceutical composition is provided comprising: a compound of formula 1 above or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0016] [Beneficial Effects]

[0017] The compounds according to the present invention have excellent effects in inhibiting the activity of autochemin (an enzyme involved in the production of lysophosphatidic acid), and therefore can be effectively used as active ingredients in pharmaceutical compositions for the prevention or treatment of autochemin-mediated diseases.

[0018] However, the effects of the present invention are not limited to those described above, and those skilled in the art will clearly understand from the following description other effects not mentioned. Detailed Implementation

[0019] First, the terminology used in this paper is defined.

[0020] Unless otherwise stated, the terms used herein have the following meanings. Any undefined term shall have the meaning as understood in the art.

[0021] Throughout this specification, unless otherwise stated, a section “includes” an element means that it may further include other elements, rather than excluding other elements.

[0022] In the structural formulas of this specification, the symbol "-" connecting atoms and / or groups can represent a single bond, and the symbol "=" can represent a double bond. These symbols may be omitted and may be indicated when necessary (e.g., when connecting atoms or connection positions are specified).

[0023] As used in this article, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0024] As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group that does not contain either double or triple bonds, and unless otherwise stated, an alkyl group may have 1 to 20 carbon atoms, 1 to 19 carbon atoms, 1 to 18 carbon atoms, 1 to 17 carbon atoms, 1 to 16 carbon atoms, 1 to 15 carbon atoms, 1 to 14 carbon atoms, 1 to 13 carbon atoms, 1 to 12 carbon atoms, 1 to 11 carbon atoms, 1 to 10 carbon atoms, for example 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, and may be straight-chain or branched. Specific examples of alkyl groups may include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methylbutyl, 1-ethylbutyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, n-heptyl, 1-methylhexyl, octyl, n-octyl, tert-octyl, 1-methylheptyl, 2-ethylhexyl, 2-propylpentyl, n-nonyl, 2,2-dimethylheptyl, 1-ethylpropyl, 1,1-dimethylpropyl, isohexyl, 4-methylhexyl, 5-methylhexyl, benzyl, etc.

[0025] As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon group comprising at least one double bond, and unless otherwise stated, an alkenyl group may have 2 to 20 carbon atoms, 2 to 19 carbon atoms, 2 to 18 carbon atoms, 2 to 17 carbon atoms, 2 to 16 carbon atoms, 2 to 15 carbon atoms, 2 to 14 carbon atoms, 2 to 13 carbon atoms, 2 to 12 carbon atoms, 2 to 11 carbon atoms, 2 to 10 carbon atoms, for example 2 to 6 carbon atoms, particularly 2 to 4 carbon atoms, and may be straight-chain or branched. Specific examples of alkenyl groups may include, but are not limited to, vinyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 3-methyl-1-butenyl, 1,3-butadienyl, allyl, 1-phenylvinyl-1-yl, 2-phenylvinyl-1-yl, 2,2-diphenylvinyl-1-yl, 2-phenyl-2-(naphthyl-1-yl)vinyl-1-yl, 2,2-bis(diphenyl-1-yl)vinyl-1-yl, stilbene, styryl, etc.

[0026] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group comprising at least one triple bond, and unless otherwise stated, an alkynyl group may have 2 to 20 carbon atoms, 2 to 19 carbon atoms, 2 to 18 carbon atoms, 2 to 17 carbon atoms, 2 to 16 carbon atoms, 2 to 15 carbon atoms, 2 to 14 carbon atoms, 2 to 13 carbon atoms, 2 to 12 carbon atoms, 2 to 11 carbon atoms, 2 to 10 carbon atoms, for example 2 to 6 carbon atoms, particularly 2 to 4 carbon atoms, and may be straight-chain or branched. Specific examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0027] Furthermore, as used herein, the term "cycloalkyl" refers to a cyclic aliphatic hydrocarbon group that does not contain either double or triple bonds, and unless otherwise stated, a cycloalkyl group may have 3 to 30 carbon atoms, 3 to 28 carbon atoms, 3 to 26 carbon atoms, 3 to 24 carbon atoms, 3 to 22 carbon atoms, 3 to 20 carbon atoms, 3 to 18 carbon atoms, 3 to 16 carbon atoms, 3 to 14 carbon atoms, 3 to 12 carbon atoms, 3 to 10 carbon atoms, for example 3 to 8 carbon atoms, particularly 3 to 6 carbon atoms, and may be monocyclic or polycyclic. A polycyclic group refers to a group in which a cycloalkyl group is directly attached to or fused with another cyclic group, wherein the other cyclic group may be a cycloalkyl group, but may also be another type of cyclic group, such as a heterocycloalkyl, aryl, heteroaryl, etc. Specific examples of cycloalkyl groups may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 3-methylcyclopentyl, 2,3-dimethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2,3-dimethylcyclohexyl, 3,4,5-trimethylcyclohexyl, 4-tert-butylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[4.4.0]decyl, bicyclo[4.1.0]heptyl, etc.

[0028] As used herein, the term "cycloalkenyl" refers to a cyclic aliphatic hydrocarbon group comprising at least one double bond, and unless otherwise stated, a cycloalkenyl group may have 3 to 30 carbon atoms, 3 to 28 carbon atoms, 3 to 26 carbon atoms, 3 to 24 carbon atoms, 3 to 22 carbon atoms, 3 to 20 carbon atoms, 3 to 18 carbon atoms, 3 to 16 carbon atoms, 3 to 14 carbon atoms, 3 to 12 carbon atoms, 3 to 10 carbon atoms, for example 3 to 8 carbon atoms, particularly 3 to 6 carbon atoms, and may be monocyclic or polycyclic. A polycyclic group refers to a group in which the cycloalkenyl group is directly attached to or fused with other cyclic groups, wherein the other cyclic groups may be cycloalkyl groups, but may also be another type of cyclic group, such as heterocycloalkyl, aryl, heteroaryl, etc. Specific examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopent-1,3-dienyl, cycloheptenyl, cyclooctenyl, and cyclooct-1,4-dienyl.

[0029] As used herein, the term "aryl" refers to an aromatic hydrocarbon group and, unless otherwise specified, may have 6 to 30 carbon atoms, 6 to 28 carbon atoms, 6 to 26 carbon atoms, 6 to 24 carbon atoms, 6 to 22 carbon atoms, 6 to 20 carbon atoms, 6 to 18 carbon atoms, 6 to 16 carbon atoms, 6 to 14 carbon atoms, for example, 6 to 12 carbon atoms, and may be monocyclic or polycyclic. A polycyclic group is a group in which the aryl group is directly attached to or fused with another cyclic group, which may be an aryl group, but may also be other types of cyclic groups, such as cycloalkyl, heterocycloalkyl, and heteroaryl. Furthermore, aryl groups include spirocyclic groups. Specific examples of aryl groups may include phenyl, biphenyl, triphenyl, naphthyl, anthracene, etc. The group includes, but is not limited to, phenanthrene, perylene, fluoranyl, benzophenanthrene, phenatenyl, pyrene, tetraphenyl, pentaphenyl, fluorenyl, indene, acenaphthene, benzofluorenyl, spirodifluorenyl, 2,3-dihydro-1H-indenyl and their fused-ring groups.

[0030] As used herein, the terms “heterocyclic alkyl,” “heterocyclic alkenyl,” and “heteroaryl” respectively mean that at least one atom of the ring constituting the aforementioned cycloalkyl, cycloalkenyl, and aryl groups is replaced by a heteroatom such as O, S, Se, N, Si, etc.

[0031] As used in this article, the term “substitution” means that a hydrogen atom bonded to a carbon atom in a structure is replaced by another substituent, and the position of substitution is not restricted, as long as it is the position where the hydrogen atom is substituted, i.e., the position where the substituent can substitute. When hydrogen atoms at two or more positions are substituted, the two or more substituents can be the same or different from each other.

[0032] As used in this article, the term "pharmaceutically acceptable" means that it can be approved or preferably approved by a federal or state regulatory agency, or listed in the United States Pharmacopeia or other recognized pharmacopoeia, and can be used in animals, and more specifically in humans, because significant toxic effects can be avoided when used with the usual drug dosage.

[0033] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is pharmaceutically acceptable and has the preferred biological or pharmacological activity of the parent compound. Examples of such salts include, but are not limited to, acid addition salts formed from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts formed from organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, trifluoroacetic acid, benzoic acid, tannic acid, dihydroxynaphthyl acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, particularly including chlorides, bromides, iodides, -O-alkyl groups, toluenesulfonates, methanesulfonates, sulfonates, phosphates, or carboxylates (e.g., benzoates, succinates, acetates, glycolates, maleates, malates, fumarates, citrates, tartrates, ascorbic acid salts, cinnamates, mandelates, and diphenylacetic acid salts). The compounds of the structural formula of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates that can be prepared by typical methods.

[0034] As used herein, the term "hydrate" refers to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of water bound together by non-covalent intermolecular forces.

[0035] As used herein, the term "solvent" refers to a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and / or acceptable for human use.

[0036] As used herein, the term "prodrug" refers to a substance that is converted into a parent drug in vivo. This refers to compounds of the present invention that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide an active compound, particularly the compounds of the present invention. Examples of prodrugs include compounds that are biologically hydrolyzed to produce compounds of the present invention, including, but not limited to, biolyzable portions such as biolyzable amides, biolyzable esters, biolyzable carbamates, biolyzable carbonates, biolyzable acylureas, and biolyzable phosphate ester analogs. Such prodrugs include compounds readily prepared based on various known literature.

[0037] As used herein, the term "isomer" refers to a compound or salt thereof of the present invention that has the same chemical formula or molecular formula but differs in structure or space. Such isomers include all structural isomers such as tautomers, R or S isomers with an asymmetric carbon center, stereoisomers such as geometric isomers (trans or cis), and enantiomers. Furthermore, all such isomers and mixtures thereof also fall within the scope of the present invention.

[0038] As used herein, the phrase “pharmaceutically acceptable carrier” refers to a diluent, adjuvant, additive, or carrier that is administered with the compounds of the present invention.

[0039] When used in this document, “prevention” means reducing the risk of developing a disease or disorder (i.e., preventing the development of one or more clinical symptoms of the disease in individuals who are exposed to or susceptible to the disease but have not yet experienced or exhibited symptoms of the disease).

[0040] When used in this document, “treatment” means alleviating a disease or disorder (i.e., stopping or reducing the progression of the disease or one or more clinical symptoms of the disease), improving one or more physical parameters that an individual may not be aware of, or modulating a disease or disorder physically (e.g., stabilizing perceptible symptoms), mentally (e.g., stabilizing physical parameters), or both.

[0041] The present invention will be described in detail below.

[0042] 1. Novel benzimidazole derivative compounds

[0043] According to one aspect of the present invention, a compound having the chemical structure of Formula 1 below, or a pharmaceutically acceptable salt, isomer, solvate, hydrate, or prodrug thereof, is provided:

[0044] [Formula 1]

[0045]

[0046] In Equation 1 above, Q1 and Q2 can each be independently selected from either carbon or nitrogen.

[0047] In Formula 1 above, X1 and X2 can each independently be selected from any of the following groups: hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted alkoxy. Specifically, X1 and X2 can each independently be selected from any of the following groups: hydrogen, halogen, unsubstituted or halogen-substituted alkyl, unsubstituted or halogen-substituted cycloalkyl, and unsubstituted or halogen-substituted alkoxy. For example, X1 and X2 can each independently be selected from any of the following groups: hydrogen, halogen, unsubstituted or halogen-substituted alkyl, unsubstituted cycloalkyl, and halogen-substituted alkoxy. In particular, X1 and X2 can each independently be selected from any of the following groups: hydrogen, halogen, unsubstituted or halogen-substituted alkyl having 1 to 3 carbon atoms, unsubstituted cycloalkyl having 3 to 6 carbon atoms, and halogen-substituted alkoxy having 1 to 3 carbon atoms.

[0048] In Formula 1 above, A can be aryl or heteroaryl. For example, A can be any of the following groups: monocyclic or polycyclic aryl and monocyclic or polycyclic heteroaryl. Specifically, A can be any of the following groups: phenyl, benzodioxanepentenyl, pyridyl, pyrimidinyl, pyrazolyl, dihydroindenyl, isoindolinyl, benzothiazolyl, dihydroisobenzofuranyl, and dihydrobenzo[a] Azine group. Specifically, A above can be any of the following groups: phenyl, benzo[d][1,3]dioxacyclopentenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, 1H-pyrazol-4-yl, 2,3-dihydro-1H-inden-5-yl, isoindolin-5-yl, benzo[d]thiazolyl-2-yl, 1,3-dihydroisobenzofuran-5-yl, and 3,4-dihydro-2H-benzo[b][1,4] Azine-7-yl.

[0049] In Formula 1 above, X3, X4, and X5 can each independently be selected from any of the following groups: hydrogen, halogen, hydroxyl, oxo, carboxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted oxoheteroalkyl, substituted or unsubstituted heterobicycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted oxazabicycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl carbonyl, and substituted or unsubstituted heterobicycloalkyl carbonyl. Specifically, X3, X4, and X5 can each independently be selected from any of the following groups: hydrogen, halogen, hydroxyl, oxo, carboxyl, substituted or unsubstituted alkoxy, alkathio, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted morpholino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azacyclobutyl, substituted or unsubstituted piperazine, substituted or unsubstituted piperidinyl, substituted or unsubstituted oxazacycloheptyl, substituted or unsubstituted oxazacyclobutyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted oxopiridinyl, substituted or unsubstituted oxo Azolanic, substituted or unsubstituted oxaazaspiryl, substituted or unsubstituted azespiryl, substituted or unsubstituted oxaazaspiryl, substituted or unsubstituted diazaspiryl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted dihydrofuranyl, substituted or unsubstituted oxaazabicycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted Diazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolidine carbonyl, substituted or unsubstituted piperazine carbonyl, substituted or unsubstituted piperidine carbonyl, substituted or unsubstituted morpholine carbonyl, substituted or unsubstituted azacyclobutane carbonyl, and substituted or unsubstituted oxazaspirane carbonyl. The substituted functional groups in X3, X4 and X5 above can each be independently substituted by at least one selected from the group consisting of: halogen, hydroxyl, alkoxy, alkoxycarbonyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, alkyloxoheterocycloalkyl, aryl, heteroaryl, haloalkylheteroaryl, acetyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, halocycloalkylcarbonyl, heterocycloalkylcarbonyl, halocycloalkylcarbonyl, hydroxyheterocycloalkylcarbonyl, alkylheterocycloalkylcarbonyl, alkylamino, cycloalkylamino, cycloalkylalkylamino and alkylaminocarbonyl. For example, X3, X4, and X5 can each independently be selected from any of the following groups: hydrogen, halogen, hydroxyl, oxo, carboxyl, methoxy, ethoxy, propoxy, isopropoxy, cyclobutylmethoxy, cyclopropylmethoxy, methylthio, dimethylamino, isobutyramide, methanesulfonamide, (2,2,2-trifluoroethyl)sulfonamide, methylcarbamoyl, dimethylcarbamoyl, (2,2,2-trifluoroethyl)carbamoyl, methanesulfonamide, etc. Acyl, morpholinosulfonyl, piperidin-1-ylsulfonyl, pyrrolidine-1-ylsulfonyl, N,N-dimethylaminosulfonyl, N-cyclopropylaminosulfonyl, N-(cyclobutylmethyl)aminosulfonyl, methyl, propyl, isopropyl, tert-butyl, butyl, 2-hydroxypropyl-2-yl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl, 2-fluoro-2-methylpropyl, 1-hydroxy-2-methylpropyl-2-yl, 1-fluoro-2 -Methylpropyl-2-yl, (2-oxopyrrolidone-1-yl)methyl, ((3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl, (4-(trifluoromethyl)-1H-imidazol-1-yl)methyl, (3-methyl-2-oxo-imidazolin-1-yl)methyl, oxetane-3-ylmethyl, 2-(dimethylamino)-2-oxoethyl, 2-oxo-2-(pyrrolidone-1-yl)ethyl, morpholinomethyl, 2-morpholino -2-Oxoethyl, 2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl, 2-(3-hydroxyazacyclobutane-1-yl)-2-oxoethyl, 2-(2-methylmorpholino)-2-oxoethyl, 2-(3-methylmorpholino)-2-oxoethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropyl, 1-(hydroxymethyl)cyclopropyl, 1-(hydroxymethyl)cyclobutyl, 1-hydroxycyclobutyl, cyclohexyl, (3r,5r,7r)-adamantane-1-yl, morpholino, 3-methyloxetane-3-yl, 3-hydroxyoxetane-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, 2-oxo-piperidin-1-yl, pyrrolidine-1-yl, 3-hydroxyazacyclobutane-1-yl, 3,3-difluoroazacyclobutane-1-yl, 3,3-difluoropyrrolidine-1-yl, 4 1-Methylpiperazin-1-yl, 4,4-difluoropiperidin-1-yl, 4-(cyclopropanecarbonyl)piperazin-1-yl, 4-(cyclobutanecarbonyl)piperazin-1-yl, 4-(isopropoxycarbonyl)piperazin-1-yl, 4-(4,4-difluorocyclohexane-1-carbonyl)piperazin-1-yl, 1-(oxecyclobutane-3-yl)piperidin-4-yl, 1-(cyclopropanecarbonyl)piperidin-4-yl 1-(cyclobutanecarbonyl)piperidin-4-yl, 1-propionylpiperidin-4-yl, 4-propionylpiperazin-1-yl, 3,6-dihydro-2H-pyran-4-yl, 2,5-dihydrofuran-3-yl, 2-azaspiro[3.3]hept-2-yl, 7-oxa-2-azaspiro[3.5]non-2-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 2 -oxa-5-azabicyclo[2.2.1]hept-5-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 1,4-oxaazabicycloheptane-4-yl, 7-acetyl-2,7-diazaspiro[3.5]non-2-yl, 7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-2-yl, 4,4-dimethyl-2-oxo-, 3-oxazolidinyl, 5-oxo-6-oxa-4-azaspiro[2.4]hept-4-yl, cyclohexen-1-yl, 4-methyl-cyclohexen-1-yl, 4',4'-dimethyl-cyclohexen-1-yl, phenyl, chlorophenyl, 5-cyclopropyl-1,3,4- Diazol-2-yl, 5-cyclopentyl-1,3,4- Diazol-2-yl, 5-cyclohexyl-1,3,4- diazol-2-yl, 5-cycloheptyl-1,3,4- Diazol-2-yl, 5-(tetrahydro-2H-pyran-4-yl)-1,3,4- Diazol-2-yl, 5-(4,4-difluorocyclohexyl)-1,3,4- Diazol-2-yl, 1-propyl-1H-pyrazol-4-yl, piperidine-1-carbonyl, morpholine-4-carbonyl, 3-methylmorpholine-4-carbonyl, pyrrolidine-1-carbonyl, azacyclobutane-1-carbonyl, 3-hydroxyazacyclobutane-1-carbonyl, 3,3-difluoroazacyclobutane-1-carbonyl, 3-methoxypyrrolidine-1-carbonyl, 3,3-difluoropyrrolidine-1-carbonyl, 4-methylpiperazine-1-carbonyl, 4-hydroxypiperidine-1-carbonyl, 4-methoxypiperidine-1-carbonyl, 4,4-difluoropiperidine-1-carbonyl, 7-oxa-2-azaspiro[3.5]nonane-2-carbonyl and 2-oxa-6-azaspiro[3.3]heptane-6-carbonyl.

[0050] In Equation 1 above, n can be an integer from 0 to 3. Specifically, n can be an integer from 0 to 2, for example, n can be 0 or 1.

[0051] In Formula 1 above, R1 and R2 can each independently be any of the group selected from: hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or R1 and R2 can be linked together to form a substituted or unsubstituted hydrocarbon ring. Specifically, R1 and R2 can each independently be hydrogen or a substituted or unsubstituted alkyl; or R1 and R2 can be linked together to form any of the group selected from: substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic aryl. For example, R1 and R2 can each independently be hydrogen or a substituted or unsubstituted alkyl having 1 to 6 carbon atoms, or R1 and R2 can be linked together to form a substituted or unsubstituted cycloalkyl. In particular, R1 and R2 can each independently be hydrogen or methyl; or R1 and R2 can be linked together to form a cycloalkyl having 3 to 6 carbon atoms.

[0052] In Formula 1 above, B can be aryl or heteroaryl. Specifically, B can be phenyl or a heteroaryl group containing at least one selected from N and O. For example, B can be phenyl, pyridine, azole or isosorbide Azole.

[0053] In Formula 1 above, X6 and X7 can each independently be selected from any of the following groups: hydrogen, halogen, hydroxyl, oxo, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl. Specifically, X6 and X7 can each independently be selected from any of the following groups: hydrogen, halogen, hydroxyl, oxo, and substituted or unsubstituted alkyl. For example, X6 and X7 can each independently be hydrogen or halogen.

[0054] Furthermore, unless otherwise specified, the substituted functional groups in X1, X2, X6, X7, R1, and R2 above may be substituted by at least one selected from the group consisting of: halogens, alkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, haloalkyl groups, cycloalkyl groups, heterocycloalkyl groups, -OR3, -(CO)-R3, -(CO)-OR3, alkylamino groups, and oxo groups. Here, R3 may be hydrogen or alkyl.

[0055] In particular, the IUPAC names of specific examples of compounds having the chemical structure of Formula 1 above may be presented in Table 1 below, but are not limited thereto.

[0056] [Table 1]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084] Compounds of the present invention having the chemical structure of Formula 1 above inhibit the enzymatic activity of autochemin. In specific experimental examples of the present invention, it has been demonstrated that compounds of the present invention having the chemical structure of Formula 1 are effective as so-called "autochemin inhibitors" for inhibiting the enzymatic activity of autochemin. Therefore, compounds of the present invention having the chemical structure of Formula 1 above, or pharmaceutically acceptable salts, isomers, solvates, hydrates, or prodrugs thereof, can be used as active ingredients in pharmaceutical compositions for the prevention or treatment of diseases related to the enzymatic activity of autochemin.

[0085] 2. Uses of novel benzimidazole derivative compounds

[0086] According to another aspect of the invention, a pharmaceutical composition is provided comprising a compound having the chemical structure of Formula 1 above, or a pharmaceutically acceptable salt, isomer, solvate, hydrate, or prodrug thereof as an active ingredient.

[0087] As described above, since compounds having the chemical structure of Formula 1 above have the activity of being autochemin inhibitors that inhibit the expression or activity of autochemins, the pharmaceutical compositions of the present invention can be used to prevent or treat autochemin-mediated diseases, i.e., so-called autochemin-mediated diseases.

[0088] Specifically, the autochemin-mediated diseases can be those caused by the overexpression or overactivation of autochemins.

[0089] In one embodiment, the autochemotactic disease can be a cell proliferation disorder or fibrosis.

[0090] The cell proliferation disorders mentioned include, but are not limited to, cancerous hyperproliferative disorders (e.g., brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, kidney, liver, ovary, prostate, colorectal, colon, epidermoid, esophageal, testis, gynecological or thyroid cancer, acute myeloid leukemia, multiple myeloma, mesothelioma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), neuroblastoma, and acute lymphoblastic leukemia (ALL)); non-cancerous hyperproliferative disorders (e.g., benign skin hyperplasia (such as psoriasis), restenosis, and benign prostatic hyperplasia (BPH)); and diseases associated with angiogenesis or neovascularization (e.g., tumor angiogenesis, hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, and epidermoid carcinoma). The cell proliferation disorders also include primary and metastatic cancers. Specifically, the aforementioned cell proliferation disorders include pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, oropharyngeal-tonsillar carcinoma (HPV-related), oropharyngeal-hypopharyngeal cancer (non-HPV-related), mycosis fungoides carcinoma, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell tumor, male breast cancer, brain tumor, pituitary adenoma, common bile duct cystic tumor, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B-cell lymphoma, hepatopancreatic duct ampullary carcinoma, bladder cancer, peritoneal cancer, parathyroid carcinoma, adrenal cancer, nasal cavity and paranasal cavity cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, juvenile brain tumor, juvenile lymphoma, juvenile leukemia, small intestinal cancer, meningioma, esophageal cancer, etc. Cancer of the genital tract, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary origin, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal tumor, Wilms' tumor, breast cancer, sarcoma, penile cancer, gestational choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone tumor, metastatic brain tumor, mediastinal cancer, rectal cancer, neuroendocrine tumor, rectal carcinoid, vaginal cancer, spinal cord tumor, vestibular schwannoma, pancreatic cancer, salivary gland cancer, Paget's disease, squamous cell carcinoma, lung adenocarcinoma, lung cancer, squamous cell lung cancer, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, and pleural cancer, but not limited to these, and including diseases resulting from metastases of these diseases, or including variants of mutations resulting from recurrence.

[0091] In addition, the fibrosis includes diseases such as cystic fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, kidney fibrosis, scleroderma, radiation-induced fibrosis, Peroni disease, scarring, and other diseases in which excessive fibrosis contributes to the pathology of the disease. Furthermore, the fibrosis is selected from mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, renal systemic fibrosis, Crohn's disease, keloids, systemic sclerosis, joint fibrosis, Dupuitren contracture, adhesive capsulitis, pancreatic fibrosis, intestinal fibrosis, liver fibrosis, pulmonary fibrosis, renal fibrosis, cardiac fibrosis, fibrotic stenosis, cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced fibrosis, Peronis disease, and scleroderma, or any condition accompanied by respiratory disease, abnormal wound healing and repair, scar formation, hypertrophic scar formation / keloids, postoperative scar formation, cardiac arrest, and any condition in which excessive or abnormal deposition of fibrous material is associated with disease, injury, implant, or surgery. In another embodiment, the fibrosis is selected from liver fibrosis, pulmonary fibrosis, renal fibrosis, cardiac fibrosis, scar formation, and scleroderma. Furthermore, the fibrosis is selected from myelofibrosis, systemic sclerosis, liver fibrosis, pulmonary fibrosis, renal fibrosis, cardiac fibrosis, and radiation-induced fibrosis. For example, renal fibrosis includes, but is not limited to, diabetic nephropathy, vesicoureteral reflux, tubulointerstitial fibrosis, glomerulonephritis, or glomerulonephritis, including focal segmental glomerulosclerosis and membranous glomerulonephritis, IgA nephropathy, and mesangial capillary glomerulonephritis. For example, liver fibrosis leads to cirrhosis and includes related conditions such as chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), biliary cirrhosis, and autoimmune hepatitis. Additionally, the fibrosis is selected from keloids, scarring, ocular scarring, hypertrophic scarring, scleroderma, Dupuytren's contracture, and Peroni's disease. For example, the hypertrophic scar formation is caused by burns. Specifically, the hypertrophic scar formation is caused by external injury. In another embodiment, the hypertrophic scar formation is caused by surgery. In one embodiment, the keloid scar is caused by external injury. In another embodiment, the keloid scar is caused by surgery. In yet another embodiment, the keloid scar is the result of skin damage caused by acne, burns, chickenpox, ear piercing, scratching, surgical incisions, or vaccination sites.

[0092] In another embodiment, the autochemoattractant-mediated disease may be an inflammatory disease, an autoimmune disease, a respiratory disease, a cardiovascular disease, a neurodegenerative disease, a skin disease, a disease associated with abnormal angiogenesis, etc., but is not limited thereto.

[0093] The pharmaceutical compositions of the present invention may also contain pharmaceutically acceptable carriers or additives.

[0094] The active ingredient of this invention can be administered alone or in combination with any convenient carrier, and the dosage form can be a single-dose unit or multiple-dose units. The pharmaceutical composition can be a solid or liquid formulation. Solid formulations include, but are not limited to, powders, granules, tablets, capsules, suppositories, etc. Solid formulations may include, but are not limited to, carriers, flavoring agents, binders, preservatives, disintegrants, lubricants, fillers, etc. Liquid formulations include, but are not limited to, water, solutions such as propylene glycol solutions, suspensions, emulsions, etc., and can be prepared by adding suitable coloring agents, flavoring agents, stabilizers, thickeners, etc. For example, powders can be prepared by simply mixing the active ingredient of this invention with a suitable pharmaceutically acceptable carrier such as lactose, starch, or microcrystalline cellulose. Granules can be prepared by mixing the active ingredient of this invention, a suitable pharmaceutically acceptable carrier, and a suitable pharmaceutically acceptable binder such as polyvinylpyrrolidone or hydroxypropyl cellulose, and then wet granulating using a solvent such as water, ethanol, or isopropanol, or dry granulating using compression. In addition, tablets can be prepared by mixing the granules with a suitable pharmaceutically acceptable lubricant such as magnesium stearate, and then compressing the mixture into tablets using a tableting machine.

[0095] The pharmaceutical compositions of the present invention can be administered in oral formulations, injectable formulations (e.g., intramuscular, intraperitoneal, intravenous, infusion, subcutaneous, implantable), inhaled, intranasal, vaginal, rectal, sublingual, transdermal, or topical forms, depending on the barrier to be treated and the individual's condition, but are not limited thereto. The compositions of the present invention can be formulated into suitable dosage units containing pharmaceutically acceptable and non-toxic carriers, additives, and solvents commonly used in the art, depending on the route of administration.

[0096] The pharmaceutical composition of the present invention can be administered at a daily dose of about 0.0001 mg / kg to about 10 g / kg, for example, about 0.001 mg / kg to about 1 g / kg. However, the dose may vary depending on the degree of purification of the mixture, the patient's condition (age, sex, weight, etc.), the severity of the disease being treated, etc. For convenience, the total daily dose of the pharmaceutical composition may be divided into multiple doses daily as needed.

[0097] In another aspect, the present invention provides a method for treating autochemoattractant-mediated diseases, such as cell proliferation disorders or fibrosis, the method comprising administering to a subject a therapeutically effective amount of a compound having the chemical structure of Formula 1 above, or a pharmaceutically acceptable salt, isomer, solvate, hydrate, or prodrug thereof.

[0098] In another aspect, the present invention provides a method for inhibiting autochemotactic activity, the method comprising administering to a subject a therapeutically effective amount of a compound having the chemical structure of Formula 1 above, or a pharmaceutically acceptable salt, isomer, solvate, hydrate, or prodrug thereof.

[0099] The present invention will be described in detail below through preparation examples, embodiments and experimental examples.

[0100] Although the following preparation examples, embodiments, and experimental examples specifically illustrate the present invention, the content of the present invention is not limited to the following preparation examples, embodiments, and experimental examples.

[0101] [Preparation Example]

[0102] Preparation Example 1: Preparation of methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate

[0103] The procedure of steps A, B, and C below gives the title compound.

[0104] Step A: Preparation of methyl 3-(((4-chloro-2-nitrophenyl)amino)methyl)benzoate

[0105] 150 mL of DMF was added to methyl 3-(aminomethyl)benzoate (17 g, 103 mmol), K₂CO₃ (28.4 g, 206 mmol), and 4-chloro-1-fluoro-2-nitrobenzene (18 g, 103 mmol), followed by purging with nitrogen. The resulting mixture was stirred at room temperature for 2 hours, and then, at the termination of the reaction, EtOAC and water were added. The organic layer was separated and dehydrated on anhydrous MgSO₄. The filtrate was distilled under reduced pressure and then purified by MPLC to give the title compound (20 g, yield: 61%).

[0106] 1 H NMR (500MHz, CDCl3) δ8.45(brs,1H),8.23(s,1H),8.02(m,2H),7.55(m,1H),7.48(m,1H),7.34(m,1H),6.75(d,1H),4.62(d,2H),3.95(s,3H)

[0107] Step B: Preparation of methyl 3-(((2-amino-4-chlorophenyl)amino)methyl)benzoate

[0108] 1 mL of EtOH and 3 mL of water were added to methyl 3-(((4-chloro-2-nitrophenyl)amino)methyl)benzoate (0.35 g, 1.09 mmol) and iron (274 mg, 4.91 mmol) obtained in step A above. The reaction solution was stirred at 100 °C for 3 hours by adding 0.6 mL of acetic acid. When the reaction was terminated, the reaction solution was diluted with EtOAc at room temperature, alkalized with 5 M NaOH aqueous solution, the resulting solid was removed by passing through diatomaceous earth, and the organic layer was washed with water and separated. The filtrate was dehydrated on anhydrous MgSO4 and distilled under reduced pressure to give the title compound (0.32 g, yield: 99%).

[0109] 1 H NMR(500MHz, CDCl3)δ8.09(brs,1H),7.98(d,1H),7.59(d,1H),7.45(t,1H),7.28(m,2H)6.75(m,2H),6.53(d,1H),4.37(s,2H),3.95(s,3H)

[0110] Step C: Methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate preparation

[0111] 15 mL of THF was added to methyl 3-(((2-amino-4-chlorophenyl)amino)methyl)benzoate (367 mg, 1.26 mmol) and CDI (408 mg, 2.52 mmol) obtained in step B above, and the resulting mixture was stirred at 70 °C for 12 hours. After the reaction was terminated, the filtrate was distilled under reduced pressure and then purified by MPLC to give the title compound (240 mg, yield: 60%).

[0112] 1 H NMR(500MHz, CDCl3)δ8.31(brs,1H),8.00(m,2H),7.51(d,1H),7.43(t,1H),7.10(s,1H),7.00(d,1H),6.74(d,1H),.5.11(s,2H),3.93(s,3H)

[0113] Preparation Example 2: Preparation of methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate

[0114] The procedure of steps A, B, and C below gives the title compound.

[0115] Step A: Preparation of methyl 3-(((4-chloro-2-nitrophenyl)amino)methyl)-2-fluorobenzoate

[0116] The title compound (2.53 g, yield: 68%) was obtained using methyl 3-(aminomethyl)-2-fluorobenzoate (2.2 g, 12.01 mmol) and 4-chloro-1-fluoro-2-nitrobenzene in the same manner as in step A of Preparation Example 1.

[0117] 1 H NMR (500MHz, CDCl3) δ8.45(brs,1H),8.23(s,1H),8.02(m,2H),7.55(m,1H),7.48(m,1H),7.34(m,1H),6.75(d,1H),4.62(d,2H),3.95(s,3H)

[0118] Step B: Preparation of methyl 3-(((2-amino-4-chlorophenyl)amino)methyl)-2-fluorobenzoate

[0119] The title compound (2.36 g, yield: 99%) was obtained using methyl 3-(((4-chloro-2-nitrophenyl)amino)methyl)-2-fluorobenzoate (2.5 g, 7.38 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 1.

[0120] 1 H NMR (500MHz, CDCl3) δ7.87(t,1H),7.70(m,1H),7.53(m,2H),7.18(t,1H),6.73(m,1H),6.51(m,1H),4.43(s,2H),3.97(s,3H).

[0121] Step C: 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid Preparation of esters

[0122] The title compound (0.66 g, yield: 28%) was obtained using methyl 3-(((2-amino-4-chlorophenyl)amino)methyl)-2-fluorobenzoate (2.36 g, 6.97 mmol) obtained in step B above, in the same manner as in step C of Preparation Example 1.

[0123] 1 H NMR(500MHz, CDCl3)δ8.95(brs,1H),7.90(t,1H),7.51(t,1H),7.18(t,1H),7.12(m,1H),7.05(d,1H),6.90(d,1H),5.17(s,2H),3.97(s,2H)

[0124] Preparation Example 3: Preparation of methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate

[0125] The title compound (97 mg, yield: 9%) was obtained using methyl 3-(1-aminocyclopropyl)benzoate (575 mg, 12.01 mmol) and 4-chloro-1-fluoro-2-nitrobenzene in the same manner as in steps A, B and C of Preparation Example 1.

[0126] 1 H NMR (500MHz, CDCl3) δ10.67(brs,1H),7.85(m,2H),7.34(m,2H),7.13(s,1H),7.03(s,2H),3.90(s,3H),1.73(s,4H)

[0127] Preparation Example 4: Preparation of methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoate

[0128] The procedure of steps A and B below gives the title compound.

[0129] Step A: Preparation of methyl 3-(1-aminocyclopropyl)-2-fluorobenzoate

[0130] 150 mL of Et₂O and 9.82 mL of Ti(O-Pr)₄ (33 mmol) were added to methyl 3-cyano-2-fluorobenzoate (5.4 g, 30 mmol), and the resulting mixture was cooled to -78 °C. Ethyl magnesium bromide (3 M Et₂O solution) was then slowly added to the mixture. The resulting mixture was stirred at room temperature for 1 hour, and then BF₃-OEt₂ (6.37 mL, 60 mmol) was added. The mixture was stirred again at room temperature for 1 hour. 90 mL of 1 N hydrochloric acid aqueous solution was added to the reaction solution, and the reaction solution was then washed with Et₂O. The aqueous layer was separated, alkalized with 2.5 M NaOH aqueous solution, and then extracted with Et₂O to obtain the organic layer. The organic layer was dehydrated with anhydrous Na₂SO₄, and the resulting solid was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (3.1 g, yield: 49%).

[0131] 1 H NMR(500MHz, CDCl3)δ7.81(m,1H),6.51(m,1H),7.14(m,1H),3.96(s,3H),2.00(brs,2H),1.05(m,2H),0.92(m,2H)

[0132] Step B: 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzyl Preparation of methyl ester

[0133] The title compound (278 mg, yield: 7%) was obtained using methyl 3-(1-aminocyclopropyl)-2-fluorobenzoate (2.2 g, 10.51 mmol) obtained in step A above and 4-chloro-1-fluoro-2-nitrobenzene in the same manner as in steps A, B and C of Preparation Example 1.

[0134] 1 H NMR(500MHz, CDCl3)δ8.39(brs,1H),8.09(t,1H),8.56(t,1H),7.44(d,1H),7.20(t,1H),7.11(d,1H),7.03(s,1H),3.93(s,3H),1.65(m,4H)

[0135] Preparation Example 5: Preparation of 6-chloro-1-phenyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0136] The procedure of steps A, B, and C below gives the title compound.

[0137] Step A: Preparation of 5-chloro-2-nitro-N-phenylaniline

[0138] 4-Chloro-2-fluoro-1-nitrobenzene (877.70 mg, 5.00 mmol), aniline (1.37 mL, 15.00 mmol), and potassium carbonate (1.72 g, 12.50 mmol) were dissolved in dimethyl sulfoxide, and the resulting mixture was stirred at 50 °C. After the reaction was terminated, water was added, and the reaction mixture was extracted with ethyl acetate to separate the organic layer, which was then dehydrated on anhydrous Na₂SO₄. The resulting solid was filtered off, and the filtrate was distilled under reduced pressure and then purified by MPLC to give the title compound (1.23 g, yield: 99%).

[0139] 1 H NMR (400MHz, CDCl3) δ9.55(s,1H),8.17(m 1H),7.45(m,2H),7.28(m,3H),7.14(m,1H),6.72(m,1H)

[0140] Step B: 5-Chloro-N 1 Preparation of 1,2-phenylphenyl-1,2-diamine

[0141] The title compound (436.00 mg, yield: 99%) was obtained using 5-chloro-2-nitro-N-phenylaniline (500.00 mg, 2.01 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 1.

[0142] 1H NMR(500MHz, CDCl3)δ7.25(m,2H),7.12(s,1H),6.94(d,2H),6.90(t,1H),6.80(d,2H),6.72(d,1H),5.17(s,1H),3.71(s,2H)

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

[0144] Using the 5-chloro-N obtained in step B above 1 -Phenylen-1,2-diamine (437.36 mg, 2.00 mmol) was used to obtain the title compound (445.90 mg, yield: 91%) in the same manner as in step C of Preparation Example 1.

[0145] 1 H NMR(400MHz, CDCl3)δ8.99(s,1H),7.59(t,2H),7.53(d,2H),7.47(t,1H),7.09(d,1H),7.05(d,2H)

[0146] Preparation Example 6: Preparation of methyl 3-(aminomethyl)-5-fluorobenzoate

[0147] 15 mL of DMF and sodium azide (0.34 g, 5.25 mmol) were added to methyl 3-(bromomethyl)-5-fluorobenzoate (1.08 g, 4.37 mmol), and the resulting mixture was stirred at 70 °C for 1 hour. After the reaction was terminated, water and Et₂O were added to separate the organic layer. The organic layer was concentrated under reduced pressure, and then 15 mL of MeOH and 15 mL of DCM were added, followed by 10 wt% Pd / C (0.40 g). The resulting mixture was stirred under hydrogen atmospheres. After the reaction was terminated, the resulting solid was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (0.61 g, yield: 76%).

[0148] 1 H-NMR(400MHz,DMSO-d6)δ7.80(d,1H),7.50(2H),3.87(s,3H),3.86(s,1H),3.76(s,1H)

[0149] Preparation Example 7: Preparation of 6-chloro-1-(6-propoxypyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0150] The procedure described in steps A, B, C, D, and E below gives the title compound.

[0151] Step A: Preparation of 5-nitro-2-propoxypyridine

[0152] 18 mL of MTBE was added to 1-propanol (0.934 mL, 12.4 mmol), the resulting mixture was cooled to 0 °C, and KOtBu (1.39 g, 12.4 mmol) and 2-fluoro-5-nitropyridine (1.61 g, 11.3 mmol) were added. After the reaction was terminated, water was added, the organic layer was separated, and dehydrated on anhydrous Na₂SO₄. The resulting solid was filtered off, and the filtrate was distilled under reduced pressure and then purified by MPLC to give the title compound (1.57 g, yield: 76%).

[0153] 1 H NMR (400MHz, CDCl3) δ9.07(d,1H),8.34(dd,1H),6.81(d,1H),4.38(t,2H),1.82(m,2H),1.04(t,3H)

[0154] Step B: Preparation of 6-propoxypyridine-3-amine

[0155] 15 mL each of THF, EtOH, and water were added to 5-nitro-2-propoxypyridine (1.57 g, 8.62 mmol) obtained in step A above. Iron (3.37 g, 60 mmol) and ammonium chloride (3.23 g, 60 mmol) were also added, and the resulting mixture was stirred under reflux for 2 hours. After the reaction was terminated, the mixture was diluted with water and EtOAc, and the resulting solid was removed by passing it through diatomaceous earth. The organic layer was separated and then dehydrated on anhydrous Na₂SO₄ to give the title compound (1.28 g, yield: 98%).

[0156] 1 H NMR(400MHz, CDCl3)δ7.65(d,1H),7.03(dd,1H),6.60(d,1H),4.14(t,2H),3.35(brs,2H),1.76(m,2H),1.00(t,3H)

[0157] Step C: Preparation of N-(5-chloro-2-nitrophenyl)-6-propoxypyridine-3-amine

[0158] 28 mL of AN and K₂CO₃ (2.30 g, 19.3 mmol) were added to 6-propoxypyridine-3-amine (1.28 g, 8.41 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (1.62 g, 9.25 mmol) obtained in step B above, and the resulting mixture was stirred at 80 °C for 3 days. The resulting solid was filtered off, and the filtrate was then purified by MPLC to give the title compound (1.05 g, yield: 40%).

[0159] 1H NMR(400MHz, CDCl3)δ9.33(brs,1H),8.16(d,1H),8.10(d,1H),7.50(dd,1H),6.84(2H),6.72(dd,1H),4.29(t,2H),1.82(m,2H),1.05(t,3H)

[0160] Step D: Preparation of 6-chloro-1-(6-propoxypyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0161] Using the N-(5-chloro-2-nitrophenyl)-6-propoxypyridine-3-amine (1.05 g, 3.41 mmol) obtained in step C above, the title compound (0.70 g, yield: 68%) was obtained in the same manner as in step B of Preparation Example 7 and step C of Preparation Example 3.

[0162] 1 H NMR(400MHz, CDCl3)δ8.92(brs,1H),8.30(d,1H),7.70(dd,1H),7.09(d,1H), 7.03(d,1H),6.93(d,1H),6.90(d,1H),4.32(t,2H),1.83(m,2H),1.06(t,3H)

[0163] Preparation Example 8: Preparation of 6-chloro-1-(4-(dimethylamino)phenyl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0164] The procedure of steps A and B below gives the title compound.

[0165] Step A: N 1 -(3-Chloro-2-fluoro-6-nitrophenyl)-N 4 N 4 Preparation of 1,4-dimethylphenyl-2-diamine

[0166] To N 1 N 1 19 mL of DMF, 1-chloro-2,3-difluoro-4-nitrobenzene (3.70 g, 19.1 mmol), and K₂CO₃ (5.28 g, 38.2 mmol) were added to dimethylbenzene-1,4-diamine (2.60 g, 19.1 mmol), and the resulting mixture was stirred at 70 °C for 2 hours. After the reaction was terminated, cold water was added, and the resulting solid was dried to give the title compound (5.92 g, yield: 99%).

[0167] 1 H NMR(400MHz,DMSO-d6)δ8.86(brs,1H),7.90(dd,1H),7.10(dd,1H),6.94(d,2H),6.66(d,2H),2.86(s,6H)

[0168] Step B: 6-Chloro-1-(4-(dimethylamino)phenyl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one preparation

[0169] Use N obtained in step A above 1 -(3-Chloro-2-fluoro-6-nitrophenyl)-N 4 N 4 -Dimethylphenyl-1,4-diamine (2.60 g, 8.39 mmol) was used to obtain 5-chloro-N-diamine in the same manner as in step B of Preparation Example 7. 1 -(4-(dimethylamino)phenyl)-6-fluorobenzene-1,2-diamine. 200 mL of DCM was added, and the resulting mixture was cooled to 0 °C. DIPEA (8.34 mL, 47.8 mmol) and triphosgene (5.67 g, 19.1 mmol) were added sequentially. After 30 minutes, water was added, and the organic layer was separated. The organic layer was dehydrated on anhydrous Na₂SO₄ and purified by MPLC, giving the title compound (3.25 g, yield: 56%).

[0170] 1 H NMR(400MHz,DMSO-d6)δ11.42(brs,1H),7.26(d,2H),7.16(dd,1H),6.89(dd,1H),6.82(m,2H),2.97(s,6H)

[0171] Preparation Example 9: Preparation of 6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0172] The procedure of steps A, B, and C below gives the title compound.

[0173] Step A: Preparation of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine

[0174] 50 mL of EtOH was added to 4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (1.44 g, 7.30 mmol), and the resulting mixture was then purged with nitrogen. 10 wt% Pd-C (0.777 g, 0.730 mmol) was added, and the mixture was stirred under atmospheric hydrogen pressure. After the reaction was terminated, the resulting solid was filtered off, and the filtrate was purified by MPLC to give the title compound (1.17 g, yield: 96%).

[0175] 1H NMR (400MHz, CDCl3) δ7.17(s,1H),7.06(s,1H),4.22(m,1H),4.08(m,2H),3.51(m,2H),2.90(brs,2H),2.01(4H)

[0176] Step B: Preparation of N-(5-chloro-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine

[0177] The title compound (0.65 g, yield: 26%) was obtained using 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-amine (1.17 g, 7.00 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (1.35 g, 7.70 mmol) obtained in step A above, in the same manner as in step C of Preparation Example 7.

[0178] 1 H NMR(500MHz,CDCl3)δ9.09(brs,1H),8.13(d,1H),7.53(s,1H),7.49(s,1H),6 .97(d,1H),6.70(dd,1H),4.40(m,1H),4.14(m,2H),3.57(m,2H),2.10(m,4H)

[0179] Step C: 6-Chloro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d] Preparation of imidazole-2-one

[0180] The title compound (0.29 g, yield: 45%) was obtained using N-(5-chloro-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (0.65 g, 2.01 mmol) obtained in step B above, in the same manner as in step B of Preparation Example 7 and Preparation Example 8.

[0181] 1 H NMR(400MHz, CDCl3)δ9.00(brs,1H),7.83(s,1H),7.78(s,1H),7.08(2H),7.01(d,1H),4.40(m,1H),4.14(m,2H),3.58(m,2H),2.18(m,4H)

[0182] Preparation Example 10: Preparation of N-(5-chloro-2-nitrophenyl)-1H-pyrazole-4-amine

[0183] The procedure of steps A, B, and C below gives the title compound.

[0184] Step A: Preparation of tert-butyl 4-nitro-1H-pyrazole-1-carboxylate

[0185] 4-Nitro-1H-pyrazole (15.0 g, 133 mmol) was dissolved in 200 mL of DCM, and then dimethylaminopyridine (1.62 g, 13.2 mmol) and BOC2O (30.4 g, 139 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour, and then 0.5 N hydrochloric acid aqueous solution was added. The organic layer was separated and dehydrated on Na2SO4 to remove the resulting solid, giving the title compound (28.3 g, yield: 100%).

[0186] 1 H NMR(400MHz, CDCl3)δ8.79(s,1H),8.22(s,1H),1.69(s,9H)

[0187] Step B: Preparation of tert-butyl 4-amino-1H-pyrazole-1-carboxylate

[0188] The title compound (8.73 g, yield: 94%) was obtained in the same manner as in step A of Preparation Example 9 using 10.8 g (50.7 mmol) of tert-butyl 4-nitro-1H-pyrazole-1-carboxylate obtained in step A above.

[0189] 1 H NMR(400MHz, CDCl3)δ7.55(s,1H),7.41(s,1H),3.12(brs,2H),1.63(s,9H)

[0190] Step C: Preparation of N-(5-chloro-2-nitrophenyl)-1H-pyrazole-4-amine

[0191] The title compound (1.00 g, yield: 19%) was obtained using tert-butyl 4-amino-1H-pyrazole-1-carboxylate (4.00 g, 21.8 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (3.83 g, 21.8 mmol) obtained in step B above, in the same manner as in step A of Preparation Example 8.

[0192] 1 H NMR (400MHz, CDCl3) δ9.14(brs,1H),8.17(d,1H),8.15(s,1H),7.76(s,1H),6.99(d,1H),6.76(dd,1H),1.67(s,9H)

[0193] Preparation Example 11: Preparation of 6-chloro-7-fluoro-1-(4-morpholinophenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0194] The procedure of steps A, B, C, and D below gives the title compound.

[0195] Step A: Preparation of 4-(4-nitrophenyl)morpholine

[0196] 17 mL of morpholine was added to 1-fluoro-4-nitrobenzene (5.0 g, 35.4 mmol), and the resulting mixture was stirred at 80 °C for 4 hours. The reaction solution was poured into 400 mL of cold water, and the resulting solid was filtered off, giving the title compound (7.38 g, yield: 99%).

[0197] 1 H NMR(400MHz,DMSO-d6)δ8.08(d,2H),7.04(d,2H),3.83(m,4H),3.41(m,4H)

[0198] Step B: Preparation of 4-morpholinoaniline

[0199] Using 4-(4-nitrophenyl)morpholine (7.38 g, 35.40 mmol) obtained in step A above, the title compound (6.22 g, yield: 98%) was obtained in the same manner as in step B of Preparation Example 7.

[0200] 1 H NMR(500MHz,DMSO-d6)δ6.68(d,2H),6.59(d,2H),4.57(brs,2H),3.67(m,4H),2.86(m,4H)

[0201] Step C: Preparation of 3-chloro-2-fluoro-N-(4-morpholinophenyl)-6-nitroaniline

[0202] Using 4-morpholinoaniline (1.38 g, 7.75 mmol) obtained in step B above and 1-chloro-2,3-difluoro-4-nitrobenzene (1.50 g, 7.75 mmol), the title compound (2.57 g, yield: 94%) was obtained in the same manner as in step A of Preparation Example 8.

[0203] 1 H NMR(400MHz,DMSO-d6)δ8.33(brs,1H),7.90(dd,1H),7.18(dd,1H),6.95(d,2H),6.87(d,2H),3.73(m,4H),3.03(m,4H)

[0204] Step D: Preparation of 6-chloro-7-fluoro-1-(4-morpholinophenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0205] The title compound (1.18 g, yield: 46%) was obtained in the same manner as in step B of Preparation Example 8 using 2.57 g (7.31 mmol) of 3-chloro-2-fluoro-N-(4-morpholinophenyl)-6-nitroaniline obtained in step C above.

[0206] 1 H NMR(400MHz,DMSO-d6)δ11.45(s,1H),7.33(d,2H),7.18(dd,1H),7.04(d,2H),6.90(dd,1H),3.77(m,4H),3.18(m,4H)

[0207] Preparation Example 12: Preparation of 6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0208] The procedure of steps A, B, and C below gives the title compound.

[0209] Step A: Preparation of 1-propyl-1H-pyrazole-4-amine

[0210] 5.3 mL of n-butanol was added to 4-bromo-1-propyl-1H-pyrazole (1.00 g, 5.29 mmol), K₂CO₃ (1.09 g, 7.93 mmol), and acetamide (0.63 g, 10.6 mmol), and the resulting mixture was purged with nitrogen. DMEDA (0.074 mL, 0.69 mmol) and CuI (0.131 g, 0.688 mmol) were then added, and the mixture was stirred at 100 °C for 16 hours. After the reaction was terminated, the solids were removed by passing through diatomaceous earth. The filtrate was concentrated, and 13 mL of EtOH and hydrochloric acid aqueous solution (0.87 mL, 10.6 mmol) were added. The resulting mixture was stirred at 70 °C for 3 days. After the reaction was terminated, the reaction mixture was concentrated under reduced pressure, the filtrate was neutralized with 1N NaOH aqueous solution, and extracted with EtOAc. The organic layer was separated and then dehydrated on anhydrous Na2SO4 to give the title compound (0.39 g, yield: 59%).

[0211] 1 H NMR(400MHz,DMSO-d6)δ7.01(s,1H),6.88(s,1H),4.00(brs,2H),3.85(t,2H),1.67(m,2H),0.81(t,3H)

[0212] Step B: Preparation of N-(5-chloro-2-nitrophenyl)-1-propyl-1H-pyrazole-4-amine

[0213] The title compound (0.41 g, yield: 46%) was obtained in the same manner as in step C of Preparation Example 7 using 1-propyl-1H-pyrazole-4-amine (0.39 g, 3.12 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (0.57 g, 3.27 mmol) obtained in step A above.

[0214] 1H NMR(500MHz, CDCl3)δ9.08(brs,1H),8.13(d,1H),7.50(s,1H),7.44(s,1H),6.97(d,1H),6.69(dd,1H),4.00(t,2H),1.83(m,2H),0.88(t,3H)

[0215] Step C: Preparation of 6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0216] The title compound (0.077 g, yield: 18%) was obtained using N-(5-chloro-2-nitrophenyl)-1-propyl-1H-pyrazole-4-amine (0.41 g, 1.5 mmol) obtained in step B above, in the same manner as in step B of Preparation Example 7 and step C of Preparation Example 3.

[0217] 1 H NMR (400MHz, CDCl3) δ8.90(brs,1H),7.78(s,1H),7.76(s,1H),7.08(2H),7.02(d,1H),4.16(t,2H),1.98(m,2H),1.00(t,3H)

[0218] Preparation Example 13: Preparation of 6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0219] The procedure of steps A and B below gives the title compound.

[0220] Step A: Preparation of N-(3-chloro-2-fluoro-6-nitrophenyl)-1-propyl-1H-pyrazole-4-amine

[0221] The title compound (0.25 g, yield: 33%) was obtained in the same manner as in step A of Preparation Example 8 using 1-propyl-1H-pyrazole-4-amine (0.32 g, 2.58 mmol) and 1-chloro-2,3-difluoro-4-nitrobenzene (0.50 g, 2.58 mmol) obtained in step A of Preparation Example 12.

[0222] 1 H NMR(400MHz, CDCl3)δ8.92(brs,1H),7.97(dd,1H),7.42(s,1H),7.34(s,1H),6.82(dd,1H),4.06(q,2H),1.88(m,2H),0.93(t,3H)

[0223] Step B: 6-Chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one Preparation

[0224] The title compound (0.14 g, yield: 58%) was obtained using N-(3-chloro-2-fluoro-6-nitrophenyl)-1-propyl-1H-pyrazole-4-amine (0.25 g, 0.84 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 7 and step C of Preparation Example 3.

[0225] 1 H NMR(400MHz, CDCl3)δ9.23(brs,1H),7.71(2H),7.11(m,1H),6.85(d,1H),4.14(t,2H),1.95(m,2H),0.98(t,3H)

[0226] Preparation Example 14: Preparation of 1-(4-(6-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)azacyclobutane-3-yl acetate

[0227] The procedure described in steps A, B, C, D, and E below gives the title compound.

[0228] Step A: Preparation of 1-(4-nitrophenyl)azacyclobut-3-ol

[0229] 180 mL of DCM, 10 mL of TEA, and Cu(OAc)₂ (3.26 g, 17.9 mmol) were added to aziridine-3-ol hydrochloride (1.97 g, 17.9 mmol) and (4-nitrophenyl)boronic acid (3.0 g, 17.9 mmol), and the resulting mixture was stirred at room temperature for two days. The reaction solution was concentrated under reduced pressure and then purified by MPLC, giving the title compound (0.58 g, yield: 16%).

[0230] 1 H NMR (400MHz, CDCl3) δ8.11(d,2H),6.33(d,2H),4.87(m,1H),4.31(m,2H),3.90(m,2H),2.16(d,1H)

[0231] Step B: Preparation of 1-(4-aminophenyl)azacyclobut-3-ol

[0232] The title compound (0.49 g, yield: 99%) was obtained in the same manner as in step B of Preparation Example 7 using 1-(4-nitrophenyl)azacyclobut-3-ol (0.58 g, 2.99 mmol) obtained in step A above.

[0233] 1H NMR (400MHz, CDCl3) δ6.64(d,2H),6.38(d,2H),4.70(m,1H),4.11(t,2H),3.67(m,2H),3.38(brs,2H)

[0234] Step C: Preparation of 1-(4-((3-chloro-2-fluoro-6-nitrophenyl)amino)phenyl)azacyclobut-3-ol

[0235] The title compound (0.77 g, yield: 76%) was obtained in the same manner as in step A of Preparation Example 8 using 1-(4-aminophenyl)azacyclobut-3-ol (0.493 g, 3 mmol) and 1-chloro-2,3-difluoro-4-nitrobenzene (0.581 g, 3.00 mmol) obtained in step B above.

[0236] 1 H NMR(400MHz, CDCl3)δ9.10(brs,1H),7.96(dd,1H),6.98(m,2H),6.81(dd,1H),7.44(d,2H),4.77(m,1H),4.19(m,2H),3.68(m,2H),2.04(d,1H)

[0237] Step D: Preparation of 1-(4-((3-chloro-2-fluoro-6-nitrophenyl)amino)phenyl)azacyclobutane-3-ylacetate Preparation

[0238] 9 mL of DMSO and KOtBu (0.256 g, 2.28 mmol) were added to 1-(4-((3-chloro-2-fluoro-6-nitrophenyl)amino)phenyl)azacyclobut-3-ol (0.77 g, 2.28 mmol) obtained in step C, and the resulting mixture was stirred at room temperature for 30 min. 4.5 mL of EtOAc was added, and the resulting mixture was stirred at room temperature for 16 h. Water and EtOAc were added to the reaction solution, and the organic layer was separated and dehydrated on anhydrous Na₂SO₄. Purification by MPLC yielded the title compound (0.367 g, yield: 42%).

[0239] 1 H-NMR(400MHz, CDCl3)δ9.08(brs,1H),7.96(dd,1H),7.00(d,2H),6.82(dd,1H),6.45(d,2H),5.31(m,1H),4.25(m,2H),3.83(m,2H),2.11(s,3H)

[0240] Step E: 1-(4-(6-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)aza-heterocyclic ring Preparation of butane-3-ylacetic acid ester

[0241] Using the 1-(4-((3-chloro-2-fluoro-6-nitrophenyl)amino)phenyl)azacyclobutane-3-ylacetate (0.38 g, 1.00 mmol) obtained in step D above, the title compound (0.21 g, yield: 56%) was obtained in the same manner as in step B of Preparation Example 8.

[0242] 1 H-NMR(400MHz, CDCl3)δ9.14(brs,1H),7.30(m,2H),7.08(dd,1H),6.81(dd,1H),6.55(d,2H),5.34(m,1H),4.30(m,2H),3.88(m,2H),2.12(s,3H)

[0243] Preparation Example 15: Preparation of methyl 3-((5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate

[0244] The procedure of steps A and B below gives the title compound.

[0245] Step A: Preparation of methyl 3-(((4-chloro-2-fluoro-6-nitrophenyl)amino)methyl)benzoate

[0246] The title compound (0.88 g, yield: 69%) was obtained using 5-chloro-1,2-difluoro-3-nitrobenzene (0.726 g, 3.75 mmol) and methyl 3-(aminomethyl)benzoate (0.62 g, 3.75 mmol) in the same manner as in step A of Preparation Example 8.

[0247] 1 H-NMR(400MHz, CDCl3)δ8.11(brs,1H),8.00(3H),7.51(dd,1H),7.46(t,1H),7.20(dd,1H),4.77(m,2H),3.96(s,3H)

[0248] Step B: Methyl 3-((5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate Preparation of esters

[0249] The title compound (0.075 g, yield: 18%) was obtained using methyl 3-(((4-chloro-2-fluoro-6-nitrophenyl)amino)methyl)benzoate (0.42 g, 1.24 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 8.

[0250] 1H-NMR(500MHz,MeOH-d4)δ7.93(2H),7.54(m,1H),7.44(m,1H),6.94(m,1H),6.90(m,1H),5.18(s,2H),3.88(s,3H)

[0251] Preparation Example 16: Preparation of 1-(4-((5-chloro-2-nitrophenyl)amino)phenyl)piperidin-2-one The procedure of steps A and B below gives the title compound.

[0252] Step A: Preparation of 1-(4-aminophenyl)piperidin-2-one

[0253] Toluene was added to 4-bromoaniline (0.97 g, 5.6 mmol), piperidin-2-one (0.40 g, 4.0 mmol), CuI (38 mg, 0.20 mmol), K₂CO₃ (1.1 g, 8.1 mmol), and DMEDA (36 mg, 0.40 mmol), and the resulting mixture was purged with nitrogen. The reaction solution was stirred at 110 °C for 16 hours, and the resulting solid was removed by passing it through diatomaceous earth. The filtrate was purified by MPLC, yielding the title compound (0.21 g, yield: 27%).

[0254] 1 H-NMR(400MHz, CDCl3)δ7.00(d,2H),6.68(d,2H),3.66(brs,2H),3.57(m,2H),2.53(m,2H),1.92(m,4H)

[0255] Step B: Preparation of 1-(4-((5-chloro-2-nitrophenyl)amino)phenyl)piperidin-2-one

[0256] The title compound (0.12 g, yield: 32%) was obtained using 1-(4-aminophenyl)piperidin-2-one (0.21 g, 1.1 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (0.19 g, 1.1 mmol) obtained in step A above, in the same manner as in step A of Preparation Example 8.

[0257] 1 H-NMR (400MHz, CDCl3) δ9.52(brs,1H),8.16(d,1H),7.35(d,2H),7.30(d,2H),7.22(m,1H),6.72(dd,1H),3.69(m,2H),2.59(m,2H),1.98(m,4H)

[0258] Preparation Example 17: Preparation of 6-cyclopropyl-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0259] The procedure of steps A, B, and C below gives the title compound.

[0260] Step A: Preparation of 4-cyclopropyl-2-fluoro-1-nitrobenzene

[0261] Add 12 mL of 1,4-dioxane to 4-bromo-2-fluoro-1-nitrobenzene (1.00 g, 4.55 mmol) and cyclopropylboronic acid (0.586 g, 6.82 mmol). Alkane and 3 mL of water were added, and nitrogen gas was introduced into the resulting mixture. Na₂CO₃ (1.44 g, 13.6 mmol) and PdCl₂(dppf)-CH₂Cl₂ (0.371 g, 0.455 mmol) were added to the mixture, and the mixture was stirred at 80 °C for 16 hours. After the reaction was terminated, the solid was filtered through diatomaceous earth, and the filtrate was purified by MPLC to give the title compound (0.52 g, 2.87 mmol, yield: 63%).

[0262] 1 H-NMR(400MHz, CDCl3)δ7.97(t,1H),6.94(dd,1H),6.90(dd,1H),1.96(m,1H),1.18(m,2H),0.83(m,2H)

[0263] Step B: Preparation of N-(5-cyclopropyl-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-amine Preparation

[0264] The title compound (0.147 g, yield: 31%) was obtained in the same manner as in step A of preparation example 8, using 4-cyclopropyl-2-fluoro-1-nitrobenzene (0.26 g, 1.43 mmol) obtained in step A of preparation example 9 and 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-amine (0.24 g, 1.43 mmol) obtained in step A of preparation example 8.

[0265] 1 H-NMR(400MHz,DMSO-d6)δ9.21(m,1H),8.00(2H),7.57(m,1H),6.78(m,1H),6.40( dd,1H),4.41(m,1H),3.97(m,2H),3.50(m,2H),1.90(5H),1.00(m,2H),0.71(m,2H)

[0266] Step C: 6-Cyclopropyl-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzene Preparation of [d]imidazol-2-one

[0267] The title compound (0.078 g, yield: 56%) was obtained using N-(5-cyclopropyl-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-amine (0.14 g, 0.43 mmol) obtained in step B above, in the same manner as in step B of Preparation Example 7 and step C of Preparation Example 3.

[0268] 1 H-NMR(400MHz, CDCl3)δ7.20(brs,1H),7.86(s,1H),7.80(s,1H),7.00(d,1H),6 / 86(dd,1H),6.82 (d,1H),4.40(m,1H),4.14(m,2H),3.59(m,2H),2.18(m,4H),1.93(m,1H),0.95(m,2H),0.64(m,2H)

[0269] Preparation Example 18: Preparation of 6-chloro-1-(1-isopropyl-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0270] The procedure of steps A and B below gives the title compound.

[0271] Step A: Preparation of N-(5-chloro-2-nitrophenyl)-1-isopropyl-1H-pyrazole-4-amine

[0272] N-(5-chloro-2-nitrophenyl)-1H-pyrazole-4-amine (250.0 mg, 1.05 mmol) obtained in Preparative Example 10 was dissolved in DMF, and 2-iodopropane (214.0 mg, 1.26 mmol) and K₂CO₃ (290.0 mg, 2.10 mmol) were added. The resulting mixture was stirred at 70 °C. After the reaction was terminated, the resulting solid was filtered off, and the filtrate was distilled under reduced pressure and then purified by MPLC to give the title compound (195.0 mg, yield: 67%).

[0273] 1 H NMR (500MHz, CDCl3) δ7.47(s,1H),7.43(s,1H),6.48(d,1H),6.39(d,1H),6.17(s,1H),4.49(m,1H),3.85(br s,1H),1.54(d,6H)

[0274] Step B: Preparation of 6-chloro-1-(1-isopropyl-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one Preparation

[0275] The title compound (15.6 mg, yield: 8%) was obtained using N-(5-chloro-2-nitrophenyl)-1-isopropyl-1H-pyrazole-4-amine (195.0 mg, 0.695 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 7 and step C of Preparation Example 1.

[0276] 1 H NMR (500MHz, CDCl3) δ10.52(m,1H)7.80(s,1H),7.77(s,1H),7.08(m,3H),4.60(m,1H),1.60(d,6H)

[0277] Preparation Example 19: Preparation of 6-chloro-1-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0278] The procedure of steps A, B, and C below gives the title compound.

[0279] Step A: Preparation of N-(5-chloro-2-nitrophenyl)-1-(cyclopropylmethyl)-1H-pyrazole-4-amine

[0280] N-(5-chloro-2-nitrophenyl)-1H-pyrazole-4-amine (250.0 mg, 1.05 mmol) obtained in Preparation Example 10 was dissolved in DMF, and (bromomethyl)cyclopropane (170.0 mg, 1.26 mmol) and K₂CO₃ (290.0 mg, 2.10 mmol) were added. The resulting mixture was stirred at 70 °C. After the reaction was terminated, the resulting solid was filtered off, and the filtrate was distilled under reduced pressure and then purified by MPLC to give the title compound (205.0 mg, yield: 67%).

[0281] Step B: 6-Chloro-1-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2- Preparation of ketones

[0282] The title compound (55.3 mg, yield: 13%) was obtained using N-(5-chloro-2-nitrophenyl)-1-(cyclopropylmethyl)-1H-pyrazole-4-amine (205.0 mg, 0.70 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 7 and step C of Preparation Example 1.

[0283] 1 H NMR(500MHz, CDCl3)δ9.02(m,1H),7.90(s,1H),7.77(s,1H),7.09(d,2H),7.03(m,1H),4.07(d,2H),1.36(m,1H),0.72(m,2H),0.45(m,2H)

[0284] Preparation Example 20: Preparation of 6-chloro-1-(1-(cyclobutylmethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0285] The procedure of steps A and B below gives the title compound.

[0286] Step A: Preparation of N-(5-chloro-2-nitrophenyl)-1-(cyclobutylmethyl)-1H-pyrazole-4-amine

[0287] N-(5-chloro-2-nitrophenyl)-1H-pyrazole-4-amine (250.0 mg, 1.05 mmol) obtained in Preparation Example 10 was dissolved in DMF, and (bromomethyl)cyclobutane (187.0 mg, 1.26 mmol) and K₂CO₃ (290.0 mg, 2.10 mmol) were added. The resulting mixture was stirred at 70 °C. After the reaction was terminated, the resulting solid was filtered off, and the filtrate was distilled under reduced pressure and then purified by MPLC to give the title compound (232.0 mg, yield: 72%).

[0288] 1 H NMR(500MHz, CDCl3)δ7.46(s,1H),7.38(s,1H),6.50(d,1H),6.42(d,1H),6.17(s,1H),4.14(d,2H),2.86(m,1H),1.96-1.78(m,6H)

[0289] Step B: 6-Chloro-1-(1-(cyclobutylmethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2- Preparation of ketones

[0290] The title compound (10.0 mg, yield: 5%) was obtained using N-(5-chloro-2-nitrophenyl)-1-(cyclobutylmethyl)-1H-pyrazole-4-amine (232 mg, 0.76 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 7 and step C of Preparation Example 1.

[0291] 1 H NMR (500MHz, CDCl3) δ10.49(br s,1H),7.75(s,2H),7.08(m,3H),4.22(d,2H),2.93(m,1H),2.17(m,2H),2.00(m,4H)

[0292] Preparation Example 21: Preparation of 4-((5-chloro-2-nitrophenyl)amino)benzoic acid

[0293] The procedure of steps A and B below gives the title compound.

[0294] Step A: Preparation of tert-butyl 4-((5-chloro-2-nitrophenyl)amino)benzoate

[0295] 4-Aminobenzoate tert-butyl ester (1.2 g, 6.27 mmol) was dissolved in DMF and cooled to 0 °C. NaH (273.0 mg, 6.84 mmol) was slowly added, followed by stirring for 30 min. Then, 4-chloro-2-fluoro-1-nitrobenzene (1.0 g, 5.70 mmol) was added at 0 °C, and the mixture was stirred while raising the temperature to room temperature. After the reaction was terminated, water was slowly added while stirring at 0 °C. The organic layer was extracted with EtOAc and a saturated aqueous solution of NH4Cl and dehydrated on Na2SO4. The resulting solid was filtered off, and the filtrate was distilled under reduced pressure and then purified by MPLC, giving the title compound (670.0 mg, yield: 34%).

[0296] 1 H NMR(500MHz, CDCl3)δ9.57(s,1H),8.18(m,1H),8.06(d,2H),7.31(m,3H),6.82(d,1H),1.61(s,9H)

[0297] Step B: Preparation of 4-((5-chloro-2-nitrophenyl)amino)benzoic acid

[0298] The tert-butyl 4-((5-chloro-2-nitrophenyl)amino)benzoate (670.0 mg, 1.92 mmol) obtained in step A above was dissolved in 20 mL of DCM, and then 8 mL of TFA was slowly added to it, followed by stirring. After the reaction was terminated, the solvent and reactants were removed by distillation under reduced pressure, giving the title compound (559.0 mg, yield: 99%).

[0299] Preparation Example 22: Preparation of 6-chloro-1-(4-(piperidin-1-carbonyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0300] The procedure of steps A, B, and C below gives the title compound.

[0301] Step A: Preparation of (4-((5-chloro-2-nitrophenyl)amino)phenyl)(piperidin-1-yl)methyl ketone

[0302] 4-((5-chloro-2-nitrophenyl)amino)benzoic acid (146.3 mg, 0.50 mmol) and piperidine (54 μl, 0.55 mmol) obtained in Preparative Example 21 were dissolved in DMF and then cooled to 0 °C. HATU (228.0 mg, 0.60 mmol) and DIPEA (262.0 μL, 1.50 mmol) were added, and the resulting mixture was stirred while raising the temperature to room temperature. After the reaction was terminated, ice was added and the mixture was stirred. The resulting solid was filtered off and washed with cold water. The resulting solid was dried under vacuum to give the title compound (170.6 mg, yield: 94%).

[0303] 1 H NMR (500MHz, CDCl3) δ9.55(s,1H),8.18(t,1H),7.49(s,2H),7.31(m,3H),6.78(m,1H),3.72-3.42(m,4H),1.72-1.55(m,6H)

[0304] Step B: Preparation of (4-((2-amino-5-chlorophenyl)amino)phenyl)(piperidin-1-yl)methyl ketone

[0305] The title compound (154.1 mg, yield: 99%) was obtained using (4-((5-chloro-2-nitrophenyl)amino)phenyl)(piperidin-1-yl)methyl ketone (170.6 mg, 0.47 mmol) from step A above, in the same manner as in step B of Preparation Example 7.

[0306] Step C: Preparation of 6-chloro-1-(4-(piperidin-1-carbonyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0307] The (4-((2-amino-5-chlorophenyl)amino)phenyl)(piperidin-1-yl)methyl ketone (154.1 mg, 0.46 mmol) obtained in step B above was dissolved in THF, and then CDI (162.0 mg, 1.00 mmol) was added. The resulting mixture was stirred at 70 °C. After the reaction was terminated, the reaction mixture was cooled to room temperature, and the organic layer was separated by adding water and EtOAc, followed by dehydration on Na2SO4. The resulting solid was filtered off, and the filtrate was distilled under reduced pressure to give a mixture of the title compounds.

[0308] Preparation Example 23: Preparation of 6-chloro-1-(4-(morpholin-4-carbonyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0309] The procedure of steps A and B below gives the title compound.

[0310] Step A: Preparation of (4-((5-chloro-2-nitrophenyl)amino)phenyl)(morpholino)methyl ketone

[0311] The title compound (169.4 mg, yield: 93%) was obtained using 4-((5-chloro-2-nitrophenyl)amino)benzoic acid (146.3 mg, 0.50 mmol) and morpholine (47.9 mg, 0.55 mmol) from Preparation Example 21 in the same manner as in step A of Preparation Example 22.

[0312] 1 H NMR(500MHz, CDCl3)δ9.54(s,1H),8.18(d,1H),7.52(d,2H),7.33(m,3H),6.80(d,1H),3.80-3.50(m,8H)

[0313] Step B: Preparation of 6-chloro-1-(4-(morpholino-4-carbonyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0314] Using the (4-((5-chloro-2-nitrophenyl)amino)phenyl)(morpholino) methyl ketone (169.4 mg, 0.47 mmol) obtained in step A above, a mixture of the title compounds was obtained in the same manner as in steps B and C of Preparation Example 22.

[0315] Preparation Example 24: Preparation of 6-chloro-1-(4-(pyrrolidine-1-carbonyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0316] The procedure of steps A and B below gives the title compound.

[0317] Step A: Preparation of (4-((5-chloro-2-nitrophenyl)amino)phenyl)(pyrrolidine-1-yl)methyl ketone

[0318] The title compound (171.5 mg, yield: 99%) was obtained using 4-((5-chloro-2-nitrophenyl)amino)benzoic acid (146.3 mg, 0.50 mmol) and pyrrolidine (39.1 mg, 0.55 mmol) obtained in Preparation Example 21 in the same manner as in step A of Preparation Example 22.

[0319] 1 H NMR (400MHz, CDCl3) δ9.55(s,1H),8.18(d,1H),7.63(d,2H),7.31(d,2H),7.24(s,1H),6.79(d,1H),3.68(m,2H),3.51(m,2H),1.99(m,4H)

[0320] Step B: Preparation of 6-chloro-1-(4-(pyrrolidine-1-carbonyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one Preparation

[0321] Using the (4-((5-chloro-2-nitrophenyl)amino)phenyl)(pyrrolidine-1-yl)methyl ketone (171.5 mg, 0.50 mmol) obtained in step A above, a mixture of the title compounds was obtained in the same manner as in steps B and C of Preparation Example 22.

[0322] Preparation Example 25: Preparation of 4-(6-chloro-3-(3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid

[0323] The procedure of steps A and B below gives the title compound.

[0324] Step A: 3-((3-(4-(tert-butoxycarbonyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)benzoate

[0325] Methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (1.0 g, 3.16 mmol), (4-(tert-butoxycarbonyl)phenyl)boronic acid (1.4 g, 6.31 mmol), and copper(II) acetate (1.7 g, 9.47 mmol) obtained in Preparation Example 1 were dissolved in DCM (30 mL). TEA (1.3 mL, 9.47 mmol) was then added, and the resulting mixture was stirred at room temperature. After the reaction was terminated, a saturated K₂CO₃ solution (1 mL) was added, and the resulting mixture was stirred further for 20 min. The reaction solution was then filtered using diatomaceous earth, and the filtrate was extracted with water and EtOAc to separate the organic layer, which was then dehydrated on Na₂SO₄. The resulting solid was filtered off, and the filtrate was distilled under reduced pressure and then purified by MPLC, giving the title compound (745.0 mg, yield: 48%).

[0326] 1 H NMR(500MHz, CDCl3)δ8.18(d,2H),8.05(s,1H),7.99(d,1H),7.65(d,2H),7.57(d,1H),7 .45(t,1H),7.13(s,1H),7.05(d,1H),6.83(d,1H),5.16(s,2H),3.91(s,3H),1.62(s,9H)

[0327] Step B: 4-(6-chloro-3-(3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of 1-(azol-1-yl)benzoic acid

[0328] Methyl 3-((3-(4-(tert-butoxycarbonyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (745.0 mg, 1.5 mmol) obtained in step A above was dissolved in 20 mL of DCM, and then 8 mL of TFA was slowly added to it, followed by stirring. After the reaction was terminated, the solvent and reactants were removed by distillation under reduced pressure, giving the title compound (619.4 mg, yield: 95%).

[0329] 1 H NMR(500MHz,DMSO-d6)δ8.14(d,2H),8.01(s,1H),7.89(d,1H),7.64(d,2H), 7.66(d,1H),7.51(t,1H),7.29(d,1H),7.19(m,2H),5.23(s,2H),3.84(s,3H)

[0330] Preparation Example 26: Preparation of 6-chloro-1-(2-morpholinopyrimidin-5-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0331] The procedure of steps A, B, C, and D below gives the title compound.

[0332] Step A: Preparation of 4-(5-nitropyrimidin-2-yl)morpholine

[0333] 38 mL of AN and morpholine (3.60 mL, 41.4 mmol) were added to 2-chloro-5-nitropyrimidine (3.00 g, 18.8 mmol), and the resulting mixture was stirred at room temperature for 1 hour. After removing the resulting solid, the filtrate was concentrated. EtOAc and aqueous hydrochloric acid were added to the filtrate to separate the organic layer, which was then dehydrated on anhydrous Na2SO4 to give the title compound (2.65 g, yield: 67%).

[0334] 1 H-NMR(400MHz, CDCl3)δ9.07(s,2H),4.00(m,4H),3.78(m,4H)

[0335] Step B: Preparation of 2-morpholinopyrimidine-5-amine

[0336] The title compound (2.27 g, yield: 99%) was obtained using 4-(5-nitropyrimidin-2-yl)morpholine (2.65 g, 12.6 mmol) obtained in step A above, in the same manner as in step A of Preparation Example 9.

[0337] 1H-NMR(400MHz, CDCl3)δ7.99(s,2H),3.77(m,4H),3.64(m,4H)

[0338] Step C: Preparation of N-(5-chloro-2-nitrophenyl)-2-morpholinopyrimidine-5-amine

[0339] 4-Chloro-2-fluoro-1-nitrobenzene (0.97 g, 5.55 mmol) and 14 mL of DMF were added to the 2-morpholinopyrimidin-5-amine (0.50 g, 2.77 mmol) obtained in step B above. The resulting mixture was then cooled to 0 °C, and KOtBu (0.31 g, 2.77 mmol) was added. The reaction solution was stirred under reflux for 3 days, and then an aqueous solution of ammonium chloride was added. The resulting solid was filtered off and separated by MPLC, giving the title compound (0.21 g, yield: 22%).

[0340] 1 H-NMR(400MHz,DMSO-d6)δ9.37(brs,1H),8.348(s,2H),8.14(d,1H),6.86(dd,1H),6.80(d,1H),3.73(m,4H),3.68(m,4H)

[0341] Step D: Preparation of 6-chloro-1-(2-morpholinopyrimidin-5-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0342] The title compound (0.045 g, yield: 22%) was obtained using N-(5-chloro-2-nitrophenyl)-2-morpholinopyrimidine-5-amine (0.21 g, 0.625 mmol) obtained in step C above, in the same manner as in step B of Preparation Example 8.

[0343] 1 H-NMR(400MHz,MeOH-d4)δ8.46(s,2H),7.11(dd,1H),7.08(dd,1H),6.95(d,1H),3.86(m,4H),3.75(m,4H)

[0344] Preparation Example 27: Preparation of 5-chloro-1-(4-(dimethylamino)phenyl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0345] Step A: N 1 -(4-Chloro-2-fluoro-6-nitrophenyl)-N 4 N 4 Preparation of 1,4-dimethylphenyl-2-diamine

[0346] Using 5-chloro-1,2-difluoro-3-nitrobenzene (0.710 g, 3.67 mmol) and N 1 N 1-Dimethylphenyl-1,4-diamine (0.50 g, 3.67 mmol) was used to obtain the title compound (1.08 g, yield: 95%) in the same manner as in step A of Preparation Example 8.

[0347] 1 H-NMR(400MHz, CDCl3)δ8.94(brs,1H),8.01(d,1H),7.21(dd,1H),6.99(d,2H),6.67(d,2H),2.93(s,6H)

[0348] Step B: 5-Chloro-1-(4-(dimethylamino)phenyl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one preparation

[0349] Use N obtained in step A above 1 -(4-Chloro-2-fluoro-6-nitrophenyl)-N 4 N 4 -Dimethylphenyl-1,4-diamine (1.08 g, 3.49 mmol) was used to obtain the title compound (0.50 g, yield: 47%) in the same manner as in step B of Preparation Example 8.

[0350] 1 H-NMR (400MHz, CDCl3) δ11.48(brs,1H),8.24(m,1H),7.28(m,1H),7.00(d,2H),6.78(d,2H),3.03(s,6H)

[0351] Preparation Example 28: Preparation of 6-chloro-1-(4-(4,4-difluoropiperidin-1-yl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0352] The procedure of steps A, B, and C below gives the title compound.

[0353] Step A: Preparation of 4-(4,4-difluoropiperidin-1-yl)aniline

[0354] The title compound (6.25 g, yield: 83%) was obtained using 1-fluoro-4-nitrobenzene (5.00 g, 35.4 mmol) and 4,4-difluoropiperidine hydrochloride (5.58 g, 35.4 mmol) in the same manner as in step A of Preparation Example 1 and step B of Preparation Example 7.

[0355] 1 H-NMR(500MHz,DMSO-d6)δ6.73(d,2H),6.50(d,2H),4.62(brs,2H),3.02(m,4H),2.05(m,4H)

[0356] Step B: Preparation of 5-chloro-N-(4-(4,4-difluoropiperidin-1-yl)phenyl)-2-nitroaniline

[0357] Using 4-(4,4-difluoropiperidin-1-yl)aniline (1.00 g, 4.71 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (0.827 g, 4.71 mmol) obtained in step A above, the title compound (1.52 g, yield: 88%) was obtained in the same manner as in step A of Preparation Example 1.

[0358] 1 H-NMR(400MHz,DMSO-d6)δ9.46(d,1H),8.13(d,1H),7.21(d,2H),7.10(d,2H),6.85(dd,1H),6.80(dd,1H),3.47(m,4H),2.06(m,4H)

[0359] Step C: 6-Chloro-1-(4-(4,4-difluoropiperidin-1-yl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one Preparation

[0360] The title compound (1.04 g, yield: 69%) was obtained using 5-chloro-N-(4-(4,4-difluoropiperidin-1-yl)phenyl)-2-nitroaniline (1.52 g, 4.13 mmol) obtained in step B above, in the same manner as in step B of Preparation Example 7 and Preparation Example 8.

[0361] 1 H-NMR(400MHz,DMSO-d6)δ11.22(brs,1H),7.34(d,2H),7.15(d,2H),7.05(2H),6.84(d,1H),3.43(m,4H),2.08(m,4H)

[0362] Preparation Example 29: Preparation of methyl 3-((5-chloro-2-oxo-3-(4-(piperazin-1-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate hydrochloride

[0363] The procedure described in steps A, B, C, D, and E below gives the title compound.

[0364] Step A: Preparation of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate

[0365] The title compound (1.60 g, yield: 51%) was obtained using 1-fluoro-4-nitrobenzene (1.59 g, 11.3 mmol) and tert-butyl piperazine-1-carboxylate (2.10 g, 11.3 mmol) in the same manner as in step A of Preparation Example 1 and step B of Preparation Example 7.

[0366] 1H-NMR(400MHz,DMSO-d6)δ6.70(d,2H),6.49(d,2H),4.61(brs,2H),3.41(m,4H),2.82(m,4H),1.41(s,9H)

[0367] Step B: Preparation of tert-butyl 4-(4-((5-chloro-2-nitrophenyl)amino)phenyl)piperazine-1-carboxylate

[0368] The title compound (2.35 g, yield: 94%) was obtained using tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (1.60 g, 5.77 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (1.01 g, 5.77 mmol) obtained in step A above, in the same manner as in step A of Preparation Example 1.

[0369] 1 H-NMR(400MHz,DMSO-d6)δ9.46(brs,1H),8.13(d,1H),7.20(d,2H),7.04(d,2H),6.82(dd,1H),6.80(m,1H),3.48(m,4H),3.14(m,4H),1.42(s,9H)

[0370] Step C: 4-(4-(6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)piperazine-1-carboxylic acid Preparation of tert-butyl ester

[0371] The title compound (1.0 g, yield: 43%) was obtained using tert-butyl 4-(4-((5-chloro-2-nitrophenyl)amino)phenyl)piperazine-1-carboxylate (2.35 g, 5.34 mmol) obtained in step B above, in the same manner as in step B of Preparation Example 7 and Preparation Example 8.

[0372] 1 H-NMR(400MHz,DMSO-d6)δ11.22(brs,1H),7.34(d,2H),7.10(d,2H),7.06(2H),6.83(d,1H),3.48(m,4H),3.19(m,4H),1.43(s,9H)

[0373] Step D: 4-(4-(6-chloro-3-(3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of imidazole-1-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0374] Using tert-butyl piperazine-1-carboxylate (1.0 g, 2.33 g) and methyl 3-(bromomethyl)benzoate (0.53 g, 2.33 mmol) obtained in step C above, the title compound (1.05 mmol, yield: 78%) was obtained in the same manner as in step C of Preparation Example 7.

[0375] 1 H-NMR(400MHz, CDCl3)δ8.05(d,1H),7.97(dd,1H),7.55(dd,1H),7.43(d,1H),7.40(d,2H),7.05( d,2H),6.99(m,2H),6.79(d,1H),5.15(s,2H),3.92(s,3H),3.62(m,4H),3.22(m,4H),1.50(s,9H)

[0376] Step E: 3-((5-chloro-2-oxo-3-(4-(piperazin-1-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol- Preparation of methyl 1-yl)methyl)benzoate hydrochloride

[0377] To the tert-butyl 4-(4-(6-chloro-3-(3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)piperazine-1-carboxylate (1.05 g, 1.82 mmol) obtained in step D above, 6 mL of DCM and 1.8 mL of hydrochloric acid (4 M EtOAc solution) were added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and then diethyl ether was added to it and the resulting solid was filtered off, giving the title compound (0.94 g, yield: 99%).

[0378] 1 H-NMR(400MHz,DMSO-d6)δ8.91(brs,2H),8.00(d,1H),7.88(dd,1H),7.67(dd,1H),7.52(t,1H),7. 45(d,2H),7.24(d,1H),7.18(3H),6.91(d,1H),5.21(s,2H),3.85(s,3H),3.45(m,4H),3.26(m,4H)

[0379] Preparation Example 30: Preparation of methyl 3-((5-chloro-2-oxo-3-(4-(piperidin-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate hydrochloride

[0380] The procedure of steps A, B, C, and D below gives the title compound.

[0381] Step A: Preparation of tert-butyl 4-(4-((5-chloro-2-nitrophenyl)amino)phenyl)piperidine-1-carboxylate

[0382] The title compound (1.65 g, yield: 67%) was obtained using tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (1.57 g, 5.70 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (1.00 g, 5.70 mmol) in the same manner as in step A of Preparation Example 1.

[0383] 1 H-NMR(400MHz, CDCl3)δ9.15(brs,1H),8.15(d,1H),7.28(d,2H),7.21(d,2H),7.12(d,1H), 6.70(dd,1H),4.28(m,2H),2.83(m,2H),2.70(m,1H),1.85(m,2H),1.65(m,2H),1.49(s,9H)

[0384] Step B: 4-(4-(6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)piperidine-1-carboxylic acid Preparation of tert-butyl ester

[0385] The title compound (0.65 g, yield: 40%) was obtained using tert-butyl 4-(4-((5-chloro-2-nitrophenyl)amino)phenyl)piperidine-1-carboxylate (1.65 g, 3.81 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 7 and step B of Preparation Example 8.

[0386] 1 H-NMR(400MHz, CDCl3)δ8.79(brs,1H),7.45(d,2H),7.38(2H),7.07(d,1H),7.02( 2H),4.28(m,2H),2.83(m,2H),2.73(m,1H),1.88(m,2H),1.65(m,2H),1.50(s,9H)

[0387] Step C: 4-(4-(6-chloro-3-(3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of tert-butyl imidazolium-1-yl)phenyl)piperidine-1-carboxylate

[0388] Using tert-butyl 4-(4-(6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)piperidine-1-carboxylate (0.65 g, 1.52 mmol) and methyl 3-(bromomethyl)benzoate (0.35 g, 1.52 mmol) obtained in step B above, the title compound (0.70 g, yield: 80%) was obtained in the same manner as in step C of Preparation Example 7.

[0389] 1H-NMR (400MHz, CDCl3) δ8.05(d,1H),7.98(dd,1H),7.57(dd,1H),7.47(d,2H),7.42(t,1H),7.38(d,2H),7.07(d,1H),7.02( dd,1H),6.81(d,1H),5.16(s,2H),4.29(m,2H),3.91(s,3H),2.83(m,2H),2.73(m,1H),1.87(m,2H),1.66(m,2H),1.50(s,9H)

[0390] Step D: 3-((5-chloro-2-oxo-3-(4-(piperidin-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol- Preparation of methyl 1-yl)methyl)benzoate hydrochloride

[0391] To the tert-butyl 4-(4-(6-chloro-3-(3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)piperidin-1-carboxylate (0.70 g, 1.21 mmol) obtained in step C above, 3 mL of DCM and 1.21 mL of hydrochloric acid (4 M EtOAc solution) were added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, then diethyl ether was added, and the resulting solid was dried to give the title compound (0.48 g, yield: 76%).

[0392] 1 H-NMR(400MHz,DMSO-d6)δ8.90(brs,2H),8.01(d,1H),7.89(dd,1H),7.66(dd,1H),7.57(d,2H),7.52(t,1H),7.455(d,2H),7.2 7(d,1H),7.16(dd,1H),7.03(d,1H),5.23(s,2H),3.85(s,3H),3.33(m,2H),3.03(m,2H),2.97(m,1H),1.98(m,2H),1.90(m,2H)

[0393] Preparation Example 31: Preparation of 6-chloro-1-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0394] The procedure of steps A, B, and C below gives the title compound.

[0395] Step A: Preparation of 4-(4-nitrophenyl)-3,6-dihydro-2H-pyran

[0396] Add 3 mL of 1,4-dioxane to 4-bromo-1-nitrobenzene (200 mg, 1.0 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (230 mg, 1.1 mmol). Alkane and 3 mL of 1 M sodium carbonate aqueous solution were added, and then nitrogen gas was introduced into the resulting mixture. A catalytic amount of Pd(PPh3)4 was added, and the mixture was stirred under reflux for 16 hours. After the reaction was terminated, the resulting solid was removed by diatomaceous earth, and the filtrate was purified by MPLC to give the title compound (185 mg, yield: 91%).

[0397] 1 H-NMR(500MHz, CDCl3)δ8.22(d,2H),7.55(d,2H),6.36(s,1H),4.39(s,2H),3.98(t,2H),2.57(s,2H)

[0398] Step B: Preparation of 4-(3,6-dihydro-2H-pyran-4-yl)aniline

[0399] The title compound (138 mg, yield: 90%) was obtained in the same manner as in step B of Preparation Example 7 using 180 mg (180 mg, 0.88 mmol) of 4-(4-nitrophenyl)-3,6-dihydro-2H-pyran obtained in step A above.

[0400] Step C: 6-Chloro-1-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol- Preparation of 2-one

[0401] The title compound (65 mg, yield: 26%) was obtained using 4-(3,6-dihydro-2H-pyran-4-yl)aniline (138 mg, 0.78 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (138 mg, 0.78 mmol) obtained in step B above, in the same manner as in step A of Preparation Example 1, step B of Preparation Example 7 and step B of Preparation Example 8.

[0402] 1 H-NMR (500MHz, CDCl3) δ8.18(d,1H),7.50(d,2H),7.26(d,2H),7.19(s,1H),6.75(d,1H),6.20(s,1H),4.38(m,2H),3.98(m,2H),2.57(m,2H)

[0403] Preparation Example 32: Preparation of 6-chloro-1-(4-(3,3-difluoropyrrolidone-1-yl)phenyl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0404] The procedure of steps A, B, C, and D below gives the title compound.

[0405] Step A: Preparation of 3,3-difluoro-1-(4-nitrophenyl)pyrrolidine

[0406] The title compound (4.28 g, yield: 88%) was obtained using 1-fluoro-4-nitrobenzene (3.0 g, 21.3 mmol) and 3,3-difluoropiperidine hydrochloride (3.05 g, 21.26 mmol) in the same manner as in step A of Preparation Example 1.

[0407] 1 H-NMR(400MHz,DMSO-d6)δ8.10(d,2H),6.70(d,2H),3.89(t,2H),3.65(t,2H),2.57(m,2H)

[0408] Step B: Preparation of 4-(3,3-difluoropyrrolidone-1-yl)aniline

[0409] The title compound (2.17 g, yield: 58%) was obtained using 3,3-difluoro-1-(4-nitrophenyl)pyrrolidine (4.28 g, 18.8 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 7.

[0410] 1 H-NMR(400MHz,DMSO-d6)δ6.51(d,2H),6.44(d,2H),4.43(brs,2H),3.50(t,2H),3.30(t,2H),2.45(m,2H)

[0411] Step C: Preparation of 3-chloro-N-(4-(3,3-difluoropyrrolidone-1-yl)phenyl)-2-fluoro-6-nitroaniline

[0412] Using 4-(3,3-difluoropyrrolidone-1-yl)aniline (1.0 g, 5.04 mmol) and 1-chloro-2,3-difluoro-4-nitrobenzene (0.98 g, 5.04 mmol) obtained in step B above, the title compound (0.87 g, yield: 48%) was obtained in the same manner as in step A of Preparation Example 1.

[0413] 1 H-NMR(400MHz, CDCl3)δ9.10(brs,1H),7.97(dd,1H),7.03(d,2H),6.83(dd,1H),6.52(d,2H),3.68(t,2H),3.53(t,2H),2.50(m,2H)

[0414] Step D: 6-Chloro-1-(4-(3,3-difluoropyrrolidone-1-yl)phenyl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazolium Preparation of 2-oxazolone

[0415] The title compound (0.48 g, yield: 56%) was obtained using 3-chloro-N-(4-(3,3-difluoropyrrolidone-1-yl)phenyl)-2-fluoro-6-nitroaniline (0.87 g, 2.34 mmol) obtained in step C above, in the same manner as in step B of Preparation Example 7 and Preparation Example 8.

[0416] 1 H-NMR(400MHz, CDCl3)δ8.21(brs,1H),7.32(d,2H),7.09(dd,1H),6.81(dd,1H),6.63(d,2H),3.73(t,2H),3.58(t,2H),2.52(m,2H)

[0417] Preparation Example 33: Preparation of 6-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one

[0418] 31 mL of THF and 0.74 mL of methyl iodide (1.0 g, 4.74 mmol) were added to 6-bromo-2,3-dihydro-1H-inden-1-one, and the resulting mixture was cooled to 0 °C and NaH (0.46 g, 11.3 mmol, 55 wt%, in mineral oil) was added. The reaction mixture was stirred at room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added. The resulting mixture was extracted with EtOAc. The organic layer was separated and purified by MPLC, giving the title compound (0.81 g, yield: 71%).

[0419] 1 H-NMR(400MHz, CDCl3)δ7.88(dd,1H),7.59(dd,1H),7.31(d,1H),2.94(s,2H),1.24(s,6H)

[0420] Preparation Example 34: Preparation of 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one

[0421] The title compound (1.06 g, yield: 94%) was obtained using 5-bromo-2,3-dihydro-1H-indanone (1.0 g, 4.74 mmol) in the same manner as in Preparation Example 33.

[0422] 1 H-NMR(400MHz, CDCl3)δ7.62(2H),7.52(dd,1H),2.98(s,2H),1.23(s,6H)

[0423] Preparation Example 35: Preparation of 6-chloro-1-(2-methyl-1-oxoisoindoline-5-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0424] The procedure of steps A and B below gives the title compound.

[0425] Step A: Preparation of 5-((5-chloro-2-nitrophenyl)amino)-2-methylisoindoline-1-one

[0426] 61 mL of THF and KOtBu (0.69 g, 6.17 mmol) were added to 5-amino-2-methylisoindolin-1-one (1.0 g, 6.17 mmol), and the resulting mixture was stirred at 70 °C for 30 min. 4-chloro-2-fluoro-1-nitrobenzene (1.62 g, 9.25 mmol) was added to the reaction solution, and the mixture was stirred at 70 °C for 16 h. Water was added to the reaction solution, and the solution was extracted with EtOAc. The organic layer was purified by MPLC, giving the title compound (0.307 g, yield: 15%).

[0427] 1 H-NMR(400MHz,DMSO-d6)δ9.60(brs,1H),8.18(d,1H),7.90(dd,1H),7.30(2H),7.24(d,1H),6.82(dd,1H),4.42(s,2H),3.22(s,3H)

[0428] Step B: 6-Chloro-1-(2-methyl-1-oxoisoindoline-5-yl)-1,3-dihydro-2H-benzo[d]imidazol-2- Preparation of ketones

[0429] Using the 5-((5-chloro-2-nitrophenyl)amino)-2-methylisoindoline-1-one (0.307 g, 0.97 mmol) obtained in step A above, the title compound (0.29 g, yield: 96%) was obtained in the same manner as in step B of Preparation Example 7 and step B of Preparation Example 8.

[0430] 1 H-NMR(400MHz,DMSO-d6)δ11.41(brs,1H),7.82(d,1H),7.79(d,1H),7.64(dd,1H),7.10(3H),4.55(s,2H),3.11(s,3H)

[0431] Preparation Example 36: Preparation of methyl 3-(2-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)benzoate

[0432] The procedure of steps A, B, C, and D below gives the title compound.

[0433] Step A: Preparation of methyl 3-(cyanomethyl)benzoate

[0434] 8 mL of DMSO and KCN (0.60 g, 9.17 mmol) were added to methyl 3-(bromomethyl)benzoate (2.00 g, 8.73 mmol), and the resulting mixture was stirred at room temperature for 16 hours. Water and Et2O were added to the reaction solution, and the organic layer was separated and purified by MPLC to give the title compound (0.78 g, yield: 51%).

[0435] 1 H-NMR(400MHz, CDCl3)δ8.01(2H),7.56(m,1H),7.49(m,1H),3.93(s,3H),3.81(s,2H)

[0436] Step B: Preparation of methyl 3-(2-aminoethyl)benzoate

[0437] Using methyl 3-(cyanomethyl)benzoate (0.70 g, 4.0 mmol) obtained in step A above, the title compound (0.71 g, yield: 99%) was obtained with reference to WO2016 / 165014.

[0438] 1 H-NMR(400MHz,DMSO-d6)δ7.83(2H),7.81(brs,2H),7.55(m,1H),7.52(m,1H),3.86(s,3H),3.07(m,2H),2.95(t,2H)

[0439] Step C: Preparation of methyl 3-(2-((4-chloro-2-nitrophenyl)amino)ethyl)benzoate

[0440] The title compound (0.24 g, yield: 18%) was obtained using methyl 3-(2-aminoethyl)benzoate (0.70 g, 4.0 mmol) and 4-chloro-1-fluoro-2-nitrobenzene (0.70 g, 7.0 mmol) obtained in step B above, in the same manner as in step A of Preparation Example 1.

[0441] 1 H-NMR(400MHz, CDCl3)δ8.16(d,1H),8.04(m,1H),7.93(2H),7.43(2H),7.30(dd,1H),6.82(d,1H),3.92(s,3H),3.58(m,2H),3.07(t,2H)

[0442] Step D: Methyl 3-(2-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)benzoate Preparation

[0443] The title compound (0.10 g, yield: 42%) was obtained using methyl 3-(2-((4-chloro-2-nitrophenyl)amino)ethyl)benzoate (0.24 g, 0.71 mmol) obtained in step C above, in the same manner as in step B of Preparation Example 7 and step B of Preparation Example 8.

[0444] 1 H-NMR(400MHz, CDCl3)δ9.52(brs,1H),7.88(2H),7.37(2H),7.09(d,1H),7.00(dd,1H),6.72(dd,1H),4.11(t,2H),3.91(s,3H),3.10(t,2H)

[0445] Preparation Example 37: Preparation of 2-(4-bromophenyl)-N,N-dimethylacetamide

[0446] 15 mL of DCM, dimethylamine hydrochloride (0.46 g, 5.58 mmol), EDC-HCl (0.98 g, 5.12 mmol), HOBt (0.78 g, 5.12 mmol), and DIPEA (2.03 mL, 11.6 mmol) were added to 2-(4-bromophenyl)acetic acid (1.0 g, 4.65 mmol), and the resulting mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the organic layer was separated and purified by MPLC to give the title compound (1.13 g, yield: 99%).

[0447] 1 H-NMR(400MHz, CDCl3)δ7.44(dd,2H),7.13(dd,2H),3.66(s,2H),3.00(s,3H),2.97(s,3H)

[0448] Preparation Example 38: Preparation of 1-(4-bromophenyl)azacyclobut-3-ol

[0449] 15 mL of DCM, Cu(OAc)₂ (0.54 g, 3.0 mol), and TEA (1.25 mL, 9 mmol) were added to (4-bromophenyl)boric acid (0.30 g, 1.49 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The resulting solid was removed by diatomaceous earth, and the filtrate was then purified by MPLC to give the title compound (0.11 g, yield: 31%).

[0450] 1H-NMR (400MHz, CDCl3) δ7.28(d,2H),6.33(d,2H),4.76(m,1H),4.15(t,2H),3.65(m,2H),2.08(m,1H)

[0451] Preparation Example 39: Preparation of 6-(4-bromophenyl)-2-oxa-6-azaspiro[3.3]heptane

[0452] The title compound (0.062 g, yield: 24%) was obtained using (4-bromophenyl)boronic acid (0.223 g, 1.11 mmol) and 2-oxa-6-azaspiro[3.3]heptane (0.10 g, 1 mmol) in the same manner as in Preparation Example 38.

[0453] 1 H-NMR(400MHz, CDCl3)δ7.29(dd,2H),6.32(dd,2H),4.83(s,4H),3.99(s,4H)

[0454] Preparation Example 40: Preparation of 2-(4-bromophenyl)-7-oxa-2-azaspiro[3.5]nonane

[0455] The title compound (0.15 g, yield: 22%) was obtained in the same manner as in Preparation Example 38 using (4-bromophenyl)boronic acid (0.50 g, 2.49 mmol) and 7-oxa-2-azaspiro[3.5]nonane hydrochloride (0.49 g, 2.74 mmol).

[0456] 1 H-NMR(500MHz, CDCl3)δ7.28(m,2H),6.31(m,2H),3.67(m,4H),3.62(s,4H),1.83(m,4H)

[0457] Preparation Example 41: Preparation of 3-(2-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)prop-2-yl)benzonitrile

[0458] The procedure described in steps A, B, C, D, and E below gives the title compound.

[0459] Step A: Preparation of (2-(3-bromophenyl)prop-2-yl)tert-butyl carbonate

[0460] 40 mL of THF, 1.0 mL of BOC2O, 1.7 mL of DIPEA, and a catalytic amount of DMAP were added to 2-(3-bromophenyl)prop-2-amine hydrochloride (1.0 g, 4.0 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The resulting solid was filtered off, and the filtrate was purified by MPLC to give the title compound (1.2 g, yield: 99%).

[0461] Step B: Preparation of (2-(3-cyanophenyl)prop-2-yl)tert-butyl carbonate

[0462] To the (2-(3-bromophenyl)prop-2-yl)tert-butyl carbonate (0.45 g, 1.8 mmol) obtained in step A above, 6 mL of DMF, Zn(CN)₂ (0.13 g, 0.85 mmol), and Pd(PPh₃)₄ (0.21 g, 0.18 mmol) were added, and the resulting mixture was stirred at 100 °C for 16 hours. EtOAc was added to the reaction solution, and the resulting mixture was washed with ammonia solution. The organic layer was separated and purified by MPLC, giving the title compound (0.20 g, yield: 42%).

[0463] 1 H-NMR(400MHz, CDCl3)δ7.68(d,1H),7.64(dd,1H),7.51(dd,1H),7.43(t,1H),5.06(m,1H),1.51(s,6H),1.39-1.10(9H)

[0464] Step C: Preparation of 3-(2-aminopropyl-2-yl)benzonitrile hydrochloride

[0465] 1.2 mL of DCM and 1.2 mL of HCl (4.0 M EtOAc solution) were added to (0.31 g, 1.2 mmol) tert-butyl carbonate (2-(3-cyanophenyl)prop-2-yl) carbonate obtained in step B above, and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound (0.20 g, yield: 85%).

[0466] 1 H-NMR(400MHz,DMSO-d6)δ8.76(brs,3H),7.05(d,1H),7.92(dd,1H),7.86(dd,1H),7.61(t,1H),1.65(s,6H)

[0467] Step D: Preparation of 3-(2-((4-chloro-2-nitrophenyl)amino)prop-2-yl)benzonitrile

[0468] The title compound (0.20 g, yield: 62%) was obtained using 3-(2-aminopropyl-2-yl)benzonitrile hydrochloride (0.20 g, 1 mmol) and 4-chloro-1-fluoro-2-nitrobenzene (0.18 g, 1 mmol) obtained in step C above, in the same manner as in step A of Preparation Example 1.

[0469] 1 H-NMR(400MHz, CDCl3)δ8.61(brs,1H),8.20(d,1H),7.72(m,1H),7.66(m,1H),7.58(m,1H),7.48(t,1H),7.07(dd,1H),6.13(d,1H),1.78(s,6H)

[0470] Step E: 3-(2-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)prop-2-yl)benzonitrile preparation

[0471] Using 3-(2-((4-chloro-2-nitrophenyl)amino)prop-2-yl)benzonitrile (0.20 g, 0.63 mmol) obtained in step D above, the title compound (0.12 g, yield: 64%) was obtained in the same manner as in step B of Preparation Example 7 and step B of Preparation Example 8.

[0472] 1 H-NMR(400MHz, CDCl3)δ8.23(brs,1H),7.64(d,1H),7.58(2H),7.47(t,1H),7.00(d,1H),6.74(dd,1H),6.10(dd,1H),2.08(s,6H)

[0473] Preparation Example 42: Preparation of methyl 3-((5-chloro-2-oxo-3-(4-(piperazin-1-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate hydrochloride

[0474] The procedure of steps A and B below gives the title compound.

[0475] Step A: 4-(4-(6-chloro-3-(2-fluoro-3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzene) Preparation of [d]imidazol-1-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0476] The title compound (0.72 g, yield: 99%) was obtained in the same manner as in step A of Preparation Example 1 using tert-butyl piperazine-1-carboxylate (0.52 g, 1.21 mmol) and methyl 3-(bromomethyl)-2-fluorobenzoate (0.30 g, 1.21 mmol) obtained in step C of Preparation Example 29.

[0477] 1 H-NMR (400MHz, CDCl3) δ7.88(t,1H),7.61(t,1H),7.37(d,2H),7.17(t,1H),7.06(3H),7. 00(d,1H),6.96(dd,1H),5.19(s,2H),3.94(s,3H),3.61(m,4H),3.21(m,4H),1.49(s,9H)

[0478] Step B: 3-((5-chloro-2-oxo-3-(4-(piperazin-1-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol- Preparation of methyl 1-yl)methyl)-2-fluorobenzoate hydrochloride

[0479] To the tert-butyl 4-(4-(6-chloro-3-(2-fluoro-3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)piperazine-1-carboxylate (0.71 g, 1.2 mmol) obtained in step A above, 4 mL of DCM and 1.2 mL of hydrochloric acid (4.0 M EtOAc solution) were added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure to give the title compound (0.55 g, yield: 86%).

[0480] 1 H-NMR(400MHz,DMSO-d6)δ8.86(brs,2H),7.83(td,1H),7.58(td,1H),7.43(d,2H),7.30(t, 1H),7.24(m,1H),7.18(3H),6.91(d,1H),5.22(s,2H),3.86(s,3H),3.45(m,4H),3.27(m,4H)

[0481] Preparation Example 43: Preparation of methyl 3-((5-chloro-4-fluoro-2-oxo-3-(4-(piperidin-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate hydrochloride

[0482] The title compound (0.27 g, yield: 13%) was obtained using tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (1.00 g, 3.62 mmol), 1-chloro-2,3-difluoro-4-nitrobenzene (0.70 g, 3.62 mmol), and methyl 3-(bromomethyl)-2-fluorobenzoate in the same manner as in Preparation Example 30.

[0483] 1H-NMR(400MHz,DMSO-d6)δ8.74(m,1H),8.55(m,1H),7.83(td,1H),7.61(td,1H),7.52(dd,2H),7.38(d,2H),7. 30(2H),7.13(d,1H),5.24(s,2H),3.86(s,3H),3.40(m,2H),3.04(m,2H),2.95(m,1H),2.02(m,2H),1.87(m,2H)

[0484] Preparation Example 44: Preparation of 6-chloro-1-(6-(3,3-difluoropyrrolidone-1-yl)pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0485] The procedure of steps A, B, C, and D below gives the title compound.

[0486] Step A: Preparation of 2-(3,3-difluoropyrrolidone-1-yl)-5-nitropyridine

[0487] The title compound (1.84 g, yield: 91%) was obtained using 2-fluoro-5-nitropyridine (1.26 g, 8.87 mmol) and 3,3-difluoropyrrolidine hydrochloride (1.40 g, 9.47 mmol) in the same manner as in step A of Preparation Example 1.

[0488] 1 H-NMR(400MHz,DMSO-d6)δ9.01(d,1H),8.30(dd,1H),6.68(m,1H),4.01(t,2H),3.79(m,2H),2.60(m,2H)

[0489] Step B: Preparation of 6-(3,3-difluoropyrrolidone-1-yl)pyridine-3-amine

[0490] The title compound (1.58 g, yield: 99%) was obtained using 2-(3,3-difluoropyrrolidone-1-yl)-5-nitropyridine (1.84 g, 8.03 mmol) obtained in step A above, in the same manner as in step A of Preparation Example 9.

[0491] 1 H-NMR(400MHz, CDCl3)δ7.77(d,1H),7.01(dd,1H),6.28(d,1H)3.78(t,2H),3.60(t,2H),3.27(brs,2H),2.48(m,2H)

[0492] Step C: Preparation of N-(5-chloro-2-nitrophenyl)-6-(3,3-difluoropyrrolidone-1-yl)pyridine-3-amine

[0493] 34 mL of toluene and BINAP (0.38 g, 0.60 mmol) were added to 2-bromo-4-chloronitrobenzene (1.30 g, 5.52 mmol) and 6-(3,3-difluoropyrrolidone-1-yl)pyridine-3-amine (1.0 g, 5.0 mmol) obtained in step B above, and the resulting mixture was then purged with nitrogen. Cs₂CO₃ (2.62 g, 8.0 mmol) and Pd₂(dba)₃ (0.46 g, 0.50 mmol) were added to the mixture, and the mixture was stirred at 100 °C for 16 hours. The resulting solid was removed by diatomaceous earth, and the filtrate was purified by MPLC to give the title compound (1.11 g, yield: 63%).

[0494] 1 H-NMR(400MHz, CDCl3)δ9.30(brs,1H),8.17(d,1H),8.12(dd,1H),7.41(dd,1H) ,6.80(d,1H),6.69(dd,1H),6.45(dd,1H),3.90(t,2H),3.74(t,2H),2.54(m,2H)

[0495] Step D: 6-Chloro-1-(6-(3,3-difluoropyrrolidone-1-yl)pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazolium Preparation of 2-oxazolone

[0496] The title compound (0.48 g, yield: 43%) was obtained using N-(5-chloro-2-nitrophenyl)-6-(3,3-difluoropyrrolidone-1-yl)pyridine-3-amine (1.12 g, 3.16 mmol) obtained in step C above, in the same manner as in step B of Preparation Example 7 and Step B of Preparation Example 8.

[0497] 1 H-NMR(400MHz,DMSO-d6)δ11.28(brs,1H),8.22(d,1H),7.70(dd,1H),7.07(2H),6.82(d,1H),6.71(dd,1H),3.90(t,2H),3.67(t,2H),2.56(m,2H)

[0498] Preparation Example 45: Preparation of 3-(4-(dimethylamino)phenyl)-5-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0499] The procedure of steps A and B below gives the title compound.

[0500] Step A: N 1 N 1 -dimethyl-N 4 Preparation of 1,4-(6-methyl-3-nitropyridin-2-yl)phenyl-1,4-diamine

[0501] Using 2-fluoro-6-methyl-3-nitropyridine (0.50 g, 3.2 mmol) and N1 N 1 -Dimethylphenyl-1,4-diamine (0.44 g, 3.2 mmol) was used to obtain the title compound (0.77 g, yield: 88%) in the same manner as in step A of Preparation Example 1.

[0502] 1 H-NMR (400MHz, CDCl3) δ10.15(brs,1H),8.37(d,1H),7.53(d,2H),6.76(d,2H),6.58(dd,1H),2.97(s,6H),2.48(s,3H)

[0503] Step B: 3-(4-(dimethylamino)phenyl)-5-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2- Preparation of ketones

[0504] Use N obtained in step A above 1 N 1 -dimethyl-N 4 -(6-methyl-3-nitropyridin-2-yl)phenyl-1,4-diamine (0.77 g, 2.83 mmol) was used to obtain the title compound (0.20 g, yield: 26%) in the same manner as in step B of Preparation Example 7 and Preparation Example 8.

[0505] 1 H-NMR(400MHz, CDCl3)δ8.07(d,1H),7.52(brs,1H),7.42(dd,2H),7.00(dd,1H),6.89(dd,2H),3.05(s,6H),2.50(s,3H)

[0506] Preparation Example 46: Preparation of methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclobutyl)benzoate

[0507] The procedure described in steps A, B, C, D, and E below gives the title compound.

[0508] Step A: Preparation of 3-(1-((tert-butoxycarbonyl)amino)cyclobutyl)benzoic acid

[0509] 196 mg (0.60 mmol) of tert-butyl (1-(3-bromophenyl)cyclobutyl)carbamate was dissolved in 3 mL of DMF. Oxalic acid (81.03 mg, 0.90 mmol), acetic anhydride (92 mg, 0.90 mmol), Pd(OAc)₂ (1.35 mg, 6 μmol), and Xantphos (3.47 mg, 6 μmol) were added, followed by the addition of DIPEA (116 mg, 0.90 mmol). The resulting mixture was then purged with nitrogen and stirred at 100 °C for 5 hours. After the reaction was terminated, the reaction solution was diluted with EtOAc and water, followed by the addition of 1 mL of 1 N HCl, and the organic layer was separated. The organic layer was dehydrated on anhydrous Na₂SO₄ and purified by MPLC, yielding the title compound (138 mg, yield: 79%).

[0510] 1 H NMR (500MHz, CDCl3) δ8.16(s,1H),7.99(d,1H),7.69(br s,1H),7.46(t,1H),2.61(m,2H),2.51(m,2H),2.15(m,1H),1.92(m,1H),1.38(m,9H)

[0511] Step B: Preparation of methyl 3-(1-((tert-butoxycarbonyl)amino)cyclobutyl)benzoate

[0512] The 3-(1-((tert-butoxycarbonyl)amino)cyclobutyl)benzoic acid (135 mg, 0.463 mmol) obtained in step A above was dissolved in 1 mL of DMF, and Na₂CO₃ (98 mg, 0.927 mmol) was added. Then, methyl iodoform (43.5 μL, 0.695 mmol) was added to the reaction solution, and the reaction solution was stirred at 40 °C. After the reaction was terminated, EtOAc and water were added, the organic layer was separated, and dehydrated on anhydrous MgSO₄. The filtrate was distilled under reduced pressure and then purified by MPLC to give the title compound (20 mg, yield: 61%).

[0513] 1 H NMR(500MHz,CDCl3)δ8.08(m,1H),7.91(m,1H),7.64(br s,1H),7.42(m,1H),5.19(s,1H),3.91(s,3H),2.54(m,4H),2.12(m,1H),1.87(m,1H),1.51(m,9H)

[0514] Step C: Preparation of methyl 3-(1-aminocyclobutyl)benzoate

[0515] The methyl 3-(1-((tert-butoxycarbonyl)amino)cyclobutyl)benzoate (125 mg, 0.409 mmol) obtained in step B above was dissolved in 20 mL of DCM, and 8 mL of TFA was added. The mixture was then stirred at room temperature for 3 hours. After the reaction was terminated, the reaction solution was distilled under reduced pressure to remove the TFA and solvent, and then the next step could be carried out without further purification.

[0516] Step D: Preparation of methyl 3-(1-((4-chloro-2-nitrophenyl)amino)cyclobutyl)benzoate

[0517] The title compound (77.1 mg, yield: 52%) was obtained in the same manner as in step A of Preparation Example 1, using 4-chloro-1-fluoro-2-nitrobenzene and methyl 3-(1-aminocyclobutyl)benzoate obtained in step C above.

[0518] 1 H NMR(500MHz, CDCl3)δ8.75(s,1H),8.18(s,2H),7.95(d,1H),7.63(d,1H),7.43(t, 1H),7.10(d,1H),6.16(d,1H),3.93(s,3H),2.78(m,2H),2.54(m,2H),2.24(m,2H)

[0519] Step E: Methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclobutyl)benzoate Preparation of esters

[0520] The title compound (26.9 mg, yield: 36%) was obtained using methyl 3-(1-((4-chloro-2-nitrophenyl)amino)cyclobutyl)benzoate obtained in step D above, in the same manner as in steps B and C of Preparation Example 1.

[0521] 1 H NMR(500MHz, CDCl3)δ10.39(s,1H),8.35(s,1H),7.95(d,1H),7.80(d,1H),7.43(t,1H),7 .08(s,1H),6.94(d,1H),6.81(d,1H),3.91(s,3H),3.20(m,2H),3.02(m,2H),2.07(m,2H)

[0522] Preparation Example 47: Preparation of methyl 3-(2-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)prop-2-yl)benzoate

[0523] The procedure described in steps A, B, C, D, and E below gives the title compound.

[0524] Step A: Preparation of 3-(2-((tert-butoxycarbonyl)amino)propyl-2-yl)benzoic acid

[0525] The title compound (139 mg, yield: 20%) was obtained using tert-butyl (2-(3-bromophenyl)prop-2-yl)carbamate (785 mg, 2.50 mmol) in the same manner as in step A of Preparation Example 46.

[0526] 1 H NMR(500MHz, CDCl3)δ8.14(s,1H),7.98(d,1H),7.66(d,1H),7.45(t,1H),1.65(s,6H),1.40(m,9H)

[0527] Step B: Preparation of methyl 3-(2-((tert-butoxycarbonyl)amino)prop-2-yl)benzoate

[0528] The title compound (145 mg, yield: 99%) was obtained using 3-(2-((tert-butoxycarbonyl)amino)propyl-2-yl)benzoic acid obtained in step A above, in the same manner as in step B of Preparation Example 46.

[0529] 1 H NMR (500MHz, CDCl3) δ8.07(s,1H),7.90(d,1H),7.60(d,1H),7.40(t,1H),4.99(br s,1H),3.90(s,3H),1.63(s,6H),1.39(m,9H)

[0530] Step C: Preparation of methyl 3-(2-aminopropyl-2-yl)benzoate

[0531] The title compound was obtained using methyl 3-(2-((tert-butoxycarbonyl)amino)propyl-2-yl)benzoate obtained in step B above, in the same manner as in step C of Preparation Example 46, and then the next step could be carried out without further purification.

[0532] Step D: Preparation of methyl 3-(2-((4-chloro-2-nitrophenyl)amino)prop-2-yl)benzoate

[0533] The title compound (41.6 mg, yield: 24%) was obtained in the same manner as in step A of Preparation Example 1, using 4-chloro-1-fluoro-2-nitrobenzene and methyl 3-(2-aminopropyl-2-yl)benzoate obtained in step C above.

[0534] Step E: Methyl 3-(2-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)prop-2-yl)benzoate Preparation of esters

[0535] The title compound (23.0 mg, yield: 58%) was obtained using methyl 3-(2-((4-chloro-2-nitrophenyl)amino)prop-2-yl)benzoate from step D above, in the same manner as in steps B and C of Preparation Example 1.

[0536] 1 H NMR(500MHz, CDCl3)δ9.73(s,1H),8.07(s,1H),7.98(d,1H),7.52(d,1H),7 .43(t,1H),7.01(s,1H),6.67(d,1H),6.04(d,1H),3.92(s,3H),2.10(s,6H)

[0537] Preparation Example 48: Preparation of methyl 3-((6-chloro-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzoate

[0538] The procedure of steps A and B below gives the title compound.

[0539] Step A: Preparation of methyl 3-(((5-chloro-3-nitropyridin-2-yl)amino)methyl)benzoate

[0540] Methyl 3-(aminomethyl)benzoate (775 mg, 4.69 mmol) was dissolved in THF and cooled to 0 °C. NaH (222 mg, 5.54 mmol) was slowly added, followed by stirring for 30 min. Then, 5-chloro-2-fluoro-3-nitropyridine (753 mg, 4.27 mmol) was added at 0 °C, and the resulting mixture was stirred while raising the temperature to room temperature. After the reaction was terminated, water was slowly added while stirring at 0 °C, and the organic layer was extracted with EtOAc and a saturated aqueous solution of NH4Cl, followed by dehydration on Na2SO4. The resulting solid was filtered off, and the filtrate was distilled under reduced pressure and then purified by MPLC, giving the title compound (448 mg, yield: 33%).

[0541] 1 H-NMR (500MHz, CDCl3) δ8.55(brs,1H),8.45(s,1H),8.39(s,1H),8.04(s,1H),7.98(d,1H),7.56(d,1H),7.44(s,1H),4.98(d,2H),3.93(s,3H).

[0542] Step B: 3-((6-chloro-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzoic acid Preparation of methyl ester

[0543] The title compound (45 mg, yield: 41%) was obtained using methyl 3-(((5-chloro-3-nitropyridin-2-yl)amino)methyl)benzoate (110 mg, 0.34 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 8.

[0544] 1H-NMR (500MHz, CDCl3) δ10.01(brs,1H),8.15(s,1H),8.05(s,1H),7.97(d,1H),7.67(d,1H),7.42(t,1H),7.36(s,1H),5.21(d,2H),3.92(s,3H).

[0545] Preparation Example 49: Preparation of methyl 3-(1-(2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate

[0546] The procedure of steps A and B below gives the title compound.

[0547] Step A: Preparation of methyl 3-(1-((2-nitro-4-(trifluoromethyl)phenyl)amino)cyclopropyl)benzoate

[0548] The title compound (0.86 g, yield: 94%) was obtained using 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.50 g, 2.39 mmol) and methyl 3-(1-aminocyclopropyl)benzoate hydrochloride (0.60 g, 2.63 mmol) in the same manner as in step A of Preparation Example 1.

[0549] 1 H-NMR(400MHz, CDCl3)δ8.82(brs,1H),7.50(d,1H),7.88(m,1H),7.76(d,1H) ,7.51(dd,1H),7.30(2H),7.04(dd,1H),3.91(s,3H),1.58(m,2H),1.44(m,2H)

[0550] Step B: 3-(1-(2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl) Preparation of methyl benzoate

[0551] The title compound (0.29 g, yield: 35%) was obtained using methyl 3-(1-((2-nitro-4-(trifluoromethyl)phenyl)amino)cyclopropyl)benzoate (0.85 g, 2.23 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 7 and step B of Preparation Example 8.

[0552] 1 H-NMR(400MHz, CDCl3)δ9.75(brs,1H),7.89(dd,1H),7.30(d,1H),7.35(4H),7.23(dd,1H),3.89(s,3H),1.72(m,4H)

[0553] Preparation Example 50: Preparation of methyl 3-(1-(2-oxo-5-(trifluoromethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate

[0554] The procedure of steps A and B below gives the title compound.

[0555] Step A: Preparation of methyl 3-(1-((2-nitro-4-(trifluoromethoxy)phenyl)amino)cyclopropyl)benzoate

[0556] The title compound (0.86 g, yield: 97%) was obtained using 1-fluoro-2-nitro-4-(trifluoromethoxy)benzene (0.50 g, 2.22 mmol) and methyl 3-(1-aminocyclopropyl)benzoate hydrochloride (0.55 g, 2.44 mmol) in the same manner as in step A of Preparation Example 1.

[0557] 1 H-NMR(400MHz, CDCl3)δ8.62(brs,1H),8.10(dd,1H),7.88(m,1H),7.76(d,1H) ,7.40(2H),7.21(dd,1H),6.96(dd,1H),3.90(s,3H),1.55(m,2H),1.42(m,2H)

[0558] Step B: 3-(1-(2-oxo-5-(trifluoromethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropane Preparation of methyl benzoate

[0559] The title compound (0.21 g, yield: 25%) was obtained using methyl 3-(1-((2-nitro-4-(trifluoromethoxy)phenyl)amino)cyclopropyl)benzoate (0.85 g, 2.14 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 7 and step B of Preparation Example 8.

[0560] 1 H-NMR (400MHz, CDCl3) δ8.81(brs,1H),7.89(dd,1H),7.81(d,1H),7.38(2H),7.10(d,1H),7.00(d,1H),6.95(dd,1H),3.89(s,3H),1.69(m,4H)

[0561] Preparation Example 51: Preparation of 4-(4-bromophenyl)-1,4-oxazacycloheptane

[0562] The procedure of steps A and B below gives the title compound.

[0563] Step A: Preparation of 4-(1,4-oxazacycloheptan-4-yl)aniline

[0564] The title compound (0.32 g, yield: 23%) was obtained using 1-fluoro-4-nitrobenzene (1.02 g, 7.23 mmol) and 1,4-oxazacycloheptane hydrochloride (0.10 g, 7.25 mmol) in the same manner as in step B of Preparation Example 1 and Preparation Example 7.

[0565] 1 H-NMR(400MHz,DMSO-d6)δ6.50(m,4H),4.36(brs,2H),3.66(t,2H),3.55(t,2H),3.41(t,4H),1.86(m,2H)

[0566] Step B: Preparation of 4-(4-bromophenyl)-1,4-oxazacycloheptane

[0567] Add 3.3 mL of 48% bromic acid aqueous solution to 4-(1,4-oxazacycloheptan-4-yl)aniline (0.32 g, 1.66 mmol) obtained in step A above. Then cool the resulting mixture to 0 °C. Slowly add 4 mL of NaNO2 aqueous solution (5 mmol) to the mixture and stir the resulting mixture at room temperature for 15 min. Cool the reaction solution to 0 °C, then add CuBr (0.36 g, 2.50 mmol), and then reflux and stir at 100 °C for 2 h. Cool the reaction solution to room temperature, then extract by adding NaOH aqueous solution and EtOAc, and then purify the organic layer by MPLC to give the title compound (0.14 g, yield: 33%).

[0568] 1 H-NMR (400MHz, CDCl3) δ7.27(d,2H),6.58(d,2H),3.81(m,2H),3.67(m,2H),3.58(m,4H),2.01(m,2H)

[0569] Preparation Example 52: Preparation of 2-(4-bromophenyl)-2-azaspiro[3.3]heptane

[0570] 10 mL of toluene was added to 1,4-dibromobenzene (0.50 g, 2.12 mmol), 2-azaspiro[3.3]heptane hydrochloride (0.31 g, 2.33 mmol), and BINAP (0.13 g, 0.21 mmol), and the resulting mixture was then purged with nitrogen. Pd₂(dba)₃ (0.10 g, 0.11 mmol) and Cs₂CO₃ (1.52 g, 4.66 mmol) were added to the mixture, and the mixture was stirred at 85 °C for 16 h. After cooling the reaction solution to room temperature, the resulting solid was removed by diatomaceous earth, and the filtrate was purified by MPLC to give the title compound (0.28 g, yield: 52%).

[0571] 1 H-NMR(400MHz,DMSO-d6)δ7.27(d,2H),6.35(d,2H),3.74(s,4H),2.15(t,4H),1.81(m,2H)

[0572] Preparation Example 53: Preparation of 6-chloro-7-fluoro-1-(4-morpholinophenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0573] The title compound (3.10 g, yield: 48%) was obtained using 4-morpholinoaniline (3.50 g, 19.6 mmol) and 1-chloro-2,3-difluoro-4-nitrobenzene (3.80 g, 19.6 mmol) in the same manner as in step A of Preparation Example 1, step B of Preparation Example 7 and step B of Preparation Example 8.

[0574] 1 H-NMR(400MHz,DMSO-d6)δ11.41(s,1H),7.32(m,2H),7.17(dd,1H),7.03(d,2H),6.90(dd,1H),3.77(m,4H),3.18(m,4H)

[0575] Preparation Example 54: Preparation of 6-chloro-1-(4-morpholinophenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0576] The title compound (7.2 g, yield: 98%) was obtained using 4-morpholinoaniline (4.00 g, 22.4 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (3.94 g, 22.4 mmol) in the same manner as in step A of Preparation Example 1, step B of Preparation Example 7 and step B of Preparation Example 8.

[0577] 1 H-NMR(400MHz,DMSO-d6)δ11.22(brs,1H),7.35(d,2H),7.06(4H),6.82(d,1H),3.77(m,4H),3.18(m,4H)

[0578] Preparation Example 55: 5-(bromomethyl)isocyanate Preparation of methyl 3-azole carboxylate

[0579] To 5-methyliso Methyl 3-oxazolium-3-carboxylate (2.0 g, 14.1 mmol) was added to 70 mL of CCl4, N-bromosuccinimide (3.28 g, 18.4 mmol), and azobisbutyronitrile (0.23 g, 1.41 mmol), and the resulting mixture was stirred at 70 °C for 16 hours. The solids were removed by filtration, and the filtrate was then purified by MPLC to give the title compound (1.5 g, yield: 48%).

[0580] 1 H-NMR(400MHz, CDCl3)δ6.75(s,1H),4.51(s,2H),4.00(s,3H)

[0581] Preparation Example 56: 2-(bromomethyl) Preparation of methyl 4-azole carboxylate

[0582] Use 2-methyl Methyl azole-4-carboxylate (2.0 g, 14.1 mmol) was used to obtain the title compound (1.14 g, yield: 36%) in the same manner as in Preparation Example 55.

[0583] 1 H-NMR(400MHz, CDCl3)δ8.25(s,1H),4.48(s,2H),3.93(s,3H)

[0584] Preparation Example 57: Preparation of ethyl 5-(bromomethyl)-2,3-difluorobenzoate

[0585] The procedure of steps A and B below gives the title compound.

[0586] Step A: Preparation of ethyl 2,3-difluoro-5-methylbenzoate

[0587] 23 mL of EtOH and a catalytic amount of sulfuric acid were added to 2,3-difluoro-5-methylbenzoic acid (2.0 g, 11.6 mmol), and the resulting mixture was stirred under reflux for 16 hours. The reaction solution was poured into ice water, and the resulting solid was dried to give the title compound (2.0 g, yield: 86%).

[0588] 1 H-NMR(400MHz, CDCl3)δ7.47(m,1H),7.15(m,1H),4.40(q,2H),2.34(s,3H),1.41(t,3H)

[0589] Step B: Preparation of ethyl 5-(bromomethyl)-2,3-difluorobenzoate

[0590] The title compound (1.34 g, yield: 48%) was obtained using ethyl 2,3-difluoro-5-methylbenzoate (2.0 g, 9.99 mmol) obtained in step A above, in the same manner as in Preparation Example 55.

[0591] 1 H-NMR(400MHz, CDCl3)δ7.72(m,1H),7.41(m,1H),4.43(s,2H),4.41(q,2H),1.41(t,3H)

[0592] Preparation Example 58: Preparation of ethyl 3-(bromomethyl)-2,6-difluorobenzoate

[0593] The procedure of steps A and B below gives the title compound.

[0594] Step A: Preparation of ethyl 2,6-difluoro-3-methylbenzoate

[0595] 23 mL of EtOH and a catalytic amount of sulfuric acid were added to 2,6-difluoro-3-methylbenzoic acid (2.0 g, 11.6 mmol), and the resulting mixture was stirred under reflux for 16 hours. The reaction solution was poured into ice water, and the resulting solid was dried to give the title compound (1.80 g, yield: 77%).

[0596] 1 H-NMR(500MHz, CDCl3)δ7.26(m,1H),6.86(m,1H),4.44(q,2H),2.27(s,3H),1.41(t,3H)

[0597] Step B: Preparation of ethyl 3-(bromomethyl)-2,6-difluorobenzoate

[0598] The title compound (0.56 g, yield: 22%) was obtained using ethyl 2,6-difluoro-3-methylbenzoate (1.80 g, 9.0 mmol) obtained in step A above, in the same manner as in Preparation Example 55.

[0599] 1 H-NMR(500MHz, CDCl3)δ7.48(m,1H),6.92(m,1H),4.47(s,2H),4.43(q,2H),1.40(t,3H)

[0600] Preparation Example 59: Preparation of ethyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-5-fluorobenzoate

[0601] The procedure of steps A and B below gives the title compound.

[0602] Step A: Preparation of ethyl 3-(1-aminocyclopropyl)-5-fluorobenzoate hydrochloride

[0603] 100 mL of Et₂O and 20 mL of THF were added to ethyl 3-cyano-5-fluorobenzoate (5.0 g, 25.9 mmol), and the resulting mixture was cooled to -78 °C. Ti(OiPr)₄ (10 mL, 34 mmol) and EtMgBr (3.0 M Et₂O solution, 20 mL, 60 mmol) were then slowly added. The reaction solution was stirred at room temperature for 1 hour, then cooled to 0 °C, and BF₃-Et₂O (6.6 mL, 52 mmol) was slowly added, with the reaction solution stirred at room temperature for 1 hour. After the reaction was terminated, 3 M HCl aqueous solution was slowly added, and the organic layer was extracted with EtOAc. After concentrating the organic layer, HCl (4 M EtOAc solution) was added, and the resulting solid was dried to give the title compound (2.6 g, yield: 38%).

[0604] 1 H-NMR(500MHz, CDCl3)δ9.06(brs,3H),7.89(d,1H),7.66(dd,1H),7.47(dd,1H),4.36(q,2H),1.68(m,4H),1.38(t,3H)

[0605] Step B: 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-5-fluorobenzo Preparation of ethyl acetate

[0606] The title compound (0.12 g, yield: 6%) was obtained using ethyl 3-(1-aminocyclopropyl)-5-fluorobenzoate hydrochloride (1.62 g, 6.2 mmol) and 4-chloro-1-fluoro-2-nitrobenzene (1.0 g, 5.7 mmol) obtained in step A above, in the same manner as in step A of preparation example 1, step B of preparation example 7 and step B of preparation example 8.

[0607] 1 H-NMR(400MHz, CDCl3)δ9.38(brs,1H),7.56(m,2H),7.14(d,1H),7.04(3H),4.37(q,2H),1.72(4H),1.38(t,3H)

[0608] Preparation Example 60: Preparation of 3-(4-bromophenyl)-8-oxa-3-azabicyclo[3.2.1]octane

[0609] The title compound (0.11 g, yield: 14%) was obtained using (4-bromophenyl)boronic acid (0.66 g, 3.29 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.44 g, 3 mmol) in the same manner as in Preparation Example 38.

[0610] 1 H-NMR (400MHz, CDCl3) δ7.33(d,2H),6.67(d,2H),4.48(m,2H),3.27(m,2H),2.98(m,2H),1.95(4H)

[0611] Preparation Example 61: Preparation of 1-(4-bromophenyl)-3,3-difluoroazacyclobutane

[0612] The title compound (0.42 g, yield: 80%) was obtained using 1,4-dibromobenzene (0.50 g, 2.12 mmol) and 3,3-difluoroazacyclobutane hydrochloride (0.31 g, 2.33 mmol) in the same manner as in Preparation Example 52.

[0613] 1 H-NMR(400MHz,DMSO-d6)δ7.38(d,2H),6.53(d,2H),4.25(t,4H)

[0614] Preparation Example 62: Preparation of 1-(4-bromophenyl)-4,4-difluoropiperidine

[0615] The title compound (0.075 g, yield: 18%) was obtained using (4-bromophenyl)boronic acid (0.30 g, 1.50 mmol) and 4,4-difluoropiperidine (0.22 g, 1.8 mmol) in the same manner as in Preparation Example 38.

[0616] 1 H-NMR(400MHz, CDCl3)δ7.36(d,2H),6.82(d,2H),3.32(m,4H),2.08(m,4H)

[0617] Preparation Example 63: Preparation of tert-butyl 2-(4-bromophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0618] The title compound (1.70 g, yield: 70%) was obtained using 1,4-dibromobenzene (1.50 g, 6.36 mmol) and tert-butyl 2,6-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (1.84 g, 7.00 mmol) in the same manner as in Preparation Example 52.

[0619] 1H-NMR(400MHz, CDCl3)δ7.28(d,2H),6.31(d,2H),3.59(s,4H),3.39(m,4H),1.75(m,4H),1.46(s,9H)

[0620] Preparation Example 64: Preparation of 2-(4-bromophenyl)-1-(3-hydroxyazacyclobutan-1-yl)ethyl-1-one

[0621] 2 mL of DMF, HATU (390 mg, 1.02 mmol), and TEA (0.26 mL, 1.86 mmol) were added to 2-(4-bromophenyl)acetic acid (200 mg, 0.93 mmol) and 3-hydroxyazacyclobutane hydrochloride (122 mg, 1.2 mmol), and the resulting mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the resulting mixture was extracted with EtOAc and purified by MPLC to give the title compound (150 mg, yield: 60%).

[0622] 1 H-NMR (500MHz, CDCl3) δ7.46(d,2H),7.16(d,2H),4.65(m,1H),4.32(t,1H),4.25(t,1H),4.00(dd,1H),3.88(dd,1H),3.43(s,2H),2.59(s,1H)

[0623] Preparation Example 65: Preparation of 2-(4-bromophenyl)-1-(4,4-difluoropiperidin-1-yl)ethyl-1-one

[0624] The title compound (102 mg, yield: 69%) was obtained in the same manner as in Preparation Example 64 using 2-(4-bromophenyl)acetic acid (100 mg, 0.46 mmol) and 4,4-difluoropiperidine (67 mg, 0.56 mmol).

[0625] 1 H-NMR (500MHz, CDCl3) δ7.48(d,2H),7.14(d,2H),3.76(m,2H),3.72(s,2H),3.55(m,2H),1.96(m,2H),1.79(m,2H)

[0626] Preparation Example 66: Preparation of (S)-2-(4-bromophenyl)-1-(3-methylmorpholino)ethyl-1-one

[0627] The title compound (160 mg, yield: 58%) was obtained in the same manner as in Preparation Example 64 using 2-(4-bromophenyl)acetic acid (200 mg, 0.93 mmol) and (S)-3-morpholine (113 mg, 1.11 mmol).

[0628] 1 H-NMR (500MHz, CDCl3) δ7.47(d,2H),7.14(m,2H),4.31(m,1H),3.86(m,2H),3.66(s,2H),3.60(m,1H),3.41(m,2H),3.30(m,1H),1.27(d,3H)

[0629] Preparation Example 67: Preparation of (R)-2-(4-bromophenyl)-1-(3-methylmorpholino)ethyl-1-one

[0630] The title compound (160 mg, yield: 58%) was obtained in the same manner as in Preparation Example 64 using 2-(4-bromophenyl)acetic acid (200 mg, 0.93 mmol) and (R)-3-morpholine (113 mg, 1.11 mmol).

[0631] 1 H-NMR (500MHz, CDCl3) δ7.47(d,2H),7.14(m,2H),4.30(m,1H),3.86(m,2H),3.66(s,2H),3.62(m,1H),3.38(m,2H),3.31(m,1H),1.27(d,3H)

[0632] Preparation Example 68: Preparation of (R)-2-(4-bromophenyl)-1-(2-methylmorpholino)ethyl-1-one

[0633] The title compound (162 mg, yield: 58%) was obtained in the same manner as in Preparation Example 64 using 2-(4-bromophenyl)acetic acid (200 mg, 0.93 mmol) and (R)-2-morpholine (113 mg, 1.11 mmol).

[0634] 1 H-NMR(500MHz, CDCl3)δ7.47(d,2H),7.14(d,2H),4.45(dd,1H),3.82(dd,1H),3.68(s,2H ),3.61(t,1H),3.47(m,1H),3.33(m,1H),3.19(m,1H),2.85(m,1H),2.82(s,3H),1.16(3H)

[0635] Preparation Example 69: Preparation of (S)-2-(4-bromophenyl)-1-(2-methylmorpholino)ethyl-1-one

[0636] The title compound (134 mg, yield: 48%) was obtained in the same manner as in Preparation Example 64 using 2-(4-bromophenyl)acetic acid (200 mg, 0.93 mmol) and (S)-2-morpholine (113 mg, 1.11 mmol).

[0637] 1 H-NMR(500MHz, CDCl3)δ7.47(d,2H),7.14(d,2H),4.45(dd,1H),3.82(dd,1H),3.68(s,2H ),3.61(t,1H),3.47(m,1H),3.33(m,1H),3.19(m,1H),2.85(m,1H),2.82(s,3H),1.16(3H)

[0638] Preparation Example 70: Preparation of 4-bromo-N,N-dimethylbenzenesulfonamide

[0639] 15 mL of THF, dimethylamine (0.79 mL, 1.56 mmol), and DIPEA (0.28 mL, 1.56 mmol) were added to 4-bromobenzenesulfonyl chloride (200 mg, 0.78 mmol), and the resulting mixture was stirred at room temperature. After the reaction was terminated, the solution was washed with water, and the organic layer was dried to give the title compound (196 mg, yield: 95%).

[0640] 1 H-NMR(500MHz, CDCl3)δδ7.71(d,2H),7.67(d,2H),2.73(s,6H)

[0641] Preparation Example 71: Preparation of 4-bromo-N-cyclopropylbenzenesulfonamide

[0642] The title compound (244 mg, yield: 90%) was obtained using 4-bromobenzenesulfonyl chloride (250 mg, 0.98 mmol) and cyclopropylamine (112 mg, 2.0 mmol) in the same manner as in Preparation Example 70.

[0643] 1 H-NMR(500MHz, CDCl3)δ7.80(d,2H),7.70(d,2H),4.85(brs,1H),2.28(m,1H),0.64(m,2H),0.63(m,2H)

[0644] Preparation Example 72: Preparation of 4-((4-bromophenyl)sulfonyl)morpholine

[0645] The title compound (273 mg, yield: 91%) was obtained in the same manner as in Preparation Example 70 using 4-bromobenzenesulfonyl chloride (250 mg, 0.98 mmol) and morpholine (0.34 mL, 2.0 mmol).

[0646] 1 H-NMR(500MHz, CDCl3)δ7.73(d,2H),7.64(d,2H),3.77(m,4H),3.02(m,4H)

[0647] Preparation Example 73: Preparation of 4-bromo-N-(cyclobutylmethyl)benzenesulfonamide

[0648] The title compound (140 mg, yield: 78%) was obtained using 4-bromobenzenesulfonyl chloride (150 mg, 0.59 mmol) and cyclobutylmethylamine (75 mg, 0.88 mmol) in the same manner as in Preparation Example 70.

[0649] 1 H-NMR (500MHz, CDCl3) δ7.74(d,2H),7.68(d,2H),4.41(t,1H),2.99(t,2H),2.42(m,1H),2.03(m,1H),1.91(m,1H),1.87(m,1H),1.62(m,2H)

[0650] Preparation Example 74: Preparation of 1-((4-bromophenyl)sulfonyl)piperidine

[0651] The title compound (149 mg, yield: 83%) was obtained using 4-bromobenzenesulfonyl chloride (150 mg, 0.59 mmol) and piperidine (100 mg, 1.17 mmol) in the same manner as in Preparation Example 70.

[0652] 1 H-NMR(500MHz, CDCl3)δ7.69(d,2H),7.64(d,2H),3.00(m,4H),1.66(m,4H),1.45(m,2H)

[0653] Preparation Example 75: Preparation of 1-((4-bromophenyl)sulfonyl)pyrrolidine

[0654] The title compound (114 mg, yield: 67%) was obtained using 4-bromobenzenesulfonyl chloride (150 mg, 0.59 mmol) and pyrrolidine (62.6 mg, 0.88 mmol) in the same manner as in Preparation Example 70.

[0655] 1H-NMR(500MHz, CDCl3)δ7.72(d,2H),7.69(d,2H),3.26(m,4H),1.80(m,4H)

[0656] Preparation Example 76: Preparation of methyl 3-(1-(6-chloro-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropyl)benzoate

[0657] The procedure of steps A and B below gives the title compound.

[0658] Step A: Preparation of methyl 3-(1-((5-chloro-3-nitropyridin-2-yl)amino)cyclopropyl)benzoate

[0659] The title compound (2.34 g, yield: 84%) was obtained using 5-chloro-2-fluoro-3-nitropyridine (1.56 g, 8.86 mmol) and methyl 3-(1-aminocyclopropyl)benzoate (1.54 g, 8.05 mmol) in the same manner as in step A of Preparation Example 1.

[0660] 1 H-NMR (500MHz, CDCl3) δ8.55(brs,1H),8.45(s,1H),8.39(s,1H),8.04(s,1H),7.98(d,1H),7.56(d,1H),7.44(t,1H),3.93(s,3H),1.74(m,4H).

[0661] Step B: 3-(1-(2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl) Preparation of methyl benzoate

[0662] The title compound (0.90 g, yield: 39%) was obtained using methyl 3-(1-((5-chloro-3-nitropyridin-2-yl)amino)cyclopropyl)benzoate (2.32 g, 6.68 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 7 and Step B of Preparation Example 8.

[0663] 1 H-NMR (500MHz, CDCl3) δ8.15(s,1H),8.05(s,1H),7.97(d,1H),7.67(d,1H),7.42(t,1H),7.36(m,1H),3.89(s,3H),1.72(m,4H).

[0664] Preparation Example 77: Preparation of methyl 3-(1-(6-chloro-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropyl)-2-fluorobenzoate

[0665] The title compound (0.26 g, yield: 32%) was obtained using 5-chloro-2-fluoro-3-nitropyridine (0.40 g, 2.28 mmol) and methyl 3-(1-aminocyclopropyl)-2-fluorobenzoate (0.43 g, 2.07 mmol) in the same manner as in step A of Preparation Example 1, step B of Preparation Example 7 and step B of Preparation Example 8.

[0666] 1 H-NMR (500MHz, CDCl3) δ10.10(brs,1H),8.10(s,1H),7.98(t,1H),7.84(t,1H),7.35(s,1H),7.16(t,1H),3.90(s,3H),1.73(m,4H).

[0667] Preparation Example 78: Preparation of methyl 3-(1-(6-chloro-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropyl)-5-fluorobenzoate

[0668] The procedure of steps A and B below gives the title compound.

[0669] Step A: Preparation of methyl 3-(1-aminocyclopropyl)-5-fluorobenzoate

[0670] The title compound (4.5 g, yield: 32%) was obtained using methyl 3-cyano-5-fluorobenzoate (12.0 g, 67.0 mmol) in the same manner as in steps A and B of Preparation Example 4.

[0671] 1 H-NMR (400MHz, CDCl3) δ7.73(s,1H),7.51(m,1H),7.19(m,1H),3.91(s,3H),1.69(s,2H),1.14(m,2H),1.03(m,2H)

[0672] Step B: 3-(1-(6-chloro-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)cyclopropyl)-5- Preparation of methyl fluorobenzoate

[0673] The title compound (1.1 g, yield: 81%) was obtained using 5-chloro-2-fluoro-3-nitropyridine (1.8 g, 8.6 mmol) and methyl 3-(1-aminocyclopropyl)-5-fluorobenzoate (1.6 g, 9.5 mmol) in the same manner as in step A of Preparation Example 1, step B of Preparation Example 7 and step B of Preparation Example 8.

[0674] 1H-NMR (400MHz, CDCl3) δ8.02(d,1H),7.74(m,1H),7.52(m,1H),7.32(d,1H),7.19(m,1H),3.86(s,3H),1.70(m,4H)

[0675] [Example]

[0676] Example 1: Preparation of 3-((5-chloro-2-oxo-3-phenyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0677]

[0678] The procedure of steps A and B below gives the title compound.

[0679] Step A: 3-((5-chloro-2-oxo-3-phenyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid Preparation of methyl ester

[0680] 1.5 mL of DCM was added to methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (30 mg, 0.095 mmol) obtained in step C of Preparation Example 1, followed by the addition of phenylboronic acid (23 mg, 0.189 mmol), copper(II) acetate (48 mg, 0.265 mmol), and TEA (0.04 mL, 0.284 mmol). After the reaction was terminated, a saturated aqueous solution of K₂CO₃ was added, and the resulting mixture was stirred for 20 minutes. The precipitate was removed by diatomaceous earth, and the organic layer obtained by extraction with EtOAc was washed with water. The separated organic layer was dehydrated on anhydrous MgSO₄ and distilled under reduced pressure, then purified by chromatography to give the title compound (27 mg, yield: 72%).

[0681] 1 H NMR (500MHz, CDCl3) δ8.08(brs,1H),8.01(d,1H),7.58(m,5H),7.45(m,2H),7.10(s,1H),7.04(d,1H),6.84(d,1H),5.19(s,2H),3.94(s,3H).

[0682] Step B: 3-((5-chloro-2-oxo-3-phenyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid Preparation

[0683] Methyl 3-((5-chloro-2-oxo-3-phenyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (14 mg, 0.035 mmol) was added to 1.5 mL of a mixture of THF / MeOH / water (7 / 2 / 1). LiOH (1.7 mg, 0.070 mmol) was added, and the resulting mixture was stirred at room temperature for 12 hours. At the end of the reaction, the mixture was diluted with EtOAc. The mixture was extracted with 1 N aqueous sodium hydroxide solution, and the resulting aqueous solution was adjusted to pH 3 with 1 N aqueous hydrochloric acid solution, followed by extraction with EtOAc. The separated organic layer was dehydrated on anhydrous MgSO4 and distilled under reduced pressure, then purified by chromatography to give the title compound (13 mg, yield: 98%).

[0684] 1 H NMR (400MHz, CDCl3) δ8.10(s,1H),8.03(d,1H),7.61(d,1H),7.54(m,4H),7.44(m,2H),7.08(d,1H),7.03(dd,1H),6.82(d,1H),5.18(s,2H)

[0685] Example 2: Preparation of 3-((5-chloro-2-oxo-3-(4-propylphenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0686]

[0687] The procedure of steps A and B below gives the title compound.

[0688] Step A: 3-((5-chloro-2-oxo-3-(4-propylphenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl Preparation of methyl benzoate

[0689] 6 mL of DCM was added to methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (100 mg, 0.316 mmol) obtained in Preparation Example 1, followed by the addition of (4-propylphenyl)boronic acid (104 mg, 0.631 mmol), copper(II) acetate (172 mg, 0.947 mmol), and TEA (0.132 mL, 0.947 mmol). After the reaction was terminated, a saturated aqueous solution of K₂CO₃ was added, and the resulting mixture was stirred for 20 minutes. The resulting solid was then removed by passing it through diatomaceous earth. The filtrate was washed with water, and the organic layer was separated and dehydrated on Na₂SO₄. The resulting solid was filtered off, and the filtrate was distilled under reduced pressure and then purified by MPLC to give the title compound (120 mg, yield: 87%).

[0690] MS[M+H]=435(M+1)

[0691] 1 H NMR(500MHz,CD3OD)δ8.08(s,1H),8.00(d,1H),7.59(d,1H),7.45(d,3H),7.38(d,2H),7.08(s, 1H),7.03(d,1H),6.82(d,1H),5.18(s,2H),3.94(s,3H),2.68(t,2H),1.72(m,2H),1.02(t,3H)

[0692] Step B: 3-((5-chloro-2-oxo-3-(4-propylphenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl Preparation of benzoic acid

[0693] 2 mL of THF and 2 mL of 1 N LiOH (2.00 mmol) were added to methyl 3-((5-chloro-2-oxo-3-(4-propylphenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (120 mg, 0.276 mmol) obtained in step A above. The resulting mixture was stirred at room temperature for 16 hours, and then 1 N hydrochloric acid aqueous solution was added. The organic layer was separated and dehydrated on Na2SO4. The resulting solid was removed, and the filtrate was distilled under reduced pressure to give the title compound (110 mg, yield: 95%).

[0694] MS[M+H]=421(M+1)

[0695] 1 H NMR(400MHz,DMSO-D6)δ7.93(s,1H),7.82(d,1H),7.58(d,1H),7.45(m,3H),7.36(d,2H),7 .22(d,1H),7.11(dd,1H),6.96(d,1H),5.17(s,2H),2.60(t,2H),1.61(td,2H),0.90(t,3H)

[0696] Example 3: Preparation of 3-((5-chloro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0697]

[0698] The procedure of steps A and B below gives the title compound.

[0699] Step A: 3-((5-chloro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl) Preparation of methyl benzoate

[0700] The title compound (0.090 g, yield: 99%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.070 g, 0.22 mmol) and 4-(fluorophenyl)boronic acid (0.062 g, 0.44 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0701] 1 H NMR(400MHz, CDCl3)δ8.05(s,1H),7.98(m,1H),7.58-7.50(3H),7.43(t,1H),7.26(m,2H),7.06-7.02(2H),6.82(d,1H),5.16(s,2H),3.92(s,3H)

[0702] Step B: 3-((5-chloro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl) Preparation of benzoic acid

[0703] The title compound (0.020 g, yield: 23%) was obtained using methyl 3-((5-chloro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.090 g, 0.22 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0704] 1 H NMR(500MHz, CDCl3)δ8.10(s,1H),8.04(dd,1H),7.61(d,1H),7.52(m,2H),7.46(t,1H),7.23(2H),7.04(2H),6.84(dd,1H),5.18(s,2H)

[0705] Example 4: Preparation of 3-((5-chloro-2-oxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0706]

[0707] The procedure of steps A and B below gives the title compound.

[0708] Step A: 3-((5-chloro-2-oxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazole-1- Preparation of methyl methyl benzoate

[0709] The title compound (105 mg, yield: 72%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (100 mg, 0.316 mmol) and 4-(trifluoromethyl)phenyl)boronic acid (120 mg, 0.631 mmol) obtained in Preparation Example 1 in the same manner as in step A of Preparation Example 2.

[0710] MS[M+H]=461(M+1)

[0711] 1 H NMR(400MHz,CD3OD)δδ8.04(s,1H),7.97(d,1H),7.82(d,2H),7.72(d,2H),7.55(d ,1H),7.42(t,1H),7.12(s,1H),7.06(d,1H),6.83(d,1H),5.15(s,2H),3.90(s,3H)

[0712] Step B: 3-((5-chloro-2-oxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazole-1- Preparation of methylbenzoic acid

[0713] The title compound (90 mg, yield: 88%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (105 mg, 0.228 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 2.

[0714] MS[M+H]=447(M+1)

[0715] 1 H NMR(400MHz,DMSO-D6)δ7.94(d,2H),7.91(s,1H),7.85(s,1H),7.82(d,2H),7 .60(d,1H),7.45(t,1H),7.26(d,1H),7.20(d,1H),7.16(dd,1H),5.19(s,2H)

[0716] Example 5: Preparation of 3-((5-chloro-3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0717]

[0718] The procedure of steps A and B below gives the title compound.

[0719] Step A: 3-((5-chloro-3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Preparation of methyl methyl benzoate

[0720] The title compound (73 mg, yield: 55%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (100 mg, 0.316 mmol) and 4-(methoxyphenyl)boronic acid (96 mg, 0.631 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0721] MS[M+H]=423(M+1)

[0722] 1 H NMR (400MHz, CD3OD) δ 8.04 (s, 1H), 7.96 (d, 1H), 7.55 (d, 1H), 7.42 (m, 3H), 7 .05(d,2H),7.00(d,2H),6.78(d,1H),5.14(s,2H),3.90(s,3H),3.86(s,3H)

[0723] Step B: 3-((5-chloro-3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Preparation of methylbenzoic acid

[0724] The title compound (62 mg, yield: 88%) was obtained using methyl 3-((5-chloro-3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (73 mg, 0.173 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0725] MS[M+H]=409(M+1)

[0726] 1 H NMR(400MHz,DMSO-D6)δ7.93(s,1H),7.82(dt,1H),7.58(d,1H),7.45(m,3H),7.20(d,1H),7.09(m,3H),6.89(d,1H),5.16(s,2H),3.79(s,3H)

[0727] Example 6: Preparation of 3-((3-([1,1'-biphenyl]-3-yl)-5-chloro-2-oxo-2,3-dihydro-1H-benzis[d]imidazol-1-yl)methyl)benzoic acid

[0728]

[0729] The procedure of steps A and B below gives the title compound.

[0730] Step A: 3-((3-([1,1'-biphenyl]-3-yl)-5-chloro-2-oxo-2,3-dihydro-1H-benzis[d]imidazole-1- Preparation of methyl methyl benzoate

[0731] The title compound (65 mg, yield: 44%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (100 mg, 0.316 mmol) and [1,1'-biphenyl]-3-ylboronic acid (125 mg, 0.631 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0732] MS[M+H]=469(M+1)

[0733] 1 H NMR(400MHz,CD3OD)δ8.06(s,1H),7.97(d,1H),7.75(m,1H),7.63(m,4H),7.57(d, 1H),7.45(m,5H),7.11(d,1H),7.02(dd,1H),6.81(d,1H),5.17(s,2H),3.90(s,3H)

[0734] Step B: 3-((3-([1,1'-biphenyl]-3-yl)-5-chloro-2-oxo-2,3-dihydro-1H-benzis[d]imidazole-1- Preparation of methylbenzoic acid

[0735] The title compound (62 mg, yield: 98%) was obtained using methyl 3-((3-([1,1'-biphenyl]-3-yl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (65 mg, 0.139 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0736] MS[M+H]=455(M+1)

[0737] 1 H NMR (400MHz, DMSO-D6) δ7.96(s,1H),7.83(m,2H),7.75(dt,1H),7.70(m,2H),7.65(t,1H),7.60(d ,1H),7.55(dt,1H),7.45(m,3H),7.37(m,1H),7.24(d,1H),7.14(dd,1H),7.07(d,1H),5.19(s,2H)

[0738] Example 7: Preparation of 3-((5-chloro-3-(4'-chloro-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0739]

[0740] The procedure of steps A and B below gives the title compound.

[0741] Step A: 3-((5-chloro-3-(4'-chloro-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d] Preparation of methyl imidazole-1-yl)methyl)benzoate

[0742] The title compound (66 mg, yield: 42%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (100 mg, 0.316 mmol) and (4'-chloro-[1,1'-biphenyl]-4-yl)boronic acid (147 mg, 0.631 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0743] MS[M+H]=504(M+1)

[0744] 1 H NMR(400MHz,CD3OD)δ8.05(s,1H),7.97(d,1H),7.72(d,2H),7.61(d,2H),7.55(t, 3H),7.44(t,3H),7.13(d,1H),7.02(dd,1H),6.82(d,1H),5.16(s,2H),3.91(s,3H)

[0745] Step B: 3-((5-chloro-3-(4'-chloro-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d] Preparation of imidazole-1-yl)methyl)benzoic acid

[0746] The title compound (55 mg, yield: 86%) was obtained using methyl 3-((5-chloro-3-(4'-chloro-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (66 mg, 0.131 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0747] MS[M+H]=490(M+1)

[0748] 1 H NMR(400MHz,DMSO-D6)δ7.95(s,1H),7.84(m,3H),7.75(dd,2H),7.66(dd,2H),7.59(d ,1H),7.53(dd,2H),7.45(t,1H),7.24(d,1H),7.14(dd,1H),7.08(d,1H),5.19(s,2H)

[0749] Example 8: Preparation of 3-((5-chloro-2-oxo-3-(p-tolyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0750]

[0751] The procedure of steps A and B below gives the title compound.

[0752] Step A: 3-((5-chloro-2-oxo-3-(p-tolyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl) Preparation of methyl benzoate

[0753] The title compound (86 mg, yield: 67%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (100 mg, 0.316 mmol) and p-tolylboronic acid (86 mg, 0.631 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0754] MS[M+H]=407(M+1)

[0755] 1 H NMR(400MHz,CD3OD)δδ8.07(s,1H),8.00(d,1H),7.58(d,1H),7.44(m,3H),7.37(m ,2H),7.06(s,1H),7.03(d,1H),6.82(d,1H),5.18(s,2H),3.94(s,3H),2.46(s,3H)

[0756] Step B: 3-((5-chloro-2-oxo-3-(p-tolyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl) Preparation of benzoic acid

[0757] The title compound (83 mg, yield: 100%) was obtained using methyl 3-((5-chloro-2-oxo-3-(p-tolyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (86 mg, 0.211 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0758] MS[M+H]=393(M+1)

[0759] 1 H NMR(500MHz,DMSO-D6)δ7.98(s,1H),7.87(d,1H),7.63(d,1H),7.50(d,1H),7.46(d ,2H),7.40(d,2H),7.26(d,1H),7.16(d,1H),6.98(s,1H),5.21(s,2H),2.42(d,3H)

[0760] Example 9: Preparation of 3-((3-(benzo[d][1,3]dioxacyclopenten-5-yl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0761]

[0762] The procedure of steps A and B below gives the title compound.

[0763] Step A: 3-((3-(benzo[d][1,3]dioxacyclopenten-5-yl)-5-chloro-2-oxo-2,3-dihydro-1H- Preparation of methyl benzo[d]imidazol-1-yl)methyl)benzoate

[0764] The title compound (58 mg, yield: 42%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (100 mg, 0.316 mmol) and benzo[d][1,3]dioxacyclopenten-5-ylboronic acid (105 mg, 0.631 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0765] MS[M+H]=437(M+1)

[0766] 1 H NMR(500MHz,CD3OD)δδ8.07(s,1H),8.00(d,1H),7.57(d,1H),7.45(t,1H),7.00(m,5H),6.81(d,1H),6.09(s,2H),5.17(s,2H),3.94(s,3H)

[0767] Step B: 3-((3-(benzo[d][1,3]dioxacyclopenten-5-yl)-5-chloro-2-oxo-2,3-dihydro-1H- Preparation of benzo[d]imidazol-1-yl)methyl)benzoic acid

[0768] The title compound (55 mg, yield: 99%) was obtained using methyl 3-((3-(benzo[d][1,3]dioxacyclopenten-5-yl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (58 mg, 0.132 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0769] MS[M+H]=423(M+1)

[0770] 1H NMR(500MHz,DMSO-D6)δ7.97(d,1H),7.86(m,1H),7.61(m,1H),7.53(m,1H),7.24(d,1H), 7.18(s,1H),7.15(d,1H),7.09(m,1H),7.03(d,1H),6.96(d,1H),6.14(s,2H),5.22(s,2H)

[0771] Example 10: Preparation of 3-((5-chloro-3-(4-(dimethylamino)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0772]

[0773] The procedure of steps A and B below gives the title compound.

[0774] Step A: 3-((5-chloro-3-(4-(dimethylamino)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- Preparation of methyl 1-yl)methyl)benzoate

[0775] The title compound (78 mg, yield: 57%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (100 mg, 0.316 mmol) and (4-(dimethylamino)phenyl)boronic acid (104 mg, 0.631 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0776] MS[M+H]=436(M+1)

[0777] 1 H NMR(500MHz,CD3OD)δ8.07(s,1H),7.99(d,1H),7.58(d,1H),7.44(t,1H),7.35(d, 2H),7.00(d,2H),6.85(d,2H),6.79(d,1H),5.17(s,2H),3.94(s,3H),3.04(s,6H)

[0778] Step B: 3-((5-chloro-3-(4-(dimethylamino)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- Preparation of 1-yl)methyl)benzoic acid

[0779] The title compound (69 mg, yield: 92%) was obtained using methyl 3-((5-chloro-3-(4-(dimethylamino)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (78 mg, 0.178 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0780] MS[M+H]=422(M+1)

[0781] 1 H NMR(500MHz,DMSO-D6)δ7.96(s,1H),7.87(d,1H),7.61(d,1H),7.49(m,1H), 7.33(d,2H),7.23(d,1H),7.12(d,1H),6.87(m,3H),5.20(s,2H),2.96(s,6H)

[0782] Example 11: Preparation of 3-((5-chloro-3-(4-isobutyramidophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0783]

[0784] The procedure of steps A and B below gives the title compound.

[0785] Step A: 3-((5-chloro-3-(4-isobutyramidophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- Preparation of methyl methyl benzoate

[0786] The title compound (78 mg, yield: 52%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (100 mg, 0.316 mmol) and 4-(isobutyramamidophenyl)boronic acid (131 mg, 0.631 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0787] MS[M+H]=478(M+1)

[0788] 1 H NMR(500MHz,CD3OD)δ8.07(s,1H),8.00(d,1H),7.73(d,2H),7.57(d,1H),7.48(m, 4H),7.04(d,2H),6.83(d,1H),5.18(s,2H),3.94(s,3H),2.56(m,1H),1.30(d,6H)

[0789] Step B: 3-((5-chloro-3-(4-isobutyramidophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- Preparation of methylbenzoic acid

[0790] The title compound (51 mg, yield: 67%) was obtained using methyl 3-((5-chloro-3-(4-isobutamidophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (78 mg, 0.163 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0791] MS[M+H]=464(M+1)

[0792] 1 H NMR(500MHz,DMSO-D6)δ10.08(s,1H),7.97(s,1H),7.87(d,1H),7.82(d,2H),7.62(d,1H), 7.50(d,3H),7.26(d,1H),7.15(d,1H),7.02(d,1H),5.21(s,2H),2.63(td,1H),1.14(d,6H)

[0793] Example 12: Preparation of 3-((3-(4-(tert-butyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0794]

[0795] The procedure of steps A and B below gives the title compound.

[0796] Step A: 3-((3-(4-(tert-butyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- Preparation of methyl methyl benzoate

[0797] The title compound (78 mg, yield: 92%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (60 mg, 0.189 mmol) and (4-(tert-butyl)phenyl)boronic acid (68 mg, 0.379 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0798] MS[M+H]=449(M+1)

[0799] 1 H NMR(400MHz,CD3OD)δ8.04(s,1H),7.96(d,1H),7.54(dd,3H),7.43(m,2H),7.41(m ,1H),7.07(s,1H),6.99(d,1H),6.79(d,1H),5.15(s,2H),3.90(s,3H),1.36(s,9H)

[0800] Step B: 3-((3-(4-(tert-butyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- Preparation of methylbenzoic acid

[0801] The title compound (66 mg, yield: 87%) was obtained using methyl 3-((3-(4-(tert-butyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (78 mg, 0.174 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0802] MS[M+H]=435(M+1)

[0803] 1 H NMR (400MHz, DMSO-D6) δ7.92(s,1H),7.82(d,1H),7.57(m,3H),7.45(m,3H),7.22(d,1H),7.12(dd,1H),6.98(d,1H),5.17(s,2H),1.31(s,9H)

[0804] Example 13: Preparation of 3-((5-chloro-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0805]

[0806] The procedure of steps A and B below gives the title compound.

[0807] Step A: 3-((5-chloro-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl Preparation of methyl benzoate

[0808] The title compound (131 mg, yield: 68%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (150 mg, 0.474 mmol) and (4-hydroxyphenyl)boronic acid (131 mg, 0.947 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0809] MS[M+H]=409(M+1)

[0810] 1H NMR(400MHz,CD3OD)δ8.05(s,1H),7.97(d,1H),7.55(d,1H),7.43(t,1H),7.25(d,1H),7.23(d, 1H),7.01(d,1H),6.94(d,1H),6.85(d,2H),6.81(d,1H),6.68(s,1H),5.16(s,2H),3.91(s,3H)

[0811] Step B: 3-((5-chloro-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl Preparation of benzoic acid

[0812] The title compound (40 mg, yield: 84%) was obtained using methyl 3-((5-chloro-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.122 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0813] MS[M+H]=395(M+1)

[0814] 1 H NMR(400MHz,DMSO-D6)δ9.81(s,1H),7.92(s,1H),7.82(m,1H),7.57(d,1H),7.44(t, 1H),7.30(td,2H),7.19(d,1H),7.09(dd,1H),6.89(td,2H),6.86(d,1H),5.15(s,2H)

[0815] Example 14: Preparation of 3-((5-chloro-3-(4-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0816]

[0817] The procedure of steps A and B below gives the title compound.

[0818] Step A: 3-((5-chloro-3-(4-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1- Preparation of methyl methyl benzoate

[0819] The title compound (50 mg, yield: 70%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.158 mmol) and (4-isopropoxyphenyl)boronic acid (56.8 mg, 0.316 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0820] MS[M+H]=451(M+1)

[0821] 1 H NMR(400MHz,CD3OD)δ8.03(s,1H),7.96(dd,1H),7.55(d,1H),7.39(m,3H),7.03(s ,1H),7.00(m,3H),6.78(d,1H),5.14(s,2H),4.59(m,1H),3.90(s,3H),1.37(d,6H)

[0822] Step B: 3-((5-chloro-3-(4-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1- Preparation of methylbenzoic acid

[0823] The title compound (40 mg, yield: 83%) was obtained using methyl 3-((5-chloro-3-(4-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.111 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0824] MS[M+H]=437(M+1)

[0825] 1 H NMR(500MHz,DMSO-D6)δ13.08(s,1H),7.97(s,1H),7.87(d,1H),7.63(d,1H),7.50(d,3H), 7.47(d,2H),7.27(d,1H),7.16(d,1H),7.01(s,1H),5.22(s,2H),3.00(m,1H),1.27(d,6H)

[0826] Example 15: Preparation of 3-((3-([1,1'-biphenyl]-4-yl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0827]

[0828] The procedure of steps A and B below gives the title compound.

[0829] Step A: 3-((3-([1,1'-biphenyl]-4-yl)-5-chloro-2-oxo-2,3-dihydro-1H-benzis[d]imidazole-1- Preparation of methyl methyl benzoate

[0830] The title compound (52 mg, yield: 70%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.158 mmol) and [1,1'-biphenyl]-4-ylboronic acid (62.5 mg, 0.316 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0831] MS[M+H]=469(M+1)

[0832] 1 H NMR(400MHz,CD3OD)δ8.06(s,1H),7.99(d,1H),7.75(d,2H),7.63(m,4H),7.58(d,1H),7.47(t, 2H),7.43(d,1H),7.38(d,1H),7.13(d,1H),7.02(d,1H),6.81(d,1H),5.17(s,2H),3.91(s,3H)

[0833] Step B: 3-((3-([1,1'-biphenyl]-4-yl)-5-chloro-2-oxo-2,3-dihydro-1H-benzis[d]imidazole-1- Preparation of methylbenzoic acid

[0834] The title compound (42 mg, yield: 84%) was obtained using methyl 3-((3-([1,1'-biphenyl]-4-yl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (52 mg, 0.110 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0835] MS[M+H]=455(M+1)

[0836] 1 H NMR(500MHz,DMSO-D6)δ13.08(s,1H),8.00(s,1H),7.89(m,3H),7.76(d,2H),7.70(d,2H), 7.65(d,1H),7.51(m,3H),7.42(t,1H),7.29(d,1H),7.18(d,1H),7.12(s,1H),5.24(s,2H)

[0837] Example 16: Preparation of 3-((3-(4-Butylphenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0838]

[0839] The procedure of steps A and B below gives the title compound.

[0840] Step A: 3-((3-(4-Butylphenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl Preparation of methyl benzoate

[0841] The title compound (55 mg, yield: 77%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.158 mmol) and (4-butylphenyl)boronic acid (56.2 mg, 0.316 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0842] MS[M+H]=449(M+1)

[0843] 1 H NMR(500MHz,CD3OD)δ8.07(s,1H),8.00(d,1H),7.58(d,1H),7.45(m,3H),7.37(d,2H),7.08(s,1H),7 .03(d,1H),6.82(d,1H),5.18(s,2H),3.94(s,3H),2.71(t,2H),1.67(m,2H),1.43(m,2H),0.98(t,3H)

[0844] Step B: 3-((3-(4-Butylphenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl Preparation of benzoic acid

[0845] The title compound (46 mg, yield: 87%) was obtained using methyl 3-((3-(4-butylphenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (54.6 mg, 0.122 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0846] MS[M+H]=435(M+1)

[0847] 1 H NMR(500MHz,DMSO-D6)δ13.07(s,1H),7.98(s,1H),7.87(d,1H),7.63(d,1H),7.49(t,3H),7.41(d,2H), 7.27(d,1H),7.16(d,1H),7.00(s,1H),5.22(s,2H),2.67(t,2H),1.62(m,2H),1.36(td,2H),0.93(t,3H)

[0848] Example 17: Preparation of 3-((5-chloro-3-(4-isopropylphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0849]

[0850] The procedure of steps A and B below gives the title compound.

[0851] Step A: 3-((5-chloro-3-(4-isopropylphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Preparation of methyl methyl benzoate

[0852] The title compound (55 mg, yield: 80%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.158 mmol) and (4-isopropylphenyl)boronic acid (51.8 mg, 0.316 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0853] MS[M+H]=435(M+1)

[0854] 1 H NMR(500MHz,CD3OD)δ8.07(s,1H),8.00(d,1H),7.59(d,1H),7.46(m,3H),7.42(m,2H),7 .09(s,1H),7.03(d,1H),6.82(d,1H),5.18(s,2H),3.94(s,3H),3.01(m,1H),1.33(d,6H)

[0855] Step B: 3-((5-chloro-3-(4-isopropylphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Preparation of methylbenzoic acid

[0856] The title compound (49 mg, yield: 92%) was obtained using methyl 3-((5-chloro-3-(4-isopropylphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (55 mg, 0.126 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0857] MS[M+H]=421(M+1)

[0858] 1H NMR(500MHz,DMSO-D6)δ13.08(s,1H),7.97(s,1H),7.87(d,1H),7.63(d,1H),7.50(d,3H), 7.47(d,2H),7.27(d,1H),7.16(d,1H),7.01(s,1H),5.22(s,2H),3.00(m,1H),1.27(d,6H)

[0859] Example 18: Preparation of 3-((5-chloro-3-(4-(2-hydroxypropyl-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0860]

[0861] The procedure of steps A and B below gives the title compound.

[0862] Step A: 3-((5-chloro-3-(4-(2-hydroxypropyl-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)benzoate

[0863] The title compound (52 mg, yield: 73%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.158 mmol) and (4-(2-hydroxypropyl-2-yl)phenyl)boronic acid (56.8 mg, 0.316 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0864] MS[M+H]=451(M+1)

[0865] 1 H NMR(500MHz,CD3OD)δ8.08(s,1H),8.00(d,1H),7.70(d,2H),7.59(d,1H),7.53(d,2H),7 .45(t,1H),7.10(s,1H),7.06(d,1H),6.83(d,1H),5.18(s,2H),3.93(s,3H),1.66(s,6H)

[0866] Step B: 3-((5-chloro-3-(4-(2-hydroxypropyl-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of 1-azolyl)methyl)benzoic acid

[0867] The title compound (27 mg, yield: 54%) was obtained using methyl 3-((5-chloro-3-(4-(2-hydroxypropyl-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (52 mg, 0.115 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0868] MS[M+H]=437(M+1)

[0869] 1 H NMR(500MHz,DMSO-D6)δ7.95(s,1H),7.85(d,1H),7.68(d,2H),7.57(d,1H),7.51(d ,2H),7.46(t,1H),7.26(d,1H),7.16(d,1H),7.01(s,1H),5.20(s,2H),1.49(s,6H)

[0870] Example 19: Preparation of 3-((5-chloro-3-(4-(methylsulfonamido)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0871]

[0872] The procedure of steps A and B below gives the title compound.

[0873] Step A: 3-((5-chloro-3-(4-(methylsulfonamido)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)benzoate

[0874] The title compound (25 mg, yield: 32%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.158 mmol) and (4-(methylsulfonamido)phenyl)boronic acid (67.9 mg, 0.316 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0875] MS[M+H]=486(M+1)

[0876] 1 H NMR(400MHz,DMSO-D6)δ9.98(s,1H),7.96(s,1H),7.84(d,1H),7.61(d,1H),7.51(m,2H),7.47( d,1H),7.34(d,2H),7.21(d,1H),7.12(d,1H),6.99(s,1H),5.17(s,2H),3.8(s,3H),3.04(s,3H)

[0877] Step B: 3-((5-chloro-3-(4-(methylsulfonamido)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of 1-azolyl)methyl)benzoic acid

[0878] The title compound (8 mg, yield: 33%) was obtained using methyl 3-((5-chloro-3-(4-(methylsulfonamido)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (24 mg, 0.049 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0879] MS[M+H]=472(M+1)

[0880] 1 H NMR(500MHz,DMSO-D6)δ7.94(s,1H),7.84(d,1H),7.59(m,2H),7.50(d,1H), 7.41(m,3H),7.25(d,1H),7.17(d,1H),7.05(s,1H),5.19(s,2H),3.09(s,3H)

[0881] Example 20: Preparation of 3-((5-chloro-3-(4-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0882]

[0883] The procedure of steps A and B below gives the title compound.

[0884] Step A: 3-((5-chloro-3-(4-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Preparation of methyl methyl benzoate

[0885] The title compound (49 mg, yield: 71%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.158 mmol) and (4-ethoxyphenyl)boronic acid (52.4 mg, 0.316 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0886] MS[M+H]=437(M+1)

[0887] 1 H NMR(500MHz,CD3OD)δ8.07(s,1H),8.00(d,1H),7.58(d,1H),7.43(d,3H),7.07(d, 2H),7.01(m,2H),6.81(d,1H),5.17(s,2H),4.12(q,2H),3.94(s,3H),1.48(t,3H)

[0888] Step B: 3-((5-chloro-3-(4-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Preparation of methylbenzoic acid

[0889] The title compound (41 mg, yield: 86%) was obtained using methyl 3-((5-chloro-3-(4-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (49 mg, 0.112 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0890] MS[M+H]=423(M+1)

[0891] 1 H NMR(500MHz,DMSO-D6)δ13.08(s,1H),7.98(s,1H),7.87(d,1H),7.62(d,1H),7.49(d d,3H),7.25(d,1H),7.13(m,3H),6.93(s,1H),5.21(s,2H),4.11(q,2H),1.38(t,3H)

[0892] Example 21: Preparation of 3-((5-chloro-3-(4-(dimethylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0893]

[0894] The procedure of steps A and B below gives the title compound.

[0895] Step A: 3-((5-chloro-3-(4-(dimethylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoate methyl benzoate

[0896] The title compound (52 mg, yield: 71%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.158 mmol) and (4-(dimethylcarbamoyl)phenyl)boronic acid (60.9 mg, 0.316 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0897] MS[M+H]=464(M+1)

[0898] 1H NMR(500MHz,CD3OD)δ8.08(s,1H),8.01(d,1H),7.64(m,4H),7.59(d,1H),7.46(t,1H),7 .14(s,1H),7.07(d,1H),6.86(d,1H),5.19(s,2H),3.94(s,3H),3.18(s,3H),3.08(s,4H)

[0899] Step B: 3-((5-chloro-3-(4-(dimethylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoic acid

[0900] The title compound (41 mg, yield: 83%) was obtained using methyl 3-((5-chloro-3-(4-(dimethylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (51 mg, 0.110 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0901] MS[M+H]=450(M+1)

[0902] 1 H NMR(500MHz,DMSO-D6)δ13.08(s,1H),7.99(s,1H),7.87(d,1H),7.64(m,5H), 7.50(t,1H),7.29(d,1H),7.19(d,1H),7.16(s,1H),5.23(s,2H),3.01(d,6H)

[0903] Example 22: Preparation of 3-((5-chloro-3-(4-(methylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0904]

[0905] The procedure of steps A and B below gives the title compound.

[0906] Step A: 3-((5-chloro-3-(4-(methylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of methyl imidazole-1-yl)methyl)benzoate

[0907] The title compound (55 mg, yield: 77%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.158 mmol) and (4-(methylcarbamoyl)phenyl)boronic acid (56.5 mg, 0.316 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0908] MS[M+H]=450(M+1)

[0909] 1 H NMR(500MHz,CD3OD)δ8.07(s,1H),8.01(d,1H),7.98(d,2H),7.68(d,2H),7.58(d,1H),7.46(t, 1H),7.15(s,1H),7.08(d,1H),6.86(d,1H),6.23(d,1H),5.19(s,2H),3.94(s,3H),3.08(d,3H)

[0910] Step B: 3-((5-chloro-3-(4-(methylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of imidazole-1-yl)methyl)benzoic acid

[0911] The title compound (46 mg, yield: 85%) was obtained using methyl 3-((5-chloro-3-(4-(methylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (55 mg, 0.122 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0912] MS[M+H]=436(M+1)

[0913] 1 H NMR(500MHz,DMSO-D6)δ13.07(s,1H),8.59(s,1H),8.03(d,2H),7.99(s,1H),7.87(d,1H),7.72( d,2H),7.64(d,1H),7.50(t,1H),7.29(d,1H),7.19(d,1H),7.14(s,1H),5.23(s,2H),2.83(d,3H)

[0914] Example 23: Preparation of 3-((5-chloro-2-oxo-3-(4-(((2,2,2-trifluoroethyl)carbamoyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0915]

[0916] The procedure of steps A and B below gives the title compound.

[0917] Step A: 3-((5-chloro-2-oxo-3-(4-((2,2,2-trifluoroethyl)carbamoyl)phenyl)-2,3-di Preparation of methyl 1H-benzo[d]imidazol-1-yl)methyl)benzoate

[0918] The title compound (75 mg, yield: 92%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.158 mmol) and (4-((2,2,2-trifluoroethyl)carbamoyl)phenyl)boronic acid (78 mg, 0.316 mmol) obtained in Preparation Example 1, in the same manner as in step A of Example 2.

[0919] MS[M+H]=518(M+1)

[0920] 1 H NMR(500MHz,CD3OD)δ8.09(s,1H),8.03(m,3H),7.73(m,2H),7.59(d,1H),7.48(t,1H),7 .16(s,1H),7.09(d,1H),6.88(t,1H),6.55(s,1H),5.20(s,2H),4.19(m,2H),3.92(s,3H)

[0921] Step B: 3-((5-chloro-2-oxo-3-(4-((2,2,2-trifluoroethyl)carbamoyl)phenyl)-2,3-di Preparation of hydrogen-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0922] The title compound (44 mg, yield: 81%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-(((2,2,2-trifluoroethyl)carbamoyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (55 mg, 0.106 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0923] MS[M+H]=504(M+1)

[0924] 1 H NMR(500MHz,DMSO-D6)δ9.27(t,1H),8.10(d,2H),7.96(s,1H),7.85(d,1H),7.75(d ,2H),7.55(d,1H),7.43(t,1H),7.27(d,1H),7.18(m,2H),5.21(s,2H),4.14(m,2H)

[0925] Example 24: Preparation of 3-((5-chloro-4-fluoro-3-(4-morpholinophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0926]

[0927] The procedure of steps A and B below gives the title compound.

[0928] Step A: 3-((5-chloro-4-fluoro-3-(4-morpholinophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol- Preparation of methyl 1-yl)methyl)benzoate

[0929] 6-Chloro-7-fluoro-1-(4-morpholinophenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.99 g, 2.85 mmol) and methyl 3-(bromomethyl)benzoate (0.65 g, 2.85 mmol) obtained in Preparative Example 11 were dissolved in 15 mL of AN, and then K2CO3 (0.78 g, 5.68 mmol) was added. The mixture was then stirred at 70 °C for 16 hours. After the reaction was terminated, the resulting solid was filtered off, and the filtrate was purified by MPLC to give the title compound (0.90 g, yield: 64%).

[0930] 1 H-NMR(400MHz,DMSO-d6)δ8.01(d,1H),7.89(dd,1H),7.65(dd,1H),7.53(t,1H),7.39(d,2H) ,7.22(dd,1H),7.10(d,1H),7.05(d,2H),5.21(s,2H),3.85(s,3H),3.77(m,4H),3.19(m,4H)

[0931] Step B: 3-((5-chloro-4-fluoro-3-(4-morpholinophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol- Preparation of 1-yl)methyl)benzoic acid

[0932] Methyl 3-((5-chloro-4-fluoro-3-(4-morpholinophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.90 g, 1.8 mmol) obtained in step A above was added to 30 mL of EtOH, 10 mL of THF, and 5.4 mL of 1N NaOH aqueous solution, and the resulting mixture was stirred at room temperature for 16 hours. After the reaction was terminated, the reaction solution was concentrated under reduced pressure and adjusted to pH 3 with 1N hydrochloric acid aqueous solution. The precipitated solid was filtered off and then dried to give the title compound (0.84 g, yield: 96%).

[0933] MS[M+H]=482(M+1)

[0934] 1 H-NMR(400MHz,DMSO-d6)δ7.94(d,1H),7.84(dd,1H),7.55(dd,1H),7.40(t,1H),7.37 (d,2H),7.24(dd,1H),7.08(d,1H),7.05(d,2H),5.18(s,2H),3.77(m,4H),3.19(m,4H)

[0935] Example 25: Preparation of 3-((5-chloro-3-(4-(dimethylamino)phenyl)-4-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0936]

[0937] The procedure of steps A and B below gives the title compound.

[0938] Step A: 3-((5-chloro-3-(4-(dimethylamino)phenyl)-4-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of methyl imidazole-1-yl)methyl)benzoate

[0939] The title compound (3.93 g, yield: 81%) was obtained using 6-chloro-1-(4-(dimethylamino)phenyl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (3.25 g, 10.6 mmol) and methyl 3-(bromomethyl)benzoate (2.43 g, 10.6 mmol) obtained in Preparation Example 8 in the same manner as in step A of Example 24.

[0940] 1 H-NMR(400MHz,DMSO-d6)δ8.00(d,1H),7.89(dd,1H),7.63(dd,1H),7.52(t,1H),7.33 (d,2H),7.24(dd,1H),7.10(d,1H),6.80(d,2H),5.21(s,2H),3.85(s,3H),2.97(s,6H)

[0941] Step B: 3-((5-chloro-3-(4-(dimethylamino)phenyl)-4-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of imidazole-1-yl)methyl)benzoic acid

[0942] The title compound (2.26 g, yield: 64%) was obtained using methyl 3-((5-chloro-3-(4-(dimethylamino)phenyl)-4-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (3.62 g, 7.98 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[0943] MS[M+H]=440(M+1)

[0944] 1H-NMR(400MHz,DMSO-d6)δ7.97(d,1H),7.86(dd,1H),7.50(dd,1H),7.48(t,1H) ,7.31(d,2H),7.22(dd,1H),7.20(d,1H),6.80(d,2H),5.20(s,2H),2.97(s,6H)

[0945] Example 26: Preparation of 3-((5-chloro-2-oxo-3-(4-(((2,2,2-trifluoroethyl)sulfonamido)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0946]

[0947] The procedure of steps A, B, C, and D below gives the title compound.

[0948] Step A: 3-((5-chloro-3-(4-nitrophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl Preparation of methyl benzoate

[0949] The title compound (0.22 g, yield: 99%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.157 g, 0.496 mmol) and (4-nitrophenyl)boronic acid (0.165 g, 0.991 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[0950] 1 H-NMR(400MHz, CDCl3)δ8.43(d,2H),8.05(d,1H),8.00(dd,1H),7.84(d,2H),7.56(d d,1H),7.46(t,1H),7.20(d,1H),7.10(dd,1H),6.87(d,1H),5.17(s,2H),3.92(s,3H)

[0951] Step B: 3-((3-(4-aminophenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl Preparation of methyl benzoate

[0952] The title compound (0.19 g, yield: 95%) was obtained using methyl 3-((5-chloro-3-(4-nitrophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.22 g, 0.50 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 7.

[0953] 1H-NMR(400MHz, CDCl3)δ8.05(d,1H),7.97(dd,1H),7.55(dd,1H),7.42(t,1H),7.26( d,2H),7.00(2H),6.81(d,2H),6.77(d,1H),5.15(s,2H),3.92(s,3H),3.85(brs,2H)

[0954] Step C: 3-((5-chloro-2-oxo-3-(4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-2,3-dihydro- Preparation of methyl 1H-benzo[d]imidazol-1-yl)methyl)benzoate

[0955] Methyl 3-((3-(4-aminophenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.086 g, 0.21 mmol) obtained in step B above was dissolved in 2 mL of DCM, then cooled to 0 °C, and 2,2,2-trifluoroethane-1-sulfonyl chloride (0.046 g, 0.25 mmol) and DIPEA (0.037 mL, 0.21 mmol) were added sequentially, followed by stirring for 1 hour. After the reaction was terminated, water and DCM were added, and the organic layer was separated. The organic layer was dehydrated and then purified by MPLC, giving the title compound (0.01 g, yield: 9%).

[0956] 1 H-NMR(400MHz, CDCl3)δ8.16(d,1H),8.00(dd,1H),7.57(3H),7.44(3H),7.07(2H),7.00(dd,1H),5.17(s,2H),3.92(s,3H),3.86(q,2H)

[0957] Step D: 3-((5-chloro-2-oxo-3-(4-((2,2,2-trifluoroethyl)sulfonamido)phenyl)-2,3-dihydro- Preparation of 1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0958] The title compound (0.007 g, yield: 77%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-(((2,2,2-trifluoroethyl)sulfonamido)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.01 g, 0.018 mmol) obtained in step C above, in the same manner as in step B of Example 24.

[0959] 1 H-NMR(400MHz, CDCl3)δ8.17(d,1H),8.03(dd,1H),7.61(2H),7.45(3H),7.08(2H),6.85(dd,1H),5.18(s,2H),4.13(q,3H)

[0960] Example 27: Preparation of 3-((5-chloro-3-(4-(cyclobutylmethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0961]

[0962] The procedure of steps A and B below gives the title compound.

[0963] Step A: 3-((5-chloro-3-(4-(cyclobutylmethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)benzoate

[0964] 2 mL of DMF was added to methyl 3-((5-chloro-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.122 mmol) obtained in step A of Example 13, followed by the addition of (bromomethyl)cyclobutane (36.5 mg, 0.245 mmol) and K₂CO₃ (33.8 mg, 0.245 mmol), and the resulting mixture was stirred at 80 °C for 16 hours. The resulting solid was filtered off, and the filtrate was then purified by MPLC to give the title compound (41 mg, yield: 70%).

[0965] MS[M+H]=477(M+1)

[0966] 1 H NMR(500MHz,CD3OD)δ8.07(s,1H),8.00(d,1H),7.58(d,1H),7.44(m,3H),7.08(d,2H),7.02(m, 2H),6.81(d,1H),5.18(s,2H),4.01(d,2H),3.94(s,3H),2.84(m,1H),2.21(m,2H),1.99(m,4H)

[0967] Step B: 3-((5-chloro-3-(4-(cyclobutylmethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of 1-azolyl)methyl)benzoic acid

[0968] The title compound (35 mg, yield: 88%) was obtained using methyl 3-((5-chloro-3-(4-(cyclobutylmethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (41 mg, 0.086 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[0969] MS[M+H]=463(M+1)

[0970] 1H NMR(500MHz,DMSO-D6)δ13.02(s,1H),7.98(s,1H),7.87(d,1H),7.63(d,1H),7.47(m,3H),7.25( d,1H),7.12(m,3H),6.93(d,1H),5.21(s,2H),4.03(d,2H),2.76(m,1H),2.13(m,2H),1.92(m,4H)

[0971] Example 28: Preparation of 3-((5-chloro-2-oxo-3-(4-(2-oxopiperidin-1-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0972]

[0973] The procedure of steps A and B below gives the title compound.

[0974] Step A: 3-((5-chloro-2-oxo-3-(4-(2-oxopiperidin-1-yl)phenyl)-2,3-dihydro-1H-benzo[d] Preparation of methyl imidazole-1-yl)methyl)benzoate

[0975] The title compound (0.055 g, 32% yield) was obtained using 1-(4-((5-chloro-2-nitrophenyl)amino)phenyl)piperidin-2-one (0.12 g, 0.35 mmol) obtained in Preparation Example 16 in the same manner as in step B of Preparation Example 8 and step A of Example 24.

[0976] 1 H-NMR(400MHz, CDCl3)δ8.05(d,1H),7.98(dd,1H),7.58(d,2H),7.55(dd,1H),7.47(d,2H),7.42(dd,1H), 7.16(d,1H),7.03(dd,1H),6.81(d,1H),5.16(s,2H),3.92(s,2H),3.73(m,2H),2.611(m,2H),1.99(m,4H)

[0977] Step B: 3-((5-chloro-2-oxo-3-(4-(2-oxopiperidin-1-yl)phenyl)-2,3-dihydro-1H-benzo[d] Preparation of imidazole-1-yl)methyl)benzoic acid

[0978] The title compound (0.020 g, yield: 37%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-(2-oxopiperidin-1-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.055 g, 0.11 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[0979] MS[M+H]=476(M+1)

[0980] 1 H-NMR(400MHz, CDCl3)δ8.09(d,1H),8.02(dd,1H),7.59(3H),7.47(d,2H),7.45(t,1H),7 .16(d,1H),7.03(dd,1H),6.82(d,1H),5.16(s,2H),3.71(m,2H),2.63(m,2H),1.99(m,4H)

[0981] Example 29: Preparation of 3-((5-chloro-2-oxo-3-(4-(pyrrolidin-1-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0982]

[0983] The procedure of steps A, B, and C below gives the title compound.

[0984] Step A: 3-((5-chloro-2-oxo-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-2,3-dihydro-1H- Preparation of methyl benzo[d]imidazol-1-yl)methyl)benzoate

[0985] 3 mL of toluene was added to methyl 3-((5-chloro-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (70 mg, 0.171 mmol) obtained in step A of Example 13, followed by the addition of TEA (26.0 mg, 0.257 mmol) and trifluoromethanesulfonic anhydride (72.5 mg, 0.257 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was terminated, water was added, and the organic layer was separated and dehydrated on Na2SO4. The resulting solid was filtered off, and the filtrate was distilled under reduced pressure and then purified by MPLC to give the title compound (82 mg, yield: 89%).

[0986] MS[M+H]=541(M+1)

[0987] Step B: 3-((5-chloro-2-oxo-3-(4-(pyrrolidone-1-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)benzoate

[0988] Toluene was added to methyl 3-((5-chloro-2-oxo-3-(4-((((trifluoromethyl)sulfonyl)oxy)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (80 mg, 0.148 mmol) obtained in step A, followed by the addition of pyrrolidine (12.6 mg, 0.177 mmol), Cs₂CO₃ (72.3 mg, 0.222 mmol), Xantphos (17.1 mg, 0.030 mmol), and Pd₂(dba)₃ (27.1 mg, 0.030 mmol). The resulting mixture was stirred at 95 °C for 16 hours. After the reaction was terminated, the solid was filtered off, and the filtrate was purified by MPLC to give the title compound (39 mg, yield: 57%).

[0989] MS[M+H]=462(M+1)

[0990] 1 H NMR(500MHz,CD3OD)δ8.07(s,1H),7.99(d,1H),7.58(d,1H),7.45(t,1H),7.32(d,2H),6 .98(s,2H),6.78(d,1H),6.68(d,2H),5.17(s,2H),3.94(s,3H),3.36(m,4H),2.07(m,4H)

[0991] Step C: 3-((5-chloro-2-oxo-3-(4-(pyrrolidone-1-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of 1-azolyl)methyl)benzoic acid

[0992] The title compound (12 mg, yield: 33%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-(pyrrolidone-1-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (38 mg, 0.082 mmol) obtained in step B above, in the same manner as in step B of Example 2.

[0993] MS[M+H]=448(M+1)

[0994] 1 H NMR(500MHz,DMSO-D6)δ7.96(s,1H),7.87(d,1H),7.62(d,1H),7.50(d,1H),7.30(d,2H), 7.23(d,1H),7.12(d,1H),6.84(s,1H),6.68(d,2H),5.20(s,2H),3.30(m,4H),2.00(m,4H)

[0995] Example 30: Preparation of 3-((5-chloro-3-(4-(cyclobutylmethoxy)-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0996]

[0997] The procedure of steps A, B, and C below gives the title compound.

[0998] Step A: 3-((5-chloro-3-(3-fluoro-4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- Preparation of methyl methyl benzoate

[0999] The title compound (77 mg, yield: 58%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (99 mg, 0.311 mmol) and (3-fluoro-4-hydroxyphenyl)boronic acid (97 mg, 0.622 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[1000] MS[M+H]=427(M+1)

[1001] 1 H NMR(500MHz,CD3OD)δ8.08(s,1H),8.01(d,1H),7.58(d,1H),7.47(t,1H),7.28(d,4H),7.19(d, 1H),7.12(t,1H),7.06(d,1H),7.03(s,1H),6.85(d,1H),6.11(s,1H),5.19(s,2H),3.94(d,3H)

[1002] Step B: 3-((5-chloro-3-(4-(cyclobutylmethoxy)-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoate methyl benzoate

[1003] 2 mL of DMF was added to methyl 3-((5-chloro-3-(3-fluoro-4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (40 mg, 0.094 mmol) obtained in step A above, followed by the addition of (bromomethyl)cyclobutane (27.9 mg, 0.187 mmol) and K₂CO₃ (25.9 mg, 0.187 mmol), and the resulting mixture was stirred at 80 °C for 16 hours. The resulting solid was filtered off, and the filtrate was purified by MPLC to give the title compound (39 mg, yield: 83%).

[1004] MS[M+H]=495(M+1)

[1005] 1H NMR(500MHz,CD3OD)δ8.03(s,1H),7.97(d,1H),7.55(d,1H),7.41(t,1H),7.30(m,1H),7.24(m,1H),7.21(d,1H),7 .09(t,1H),7.01(m,2H),6.79(d,1H),5.13(s,2H),4.05(d,2H),3.90(s,3H),2.84(m,1H),2.17(m,2H),1.93(m,4H)

[1006] Step C: 3-((5-chloro-3-(4-(cyclobutylmethoxy)-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoic acid

[1007] The title compound (32 mg, yield: 80%) was obtained using methyl 3-((5-chloro-3-(4-(cyclobutylmethoxy)-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (41 mg, 0.083 mmol) obtained in step B above, in the same manner as in step B of Example 2.

[1008] MS[M+H]=481(M+1)

[1009] 1 H NMR (500MHz, DMSO-D6) δ13.05(s,1H),7.99(s,1H),7.87(d,1H),7.62(d,1H),7.53(d,1H),7.49(t,1H),7.36( m,2H),7.25(d,1H),7.16(d,1H),7.03(s,1H),5.20(s,2H),4.12(d,2H),2.78(m,1H),2.10(m,2H),1.90(m,4H)

[1010] Example 31: Preparation of 3-(1-(5-chloro-2-oxo-3-(4-propylphenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoic acid

[1011]

[1012] The title compound (32 mg, yield: 47%) was obtained using methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)chloropropyl)benzoate (52 mg, 0.152 mmol) and (4-propylphenyl)boronic acid, obtained in Preparation Example 3, in the same manner as in steps A and B of Example 1.

[1013] 1H NMR(400MHz,MeOD)δ7.82(m,2H),7.35(m,6H),7.23(m,1H),7.12(m,1H),6.96(m,1H),2.67(m,2H),1.70(m,6H),0.97(t,3H)

[1014] Example 32: Preparation of 3-((5-chloro-2-oxo-3-phenyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-4-fluorobenzoic acid

[1015]

[1016] The title compound (25 mg, yield: 51%) was obtained using 6-chloro-1-phenyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (30 mg, 0.123 mmol) and methyl 3-(bromomethyl)-4-fluorobenzoate obtained in Preparation Example 5, in the same manner as in step A of Preparation Example 21 and step B of Example 1.

[1017] 1 H NMR (400MHz, MeOD) δ7.99(m,2H),7.54(m,5H),7.21(t,1H),7.10(m,2H),7.00(m,1H),5.25(s,2H).

[1018] Example 33: Preparation of 3-((5-chloro-2-oxo-3-phenyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1019]

[1020] The title compound (21 mg, yield: 43%) was obtained using 6-chloro-1-phenyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (30 mg, 0.123 mmol) and methyl 3-(aminomethyl)-2-fluorobenzoate obtained in Preparation Example 5, in the same manner as in step A of Preparation Example 21 and step B of Example 1.

[1021] 1 H NMR (400MHz, MeOD) δ7.84(t,1H),7.56(m,2H),7.50(m,4H),7.21(t,1H),7.12(m,2H),7.00(m,1H),5.25(s,2H).

[1022] Example 34: Preparation of 3-((5-chloro-2-oxo-3-phenyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-5-fluorobenzoic acid

[1023]

[1024] The title compound (13 mg, yield: 27%) was obtained using 6-chloro-1-phenyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (30 mg, 0.123 mmol) and methyl 3-(bromomethyl)-5-fluorobenzoate obtained in Preparation Example 5, in the same manner as in step A of Preparation Example 21 and step B of Example 1.

[1025] 1 H NMR (400MHz, MeOD) δ7.83(t,1H),7.56(m,6H),7.32(m,1H),7.11(m,2H),7.04(m,1H),5.21(s,2H).

[1026] Example 35: Preparation of 5-((5-chloro-2-oxo-3-phenyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1027]

[1028] The title compound (31 mg, yield: 64%) was obtained using 6-chloro-1-phenyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (30 mg, 0.123 mmol) and methyl 5-(bromomethyl)-2-fluorobenzoate in the same manner as in step A of Preparation Example 21 and step B of Example 1.

[1029] 1 H NMR(400MHz,MeOD)δ7.93(t,1H),7.54(m,6H),7.17(m,1H),7.11(m,2H),7.00(m,1H),5.17(s,2H)

[1030] Example 36: Preparation of 3-((5-chloro-3-(4-(dimethylcarbamoyl)-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1031]

[1032] The procedure of steps A, B, and C below gives the title compound.

[1033] Step A: 3-((5-chloro-3-(3-fluoro-4-(methylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzene) Preparation of [d]imidazol-1-yl)methyl)benzoate

[1034] The title compound (55 mg, yield: 75%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.158 mmol) and (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (62.2 mg, 0.316 mmol) obtained in Preparation Example 1, in the same manner as in step A of Example 2.

[1035] MS[M+H]=468(M+1)

[1036] 1 H NMR(500MHz,CD3OD)δ8.18(t,1H),8.07(s,1H),8.02(d,1H),7.58(d,1H),7.51(m,2H),7 .47(d,1H),7.23(s,1H),7.11(d,1H),6.88(d,1H),5.18(s,2H),4.00(s,3H),3.94(s,3H)

[1037] Step B: 3-((5-chloro-3-(4-(dimethylcarbamoyl)-3-fluorophenyl)-2-oxo-2,3-dihydro-1H- Preparation of methyl benzo[d]imidazol-1-yl)methyl)benzoate

[1038] 2 mL of THF was added to methyl 3-((5-chloro-3-(3-fluoro-4-(methylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (55 mg, 0.118 mmol) obtained in step A above, followed by the addition of NaOH (7.05 mg, 0.294 mmol) at 0 °C and stirring for 30 min. Iodimethane (25.0 mg, 0.176 mmol) was then added, and the resulting mixture was stirred at room temperature for 16 h. After the reaction was terminated, water was added, the organic layer was separated, and dehydrated on Na₂SO₄. The resulting solid was removed, and the filtrate was distilled under reduced pressure and then separated by MPLC, giving the title compound (29 mg, yield: 51%).

[1039] MS[M+H]=482(M+1)

[1040] 1 H NMR(500MHz,CD3OD)δ8.07(s,1H),8.01(d,1H),7.62(t,1H),7.58(d,1H),7.48(m,2H),7.43(d, 1H),7.18(s,1H),7.09(d,1H),6.86(d,1H),5.18(s,2H),3.94(s,3H),3.19(s,3H),3.04(s,3H)

[1041] Step C: 3-((5-chloro-3-(4-(dimethylcarbamoyl)-3-fluorophenyl)-2-oxo-2,3-dihydro-1H- Preparation of benzo[d]imidazol-1-yl)methyl)benzoic acid

[1042] The title compound (18 mg, yield: 64%) was obtained using methyl 3-((5-chloro-3-(4-(dimethylcarbamoyl)-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (29 mg, 0.060 mmol) obtained in step B above, in the same manner as in step B of Example 2.

[1043] MS[M+H]=468(M+1)

[1044] 1 H NMR(500MHz,DMSO-D6)δ7.99(s,1H),7.87(d,1H),7.63(m,3H),7.56(d,1H), 7.50(t,1H),7.27(m,2H),7.20(d,1H),5.22(s,2H),3.04(s,3H),2.93(s,3H)

[1045] Example 37: Preparation of 3-((6-chloro-3-(4-(dimethylamino)phenyl)-4-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1046]

[1047] The title compound (0.020 g, yield: 28%) was obtained using 5-chloro-1-(4-(dimethylamino)phenyl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.050 g, 0.16 mmol) and methyl 3-(bromomethyl)benzoate (0.037 g, 0.16 mmol) obtained in Preparation Example 27 in the same manner as in steps A and B of Example 24.

[1048] MS[M+H]=440(M+1)

[1049] 1 H-NMR (400MHz, CDCl3) δ8.05(2H),7.60(dd,1H),7.48(t,1H),7.32(d,2H),6.85(dd,1H),6.78(d,2H),6.71(d,1H),5.15(s,2H),3.01(s,6H)

[1050] Example 38: Preparation of 3-((5-chloro-3-(4-(dimethylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1051]

[1052] The title compound (43 mg, yield: 62%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (50 mg, 0.149 mmol) and (4-dimethylcarbamoyl)phenyl)boronic acid, obtained in step C of Preparation Example 2, in the same manner as in steps A and B of Example 1.

[1053] 1 H NMR(500MHz,MeOD)δ8.27(m,1H),7.89(m,1H),7.72(m,3H),7.57(m,1H),7.22(m,4H),5.30(s,2H),3.10(d,6H)

[1054] Example 39: Preparation of 3-((5-chloro-3-(4-(dimethylamino)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1055]

[1056] The title compound (39 mg, yield: 60%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (50 mg, 0.149 mmol) and (4-dimethylamino)phenyl)boronic acid, obtained in step C of Preparation Example 2, in the same manner as in steps A and B of Example 1.

[1057] 1 H NMR(500MHz,MeOD)δ7.90(t,1H),7.55(t,1H),7.26(m,3H),7.13(m,2H),6.93(m,3H),5.28(s,2H),3.04(s,6H)

[1058] Example 40: Preparation of 3-((5-chloro-3-(4-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1059]

[1060] The title compound (35 mg, yield: 52%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (50 mg, 0.149 mmol) and (4-isopropoxyphenyl)boronic acid, obtained in step C of Preparation Example 2, in the same manner as in steps A and B of Example 1.

[1061] 1 H NMR (500MHz, MeOD) δ7.90(t,1H),7.56(t,1H),7.42(d,2H),7.25(t,1H),7.12(m,4H),6.97(s,1H),5.28(s,2H),4.71(m,1H),1.38(d,6H).

[1062] Example 41: Preparation of 3-((5-chloro-3-(4-(methylsulfonamido)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1063]

[1064] The title compound (31 mg, yield: 43%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (50 mg, 0.149 mmol) and 4-(methylsulfonamido)phenyl)boronic acid, obtained in step C of Preparation Example 2, in the same manner as in steps A and B of Example 1.

[1065] 1 H NMR(500MHz,MeOD)δ7.90(t,1H),7.53(m,5H),7.25(t,1H),7.15(m,2H),7.05(s,1H),5.28(s,2H),3.07(s,3H)

[1066] Example 42: Preparation of 3-((5-chloro-3-(4-(cyclopropylmethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1067]

[1068] The procedure of steps A and B below gives the title compound.

[1069] Step A: 3-((5-chloro-3-(4-(cyclopropylmethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)benzoate

[1070] The title compound (47 mg, yield: 59%) was obtained in the same manner as in step A of Example 27 using methyl 3-((5-chloro-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (70 mg, 0.171 mmol) and (bromomethyl)cyclopropane (46.2 mg, 0.342 mmol) obtained in step A of Example 13.

[1071] MS[M+H]=463(M+1)

[1072] 1 H NMR(500MHz,CD3OD)δ8.07(s,1H),8.00(d,1H),7.56(d,1H),7.42(m,3H),7.08(d,2H),7.01(m, 2H),6.81(d,1H),5.17(s,2H),3.94(s,3H),3.88(d,2H),1.33(m,1H),0.70(m,2H),0.41(m,2H)

[1073] Step B: 3-((5-chloro-3-(4-(cyclopropylmethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of 1-azolyl)methyl)benzoic acid

[1074] The title compound (39 mg, yield: 98%) was obtained using methyl 3-((5-chloro-3-(4-(cyclopropylmethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (41 mg, 0.089 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[1075] MS[M+H]=449(M+1)

[1076] 1 H NMR(400MHz,DMSO-D6)δ7.98(s,1H),7.81(d,1H),7.58(d,1H),7.42(m,3H),7.20(d,1H), 7.08(m,3H),6.87(s,1H),5.15(s,2H),3.85(d,2H),1.22(m,1H),0.55(m,2H),0.31(m,2H)

[1077] Example 43: Preparation of 3-((5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1078]

[1079] The procedure of steps A and B below gives the title compound.

[1080] Step A: 3-((5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)benzoate

[1081] The title compound (62.1 mg, yield: 44%) was obtained in the same manner as in step A of Preparation Example 1 using 6-chloro-1-(4-(piperidin-1-carbonyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (100.0 mg, 0.28 mmol) and methyl 3-(bromomethyl)benzoate obtained in Preparation Example 22.

[1082] MS[M+H]=504(M+1)

[1083] 1 H NMR(500MHz, CDCl3)δ8.05(s,1H),7.99(d,1H),7.62(m,5H),7.45(m,1H),7.11(s,1H),7.05(d, 1H),6.84(d,1H),5.16(s,2H),3.92(s,3H),3.74(m,2H),3.48(m,2H),1.71(m,4H),1.56(m,2H)

[1084] Step B: 3-((5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of 1-azolyl)methyl)benzoic acid

[1085] The title compound (54.4 mg, yield: 90%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (62.0 mg, 0.12 mmol) obtained in step A above, in the same manner as in step B of Example 1.

[1086] MS[M+H]=490(M+1)

[1087] 1 H NMR(500MHz, CDCl3)δ8.10(s,1H),8.04(d,1H),7.61(m,5H),7.48(t,1H),7.11(s,1H),7 .06(d,1H),6.85(s,1H)5.18(s,2H),3.75(m,2H),3.42(m,2H),1.71(m,4H),1.56(m,2H)

[1088] Example 44: Preparation of 3-((5-chloro-3-(4-(morpholin-4-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1089]

[1090] The procedure of steps A and B below gives the title compound.

[1091] Step A: 3-((5-chloro-3-(4-(morpholin-4-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)benzoate

[1092] The title compound (96.9 mg, yield: 69%) was obtained in the same manner as in step A of Preparation Example 1, using 6-chloro-1-(4-(morpholino-4-carbonyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (100.0 mg, 0.28 mmol) and methyl 3-(bromomethyl)benzoate obtained in Preparation Example 23.

[1093] MS[M+H]=506(M+1)

[1094] 1 H NMR(500MHz, CDCl3)δ8.05(s,1H),7.99(d,1H),7.65(m,4H),7.57(d,1H),7.45(m,1H ),7.11(s,1H),7.06(d,1H),6.84(d,1H),5.16(s,2H),3.91(s,3H),3.80-3.45(m,8H)

[1095] Step B: 3-((5-chloro-3-(4-(morpholino-4-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of 1-azolyl)methyl)benzoic acid

[1096] The title compound (78.4 mg, yield: 84%) was obtained using methyl 3-((5-chloro-3-(4-(morpholino-4-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (96.0 mg, 0.19 mmol) obtained in step A above, in the same manner as in step B of Example 1.

[1097] MS[M+H]=492(M+1)

[1098] 1 H NMR(500MHz, CDCl3)δ8.10(1,1H),8.05(d,1H),7.65(m,5H),7.48(m,1H),7.12(s,1H),7.07(d,1H),6.86(d,1H),5.18(s,2H),3.80-3.49(m,8H)

[1099] Example 45: Preparation of 3-((5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1100]

[1101] The procedure of steps A and B below gives the title compound.

[1102] Step A: 3-((5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)benzoate

[1103] The title compound (68.0 mg, yield: 86%) was obtained in the same manner as in step A of Preparation Example 1 using 6-chloro-1-(4-(pyrrolidine-1-carbonyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (55.0 mg, 0.16 mmol) and methyl 3-(bromomethyl)benzoate obtained in Preparation Example 24.

[1104] MS[M+H]=490(M+1)

[1105] 1 H NMR(500MHz, CDCl3)δ8.05(s,1H),7.99(d,1H),7.73(d,2H),7.62(d,2H),7.57(t,1H),7.11(s,1H),7 .05(d,1H),6.83(d,1H),5.16(d,2H),3.92(s,3H),3.70(t,2H),3.52(t,2H),2.00(m,2H),1.93(m,2H)

[1106] Step B: 3-((5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of 1-azolyl)methyl)benzoic acid

[1107] The title compound (63.6 mg, yield: 96%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (68.0 mg, 0.14 mmol) obtained in step A above, in the same manner as in step B of Example 1.

[1108] MS[M+H]=476(M+1)

[1109] 1H NMR(500MHz, CDCl3)δ8.10(s,2H),8.04(d,1H),7.74(d,2H),7.63(m,3H),7.47(m,1H),7.11(s, 1H),7.06(d,1H),6.85(d,1H),5.18(s,2H),3.71(t,2H),3.52(t,2H),2.01(m,2H),1.93(m,2H)

[1110] Example 46: Preparation of 4-(3-(3-carboxybenzyl)-6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-fluorobenzoic acid

[1111]

[1112] The procedure of steps A and B below gives the title compound.

[1113] Step A: 3-((5-chloro-3-(2-fluoro-4-(methylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzene) Preparation of [d]imidazol-1-yl)methyl)benzoate

[1114] The title compound (25 mg, yield: 11%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (150 mg, 0.474 mmol) and (2-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (187 mg, 0.947 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[1115] MS[M+H]=468(M+1)

[1116] 1 H NMR(500MHz,CD3OD)δ8.19(d,2H),7.91(t,1H),7.64(d,3H),7.20(t,1H),7.13(m,2H),7.03(d,1H),5.22(s,2H),3.97(s,3H),1.64(s,3H)

[1117] Step B: 4-(3-(3-carboxybenzyl)-6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)- Preparation of 3-fluorobenzoic acid

[1118] The title compound (10 mg, yield: 91%) was obtained using methyl 3-((5-chloro-3-(2-fluoro-4-(methylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (12 mg, 0.025 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[1119] MS[M+H]=441(M+1)

[1120] 1 H NMR(500MHz,DMSO-D6)δ7.98(m,3H),7.86(m,2H),7.63(d,1H),7.50(t,1H),7.30(d,1H),7.20(d,1H),7.03(s,1H),5.24(s,2H)

[1121] Example 47: Preparation of 3-((5-chloro-3-(4-morpholinophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1122]

[1123] The procedure of steps A and B below gives the title compound.

[1124] Step A: 3-((5-chloro-3-(4-morpholinophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Preparation of methyl methyl benzoate

[1125] The title compound (17 mg, yield: 38%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-((((trifluoromethyl)sulfonyl)oxy)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.092 mmol) and morpholine (8.05 mg, 0.092 mmol) obtained in step A of Example 29, in the same manner as in step B of Example 29.

[1126] MS[M+H]=478(M+1)

[1127] 1 H NMR(500MHz,CD3OD)δ8.07(s,1H),8.00(d,1H),7.65(m,1H),7.59(d,1H),7.51(1H),7.46(m,2 H),7.06(d,2H),7.01(s,1H),6.80(d,1H),5.17(s,2H),3.94(s,3H),3.92(m,4H),3.25(m,4H)

[1128] Step B: 3-((5-chloro-3-(4-morpholinophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Preparation of methylbenzoic acid

[1129] The title compound (5 mg, yield: 32%) was obtained using methyl 3-((5-chloro-3-(4-morpholinophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (16 mg, 0.033 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[1130] MS[M+H]=464(M+1)

[1131] 1 H NMR(500MHz,DMSO-D6)7.95(s,1H),7.85(d,1H),7.58(d,1H),7.46(t,1H),7.40(d ,2H),7.23(d,1H),7.12(m,3H),6.91(s,1H),5.19(s,2H),3.78(m,4H),3.20(m,4H)

[1132] Example 48: Preparation of 5-((5-chloro-4-fluoro-3-(4-morpholinophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1133]

[1134] The title compound (21 mg, yield: 70%) was obtained using 6-chloro-7-fluoro-1-(4-morpholinophenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (30 mg, 0.086 mmol) obtained in step D of Preparation Example 11, in the same manner as in step C of Preparation Example 7 and step B of Example 1.

[1135] 1 H NMR(500MHz,MeOD)δ7.95(m,1H),7.59(m,1H),7.39(m,2H),7.19(m,2H),7.12(m,2H),7.00(m,1H),5.19(s,2H),3.88(m,4H),3.26(m,4H)

[1136] Example 49: Preparation of 3-((5-chloro-4-fluoro-3-(4-morpholinophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-5-fluorobenzoic acid

[1137]

[1138] The title compound (17 mg, yield: 55%) was obtained using 6-chloro-7-fluoro-1-(4-morpholinophenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (30 mg, 0.086 mmol) and methyl 3-(bromomethyl)-5-fluorobenzoate obtained in step D of Preparation Example 11, in the same manner as in step C of Preparation Example 7 and step B of Example 1.

[1139] 1 H NMR (500MHz, CDCl3) δ7.85(s,1H),7.63(d,1H),7.37(d,3H),7.17(t,1H),7.10(d,1H),6.96(d,1H),5.22(s,2H),3.85(m,4H),3.23(m,4H).

[1140] Example 50: Preparation of 3-((5-chloro-4-fluoro-3-(4-morpholinophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-4-fluorobenzoic acid

[1141]

[1142] The title compound (26 mg, yield: 72%) was obtained using 6-chloro-7-fluoro-1-(4-morpholinophenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (30 mg, 0.086 mmol) and methyl 3-(bromomethyl)-4-fluorobenzoate obtained in step D of Preparation Example 11, in the same manner as in step C of Preparation Example 7 and step B of Example 1.

[1143] 1 H NMR(500MHz, CDCl3)δ8.01(m,2H),7.36(d,2H),7.26(t,1H),7.18(t,1H),7.10(d,2H),6.96(d,1H),5.26(s,2H),3.85(m,4H),3.24(m,4H)

[1144] Example 51: Preparation of 3-((5-chloro-4-fluoro-3-(4-morpholinophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1145]

[1146] The title compound (25 mg, yield: 67%) was obtained using 6-chloro-7-fluoro-1-(4-morpholinophenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (30 mg, 0.086 mmol) and methyl 3-(bromomethyl)-2-fluorobenzoate obtained in step D of Preparation Example 11, in the same manner as in step C of Preparation Example 7 and step B of Example 1.

[1147] 1 H NMR(500MHz,MeOD)δ7.83(m,1H),7.50(m,1H),7.36(d,3H),7.19(m,2H),7.07(d,1H),6.98(d,1H),5.25(s,2H),3.86(m,4H),3.24(m,4H)

[1148] Example 52: Preparation of 6-((5-chloro-4-fluoro-3-(4-morpholinophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)pyridinecarboxylic acid

[1149]

[1150] The title compound (17 mg, yield: 74%) was obtained using 6-chloro-7-fluoro-1-(4-morpholinophenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (30 mg, 0.086 mmol) and methyl 6-(bromomethyl)pyridinecarboxylate, obtained in step D of Preparation Example 11, in the same manner as in step C of Preparation Example 7 and step B of Example 1.

[1151] 1 H NMR(500MHz,MeOD)δ8.07(m,1H),7.96(m,1H),7.52(m,1H),7.41(m,2H),7. 17(m,1H),7.12(m,2H),7.05(m,1H),5.35(s,2H),3.89(m,4H),3.26(m,4H)

[1152] Example 53: Preparation of 3-((5-chloro-4-fluoro-3-(4-(3-hydroxyazacyclobutane-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1153]

[1154] The title compound (0.022 g, yield: 44%) was obtained using 1-(4-(6-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)azacyclobutane-3-yl acetate (0.04 g, 0.10 mmol) and methyl 3-(bromomethyl)benzoate (0.024 g, 0.10 mmol) obtained in Preparation Example 14 in the same manner as in steps A and B of Example 24.

[1155] MS[M+H]=468(M+1)

[1156] 1 H-NMR(500MHz,MeOH-d4)δ8.01(m,1H),7.96(m,1H),7.57(m,1H),7.45(t,1H),7.29(d,2H) ,7.13(m,1H),6.92(m,1H),6.60(d,2H),5.21(s,2H),4.70(m,1H),4.20(m,2H),3.68(m,2H)

[1157] Example 54: Preparation of 3-((5-chloro-3-(4-(dimethylcarbamoyl)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1158]

[1159] The procedure of steps A and B below gives the title compound.

[1160] Step A: 3-((5-chloro-3-(4-(dimethylcarbamoyl)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H- Preparation of methyl benzo[d]imidazol-1-yl)methyl)benzoate

[1161] The title compound (0.095 g, yield: 88%) was obtained using methyl 3-((5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.075 g, 0.22 mmol) and (4-(dimethylcarbamoyl)phenyl)boronic acid (0.086 g, 0.44 mmol) obtained in Preparation Example 15 in the same manner as in step A of Example 2.

[1162] 1 H-NMR(500MHz,MeOH-d4)δ8.02(m,1H),7.97(m,1H),7.62(m,1H),7.48(m,1H),7.30( d,2H),7.06(m,1H),6.99(m,1H),6.82(d,2H),5.30(s,2H),3.89(s,3H),3.07(s,6H)

[1163] Step B: 3-((5-chloro-3-(4-(dimethylcarbamoyl)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H- Preparation of benzo[d]imidazol-1-yl)methyl)benzoic acid

[1164] The title compound (0.020 g, yield: 21%) was obtained using methyl 3-((5-chloro-3-(4-(dimethylcarbamoyl)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.095 g, 0.20 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1165] MS[M+H]=468(M+1)

[1166] 1 H-NMR(400MHz,MeOH-d4)δ8.02(m,1H),7.95(dd,1H),7.68(m,4H),7.58(dd,1H) ,7.45(t,1H),7.06(dd,1H),6.98(d,1H),5.30(s,2H),3.14(s,3H),3.07(s,3H)

[1167] Example 55: Preparation of 3-((5-chloro-3-(4-(methylthio)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1168]

[1169] The procedure of steps A and B below gives the title compound.

[1170] Step A: 3-((5-chloro-3-(4-(methylthio)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- Preparation of methyl 2-fluorobenzoate

[1171] The title compound (58 mg, yield: 85%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (50 mg, 0.15 mmol) and (4-(methylthio)phenyl)boronic acid (38 mg, 0.22 mmol) obtained in Preparation Example 2 in the same manner as in step A of Example 2.

[1172] Step B: 3-((5-chloro-3-(4-(methylthio)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- Preparation of (methyl)-2-fluorobenzoic acid

[1173] The title compound (39 mg, yield: 70%) was obtained using methyl 3-((5-chloro-3-(4-(methylthio)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (58 mg, 0.12 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[1174] 1 H NMR(500MHz,DMSO-D6)δ7.76(t,1H),7.48(m,3H),7.41(d,2H),7.17(m,2H),7.14(d,1H),6.98(s,1H),5.17(s,2H),2.50(s,3H)

[1175] Example 56: Preparation of 3-((5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1176]

[1177] The procedure of steps A, B, C, and D below gives the title compound.

[1178] Step A: 3-((3-(4-(tert-butoxycarbonyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)-2-fluorobenzoate

[1179] The title compound (120 mg, yield: 40%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (200 mg, 0.60 mmol) and (4-(tert-butoxycarbonylphenyl)boronic acid (265 mg, 1.20 mmol) obtained in Preparation Example 2, in the same manner as in step A of Example 2.

[1180] 1 H-NMR(500MHz, CDCl3)δ8.17(d,2H),7.89(t,1H),7.61(d,3H),7.18(t,1H),7.11(d,2H),7.00(d,1H),5.20(s,2H),3.94(s,3H),1.62(s,9H)

[1181] Step B: 4-(6-chloro-3-(2-fluoro-3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)benzoic acid

[1182] The methyl 3-((3-(4-(tert-butoxycarbonyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (120 mg, 0.23 mmol) obtained in step A above was dissolved in 1 mL of DCM and 1 mL of LTFA, and the solution was stirred at room temperature for 2 hours. After the reaction was terminated, the reaction solution was concentrated under reduced pressure and purified by MPLC to give the title compound (105 mg, yield: 98%).

[1183] Step C: 3-((5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)-2-fluorobenzoate

[1184] To the 4-(6-chloro-3-(2-fluoro-3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid (50 mg, 0.11 mmol) obtained in step B above, 2 mL of DMF, pyrrolidine (7.8 mg, 0.11 mmol), HATU (63 mg, 0.16 mmol), and TEA (30 μL, 0.22 mmol) were added, and the resulting mixture was stirred at room temperature for 16 hours. Water and EtOAc were added to the reaction solution, and the organic layer was separated and dehydrated on anhydrous Na2SO4. The organic layer was purified by MPLC, giving the title compound (57 mg, yield: 99%).

[1185] 1 H-NMR(500MHz, CDCl3)δ7.89(t,1H),7.71(d,2H),7.60(m,3H),7.18(t,1H),7.11(m,2H), 7.00(d,1H),5.20(s,2H),3.94(s,3H),3.68(t,2H),3.49(t,2H),1.99(m,2H),1.92(m,2H)

[1186] Step D: 3-((5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of (1-azolyl)methyl)-2-fluorobenzoic acid

[1187] The title compound (35 mg, yield: 62%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (57 mg, 0.11 mmol) obtained in step C above, in the same manner as in step B of Example 2.

[1188] 1H NMR (400MHz, DMSO-D6) δ7.78(t,1H),7.68(d,2H),7.62(d,2H),7.52(t,1H),7.20(m,3H),7.11(s,1H),5.20(s,2H),3.45(m,4H),1.82(m,4H)

[1189] Example 57: Preparation of 3-((5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1190]

[1191] The procedure of steps A and B below gives the title compound.

[1192] Step A: 3-((5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)-2-fluorobenzoate

[1193] The title compound (61 mg, yield: 99%) was obtained in the same manner as in step C of Example 56 using 4-(6-chloro-3-(2-fluoro-3-(methoxycarbonyl)benzylmethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid (50 mg, 0.11 mmol) and piperidine (14 mg, 0.16 mmol) obtained in step B of Example 56.

[1194] 1 H-NMR (500MHz, CDCl3) δ7.89(t,1H),7.62(t,1H),7.57(m,4H),7.18(t,1H),7.01(m,2H),6. 74(m,1H),5.20(s,2H),3.94(s,3H),3.74(br,2H),3.41(br,2H),1.70(br,4H),1.55(br,2H)

[1195] Step B: 3-((5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of (1-azolyl)methyl)-2-fluorobenzoic acid

[1196] The title compound (46 mg, yield: 78%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (60 mg, 0.11 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[1197] 1H-NMR(400MHz, CDCl3)δ7.95(t,1H),7.66(t,1H),7.58(m,4H),7.19(t,1H),7.10(m,2 H),7.01(d,1H),5.20(s,2H),3.75(br,2H),3.40(br,2H),1.70(br,2H),1.55(br,2H)

[1198] Example 58: Preparation of 3-((3-(4-(azacyclobutane-1-carbonyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1199]

[1200] The procedure of steps A and B below gives the title compound.

[1201] Step A: 3-((5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)benzoate

[1202] 4-(6-chloro-3-(3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid (43.6 mg, 0.10 mmol) and aziridine (6.27 mg, 0.11 mmol) obtained in Preparative Example 25 were dissolved in DMF and cooled to 0 °C. HATU (45.5 mg, 0.12 mmol) and DIPEA (52.3 μL, 0.30 mmol) were added, and the resulting mixture was stirred while raising the temperature to room temperature. After the reaction was terminated, DMF was removed by distillation under reduced pressure, and the mixture was diluted again with EtOAc. The organic layer was then extracted with EtOAc and a saturated aqueous solution of NH4Cl and dehydrated on Na2SO4. The resulting solid was filtered off, and the filtrate was distilled under reduced pressure and then purified by MPLC to give the title compound (43.0 mg, yield: 90%).

[1203] MS[M+H]=476(M+1)

[1204] 1 H NMR(500MHz, CDCl3)δ8.05(s,1H),7.99(d,1H),7.83(d,2H),7.63(d,2H),7.56(d,1H),7.45(t,1H),7 .12(s,1H),7.06(d,1H),6.84(d,1H),5.16(s,2H),4.37(m,2H),4.27(m,2H),3.91(s,3H),2.40(m,2H)

[1205] Step B: 3-((3-(4-(azacyclobutane-1-carbonyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoic acid

[1206] The title compound (38.2 mg, yield: 92%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (43.0 mg, 0.090 mmol) obtained in step A above, in the same manner as in step B of Example 1.

[1207] MS[M+H]=462(M+1)

[1208] 1 H NMR(500MHz, CDCl3)δ8.09(s,1H),8.04(d,1H),7.84(d,2H),7.64(m,3H),7.48(t,1H),7 .13(s,1H),7.07(d,1H),6.85(d,1H),5.18(s,2H),4.37(m,2H),4.28(m,2H),2.40(m,2H)

[1209] Example 59: Preparation of 3-((5-chloro-3-(4-(3-methoxypyrrolidine-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1210]

[1211] The procedure of steps A and B below gives the title compound.

[1212] Step A: 3-((5-chloro-3-(4-(3-methoxypyrrolidine-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H- Preparation of methyl benzo[d]imidazol-1-yl)methyl)benzoate

[1213] The title compound (51.2 mg, yield: 99%) was obtained using 4-(6-chloro-3-(3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid (43.6 mg, 0.10 mmol) and 3-methoxypyrrolidine (11.10 mg, 0.11 mmol) obtained in Preparation Example 25 in the same manner as in step A of Example 58.

[1214] MS[M+H]=520(M+1)

[1215] 1H NMR(400MHz, CDCl3)δ8.05(s,1H),8.01(d,1H),7.75(m,2H),7.63(d,2H),7.57(d,1H),7.45(m,1H),7.11(s,1H),7.05(d, 1H),6.84(d,1H),5.16(s,2H),4.07(s,1H),3.91(s,3H),3.79(m,2H),3.69(m,1H),3.59(m,1H),3.39(s,3H),2.13(m,2H)

[1216] Step B: 3-((5-chloro-3-(4-(3-methoxypyrrolidine-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H- Preparation of benzo[d]imidazol-1-yl)methyl)benzoic acid

[1217] The title compound (38.2 mg, yield: 92%) was obtained using methyl 3-((5-chloro-3-(4-(3-methoxypyrrolidine-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (43.0 mg, 0.090 mmol) obtained in step A above, in the same manner as in step B of Example 1.

[1218] MS[M+H]=506(M+1)

[1219] 1 H NMR(500MHz, CDCl3)δ8.10(s,1H),8.05(d,1H),7.76(m,2H),7.63(m,3H),7.48(t,1H),7.12(s,1H),7.06(d ,1H),6.85(d,1H)5.18(s,2H),4.07(s,1H),3.83(m,2H),3.70(m,1H),3.57(m,1H),3.39(s,3H),2.13(m,2H)

[1220] Example 60: Preparation of 3-((5-chloro-3-(4-(4-methylpiperazin-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1221]

[1222] The procedure of steps A and B below gives the title compound.

[1223] Step A: 3-((5-chloro-3-(4-(4-methylpiperazin-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoate methyl benzoate

[1224] The title compound (43.3 mg, yield: 83%) was obtained using 4-(6-chloro-3-(3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid (43.6 mg, 0.10 mmol) and 1-methylpiperazine (11.00 mg, 0.110 mmol) obtained in Preparation Example 25 in the same manner as in step A of Example 58.

[1225] MS[M+H]=520(M+1)

[1226] 1 H NMR(500MHz, CDCl3)δ8.05(s,1H),7.99(d,1H),7.63(m,4H),7.57(d,1H),7.45(t,1H),7.11(s,1H),7.06(d, 1H),6.84(d,1H),5.16(s,2H),3.91(s,3H),3.84(m,2H),3.53(m,2H),2.53(m,2H),2.41(m,2H),2.35(s,3H)

[1227] Step B: 3-((5-chloro-3-(4-(4-methylpiperazin-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoic acid

[1228] The title compound (17.0 mg, yield: 92%) was obtained using methyl 3-((5-chloro-3-(4-(4-methylpiperazin-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (43.3 mg, 0.083 mmol) obtained in step A above, in the same manner as in step B of Example 1.

[1229] MS[M+H]=505(M+1)

[1230] 1 H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.87(d,1H),7.70-7.60(m,6H),7.51(t,1H),7.30(d,1H ),7.20(m,2H),5.22(s,2H),3.56(m,2H),3.49(m,2H),2.53(m,2H),2.41(m,2H),2.35(s,3H)

[1231] Example 61: Preparation of 3-((5-chloro-3-(4-(4-hydroxypiperidin-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1232]

[1233] The procedure of steps A and B below gives the title compound.

[1234] Step A: 3-((5-chloro-3-(4-(4-hydroxypiperidin-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoate methyl benzoate

[1235] 4-(6-chloro-3-(3-(methoxycarbonyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid (43.6 mg, 0.10 mmol) obtained in Preparation Example 25 was dissolved in DCM, then cooled to 0 °C, and SOCl2 (59.49 mg, 0.50 mmol) and a catalytic amount of DMF were added. The resulting mixture was stirred for 3 hours while the temperature was raised to room temperature. The residual solvent and reactants were then removed under reduced pressure, and the condensed reactants were redissolved in DCM. The reactants were cooled to 0 °C, and 4-hydroxypiperidine (11.13 mg, 0.110 mmol) and TEA (20.24 mg, 0.20 mmol) were added. The resulting mixture was stirred while the temperature was raised to room temperature. After the reaction was terminated, the organic layer was extracted with DCM and a saturated aqueous NaCl solution and dehydrated on Na2SO4. The obtained solid was filtered off, the filtrate was distilled under reduced pressure, and then purified by MPLC to give the title compound (43.1 mg, yield: 91%).

[1236] MS[M+H]=520(M+1)

[1237] 1 H NMR(500MHz, CDCl3)δ8.05(s,1H),7.99(m,1H),7.63(m,4H),7.57(m,1H),7.45(t,1H),7.11(s,1H),7.05(d,1H),6 .84(d,1H),5.16(s,2H),4.21(m,1H),4.02(m,1H),3.92(s,3H),3.77(m,1H),3.44(m,2H),2.02(m,2H),1.65(m,2H)

[1238] Step B: 3-((5-chloro-3-(4-(4-hydroxypiperidin-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoic acid

[1239] The title compound (25.4 mg, yield: 61%) was obtained using methyl 3-((5-chloro-3-(4-(4-hydroxypiperidin-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (43.1 mg, 0.083 mmol) obtained in step A above, in the same manner as in step B of Example 1.

[1240] MS[M+H]=506(M+1)

[1241] 1 H NMR(500MHz, CDCl3)δ8.09(s,1H),8.04(d,1H),7.62(m,5H),7.48(d,1H),7.12(s,1H),7.07(d,1H),6 .85(d,1H),5.18(s,2H),4.22(m,1H),4.02(m,1H),3.75(m,1H),3.45(m,2H),2.00(m,2H),1.66(m,2H)

[1242] Example 62: Preparation of 3-((5-chloro-3-(4-(4-methoxypiperidin-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1243]

[1244] The procedure of steps A and B below gives the title compound.

[1245] Step A: 3-((5-chloro-3-(4-(4-methoxypiperidin-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzene Preparation of [d]imidazol-1-yl)methyl)benzoate

[1246] The title compound (46.0 mg, yield: 86%) was obtained using 4-(6-chloro-3-(3-(methoxycarbonyl)benzylmethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid (43.6 mg, 0.10 mmol) and 4-methoxypiperidine (12.64 mg, 0.110 mmol) obtained in Preparation Example 25 in the same manner as in step A of Example 58.

[1247] MS[M+H]=535(M+1)

[1248] Step B: 3-((5-chloro-3-(4-(4-methoxypiperidin-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzene Preparation of [d]imidazol-1-yl)methyl)benzoic acid

[1249] The title compound (29.5 mg, yield: 66%) was obtained using methyl 3-((5-chloro-3-(4-(4-methoxypiperidin-1-carbonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (43.0 mg, 0.090 mmol) obtained in step A above, in the same manner as in step B of Example 1.

[1250] MS[M+H]=520(M+1)

[1251] 1 H NMR(500MHz, CDCl3)δ8.10(s,1H),8.04(d,1H),7.63(m,5H),7.48(t,1H),7.12(s,1H),7.07(d,1H),6.85(d,1H ),5.18(d,2H),4.04(m,1H),3.68(m,1H),3.58(m,1H),3.51(m,1H),3.38(s,3H),3.31(m,1H),1.96-1.60(m,4H)

[1252] Example 63: Preparation of 3-(1-(5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoic acid

[1253]

[1254] The procedure of steps A, B, C, and D below gives the title compound.

[1255] Step A: 3-(1-(3-(4-(tert-butoxycarbonyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of methyl imidazole-1-yl)cyclopropyl)benzoate

[1256] The title compound (181 mg, yield: 60%) was obtained using methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate (200 mg, 0.58 mmol) and (4-(tert-butoxycarbonylphenyl)boronic acid (194 mg, 0.88 mmol) obtained in Preparation Example 3, in the same manner as in step A of Example 2.

[1257] 1 H-NMR(500MHz, CDCl3)δ8.16(d,2H),7.90(d,1H),7.88(s,1H),7.62(d,2H),7.50(d ,1H),7.36(t,1H),7.12(m,3H),3.90(s,3H),1.73(m,2H),1.68(m,2H),1.62(s,9H)

[1258] Step B: 4-(6-chloro-3-(1-(3-(methoxycarbonyl)phenyl)cyclopropyl)-2-oxo-2,3-dihydro-1H-benzene Preparation of [d]imidazol-1-yl)benzoic acid

[1259] The title compound (161 mg, yield: 99%) was obtained using methyl 3-(1-(3-(4-(tert-butoxycarbonyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate (181 mg, 0.35 mmol) obtained in step A above, in the same manner as in step B of Example 56.

[1260] Step C: 3-(1-(5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]) Preparation of methyl imidazole-1-yl)cyclopropyl)benzoate

[1261] The title compound (54 mg, yield: 98%) was obtained using 4-(6-chloro-3-(1-(3-(methoxycarbonyl)phenyl)cyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid (50 mg, 0.11 mmol) and pyrrolidine (9.2 mg, 0.13 mmol) obtained in step B above, in the same manner as in step C of Example 56.

[1262] 1 H-NMR(500MHz, CDCl3)δ7.90(d,1H),7.88(s,1H),7.71(d,2H),7.60(d,2H),7.50(d,1H),7.36(t,1H),7.15(d ,1H),7.10(d,2H),3.90(s,3H),3.68(t,2H),3.49(t,2H),1.98(m,2H),1.93(m,2H),1.73(m,2H),1.68(m,2H)

[1263] Step D: 3-(1-(5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]) Preparation of imidazole-1-yl)cyclopropyl)benzoic acid

[1264] The title compound (20 mg, yield: 38%) was obtained using methyl 3-(1-(5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate (54 mg, 0.10 mmol) obtained in step C above, in the same manner as in step B of Example 2.

[1265] 1H NMR(500MHz,DMSO-D6)δ7.81(d,1H),7.73(d,3H),7.66(d,2H),7.46(m,2H),7.28(d,1H), 7.20(d,1H),7.16(s,1H),3.51(m,2H),3.47(m,2H),1.87(m,2H),1.84(m,2H),1.69(m,4H)

[1266] Example 64: Preparation of 3-(1-(5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoic acid

[1267]

[1268] The procedure of steps A and B below gives the title compound.

[1269] Step A: 3-(1-(5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azol-1-yl)cyclopropyl)benzoate

[1270] The title compound (53 mg, yield: 92%) was obtained using 4-(6-chloro-3-(1-(3-(methoxycarbonyl)phenyl)cyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid (53 mg, 0.10 mmol) and piperidine (11 mg, 0.13 mmol) obtained in step B of Example 63, in the same manner as in step C of Example 56.

[1271] 1 H-NMR(500MHz, CDCl3)δ7.92(m,2H),7.60(m,4H),7.53(d,1H),7.38(t,1H),7.17(d, 1H),7.13(d,2H),3.92(s,3H),3.76(br,2H),3.43(br,2H),1.71(m,6H),1.58(m,4H)

[1272] Step B: 3-(1-(5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of 1-azolyl-1-yl)cyclopropyl)benzoic acid

[1273] The title compound (31 mg, yield: 60%) was obtained using methyl 3-(1-(5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate (53 mg, 0.10 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[1274] 1H NMR(500MHz,DMSO-D6)δ13.04(s,1H),7.81(d,1H),7.72(s,1H),7.66(d,2H),7.58(d,2H),7 .46(m,2H),7.28(d,1H),7.19(m,2H),3.62(br,2H),3.32(br,2H),1.64(m,6H),1.54(m,4H)

[1275] Example 65: Preparation of 3-((5-chloro-3-(4-(dimethylamino)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-5-fluorobenzoic acid

[1276]

[1277] The procedure of steps A and B below gives the title compound.

[1278] Step A: 3-((5-chloro-3-(4-(dimethylamino)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of methyl imidazole-1-yl)methyl)-5-fluorobenzoate

[1279] The title compound (15 mg) was obtained using 5-chloro-1,2-difluoro-3-nitrobenzene (0.641 g, 3.31 mmol) and methyl 3-(aminomethyl)-5-fluorobenzoate (0.607 g, 3.31 mmol) obtained in Preparation Example 6, in the same manner as in steps A and B of Preparation Example 8 and step B of Example 2.

[1280] 1 H-NMR(400MHz, CDCl3)δ7.88(d,1H),7.64(dd,1H),7.30(dd,1H),7.27(d,2H),6.82(4H),5.23(s,2H),3.93(s,3H),3.00(s,6H)

[1281] Step B: 3-((5-chloro-3-(4-(dimethylamino)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of imidazole-1-yl)methyl)-5-fluorobenzoic acid

[1282] The title compound (7 mg, yield: 48%) was obtained using methyl 3-((5-chloro-3-(4-(dimethylamino)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-5-fluorobenzoate (15 mg, 0.032 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1283] MS[M+H]=458(M+1)

[1284] 1H-NMR (400MHz, CDCl3) δ7.95(d,1H),7.68(dd,1H),7.36(dd,1H),7.27(d,2H),6.83(4H),5.26(s,2H),3.01(s,6H)

[1285] Example 66: Preparation of 3-((5-chloro-3-(4-(dimethylamino)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1286]

[1287] The procedure of steps A and B below gives the title compound.

[1288] Step A: 3-((5-chloro-3-(4-(dimethylamino)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of methyl imidazole-1-yl)methyl)benzoate

[1289] The title compound (0.09 g, yield: 83%) was obtained using methyl 3-((5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.080 g, 0.24 mmol) and (4-(dimethylamino)phenyl)boronic acid (0.079 g, 0.48 mmol) obtained in Preparation Example 15 in the same manner as in step A of Example 2.

[1290] 1 H-NMR(500MHz, CDCl3)δ8.08(d,1H),7.97(dd,1H),7.61(dd,1H),7.41(t,1H),7.28(d,2H),6.80(4H),5.25(s,2H),3.91(s,3H),3.01(s,6H)

[1291] Step B: 3-((5-chloro-3-(4-(dimethylamino)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of imidazole-1-yl)methyl)benzoic acid

[1292] The title compound (0.075 g, yield: 86%) was obtained using methyl 3-((5-chloro-3-(4-(dimethylamino)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.09 g, 0.20 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1293] MS[M+H]=440(M+1)

[1294] 1H-NMR(400MHz, CDCl3)δ8.14(d,1H),8.01(dd,1H),7.66(dd,1H),7.44(t,1H),7.30(d,2H),6.84(4H),5.27(s,2H),3.02(s,6H)

[1295] Example 67: Preparation of 3-(1-(5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoic acid

[1296]

[1297] The procedure of steps A, B, C, and D below gives the title compound.

[1298] Step A: 3-(1-(3-(4-(tert-butoxycarbonyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of methyl imidazole-1-yl)cyclopropyl)-2-fluorobenzoate

[1299] The title compound (198 mg, yield: 67%) was obtained using methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoate (200 mg, 0.55 mmol) and (4-(tert-butoxycarbonylphenyl)boronic acid (194 mg, 0.88 mmol) obtained in Preparation Example 4, in the same manner as in step A of Example 2.

[1300] 1 H-NMR (400MHz, CDCl3) δ8.12(m,3H),7.85(m,2H),7.53(d,3H),7.18(t,2H),7.05(d,1H),3.90(s,3H),1.68(m,2H),1.63(m,2H),1.58(s,9H)

[1301] Step B: 4-(6-chloro-3-(1-(2-fluoro-3-(methoxycarbonyl)phenyl)cyclopropyl)-2-oxo-2,3-dihydro- Preparation of 1H-benzo[d]imidazol-1-yl)benzoic acid

[1302] The title compound (156 mg, yield: 88%) was obtained using methyl 3-(1-(3-(4-(tert-butoxycarbonyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoate (198 mg, 0.37 mmol) obtained in step A above, in the same manner as in step B of Example 56.

[1303] 1H-NMR(500MHz, CDCl3)δ8.25(d,2H),8.15(t,1H),7.86(t,1H),7.63(d,2H ),7.57(d,1H),7.20(m,2H),7.10(s,1H),3.91(s,3H),1.66(m,2H),1.64(m 2H)

[1304] Step C: 3-(1-(5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]) Preparation of methyl imidazole-1-yl)cyclopropyl)-2-fluorobenzoate

[1305] The title compound (50 mg, yield: 89%) was obtained using 4-(6-chloro-3-(1-(2-fluoro-3-(methoxycarbonyl)phenyl)cyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid (50 mg, 0.10 mmol) and pyrrolidine (8.9 mg, 0.12 mmol) obtained in step B above, in the same manner as in step C of Example 56.

[1306] 1 H-NMR(500MHz, CDCl3)δ8.15(t,1H),7.85(t,1H),7.67(d,2H),7.53(m,3H),7.19(m,2H),7.04(s ,1H),3.90(s,3H),3.66(t,2H),3.46(t,2H),1.98(m,2H0,1.91(m,2H),1.68(m,2H),1.64(m,2H)

[1307] Step D: 3-(1-(5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]) Preparation of imidazole-1-yl)cyclopropyl)-2-fluorobenzoic acid

[1308] The title compound (42 mg, yield: 87%) was obtained using methyl 3-(1-(5-chloro-2-oxo-3-(4-(pyrrolidine-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoate (50 mg, 0.09 mmol) obtained in step C above, in the same manner as in step B of Example 2.

[1309] MS[M+H]=520(M+1)

[1310] 1 H-NMR(400MHz,DMSO-d6)δ7.92(t,1H),7.73(t,1H),7.65(dt,2H),7.55(d,2H),7.46( dd,1H),7.23(m,2H),7.03(d,1H),3.45(t,2H),3.40(t,2H),1.83(m,4H),1.60(d,4H)

[1311] Example 68: Preparation of 3-(1-(5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoic acid

[1312]

[1313] The procedure of steps A and B below gives the title compound.

[1314] Step A: 3-(1-(5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-(azol-1-yl)cyclopropyl)-2-fluorobenzoate

[1315] The title compound (53 mg, yield: 92%) was obtained using 4-(6-chloro-3-(1-(2-fluoro-3-(methoxycarbonyl)phenyl)cyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid (50 mg, 0.10 mmol) and piperidine (8.9 mg, 0.10 mmol) obtained in step B of Example 67, in the same manner as in step C of Example 56.

[1316] MS[M+H]=549(M+1)

[1317] 1 H-NMR(500MHz, CDCl3)δ8.14(t,1H),7.85(t,1H),7.52(m,5H),7.18(m,2H),7.03(s ,1H),3.90(s,3H),3.72(m,2H),3.38(m,2H),1.69(m,6H),1.63(m,2H),1.56(m,2H)

[1318] Step B: 3-(1-(5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of (-1-yl)cyclopropyl)-2-fluorobenzoic acid

[1319] The title compound (48 mg, yield: 87%) was obtained using methyl 3-(1-(5-chloro-2-oxo-3-(4-(piperidin-1-carbonyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoate (53 mg, 0.096 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[1320] MS[M+H]=534(M+1)

[1321] 1H-NMR(500MHz, CDCl3)δ8.22(t,1H),7.95(t,1H),7.57(d,3H),7.54(d,2H),7.23(t,1H), 7.18(d,1H),7.05(s,1H),3.76(m,2H),3.41(m,2H),1.72(m,6H),1.65(m,2H),1.55(m,2H)

[1322] Example 69: Preparation of 3-(1-(5-chloro-3-(4-(dimethylamino)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoic acid

[1323]

[1324] The title compound (20 mg, yield: 38%) was obtained using methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate (40 mg, 0.117 mmol) and (4-dimethylamino)phenyl)boronic acid obtained in Preparation Example 3, in the same manner as in steps A and B of Example 1.

[1325] 1 H NMR(500MHz, CDCl3)δ7.96(d,1H),7.92(s,1H),7.56(d,1H),7.41(t,1H),7. 35(d,2H),7.09(dd,2H),7.03(s,1H),7.85(m,2H),3.04(s,6H),1.74(m,4H)

[1326] Example 70: Preparation of 3-(1-(5-chloro-3-(4-(dimethylamino)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoic acid

[1327]

[1328] The title compound (10 mg, yield: 19%) was obtained using methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoate (40 mg, 0.111 mmol) and (4-dimethylamino)phenyl)boronic acid obtained in Preparation Example 4, in the same manner as in steps A and B of Example 1.

[1329] 1H NMR(500MHz, CDCl3)δ8.26(t,1H),7.95(t,1H),7.53(d,1H),7.24(m,3H),7.14(d,1H),6.95(s,1H),6.81(d,2H),3.01(s,6H),1.69(m,4H)

[1330] Example 71: Preparation of 3-(1-(5-chloro-3-(4-(dimethylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoic acid

[1331]

[1332] The title compound (20 mg, yield: 36%) was obtained using methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate (40 mg, 0.117 mmol) and (4-dimethylcarbamoyl)phenyl)boronic acid obtained in Preparation Example 3, in the same manner as in steps A and B of Example 1.

[1333] 1 H NMR (500MHz, CDCl3) δ7.97(d,1H),7.94(s,1H),7.63(m,4H),7.55(d,1H),7.41(t,1H),7.15(m,3H),3.13(d,6H),1.74(m,4H).

[1334] Example 72: Preparation of 3-(1-(5-chloro-3-(4-(dimethylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoic acid

[1335]

[1336] The title compound (25 mg, yield: 46%) was obtained using methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoate (40 mg, 0.111 mmol) and (4-dimethylcarbamoyl)phenyl)boronic acid obtained in Preparation Example 4, in the same manner as in steps A and B of Example 1.

[1337] 1H NMR (500MHz, CDCl3) δ8.22(t,1H),7.95(t,1H),7.58(m,5H),7.23(t,1H),7.19(d,1H),7.05(s,1H),3.11(d,6H),1.69(m,4H)

[1338] Example 73: Preparation of 3-((5-chloro-2-oxo-3-(pyridin-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1339]

[1340] The procedure of steps A and B below gives the title compound.

[1341] Step A: 3-((5-chloro-2-oxo-3-(pyridin-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl Preparation of methyl benzoate

[1342] The title compound (11 mg, yield: 18%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (50 mg, 0.158 mmol) and pyridin-3-ylboronic acid (19.4 mg, 0.158 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[1343] MS[M+H]=394(M+1)

[1344] 1 H NMR(400MHz,CD3OD)δ8.89(s,1H),8.70(s,1H),8.04(s,1H),7.98(dt,1H),7.94(d,1H),7 .56(d,2H),7.42(t,1H),7.09(d,1H),7.04(dd,1H),6.82(d,1H),5.19(s,2H),3.90(s,3H)

[1345] Step B: 3-((5-chloro-2-oxo-3-(pyridin-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl Preparation of benzoic acid

[1346] The title compound (10 mg, yield: 94%) was obtained using methyl 3-((5-chloro-2-oxo-3-(pyridin-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (11 mg, 0.028 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[1347] MS[M+H]=380(M+1)

[1348] 1 H NMR(500MHz,DMSO-D6)δ8.80(d,1H),8.63(dd,1H),8.05(dq,1H),7.95(s,1H),7.82(d ,1H),7.60(dd,2H),7.44(t,1H),7.25(d,1H),7.15(dd,1H),7.10(d,1H),5.18(s,2H)

[1349] Example 74: Preparation of 3-((5-chloro-3-(6-fluoropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1350]

[1351] The procedure of steps A and B below gives the title compound.

[1352] Step A: 3-((5-chloro-3-(6-fluoropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Preparation of methyl methyl benzoate

[1353] The title compound (64 mg, yield: 41%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (120 mg, 0.379 mmol) and (6-fluoropyridin-3-yl)boronic acid (107 mg, 0.758 mmol) obtained in Preparation Example 1 in the same manner as in step A of Example 2.

[1354] MS[M+H]=412(M+1)

[1355] 1 H NMR(400MHz,CD3OD)δ8.45(s,1H),8.03(m,2H),7.98(d,1H),7.53(d,1H),7.42(t, 1H),7.15(dd,1H),7.07(d,1H),7.04(d,1H),6.84(d,1H),5.15(s,2H),3.90(s,3H)

[1356] Step B: 3-((5-chloro-3-(6-fluoropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Preparation of methylbenzoic acid

[1357] The title compound (58 mg, yield: 94%) was obtained using methyl 3-((5-chloro-3-(6-fluoropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (64 mg, 0.155 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[1358] MS[M+H]=398(M+1)

[1359] 1 H NMR(400MHz,DMSO-D6)δ8.49(d,1H),8.25(ddd,1H),7.96(s,1H),7.83(m,1H), 7.59(d,1H),7.44(t,1H),7.40(dd,1H),7.23(m,1H),7.14(m,2H),5.18(s,2H)

[1360] Example 75: Preparation of 3-((5-chloro-3-(6-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1361]

[1362] 2 mL of DMF was added to 3-((5-chloro-3-(6-fluoropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid (25 mg, 0.063 mmol) obtained in Example 74, followed by the addition of NaOH (2.41 mg, 0.101 mmol) at 0 °C, and stirring for 30 min. EtOH (4.34 mg, 0.094 mmol) was then added, and the resulting mixture was stirred at room temperature for 16 h. After the reaction was terminated, water was added, the organic layer was separated, and dehydrated over Na₂SO₄. The resulting solid was removed, and the filtrate was distilled under reduced pressure and then separated by MPLC, giving the title compound (17 mg, yield: 63%).

[1363] MS[M+H]=424(M+1)

[1364] 1 H NMR(400MHz,CD3OD)δ8.33(d,1H),7.94(s,1H),7.89(dd,1H),7.82(d,1H),7.57(d,1H),7.44(t, 1H),7.21(d,1H),7.12(dd,1H),6.98(d,1H),6.96(d,1H),5.16(s,2H),4.34(q,2H),1.32(t,3H)

[1365] Example 76: Preparation of 3-((5-chloro-2-oxo-3-(6-propoxypyridin-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1366]

[1367] The title compound (0.10 g, yield: 35%) was obtained using 6-chloro-1-(6-propoxypyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.20 g, 0.66 mmol) and methyl 3-(bromomethyl)benzoate (0.17 g, 0.72 mmol) obtained in Preparation Example 7 in the same manner as in steps A and B of Example 24.

[1368] MS[MH]=436(M-1)

[1369] 1 H-NMR(400MHz, CDCl3)δ8.32(d,1H),8.10(d,1H),8.03(dd,1H),7.74(dd,1H),7.60(m,1H),7.46(t,1H), 7.03(dd,1H),7.00(d,1H),6.91(d,1H),6.83(d,1H),5.17(s,2H),4.32(t,2H),1.83(m,2H),1.05(t,3H)

[1370] Example 77: Preparation of 3-((5-chloro-3-(6-(3-hydroxyazacyclobutane-1-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1371]

[1372] The procedure of steps A and B below gives the title compound.

[1373] Step A: 3-((5-chloro-3-(6-(3-hydroxyazacyclobutane-1-yl)pyridin-3-yl)-2-oxo-2,3-di Preparation of methyl 1H-benzo[d]imidazol-1-yl)methyl)benzoate

[1374] The title compound (0.020 g, yield: 27%) was obtained using methyl 3-((5-chloro-3-(6-fluoropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.065 g, 0.16 mmol) and aziridine-3-ol hydrochloride (0.052 g, 0.47 mmol) obtained in step A of Example 24 in the same manner as in step A of Example 24.

[1375] 1H-NMR (400MHz, CDCl3) δ8.28(m,1H),8.05(m,1H),7.97(m,1H),7.59(m,2H),7.43(m,1H),7.02(m,1H), 6.96(m,1H),6.80(m,1H),6.45(m,1H),5.15(s,2H),4.85(m,1H),4.38(m,2H),3.97(m,2H),3.92(s,3H)

[1376] Step B: 3-((5-chloro-3-(6-(3-hydroxyazacyclobutane-1-yl)pyridin-3-yl)-2-oxo-2,3-di Preparation of hydrogen-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1377] The title compound (0.01 g, yield: 52%) was obtained using methyl 3-((5-chloro-3-(6-(3-hydroxyazacyclobutane-1-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.02 g, 0.043 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1378] MS[M+H]=451(M+1)

[1379] 1 H-NMR(400MHz,MeOH-d4)δ8.18(d,1H),7.03(d,1H),7.96(dd,1H),7.69(dd,1H),7,61(dd,1H),7. 47(t,1H),7.10(2H),6.95(d,1H),6.61(d,1H),5.22(s,2H),4.70(m,1H),4.35(m,2H),3.91(m,2H)

[1380] Example 78: Preparation of 3-((5-chloro-3-(6-morpholinopyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1381]

[1382] The procedure of steps A and B below gives the title compound.

[1383] Step A: 3-((5-chloro-3-(6-morpholinopyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol- Preparation of methyl 1-yl)methyl)benzoate

[1384] The title compound (0.063 g, yield: 45%) was obtained using methyl 3-((5-chloro-3-(6-fluoropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.12 g, 0.29 mmol) and morpholine (0.051 g, 0.58 mmol) obtained in step A of Example 24 in the same manner as in step A of Example 24.

[1385] 1 H-NMR(400MHz, CDCl3)δ8.33(dd,1H),8.05(d,1H),7.98(dd,1H),7.65(dd,1H),7.56(dd, 1H),7.43(t,1H),7.00(2H),6.78(2H),5.15(s,2H),3.92(s,3H),3.85(m,4H),3.59(m,4H)

[1386] Step B: 3-((5-chloro-3-(6-morpholinopyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol- Preparation of 1-yl)methyl)benzoic acid

[1387] The title compound (0.052 g, 89%) was obtained using methyl 3-((5-chloro-3-(6-morpholinopyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.06 g, 0.12 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1388] MS[M+H]=465(M+1)

[1389] 1 H-NMR(400MHz, CDCl3)δ8.34(d,1H),8.09(d,1H),8.03(dd,1H),7.65(dd,1H),7.60(dd,1H ),7.49(t,1H),7.03(dd,1H),7.01(d,1H),6.80(2H),5.17(s,2H),3.86(m,4H),3.50(m,4H)

[1390] Example 79: Preparation of 3-((5-chloro-3-(6-(dimethylamino)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1391]

[1392] The procedure of steps A and B below gives the title compound.

[1393] Step A: 3-((5-chloro-3-(6-(dimethylamino)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of methyl imidazole-1-yl)methyl)benzoate

[1394] The title compound (0.022 g, yield: 30%) was obtained using methyl 3-((5-chloro-3-(6-fluoropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.07 g, 0.17 mmol) and dimethylamine hydrochloride (0.042 g, 0.51 mmol) obtained in step A of Example 24 in the same manner as in step A of Example 24.

[1395] 1 H-NMR(400MHz, CDCl3)δ8.28(dd,1H),8.06(m,1H),8.00(dd,1H),7.55(2H),7.43( t,1H),6.98(2H),6.78(d,1H),6.64(dd,1H),5.15(s,2H),3.92(s,3H),3.15(s,6H)

[1396] Step B: 3-((5-chloro-3-(6-(dimethylamino)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of imidazole-1-yl)methyl)benzoic acid

[1397] The title compound (0.018 g, yield: 85%) was obtained using methyl 3-((5-chloro-3-(6-(dimethylamino)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.022 g, 0.05 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1398] MS[M+H]=423(M+1)

[1399] 1 H-NMR(400MHz, CDCl3)δ8.35(d,1H),8.07(d,1H),8.02(dd,1H),7.70(m,1H),7.59(dd,1H), 7.45(t,1H),7.03(dd,1H),7.00(d,1H),6.83(d,1H),6.74(m,1H),5.16(s,2H),3.25(s,6H)

[1400] Example 80: Preparation of 3-((5-chloro-3-(6-(3,3-difluoropyrrolidone-1-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1401]

[1402] The title compound (0.005 g, yield: 23%) was obtained using methyl 3-((5-chloro-3-(6-fluoropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.07 g, 0.17 mmol) and 3,3-difluoropyrrolidine hydrochloride (0.066 g, 0.51 mmol) obtained in step A of Example 74, in the same manner as in steps A and B of Example 24.

[1403] MS[M+H]=485(M+1)

[1404] 1 H-NMR(400MHz, CDCl3)δ8.34(d,1H),8.09(d,1H),8.03(dd,1H),7.65(dd,1H),7.60(dd,1H),7.46(t,1H) ,7.02(dd,1H),6.97(d,1H),6.81(d,1H),6.53(d,1H),5.17(s,2H),3.92(t,2H),3.76(t,2H),2.54(m,2H)

[1405] Example 81: Preparation of 3-((5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1406]

[1407] The procedure of steps A and B below gives the title compound.

[1408] Step A: 3-((5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzene) Preparation of [d]imidazol-1-yl)methyl)benzoate

[1409] The title compound (0.033 g, yield: 40%) was obtained using methyl 3-((5-chloro-3-(6-fluoropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.07 g, 0.17 mmol) and 1-methylpiperazine (0.051 g, 0.051 mmol) obtained in step A of Example 74 in the same manner as in step A of Example 24.

[1410] 1H-NMR (400MHz, CDCl3) δ8.31(d,1H),8.05(d,1H),7.97(dd,1H),7.63(dd,1H),7.56(dd,1H),7. 42(t,1H),7.00(2H),6.78(2H),5.15(s,2H),3.92(s,3H),3.66(m,4H),2.55(m,4H),2.37(s,3H)

[1411] Step B: 3-((5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzene) Preparation of [d]imidazol-1-yl)methyl)benzoic acid

[1412] The title compound (0.028 g, 85%) was obtained using methyl 3-((5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.033 g, 0.067 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1413] MS[M+H]=478(M+1)

[1414] 1 H-NMR(400MHz,DMSO-d6)δ8.26(d,1H),7.96(d,1H),7.84(dd,1H),7.71(dd,1H),7.60(dd,1H),7.50(t,1H ),7.20(d,1H),7.13(d,1H),7.01(d,1H),6.93(d,1H),5.18(s,2H),3.60(m,4H),2.52(m,4H),2.31(s,3H)

[1415] Example 82: Preparation of 3-((5-chloro-3-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1416]

[1417] The procedure of steps A and B below gives the title compound.

[1418] Step A: 3-((5-chloro-3-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H- Preparation of methyl benzo[d]imidazol-1-yl)methyl)benzoate

[1419] The title compound (0.032 g, yield: 37%) was obtained using methyl 3-((5-chloro-3-(6-fluoropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.07 g, 0.17 mmol) and 4,4-difluoropiperidine hydrochloride (0.070 g, 0.51 mmol) obtained in step A of Example 24 in the same manner as in step A of Example 24.

[1420] 1 H-NMR(400MHz, CDCl3)δ8.32(d,1H),8.05(d,1H),7.98(dd,1H),7.65(dd,1H),7.55(dd,1H),7.4 3(t,1H),7.02(2H),6.85(d,1H),6.80(d,1H),5.15(s,2H),3.92(s,3H),3.82(m,4H),2.05(m,4H)

[1421] Step B: 3-((5-chloro-3-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H- Preparation of benzo[d]imidazol-1-yl)methyl)benzoic acid

[1422] The title compound (10 mg, yield: 32%) was obtained using methyl 3-((5-chloro-3-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.032 g, 0.17 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1423] MS[M+H]=499(M+1)

[1424] 1 H-NMR(400MHz, CDCl3)δ8.33(d,1H),8.10(d,1H),8.04(dd,1H),7.66(dd,1H),7.63(dd,1H),7.46( t,1H),7.03(dd,1H),7.00(d,1H),6.85(d,1H),6.82(d,1H),5.18(s,2H),3.82(m,4H),2.05(m,4H)

[1425] Example 83: Preparation of 3-((5-chloro-3-(2-morpholinopyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1426]

[1427] The title compound (0.040 g, yield: 63%) was obtained using 6-chloro-1-(2-morpholinopyrimidin-5-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.045 g, 0.136 mmol) and methyl 3-(bromomethyl)benzoate (0.031 g, 0.136 mmol) obtained in Preparation Example 26 in the same manner as in steps A and B of Example 24.

[1428] MS[M+H]=466(M+1)

[1429] 1 H-NMR(400MHz,MeOH-d4)δ8.52(s,2H),8.03(d,1H),7.95(dd,1H),7.60(dd,1H ),7.47(t,1H),7.11(m,2H),7.01(d,1H),5.22(s,2H),3.88(m,4H),3.77(m,4H)

[1430] Example 84: Preparation of 3-((5-chloro-2-oxo-3-(1-propyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1431]

[1432] The procedure of steps A and B below gives the title compound.

[1433] Step A: 3-((5-chloro-2-oxo-3-(1-propyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)benzoate

[1434] The title compound (0.011 g, yield: 46%) was obtained using 6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.015 g, 0.054 mmol) and methyl 3-(bromomethyl)benzoate (0.013 g, 0.054 mmol) obtained in Preparation Example 12 in the same manner as in step A of Example 21.

[1435] 1 H-NMR(500MHz, CDCl3)δ8.00(2H),7.82(s,1H),7.78(s,1H),7.53(m,1H),7.40(m,1H),7.11(s, 1H),7.02(d,1H),6.79(d,1H),5.14(s,2H),4.16(t,2H),3.91(s,3H),1.97(m,2H),0.99(t,3H)

[1436] Step B: 3-((5-chloro-2-oxo-3-(1-propyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of 1-azolyl)methyl)benzoic acid

[1437] The title compound (5 mg, yield: 61%) was obtained using methyl 3-((5-chloro-2-oxo-3-(1-propyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (8.5 mg, 0.02 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1438] MS[M+H]=411(M+1)

[1439] 1 H-NMR (400MHz, CDCl3) δ8.00(m,1H),7.97(m,1H),7.75(s,1H),7.75(s,1H),7.48(m,1H),7.40(m ,1H),7.08(m,1H),7.00(m,1H),6.78(m,1H),5.11(s,2H),4.12(t,2H),1.94(m,2H),0.96(t,3H)

[1440] Example 85: Preparation of 3-((5-cyclopropyl-2-oxo-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1441]

[1442] The title compound (0.020 g, yield: 20%) was obtained using 6-cyclopropyl-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.075 g, 0.23 mmol) and methyl 3-(bromomethyl)benzoate (0.064 g, 0.28 mmol) obtained in Preparation Example 17 in the same manner as in steps A and B of Example 24.

[1443] MS[M+H]=459(M+1)

[1444] 1H-NMR (400MHz, CDCl3) δ8.10(m,1H),8.01(m,1H),7.91(s,1H),7.83(s,1H),7.58(m,1H),7.43(t,1H),6.88(m,1H), 6.80(m,2H),5.15(s,2H),4.42(m,1H),4.15(m,2H),3.57(m,2H),2.17(m,4H),1.90(m,1H),0.92(m,2H),0.63(m,2H)

[1445] Example 86: Preparation of 3-((5-chloro-2-oxo-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1446]

[1447] The procedure of steps A and B below gives the title compound.

[1448] Step A: 3-((5-chloro-2-oxo-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-2,3-di Preparation of methyl 1H-benzo[d]imidazol-1-yl)methyl)benzoate

[1449] The title compound (0.090 g, yield: 56%) was obtained using 6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.11 g, 0.34 mmol) and methyl 3-(bromomethyl)benzoate (0.10 g, 0.45 mmol) obtained in Preparation Example 9 in the same manner as in step A of Example 24.

[1450] 1 H-NMR (400MHz, CDCl3) δ8.03(m,1H),7.98(dd,1H),7.87(s,1H),7.80(s,1H),7.53(dd,1H),7.42(t,1H),7.11( d,1H),7.03(dd,1H),6.80(d,1H),5.14(s,2H),4.40(m,1H),4.14(m,2H),3.91(s,3H),3.60(m,2H),2.15(m,4H)

[1451] Step B: 3-((5-chloro-2-oxo-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-2,3-di Preparation of hydrogen-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1452] The title compound (0.035 g, yield: 40%) was obtained using methyl 3-((5-chloro-2-oxo-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.09 g, 0.19 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1453] MS[M+H]=453(M+1)

[1454] 1 H-NMR(400MHz, CDCl3)δ8.19(d,1H),8.03(dd,1H),7.89(s,1H),7.81(s,1H),7.58(m,1H),7.48(t,1H), 7.12(d,1H),7.06(dd,1H),6.82(d,1H),5.17(s,2H),4.41(m,1H),4.14(m,2H),3.58(m,2H),2.17(m,4H)

[1455] Example 87: Preparation of 3-((5-chloro-2-oxo-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1456]

[1457] The procedure of steps A, B, and C below gives the title compound.

[1458] Step A: Preparation of N-(5-chloro-2-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-amine

[1459] N-(5-chloro-2-nitrophenyl)-1H-pyrazole-4-amine (0.16 g, 0.67 mmol) obtained in Preparation Example 10 was dissolved in 3 mL of DMF, cooled to 0 °C, and NaH (0.021 g, 0.87 mmol) was added. The resulting mixture was then stirred for 20 min. 2,2,2-trifluoroethyl 4-methylbenzenesulfonic acid (0.20 g, 0.80 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 16 h. After the reaction was terminated, an aqueous solution of ammonium chloride was added, and the resulting solution was extracted with EtOAc. The organic layer was separated and purified by MPLC, giving the title compound (0.069 g, yield: 32%).

[1460] 1H-NMR(400MHz, CDCl3)δ9.19(brs,1H),8.16(d,1H),7.63(s,1H),7.60(s,1H),6.75(d,1H),6.73(dd,1H),4.74(q,2H)

[1461] Step B: 6-Chloro-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazolium Preparation of 2-oxazolone

[1462] The title compound (0.024 g, yield: 37%) was obtained using N-(5-chloro-2-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-amine (0.065 g, 0.20 mmol) obtained in step A above, in the same manner as in step B of Preparation Example 7 and step C of Preparation Example 3.

[1463] 1 H-NMR(400MHz, CDCl3)δ8.19(brs,1H),7.97(s,1H),7.90(s,1H),7.12(2H),7.00(d,1H),4.78(q,2H)

[1464] Step C: 3-((5-chloro-2-oxo-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-2,3-dihydro- Preparation of 1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1465] The title compound (0.010 g, yield: 29%) was obtained using 6-chloro-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.024 g, 0.076 mmol) and methyl 3-(bromomethyl)benzoate (0.017 g, 0.076 mmol) obtained in step B above, in the same manner as in steps A and B of Example 24.

[1466] MS[M+H]=451(M+1)

[1467] 1 H-NMR (400MHz, CDCl3) δ8.17-8.02(3H),7.92(s,1H),7.58(m,1H),7.47(m,1H),7.15(d,1H),7.06(dd,1H),6.83(d,1H),5.15(s,2H),4.80(q,2H)

[1468] Example 88: Preparation of 3-((5-chloro-4-fluoro-2-oxo-3-(1-propyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1469]

[1470] The title compound (0.097 g, yield: 80%) was obtained using 6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.083 g, 0.28 mmol) and methyl 3-(bromomethyl)benzoate (0.065 g, 0.28 mmol) obtained in Preparation Example 13 in the same manner as in steps A and B of Example 24.

[1471] MS[M+H]=430(M+1)

[1472] 1 H-NMR(400MHz,MeOH-d4)δ8.03(m,1H),8.01(m,1H),7.95(dd,1H),7.74(d,1H),7.57(m,1H) ,7.47(t,1H),7.16(dd,1H),6.94(d,1H),5.21(s,2H),4.18(t,2H),1.92(m,2H),0.95(t,3H)

[1473] Example 89: Preparation of 3-((5-chloro-3-(1-isopropyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1474]

[1475] The procedure of steps A and B below gives the title compound.

[1476] Step A: 3-((5-chloro-3-(1-isopropyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of methyl 1-azolyl)methyl)benzoate

[1477] The title compound (15.4 mg, yield: 67%) was obtained using 6-chloro-1-(1-isopropyl-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (15.6 mg, 0.054 mmol) and methyl 3-(bromomethyl)benzoate obtained in Preparation Example 18 in the same manner as in step A of Example 1.

[1478] MS[M+H]=425(M+1)

[1479] Step B: 3-((5-chloro-3-(1-isopropyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Preparation of 1-azolyl)methyl)benzoic acid

[1480] The title compound (9.9 mg, yield: 68%) was obtained using methyl 3-((5-chloro-3-(1-isopropyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (15.4 mg, 0.035 mmol) obtained in step A above, in the same manner as in step B of Example 1.

[1481] MS[M+H]=411(M+1)

[1482] 1 H NMR(400MHz, CDCl3)δ8.09(s,1H),8.04(d,1H),7.87(s,1H),7.80(s,1H),7.59(d,1H),7 .46(t,1H),7.12(m,1H),7.04(m,1H),6.83(d,1H),5.16(s,1H),4.63(m,1H),1.59(d,6H)

[1483] Example 90: Preparation of 3-((5-chloro-3-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1484]

[1485] The procedure of steps A and B below gives the title compound.

[1486] Step A: 3-((5-chloro-3-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-1H-benzene) Preparation of [d]imidazol-1-yl)methyl)benzoate

[1487] The title compound (52.1 mg, yield: 63%) was obtained using 6-chloro-1-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (55.3 mg, 0.19 mmol) and methyl 3-(bromomethyl)benzoate obtained in Preparation Example 19, in the same manner as in step A of Preparation Example 1.

[1488] MS[M+H]=437(M+1)

[1489] Step B: 3-((5-chloro-3-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-1H-benzene) Preparation of [d]imidazol-1-yl)methyl)benzoic acid

[1490] The title compound (25.6 mg, yield: 52%) was obtained using methyl 3-((5-chloro-3-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (52.1 mg, 0.12 mmol) obtained in step A above, in the same manner as in step B of Example 1.

[1491] MS[M+H]=423(M+1)

[1492] 1 H NMR(500MHz, CDCl3)δ8.07(s,1H),8.03(d,1H),7.95(s,1H),7.78(s,1H),7.59(d,1H),7.47(m,1H),7 .13(s,1H),7.04(d,1H),6.81(d,1H),5.16(s,2H),4.07(d,2H),1.36(m,1H),0.88(m,2H),0.45(m,2H)

[1493] Example 91: Preparation of 3-((5-chloro-3-(1-cyclobutylmethyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1494]

[1495] The procedure of steps A and B below gives the title compound.

[1496] Step A: 3-((5-chloro-3-(1-(cyclobutylmethyl)-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-1H-benzene) Preparation of [d]imidazol-1-yl)methyl)benzoate

[1497] The title compound (10.1 mg, yield: 68%) was obtained using 6-chloro-1-(1-(cyclobutylmethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (10.6 mg, 0.033 mmol) and methyl 3-(bromomethyl)benzoate obtained in Preparation Example 20, in the same manner as in step A of Example 1.

[1498] MS[M+H]=451(M+1)

[1499] 1H NMR(500MHz, CDCl3)δ8.02(s,1H),7.97(d,2H),7.79(m,2H),7.54(m,1H),7.43(m,1H),7.11(s,1H),7 .02(d,1h),6.79(d,1H),5.14(s,2H),4.21(d,2H),3.91(s,3H),2.91(m,1H),2.16(m,2H),1.97(m,4H)

[1500] Step B: 3-((5-chloro-3-(1-(cyclobutylmethyl)-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-1H-benzene) Preparation of [d]imidazol-1-yl)methyl)benzoic acid

[1501] The title compound (7.6 mg, yield: 79%) was obtained using methyl 3-((5-chloro-3-(1-(cyclobutylmethyl)-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (10.1 mg, 0.022 mmol) obtained in step A above, in the same manner as in step B of Example 1.

[1502] MS[M+H]=437(M+1)

[1503] 1 H NMR(500MHz, CDCl3)δ8.08(s,1H),8.04(d,1H),7.80(d,2H),7.58(d,2H),7.46(t,1H),7.12(s, 1H),7.04(d,1H),6.82(d,1H),5.16(s,2H),4.22(d,2H),2.92(m,1H),2.14(m,2H),1.96(m,4H)

[1504] Example 92: Preparation of 3-((5-chloro-4-fluoro-2-oxo-3-(1-propyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1505]

[1506] The title compound (0.052 g, yield: 61%) was obtained using 6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.056 g, 0.19 mmol) and methyl 3-(bromomethyl)-2-fluorobenzoate (0.047 g, 0.190 mmol) obtained in Preparation Example 12 in the same manner as in steps A and B of Example 24.

[1507] MS[M+H]=447(M+1)

[1508] 1 H-NMR(500MHz,DMSO-d6)δ13.5(brs,1H),8.13(m,1H),7.69(s,1H),7.65(m,1H),7.28(m,1H ),7.25(m,1H),7.16(m,1H),7.07(m,1H),5.17(s,2H),4.11(t,2H),1.82(m,2H),0.84(t,3H)

[1509] Example 93: Preparation of 3-(1-(3-(4-(7-oxa-2-azaspiro[3.5]nonane-2-carbonyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoic acid

[1510]

[1511] The procedure of steps A and B below gives the title compound.

[1512] Step A: 3-(1-(3-(4-(7-oxa-2-azaspiro[3.5]nonane-2-carbonyl)phenyl)-5-chloro-2-oxo- Preparation of methyl 2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate

[1513] The title compound (63 mg, yield: 51%) was obtained in the same manner as in step C of Example 56 using 4-(6-chloro-3-(1-(3-(methoxycarbonyl)phenyl)cyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid (100 mg, 0.22 mmol) and 7-oxa-2-azaspiro[3.5]nonane (32 mg, 0.26 mmol) obtained in step B of Example 63.

[1514] 1 H NMR (400MHz, CDCl3) δ7.91(m,1H),7.89(m,1H),7.83(d,2H),7.62(d,2H),76.49(m,1H),7.37( t,1H),7.13(3H),4.13(s,2H),4.03(s,2H),3.91(s,3H),3.65(m,4H),1.84(m,4H),1.70(m,4H)

[1515] Step B: 3-(1-(3-(4-(7-oxa-2-azaspiro[3.5]nonane-2-carbonyl)phenyl)-5-chloro-2-oxo- Preparation of 2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoic acid

[1516] The title compound (43 mg, 70% yield) was obtained using methyl 3-(1-(3-(4-(7-oxa-2-azaspiro[3.5]nonane-2-carbonyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate (63 mg, 0.11 mmol) obtained in step A above, in the same manner as in step B of Example 2.

[1517] 1 H NMR(400MHz,DMSO-d6)δ7.87(d,2H),7.85(m,1H),7.68(3H),7.45(2H),7.28(d ,1H),7.21(m,1H),7.15(m,1H),4.14(s,2H),3.83(s,2H),3.53(4H),1.70(8H)

[1518] Example 94: Preparation of 3-((5-chloro-3-(4-(4,4-difluoropiperidin-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1519]

[1520] The procedure of steps A and B below gives the title compound.

[1521] Step A: 3-((5-chloro-3-(4-(4,4-difluoropiperidin-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoate methyl benzoate

[1522] The title compound (0.35 g, yield: 99%) was obtained using 6-chloro-1-(4-(4,4-difluoropiperidin-1-yl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.25 g, 0.68 mmol) and methyl 3-(bromomethyl)benzoate (0.16 g, 0.68 mmol) obtained in Preparation Example 28 in the same manner as in step A of Example 24.

[1523] 1 H-NMR(400MHz, CDCl3)δ8.05(d,1H),7.97(dd,1H),7.56(dd,1H),7.43(d,1H),7.40(d,2H) ,7.07(d,2H),7.00(d,2H),6.78(d,1H),5.15(s,2H),3.92(s,3H),3.44(m,4H),2.12(m,4H)

[1524] Step B: 3-((5-chloro-3-(4-(4,4-difluoropiperidin-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoic acid

[1525] The title compound (0.34 g, yield: 99%) was obtained using methyl 3-((5-chloro-3-(4-(4,4-difluoropiperidin-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.35 g, 0.68 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1526] MS[M+H]=498(M+1)

[1527] 1 H-NMR(400MHz,DMSO-d6)δ7.96(d,1H),7.85(dd,1H),7.60(dd,1H),7.47(t,1H),7.39(d,2H) ,7.23(d,1H),7.18(d,2H),7.13(dd,1H),6.92(d,1H),5.19(s,2H),3.45(m,4H),2.08(m,4H)

[1528] Example 95: Preparation of 3-((5-chloro-3-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1529]

[1530] The procedure of steps A and B below gives the title compound.

[1531] Step A: 3-((5-chloro-3-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenyl)-2-oxo-2,3-dihydro- Preparation of methyl 1H-benzo[d]imidazol-1-yl)methyl)benzoate

[1532] The title compound (0.083 g, yield: 78%) was obtained using methyl benzoate hydrochloride (0.10 g, 0.19 mmol) of 3-((5-chloro-2-oxo-3-(4-(piperazin-1-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate obtained in Preparation Example 29 and cyclopropane carbonyl chloride (0.022 g, 0.21 mmol), in the same manner as in step C of Example 26.

[1533] 1H-NMR(400MHz, CDCl3)δ8.05(d,1H),7.97(dd,1H),7.56(dd,1H),7.42(3H),7.06(d,2H),7.00(2H),6 .79(d,1H),5.15(s,2H),3.92(s,3H),3.88(m,4H),3.28(m,4H),1.80(m,1H),1.04(m,2H),0.81(m,2H)

[1534] Step B: 3-((5-chloro-3-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenyl)-2-oxo-2,3-dihydro- Preparation of 1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1535] The title compound (0.065 g, yield: 80%) was obtained using methyl 3-((5-chloro-3-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.083 g, 0.15 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1536] MS[M+H]=531(M+1)

[1537] 1 H-NMR(400MHz, CDCl3)δ8.10(d,1H),8.01(dd,1H),7.59(dd,1H),7.45(3H),7.12(d,2H),7.02( 2H),6.82(d,1H),5.18(s,2H),3.91(m,4H),3.31(m,4H),1.80(m,1H),1.06(m,2H),0.84(m,2H)

[1538] Example 96: Preparation of 3-((5-chloro-3-(4-(4-(isopropoxycarbonyl)piperazin-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1539]

[1540] The procedure of steps A and B below gives the title compound.

[1541] Step A: 3-((5-chloro-3-(4-(4-(isopropoxycarbonyl)piperazin-1-yl)phenyl)-2-oxo-2,3-dihydro- Preparation of methyl 1H-benzo[d]imidazol-1-yl)methyl)benzoate

[1542] Add 3 mL of DCM and 0.068 mL of DIPEA (0.39 mmol) to triphosgene (0.058 g, 0.19 mmol), and then cool the resulting mixture to 0 °C. Slowly add 2-propanol (0.030 mL, 0.39 mmol), and then stir the resulting mixture at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, and then add 5 mL of DCM, methyl 3-((5-chloro-2-oxo-3-(4-(piperazin-1-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate hydrochloride (0.10 g, 0.19 mmol), and DIPEA (0.068 mL, 0.39 mmol) obtained in Preparative Example 29, and then stir at room temperature for 1 hour. Add water to the reaction solution, and then separate the organic layer and purify by MPLC to give the title compound (0.044 g, yield: 40%).

[1543] 1 H-NMR(400MHz, CDCl3)δ8.05(d,1H),7.97(dd,1H),7.55(dd,1H),7.42(3H),7.05(d,2H),7.00( 2H),6.79(d,1H),5.15(s,2H),4.97(m,1H),3.92(s,3H),3.66(m,4H),3.23(m,4H),1.27(d,6H)

[1544] Step B: 3-((5-chloro-3-(4-(4-(isopropoxycarbonyl)piperazin-1-yl)phenyl)-2-oxo-2,3-dihydro- Preparation of 1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1545] The title compound (0.032 g, yield: 83%) was obtained using methyl 3-((5-chloro-3-(4-(4-(isopropoxycarbonyl)piperazin-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.044 g, 0.075 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1546] MS[MH]=547(M-1)

[1547] 1 H-NMR(400MHz, CDCl3)δ8.11(d,1H),8.03(dd,1H),7.60(dd,1H),7.45(t,1H),7.41(d,2H),7.06 (d,2H),7.01(2H),6.81(d,1H),5.18(s,2H),4.98(m,1H),3.66(m,4H),3.22(m,4H),1.28(d,6H)

[1548] Example 97: Preparation of 3-((5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1549]

[1550] The procedure of steps A and B below gives the title compound.

[1551] Step A: 3-((5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of methyl imidazole-1-yl)methyl)benzoate

[1552] 6 mL of dichloroethane, paraformaldehyde (0.044 g, 1.46 mmol), and acetic acid (0.033 mL, 0.58 mmol) were added to methyl 3-((5-chloro-2-oxo-3-(4-(piperazin-1-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate hydrochloride (0.15 g, 0.29 mmol) obtained in Preparation Example 29, and the resulting mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (0.155 g, 0.73 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the filtrate to separate the organic layer, which was then dehydrated on anhydrous Na₂SO₄ to give the title compound (0.075 g, yield: 52%).

[1553] 1 H-NMR (400MHz, CDCl3) δ8.05(d,1H),7.97(dd,1H),7.55(dd,1H),7.42(t,1H),7.38(d,2H),7. 05(d,2H),7.00(2H),6.78(d,1H),5.15(s,2H),3.91(s,3H),3.32(4H),2.65(4H),2.40(s,3H)

[1554] Step B: 3-((5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]) Preparation of imidazole-1-yl)methyl)benzoic acid

[1555] The title compound (0.044 g, yield: 60%) was obtained using methyl 3-((5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (0.075 g, 0.15 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1556] MS[M+H]=477(M+1)

[1557] 1 H-NMR(400MHz,DMSO-d6)δ7.96(d,1H),7.86(dd,1H),7.61(dd,1H),7.49(t,1H),7.37(d,2 H),7.23(d,1H),7.12(3H),6.91(d,1H),5.20(s,2H),3.25(m,4H),2.55(m,4H),2.29(s,3H)

[1558] Example 98: Preparation of 3-(1-(5-chloro-3-(4-cyclohexylphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoic acid

[1559]

[1560] The title compound (20 mg, yield: 28%) was obtained using methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate (50 mg, 0.145 mmol) and (4-cyclohexylphenyl)boronic acid (59 mg, 0.29 mmol) obtained in Preparation Example 3 in the same manner as in steps A and B of Example 1.

[1561] 1 H-NMR (400MHz, CDCl3) δ7.97(d,1H),7.94(s,1H),7.57(d,1H),7.41(m,5H),7.13(m,3H),2.60(m,1H),1.92(m,4H),1.75(m,6H),1.45(m,4H).

[1562] Example 99: Preparation of 3-(1-(5-chloro-2-oxo-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoic acid

[1563]

[1564] The procedure of steps A and B below gives the title compound.

[1565] Step A: 3-(1-(5-chloro-2-oxo-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,3-dihydro-1H-benzene Preparation of [d]imidazol-1-yl)cyclopropyl)benzoate methyl ester

[1566] The title compound (58 mg, yield: 50%) was obtained using methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate (78 mg, 0.23 mmol) and (4-(tetrahydro-2H-pyran-4-yl)boronic acid (60 mg, 0.29 mmol) obtained in Preparation Example 3, in the same manner as in step A of Example 1.

[1567] 1 H-NMR(400MHz, CDCl3)δ8.05(d,1H),7.98(dd,1H),7.56(dd,1H),7.48(d,2H),7.40(3H),7.01(d,1H),7 .03(dd,1H),6.81(d,1H),5.16(s,2H),4.11(m,2H),3.82(s,3H),3.58(m,2H),2.85(m,1H),1.83(m,4H)

[1568] Step B: 3-(1-(5-chloro-2-oxo-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,3-dihydro-1H-benzene Preparation of [d]imidazol-1-yl)cyclopropyl)benzoic acid

[1569] The title compound (46 mg, yield: 82%) was obtained using methyl 3-(1-(5-chloro-2-oxo-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)benzoate (58 mg, 0.115 mmol) obtained in step A above, in the same manner as in step B of Example 1.

[1570] 1 H-NMR(400MHz, CDCl3)δ7.94(dd,1H),7.91(d,1H),7.54(dd,1H),7.47(d,2H),7.40(3H),7.13 (d,1H),7.08(2H),4.10(m,2H),3.56(m,2H),2.83(m,1H),1.85(4H),1.74(m,2H),1.68(m,2H)

[1571] Example 100: Preparation of 3-((5-chloro-3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1572]

[1573] The procedure of steps A and B below gives the title compound.

[1574] Step A: 3-((5-chloro-3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)phenyl)-2-oxo-2,3-dihydro- Preparation of methyl 1H-benzo[d]imidazol-1-yl)methyl)benzoate

[1575] 2 mL of DCM, 19 μL of cyclopropane carbonyl chloride, and 85 μL of DIPEA (0.49 mmol) were added to methyl 3-((5-chloro-2-oxo-3-(4-(piperidin-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate hydrochloride (0.10 g, 0.19 mmol) obtained in Preparative Example 30. The resulting mixture was then stirred at room temperature for 1 hour. Water was added to the reaction solution and the organic layer was separated, followed by purification by MPLC to give the title compound (0.095 g, yield: 89%).

[1576] 1 H-NMR(400MHz, CDCl3)δ8.05(d,1H),7.98(dd,1H),7.56(dd,1H),7.48(d,2 H),7.43(t,1H),7.39(d,2H),7.07(d,1H),7.02(dd,1H),6.81(d,1H),5.16 (s,2H),4.82(m,1H),4.40(m,1H),3.91(s,3H),3.24(m,1H),2.87(m,1H),2 .70(m,1H),1.98(m,2H),1.81(m,1H),1.71(m,2H),1.02(m,2H),0.79(m,2H)

[1577] Step B: 3-((5-chloro-3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)phenyl)-2-oxo-2,3-dihydro- Preparation of 1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1578] The title compound (74 mg, yield: 80%) was obtained using methyl 3-((5-chloro-3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (95 mg, 0.17 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1579] MS[M+H]=530(M+1)

[1580] 1H-NMR (400MHz, CDCl3) δ8.11(d,1H),8.03(dd,1H),7.60(dd,1H),7.46(3H),7.39(d,2H),7.08(d,1H),7.04(dd,1H),6.83(d,1H),5.18( s,2H),4.80(m,1H),4.40(m,1H),3.20(m,1H),2.87(m,1H),2.70(m,1H),1.96(m,2H),1.81(m,1H),1.70(m,2H),1.04(m,2H),0.80(m,2H)

[1581] Example 101: Preparation of 3-((5-chloro-3-(4-(1-(cyclobutanecarbonyl)piperidin-4-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1582]

[1583] The procedure of steps A and B below gives the title compound.

[1584] Step A: 3-((5-chloro-3-(4-(1-(cyclobutanecarbonyl)piperidin-4-yl)phenyl)-2-oxo-2,3-dihydro- Preparation of methyl 1H-benzo[d]imidazol-1-yl)methyl)benzoate

[1585] 2 mL of DCM, cyclobutanecarboxylic acid (21 mg, 0.22 mmol), HATU (82 mg, 0.22 mmol), and DIPEA (85 μL, 0.49 mmol) were added to methyl 3-((5-chloro-2-oxo-3-(4-(piperidin-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate hydrochloride (100 mg, 0.19 mmol) obtained in Preparative Example 30. The resulting mixture was then stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and then purified by MPLC to give the title compound (90 mg, yield: 83%).

[1586] 1H-NMR(400MHz, CDCl3)δ8.05(d,1H),7.98(dd,1H),7.56(dd,1H),7.48(d,2 H),7.45(t,1H),7.36(d,2H),7.07(d,1H),7.02(dd,1H),6.80(d,1H),5.16 (s,2H),4.81(m,1H),3.92(s,3H),3.87(m,1H),3.30(m,1H),3.08(m,1H),2 .82(m,1H),2.66(m,1H),2.38(m,2H),2.20(m,1H),1.94(m,4H),1.60(m,3H)

[1587] Step B: 3-((5-chloro-3-(4-(1-(cyclobutanecarbonyl)piperidin-4-yl)phenyl)-2-oxo-2,3-dihydro- Preparation of 1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1588] The title compound (88 mg, yield: 99%) was obtained using methyl 3-((5-chloro-3-(4-(1-(cyclobutanecarbonyl)piperidin-4-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (90 mg, 0.16 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1589] MS[M+H]=544(M+1)

[1590] 1 H-NMR (400MHz, CDCl3) δ8.10(d,1H),8.03(dd,1H),7.60(dd,1H),7.46(3H),7.36(d,2H),7.07(d,1H),7.03(dd,1H),6.82(d,1H),5.18 (s,2H),4.80(m,1H),3.85(m,1H),3.32(m,1H),3.08(m,1H),2.82(m,1H),2.67(m,1H),2.40(m,2H),2.17(m,2H),1.92(4H),1.62(m,2H)

[1591] Example 102: Preparation of 3-((5-chloro-2-oxo-3-(4-(1-propionylpiperidin-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1592]

[1593] The procedure of steps A and B below gives the title compound.

[1594] Step A: 3-((5-chloro-2-oxo-3-(4-(1-propionylpiperidin-4-yl)phenyl)-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoate methyl benzoate

[1595] 2 mL of DCM, 20 mg of propionyl chloride, and 85 μL of DIPEA (0.49 mmol) were added to methyl 3-((5-chloro-2-oxo-3-(4-(piperidin-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate hydrochloride (100 mg, 0.19 mmol) obtained in Preparative Example 30. The resulting mixture was then stirred at room temperature for 1 hour. Water was added to the reaction solution and the organic layer was separated, followed by purification by MPLC to give the title compound (82 mg, yield: 79%).

[1596] 1 H-NMR(400MHz, CDCl3)δ8.05(d,1H),7.98(dd,1H),7.56(dd,1H),7.48(d,2H),7.43(t,1H),7.37(d,2H),7.07(d,1H),7.02(dd,1H),6.81(d,1H) ,5.16(s,2H),4.85(m,1H),4.04(m,1H),3.90(s,3H),3.16(m,1H),2.85 (m,1H),2.66(m,1H),2.42(q,2H),1.95(m,2H),1.66(m,2H),1.32(t,3H)

[1597] Step B: 3-((5-chloro-2-oxo-3-(4-(1-propionylpiperidin-4-yl)phenyl)-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoic acid

[1598] The title compound (75 mg, yield: 96%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-(1-propionylpiperidin-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (80 mg, 0.15 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1599] MS[M+H]=518(M+1)

[1600] 1H-NMR(400MHz, CDCl3)δ8.10(d,1H),8.03(dd,1H),7.61(dd,1H),7.48(3H),7.37(d,2H),7.07(d,1H),7.03(dd,1H),6.82(d,1H), 5.18(s,2H),4.87(m,1H),4.02(m,1H),3.17(m,1H),2.83(m,1H),2.68(m,1H),2.42(q,2H),1.96(m,2H),1.67(m,2H),1.18(t,3H)

[1601] Example 103: Preparation of 3-((5-chloro-2-oxo-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1602]

[1603] The procedure of steps A and B below gives the title compound.

[1604] Step A: 3-((5-chloro-2-oxo-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoate methyl benzoate

[1605] The title compound (114 mg, yield: 75%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (100 mg, 0.32 mmol) and (4-(tetrahydro-2H-pyran-4-yl)phenyl)boronic acid (130 mg, 0.63 mmol) obtained in Preparation Example 1, in the same manner as in step A of Example 1.

[1606] 1 H-NMR(400MHz, CDCl3)δ8.05(d,1H),7.98(dd,1H),7.56(dd,1H),7.48(d,2H),7.40(3H),7.01(d,1H),7 .03(dd,1H),6.81(d,1H),5.16(s,2H),4.11(m,2H),3.82(s,3H),3.58(m,2H),2.85(m,1H),1.83(m,4H)

[1607] Step B: 3-((5-chloro-2-oxo-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)benzoic acid

[1608] The title compound (100 mg, yield: 91%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (114 mg, 0.29 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1609] MS[M+H]=463(M+1)

[1610] 1 H-NMR (400MHz, CDCl3) δ8.11(d,1H),8.03(dd,1H),7.62(dd,1H),7.48(3H),7.41(d,2H),7.08( d,1H),7.03(dd,1H),6.83(d,1H),5.18(s,2H),4.12(m,2H),3.57(m,2H),2.85(m,1H),1.83(4H)

[1611] Example 104: Preparation of 3-((5-chloro-3-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1612]

[1613] The procedure of steps A and B below gives the title compound.

[1614] Step A: 3-((5-chloro-3-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)-2-oxo-2,3-dihydro-1H- Preparation of methyl benzo[d]imidazol-1-yl)methyl)benzoate

[1615] The title compound (60 mg, yield: 69%) was obtained in the same manner as in step C of Preparation Example 7, using 6-chloro-1-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (60 mg, 0.184 mmol) and methyl 3-(bromomethyl)benzoate (42 mg, 0.184 mmol) obtained in Preparation Example 31.

[1616] 1 H-NMR(500MHz, CDCl3)δ8.09(s,1H),8.00(d,1H),7.54(m,4H),7.45(m,2H),7.11(s,1H), 7.05(d,1H),6.83(d,1H),6.28(s,1H),5.18(s,2H),4.38(m,2H),3.99(m,2H),2.59(m,2H)

[1617] Step B: 3-((5-chloro-3-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)-2-oxo-2,3-dihydro-1H- Preparation of benzo[d]imidazol-1-yl)methyl)benzoic acid

[1618] The title compound (11 mg, yield: 19%) was obtained using methyl 3-((5-chloro-3-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (60 mg, 0.126 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1619] MS[M+H]=461(M+1)

[1620] 1 H-NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.87(d,1H),7.66(d,2H),7.62(d,1H),7.59(d,2H),7.50(m,1H) ,7.27(d,1H),7.17(d,1H),7.06(s,1H),6.38(s,1H),5.22(s,2H),4.27(m,2H),3.86(t,2H),2.50(m,2H)

[1621] Example 105: Preparation of 3-((5-chloro-3-(4-(3,3-difluoropyrrolidone-1-yl)phenyl)-4-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1622]

[1623] The procedure of steps A and B below gives the title compound.

[1624] Step A: 3-((5-chloro-3-(4-(3,3-difluoropyrrolidone-1-yl)phenyl)-4-fluoro-2-oxo-2,3-dihydro- Preparation of methyl 1H-benzo[d]imidazol-1-yl)methyl)benzoate

[1625] The title compound (70 mg, yield: 99%) was obtained using 6-chloro-1-(4-(3,3-difluoropyrrolidone-1-yl)phenyl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.136 mmol) and methyl 3-(bromomethyl)benzoate (31 mg, 0.136 mmol) obtained in Preparation Example 32 in the same manner as in step C of Preparation Example 7.

[1626] 1H-NMR(400MHz, CDCl3)δ8.03(d,1H),7.98(dd,1H),7.57(dd,1H),7.36(t,1H),7.34(d,2H) ,7.02(dd,1H),6.64(3H),5.14(s,2H),3.92(s,3H),3.73(t,2H),3.58(t,2H),2.52(m,2H)

[1627] Step B: 3-((5-chloro-3-(4-(3,3-difluoropyrrolidone-1-yl)phenyl)-4-fluoro-2-oxo-2,3-dihydro- Preparation of 1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1628] The title compound (35 mg, yield: 51%) was obtained using methyl 3-((5-chloro-3-(4-(3,3-difluoropyrrolidone-1-yl)phenyl)-4-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (70 mg, 0.136 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1629] MS[M+H]=502(M+1)

[1630] 1 H-NMR(400MHz, CDCl3+MeOH-d4)δ8.06(d,1H),8.00(dd,1H),7.58(dd,1H),7.45(t,1H), 7.35(d,2H),7.03(m,1H),6.64(3H),5.16(s,2H),3.73(t,2H),3.59(t,2H),2.53(m,2H)

[1631] Example 106: Preparation of 3-(1-(5-chloro-2-oxo-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoic acid

[1632]

[1633] The title compound (20 mg, yield: 24%) was obtained using methyl 3-(1-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoate (59 mg, 0.16 mmol) and (4-(tetrahydro-2H-pyran-4-yl)phenyl)boronic acid (67 mg, 0.32 mmol) obtained in Preparation Example 4, in the same manner as in step A of Example 1 and step B of Example 24.

[1634] 1H-NMR(400MHz, CDCl3)δ8.10(t,1H),7.81(t,1H),7.47(d,1H),7.35(dd,4H),7.09(t,1H), 7.04(d,1H),6.97(s,1H),4.10(d,2H),3.53(t,2H),2.79(m,1H),1.79(m,4H),1.59(m,4H)

[1635] Example 107: Preparation of 3-(1-(3-(4-(7-oxa-2-azaspiro[3.5]nonane-2-carbonyl)phenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclopropyl)-2-fluorobenzoic acid

[1636]

[1637] The title compound (16 mg, yield: 28%) was obtained using 4-(6-chloro-3-(1-(2-fluoro-3-(methoxycarbonyl)phenyl)cyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid (50 mg, 0.10 mmol) and 7-oxa-2-azaspiro[3.5]nonane (16 mg, 0.13 mmol) obtained in step B of Example 67, in the same manner as in step C of Example 56 and step B of Example 24.

[1638] MS[M+H]=576(M+1)

[1639] 1 H-NMR(400MHz,DMSO-d6)δ7.93(m,1H),7.83(d,2H),7.75(m,1H),7.61(dd,2H),7.50(m,1H) ,7.27(m,2H),7.06(d,1H),4.12(s,2H),3.82(s,2H),3.50(m,4H),1.82(m,4H),1.64(m,4H)

[1640] Example 108: Preparation of 3-((5-chloro-2-oxo-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1641]

[1642] The procedure of steps A and B below gives the title compound.

[1643] Step A: 3-((5-chloro-2-oxo-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)-2-fluorobenzoate methyl ester

[1644] The title compound (0.028 g, yield: 38%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (0.050 g, 0.149 mmol) and (4-(tetrahydro-2H-pyran-4-yl)phenyl)boronic acid (0.092 g, 0.448 mmol) obtained in Preparation Example 2, in the same manner as in step A of Example 1.

[1645] 1 H-NMR(400MHz, CDCl3)δ7.89(m,1H),7.62(m,1H),7.45(d,2H),7.40(d,2H),7.17(t,1H),7.07(m,1H), 6.97(d,1H),6.72(d,1H),5.20(s,2H),4.10(m,2H),3.95(s,3H),3.55(m,2H),2.85(m,1H),1.84(m,4H)

[1646] Step B: 3-((5-chloro-2-oxo-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1647] The title compound (0.027 g, yield: 99%) was obtained using methyl 3-((5-chloro-2-oxo-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (0.028 g, 0.057 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1648] MS[MH]=479(M-1)

[1649] 1 H-NMR(400MHz,DMSO-d6)δ7.80(td,1H),7.50(5H),7.25(t,1H),7.22(d,1H),7.16(d d,1H),7.01(d,1H),5.22(s,2H),3.98(m,2H),3.48(m,2H),2.88(m,1H),1.75(m,4H)

[1650] Example 109: Preparation of 3-((5-chloro-2-oxo-3-(2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-2,3-dihydro-1H-benzis[d]imidazol-1-yl)methyl)benzoic acid

[1651]

[1652] The procedure of steps A, B, and C below gives the title compound.

[1653] Step A: 3-((3-(4-bromophenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl) Preparation of methyl benzoate

[1654] The title compound (193 mg, yield: 76%) was obtained in the same manner as in step A of Preparation Example 25, using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (170 mg, 0.537 mmol) and (4-bromophenyl)boronic acid (216 mg, 1.07 mmol) obtained in Preparation Example 1.

[1655] MS[M+H]=472(M+1)

[1656] 1 H-NMR(400MHz, CDCl3)δ8.03(s,1H),7.97(d,1H),7.68(d,2H),7.53(d,1H),7.43(m,3H),7.05(m,2H),6.80(d,1H),5.14(s,2H),3.90(s,3H)

[1657] Step B: 3-((5-chloro-2-oxo-3-(2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-2,3-dihydro- Preparation of methyl 1H-benzo[d]imidazol-1-yl)methyl)benzoate

[1658] To the methyl 3-((3-(4-bromophenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (60 mg, 0.127 mmol) obtained in step A above, 2-(cyclohexyl-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (29.1 mg, 0.14 mmol), Cs₂CO₃ (124 mg, 0.382 mmol), and 2.5 mL of 1,4-dioxane were added. Alkane was added, and then nitrogen gas was introduced into the resulting mixture. PdCl2(dppf)-CH2Cl2 (9.31 mg, 0.013 mmol) was added to the mixture, and then the mixture was stirred at 80 °C for 16 hours. After the reaction was terminated, the solid obtained was filtered through diatomaceous earth, and the filtrate was purified by MPLC to give the title compound (28 mg, yield: 46.5%).

[1659] 1H-NMR(400MHz, CDCl3)δ8.04(s,1H),7.96(d,1H),7.53(m,3H),7.43(m,3H),7.06(s,1H),7.00(d,1H), 6.79(d,1H),6.18(s,1H),5.14(s,2H),3.90(s,3H),2.43(m,2H),2.23(m,2H),1.80(m,2H),1.68(m,2H)

[1660] Step C: 3-((5-chloro-2-oxo-3-(2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-2,3-dihydro- Preparation of 1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[1661] The title compound (25 mg, yield: 91.5%) was obtained using methyl 3-((5-chloro-2-oxo-3-(2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (28 mg, 0.059 mmol) obtained in step B of Example 24 in the same manner as in step B of Example 24.

[1662] MS[M+H]=459(M+1)

[1663] 1 H-NMR(500MHz,DMSO-d6)δ7.99(s,1H),7.87(d,1H),7.61(m,3H),7.51(m,3H),7.27(d,1H),7.18( d,1H),7.03(s,1H),6.28(s,1H),5.21(s,2H),2.43(m,2H),2.22(m,2H),1.76(m,2H),1.63(m,2H)

[1664] Example 110: Preparation of 3-((5-chloro-3-(4-(2,5-dihydrofuran-3-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1665]

[1666] The procedure of steps A, B, and C below gives the title compound.

[1667] Step A: 3-((3-(4-bromophenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl Preparation of methyl 2-fluorobenzoate

[1668] The title compound (385 mg, yield: 88%) was obtained using methyl 3-((5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (300 mg, 0.896 mmol) and (4-bromophenyl)boronic acid (360 mg, 1.79 mmol) obtained in Preparation Example 2, in the same manner as in step A of Preparation Example 25.

[1669] Step B: 3-((5-chloro-3-(4-(2,5-dihydrofuran-3-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)-2-fluorobenzoate methyl ester

[1670] The title compound (7.9 mg, yield: 16.2%) was obtained using methyl 3-((3-(4-bromophenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (50 mg, 0.102 mmol) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (22 mg, 0.112 mmol) in the same manner as in step B of Example 109.

[1671] 1 H-NMR(500MHz, CDCl3)δ7.91(t,1H),7.64(t,1H),7.53(t,4H),7.20(t,1H),7.11(m ,2H),7.02(d,1H),6.33(s,1H),5.22(s,2H),5.06(s,2H),4.91(s,2H),3.97(s,3H)

[1672] Step C: 3-((5-chloro-3-(4-(2,5-dihydrofuran-3-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1673] The title compound (7 mg, yield: 91%) was obtained using methyl 3-((5-chloro-3-(4-(2,5-dihydrofuran-3-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (7.9 mg, 0.016 mmol) obtained in step B above, in the same manner as in step B of Example 24.

[1674] MS[M+H]=465(M+1)

[1675] 1H-NMR(500MHz,DMSO-d6)δ7.80(t,1H),7.71(m,1H),7.61(m,3H),7.54(m,1H),7.28( m,2H),7.17(m,1H),7.08(s,1H),6.61(s,1H),5.23(s,2H),4.96(s,2H),4.78(s,2H)

[1676] Example 111: Preparation of 3-((5-chloro-3-(4'-methyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1677]

[1678] The procedure of steps A and B below gives the title compound.

[1679] Step A: 3-((5-chloro-3-(4'-methyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-2-oxo- Preparation of methyl 2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate

[1680] The title compound (32 mg, yield: 62%) was obtained in the same manner as in step B of Example 109 using methyl 3-((3-(4-bromophenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (50 mg, 0.102 mmol) and (4-methylcyclohexyl-1-en-1-yl)boronic acid (15.7 mg, 0.112 mmol) obtained in step A of Example 110.

[1681] 1 H-NMR(500MHz, CDCl3)δ7.90(t,1H),7.64(t,1H),7.56(d,2H),7.46(d,2H),7.19(t,1H),7.09(m,2H),7.00(d,1H), 6.18(s,1H),5.22(s,2H),3.97(s,3H),2.50(m,2H),2.35(d,1H),1.90(m,2H),1.78(m,1H),1.45(m,1H),1.05(d,3H)

[1682] Step B: 3-((5-chloro-3-(4'-methyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-2-oxo- Preparation of 2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1683] The title compound (25 mg, 81% yield) was obtained using methyl 3-((5-chloro-3-(4'-methyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (32 mg, 0.063 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1684] MS[M+H]=491(M+1)

[1685] 1 H-NMR(500MHz,DMSO-d6)δ7.80(t,1H),7.61(d,2H),7.52(m,3H),7.28(m,1H),7.25(m,1H),7.18(d,1H),7.03( s,1H),6.25(s,1H),5.22(s,2H),2.48(m,2H),2.31(d,1H),1.85(m,2H),1.70(m,1H),1.35(m,1H),1.01(d,3H)

[1686] Example 112: Preparation of 3-((5-chloro-3-(4',4'-dimethyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-benzis[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1687]

[1688] The procedure of steps A and B below gives the title compound.

[1689] Step A: 3-((5-chloro-3-(4',4'-dimethyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-2- Preparation of methyl oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate

[1690] The title compound (71 mg, yield: 67%) was obtained in the same manner as in step B of Example 109 using methyl 3-((3-(4-bromophenyl)-5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (100 mg, 0.204 mmol) and 2-(4,4-dimethylcyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (53 mg, 0.225 mmol).

[1691] 1H-NMR(500MHz, CDCl3)δ7.87(t,1H),7.62(t,1H),7.53(m,2H),7.43(d,2H),7.15(t,1H),7.05(m,2H), 6.97(s,1H),6.12(s,1H),5.18(s,2H),3.93(s,3H),2.44(m,2H),2.02(m,2H),1.54(m,2H),0.97(s,6H)

[1692] Step B: 3-((5-chloro-3-(4',4'-dimethyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-2- Preparation of oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoic acid

[1693] The title compound (61 mg, 88%) was obtained using methyl 3-((5-chloro-3-(4',4'-dimethyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzoate (71 mg, 0.137 mmol) obtained in step A above, in the same manner as in step B of Example 24.

[1694] MS[M+H]=505(M+1)

[1695] 1 H-NMR(500MHz,DMSO-d6)δ7.75(t,1H),7.59(d,2H),7.48(m,3H),7.22(m,2H),7.14(d,1H) ,6.99(s,1H),6.18(s,1H),5.18(s,2H),2.40(m,2H),1.97(m,2H),1.47(m,2H),0.91(s,6H)

[1696] Example 113: Preparation of 3-(2-(5-chloro-3-(4-(dimethylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)benzoic acid

[1697]

[1698] The procedure of steps A and B below gives the title compound.

[1699] Step A: 3-(2-(5-chloro-3-(4-(dimethylcarbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[] Preparation of [d]imidazol-1-yl)ethyl)benzoate methyl ester

[1700] The title compound (97 mg, yield: 67%) was obtained using methyl 3-(2-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)benzoate (100 mg, 0.30 mmol) and (4-(dimethylcarbamoyl)phenyl)boronic acid (117 mg, 0.60 mmol) obtained ...

Claims

1. A compound having the chemical structure of Formula 1 below, or a pharmaceutically acceptable salt thereof: [Formula 1] In equation 1 above, Q1 and Q2 are each independently selected from either of the following groups: carbon and nitrogen. X1 and X2 are each independently selected from any of the following groups: hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted alkoxy. A is an aryl or heteroaryl group. X3, X4, and X5 are each independently selected from any of the following groups: hydrogen, halogen, hydroxyl, oxo, carboxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted oxoheteroalkyl, substituted or unsubstituted heterobicycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted oxazabicycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl carbonyl, and substituted or unsubstituted heterobicycloalkyl carbonyl. The substituted functional groups in X3, X4, and X5 above are each independently substituted by at least one selected from the group consisting of: halogen, hydroxyl, alkoxy, alkoxycarbonyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, alkyloxoheterocycloalkyl, aryl, heteroaryl, haloalkylheteroaryl, acetyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, halocycloalkylcarbonyl, heterocycloalkylcarbonyl, haloheterocycloalkylcarbonyl, hydroxyheterocycloalkylcarbonyl, alkylheterocycloalkylcarbonyl, alkylamino, cycloalkylamino, cycloalkylalkylamino, and alkylaminocarbonyl. n is an integer between 0 and 3. R1 and R2 are each independently selected from any of the following groups: hydrogen, substituted or unsubstituted alkyl groups, and substituted or unsubstituted cycloalkyl groups, or R1 and R2 are connected to each other to form a substituted or unsubstituted hydrocarbon ring. B is an aryl or heteroaryl group. X6 and X7 are each independently selected from any of the following groups: hydrogen, halogen, hydroxyl, oxo, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl. The functional groups substituted in X1, X2, X6, X7, R1 and R2 above are substituted by at least one of the following groups: halogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, -OR3, -(CO)-R3, -(CO)-OR3, alkylamino and oxo, wherein R3 is hydrogen or alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein both Q1 and Q2 are carbon, or either Q1 or Q2 is nitrogen. X1 and X2 above are each independently selected from any of the following groups: hydrogen, halogen, unsubstituted or halogen-substituted alkyl, unsubstituted or halogen-substituted cycloalkyl, and unsubstituted or halogen-substituted alkoxy. n is an integer between 0 and 1. R1 and R2 are each independently hydrogen or a substituted or unsubstituted alkyl group; or R1 and R2 are connected to each other to form any one of the following: substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycloaryl. B is a phenyl group or a heteroaryl group containing at least one selected from N and O, and X6 and X7 are each independently selected from any of the following groups: hydrogen, halogen, hydroxyl, oxo and substituted or unsubstituted alkyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are each independently selected from any of the following group: hydrogen, halogen, unsubstituted or halogen-substituted alkyl, unsubstituted cycloalkyl, and halogen-substituted alkoxy. R1 and R2 are each independently hydrogen or substituted or unsubstituted alkyl groups having 1 to 6 carbon atoms, or R1 and R2 are connected to each other to form substituted or unsubstituted cycloalkyl groups. B above is selected from any of the following groups: phenyl, azole and isosorbide azole, and X6 and X7 are each independently hydrogen or halogen.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are each independently selected from any of the following groups: hydrogen, halogen, unsubstituted or halogen-substituted alkyl groups having 1 to 3 carbon atoms, unsubstituted cycloalkyl groups having 3 to 6 carbon atoms, and halogen-substituted alkoxy groups having 1 to 3 carbon atoms, and... R1 and R2 are each independently hydrogen or methyl; or R1 and R2 are connected to each other to form a cycloalkyl group having 3 to 6 carbon atoms.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein A is selected from any of the following groups: phenyl, benzodioxanepentenyl, pyridyl, pyrimidinyl, pyrazolyl, dihydroindenyl, isoindolinyl, benzothiazolyl, dihydroisobenzofuranyl, and dihydrobenzo[a] Azine group, and X3, X4, and X5 above are each independently selected from any of the following groups: hydrogen, halogen, hydroxyl, oxo, carboxyl, substituted or unsubstituted alkoxy, alkathio, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted morpholino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azacyclobutyl, substituted or unsubstituted piperazine, substituted or unsubstituted piperidinyl, substituted or unsubstituted oxazacycloheptyl, substituted or unsubstituted oxazacyclobutyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted oxopiridinyl, substituted or unsubstituted oxo Azolanic, substituted or unsubstituted oxaazaspiryl, substituted or unsubstituted azespiryl, substituted or unsubstituted oxaazaspiryl, substituted or unsubstituted diazaspiryl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted dihydrofuranyl, substituted or unsubstituted oxaazabicycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted Diazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolidine carbonyl, substituted or unsubstituted piperazine carbonyl, substituted or unsubstituted piperidine carbonyl, substituted or unsubstituted morpholine carbonyl, substituted or unsubstituted azacyclobutane carbonyl, and substituted or unsubstituted oxazaspirane carbonyl.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein A is selected from any of the following groups: phenyl, benzo[d][1,3]dioxanepentenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, 1H-pyrazol-4-yl, 2,3-dihydro-1H-inden-5-yl, isoindolin-5-yl, benzo[d]thiazolyl-2-yl, 1,3-dihydroisobenzofuran-5-yl, and 3,4-dihydro-2H-benzo[b][1,4] Azine-7-yl, and X3, X4, and X5 are each independently selected from any of the following groups: hydrogen, halogen, hydroxyl, oxo, carboxyl, methoxy, ethoxy, propoxy, isopropoxy, cyclobutylmethoxy, cyclopropylmethoxy, methylthio, dimethylamino, isobutamido, methylsulfonamide, (2,2,2-trifluoroethyl)sulfonamide, methylcarbamoyl, dimethylcarbamoyl, (2,2,2-trifluoroethyl)carbamoyl, methylsulfonyl, morpholinosulfonyl, piperidin-1-ylsulfonyl, pyrrolidine-1-ylsulfonyl, N,N-dimethylaminosulfonyl, N-cyclopropylaminosulfonyl, N-(cyclobutylmethyl)aminosulfonyl, methyl, propyl, isopropyl, tert-butyl, butyl, 2-hydroxypropyl-2-yl, trifluoromethyl, 2, 2,2-Trifluoroethyl, 2-hydroxy-2-methylpropyl, 2-fluoro-2-methylpropyl, 1-hydroxy-2-methylpropyl-2-yl, 1-fluoro-2-methylpropyl-2-yl, (2-oxopyrrolidone-1-yl)methyl, ((3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl, (4-(trifluoromethyl)-1H-imidazol-1-yl)methyl, (3-methyl-2-oxo-imidazolin-1-yl)methyl, oxetane-3-ylmethyl, 2-(dimethylamino)-2-oxoethyl, 2-oxo-2-(pyrrolidone-1-yl)ethyl, morpholinomethyl, 2-morpholino-2-oxoethyl, 2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl, 2-(3-hydroxyazacyclobutane) Alkyl-1-yl)-2-oxoethyl, 2-(2-methylmorpholino)-2-oxoethyl, 2-(3-methylmorpholino)-2-oxoethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropyl, 1-(hydroxymethyl)cyclopropyl, 1-(hydroxymethyl)cyclobutyl, 1-hydroxycyclobutyl, cyclohexyl, (3r,5r,7r)-adamantane-1-yl, morpholino, 3-methyloxetane-3-yl, 3-hydroxyoxetane-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, 2-oxo-piperidin-1-yl, pyrrolidine-1-yl, 3-hydroxyazacyclobutane-1-yl, 3,3-difluoroazacyclobutane-1-yl, 3,3-difluoropyrrolidine-1-yl, 4-methylpiperazine -1-yl, 4,4-difluoropiperidin-1-yl, 4-(cyclopropanecarbonyl)piperazin-1-yl, 4-(cyclobutanecarbonyl)piperazin-1-yl, 4-(isopropoxycarbonyl)piperazin-1-yl, 4-(4,4-difluorocyclohexane-1-carbonyl)piperazin-1-yl, 1-(oxacyclobutane-3-yl)piperidin-4-yl, 1-(cyclopropanecarbonyl)piperidin- 4-yl, 1-(cyclobutanecarbonyl)piperidin-4-yl, 1-propionylpiperidin-4-yl, 4-propionylpiperazin-1-yl, 3,6-dihydro-2H-pyran-4-yl, 2,5-dihydrofuran-3-yl, 2-azaspiro[3.3]hept-2-yl, 7-oxa-2-azaspiro[3.5]non-2-yl, 2-oxa-6-azaspiro[3.3] Hept-6-yl, 2-oxa-5-azabicyclo[2.2.1] Hept-5-yl, 8-oxa-3-azabicyclo[3.2.1] Oct-3-yl, 1,4-oxaazabicycloheptane-4-yl, 7-acetyl-2,7-diazaspiro[3.5] Non-2-yl, 7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5] Non-2-yl, 4,4-dimethyl-2-oxo- 3-oxazolidinyl, 5-oxo-6-oxa-4-azaspiro[2.4]hept-4-yl, cyclohexen-1-yl, 4-methyl-cyclohexen-1-yl, 4',4'-dimethyl-cyclohexen-1-yl, phenyl, chlorophenyl, 5-cyclopropyl-1,3,4- Diazol-2-yl, 5-cyclopentyl-1,3,4- Diazol-2-yl, 5-cyclohexyl-1,3,4- diazol-2-yl, 5-cycloheptyl-1,3,4- Diazol-2-yl, 5-(tetrahydro-2H-pyran-4-yl)-1,3,4- Diazol-2-yl, 5-(4,4-difluorocyclohexyl)-1,3,4- Diazol-2-yl, 1-propyl-1H-pyrazol-4-yl, piperidine-1-carbonyl, morpholine-4-carbonyl, 3-methylmorpholine-4-carbonyl, pyrrolidine-1-carbonyl, azacyclobutane-1-carbonyl, 3-hydroxyazacyclobutane-1-carbonyl, 3,3-difluoroazacyclobutane-1-carbonyl, 3-methoxypyrrolidine-1-carbonyl, 3,3-difluoropyrrolidine-1-carbonyl, 4-methylpiperazine-1-carbonyl, 4-hydroxypiperidine-1-carbonyl, 4-methoxypiperidine-1-carbonyl, 4,4-difluoropiperidine-1-carbonyl, 7-oxa-2-azaspiro[3.5]nonane-2-carbonyl and 2-oxa-6-azaspiro[3.3]heptane-6-carbonyl.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein the compound having the chemical structure of Formula 1 above is selected from at least one of the groups consisting of the compounds listed in Table 3 below: [Table 3] 8. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is used for the prevention or treatment of autochemoattractant-mediated diseases.

10. The pharmaceutical composition of claim 9, wherein the autochemin-mediated disease is a disease caused by overexpression or overactivation of autochemins.

11. The pharmaceutical composition of claim 10, wherein the autochemoattractant-mediated disease is cancer or fibrosis.

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